Erythremia Vaquez disease. Polycythemia vera

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Erythremia is a disease of a tumor nature, in which there is a progressive increase in the content of red blood cells in the blood. Patients with this disease need timely treatment, since the lack of it can lead to death.

Causes and classification

The exact causes of Vaquez disease have not yet been established. However, there are a number of factors that increase the risk of its development. These include:

• Genetic predisposition. Blood erythremia disease is often found in people with genetic pathologies such as Down syndrome, Klinefelter syndrome, Marfan syndrome, Bloom syndrome.
• Exposure to toxic substances. Toxins can penetrate the blood and cause the development of mutations. Chemical mutagens include antibacterial agents (chloramphenicol), cytostatics, and benzene.
• Ionizing radiation. Radiation radiation is partially absorbed by the cells of the human body, causing all sorts of disorders. At risk are residents of unfavorable (from an environmental point of view) areas and patients who have undergone radiotherapy due to the presence of malignant neoplasms.

Pathology is a type of leukemia. The classification of the disease is based on the following factors:

• form of occurrence: acute, chronic;
• type of development: true, relative (false);
• mechanism of generation: primary, secondary.

Stages and their symptoms

In the early stages of development, the disease does not reveal itself in any way, so the person is not aware of its presence. As it progresses, the first symptoms of erythremia appear.

Initial

Signs of the disease at stage 1:

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21.10.2019

• Redness of the skin and mucous membranes. The cause of hyperemia lies in the increase in the concentration of red blood cells in the blood. The skin becomes pale pink or red, and in all parts of the body.
• Unpleasant sensations in fingers and limbs. The presence of pain in erythremia is due to impaired circulation in small vessels.

Some patients may experience headaches.

Erythremic

As the disease develops, the next stage of erythremia occurs, the symptoms of which are more pronounced. These include:

• Deterioration in general health. Pathological processes occurring in the body cause weakness, dizziness, increased fatigue, tinnitus and other unpleasant symptoms.
• Erythromelalgia. Accompanied by the appearance of purple spots and burning pain localized in the tips of the fingers and toes.
• Splenomegaly and hepatomegaly (enlarged spleen and liver).
• Increased hyperemia of the skin and mucous membranes, the appearance of swollen veins.
• Gastrointestinal diseases. Trophic processes prevent the normal flow of blood to the tissues, which leads to the development of peptic ulcer of the duodenum and stomach.
• Bleeding (including increased bleeding of gums).
• Skin itching (especially after contact with water).
• Severe joint pain.
• High blood pressure.

Anemic

As Vaquez's disease progresses, symptoms worsen. The patient faces the following pathological conditions:

• Heavy bleeding. They occur spontaneously or as a result of injuries. In some cases, bleeding cannot be stopped within several hours.
• Anemia. Iron deficiency is accompanied by pale skin, deterioration of general health, weakness and dizziness.
• Thrombosis. The formation of thrombotic plaques leads to impaired blood circulation in the vessels of the brain, lower extremities, etc. In such cases, the likelihood of death increases sharply.

Diagnostics

Diagnosis of Vaquez disease is complex. To establish the presence of pathology, the following activities are carried out:

• general and biochemical blood test;
• ultrasonography;
• bone marrow puncture;
• dopplerography.

Blood analysis

The first test that is performed on patients with suspected erythremia is a complete blood count. Biological material is collected on an empty stomach, in a separate room. The nurse wipes the tip of the finger with alcohol, then makes a puncture and draws a few milliliters of blood.

If a person suffers from a disease, this is detected by changes in several indicators. In the initial stages of erythremia, there is an increase in hemoglobin, the content of red blood cells, platelets and leukocytes. Late stages are characterized by a decrease in indicators due to the development of anemia.

Blood biochemistry

A biochemical blood test is used to determine the following indicators:

• bilirubin level (depending on intensity);
• the amount of iron in the blood;
• uric acid content;
• level of liver tests (depends on the intensity of liver cell destruction).

With a benign course. The pathology is characterized by an increase in the concentration of red blood cells in the bloodstream, which causes many negative symptoms. Treatment of the disease is quite complex; it consists of normalizing the function of the red bone marrow and improving blood composition. Without proper therapy, the patient develops severe complications, often incompatible with life.

Development mechanism

During erythremia, the body produces increased production of red blood cells - erythrocytes, and accordingly, the amount of hemoglobin increases. Red blood cells are synthesized by red bone marrow tissue. A necessary condition for this process is the participation of the hormone erythropoietin, which is produced by kidney and liver cells. Primary or true polycythemia is a consequence of impaired production of this hormone and is very rare in patients. In this case, a benign tumor forms in the bone marrow, where the main catalyst is the rapid proliferation of immature red blood cells.

Unlike the primary form, secondary erythremia is caused by various pathologies in humans, characterized by blood thickening.

Causes of the disease

True Vaquez disease is a rare type that can be transmitted through an autosomal recessive mode of inheritance. That is, a violation of the production of red blood cells occurs when one recessive gene is transmitted to the child from the mother and father. In this case, tumor growth is associated with the production of cells that do not correspond in size and shape to normal red blood cells. These are the so-called progenitor cells.

Secondary polycythemia occurs under the influence of such provoking factors:

• dehydration of the body, which is caused by severe vomiting, diarrhea and other conditions;
• lack of oxygen. This occurs at high body temperature, hot climate, being in the mountains;
• lung diseases (bronchitis, pneumonia, emphysema);
• increased pulmonary resistance;
• heart failure;
• apnea syndrome;
• impaired blood supply to the kidneys;
• neoplasms in the uterus, kidneys, adrenal glands, liver.

The lack of oxygen and water forces the body to make up for this deficiency through increased synthesis of red blood cells. At the same time, red blood cells continue to fully perform their functions, their size and shape correspond to the norm. Reasons for increased production of the hormone erythropoietin also include kidney cysts, long-term smoking and some other factors.

Lung and heart diseases are becoming common causes of secondary erythremia

Important! Vaquez disease is a tumor disease of hematopoietic tissue that develops at the level of erythropoiesis stem cells.

Stages of development

Signs of polycythemia do not appear immediately. The above-described manifestations may take years to develop. There are three stages of pathology.

First stage

Often at this stage the patient does not even suspect that he is developing the disease. General health is normal. Symptoms are mild or absent. Often, a blood disorder is discovered by chance during preventive medical examinations or when going to the hospital for another reason. The total duration of this stage is approximately 5 years.

Period of exacerbation of all symptoms

This period occurs in two stages. In the first, myeloid metaplasia of the spleen is absent, but the clinical picture of Vaquez disease is clearly visible. Duration ranges from 10 to 15 years.

The second stage is characterized by pronounced myeloid metaplasia of the spleen, which greatly increases in size. In addition, there is an enlargement of the liver and an exacerbation of all symptoms of erythremia.

Terminal stage

Here there are manifestations of the malignant course of the pathology. A person complains of pain and discomfort throughout the body. Leukemia develops after the cells lose their ability to differentiate, causing erythremia to develop into acute leukemia.

The course of this stage is very complex. The following violations are present:

• severe bleeding;
• serious infectious and inflammatory processes;
• splenic rupture;
• liver failure and others.

Due to a severe decrease in immune defense, treatment of developing diseases becomes difficult or impossible. Most often, polycythemia is fatal.

Erythremia in newborns

Vaquez disease in newborns is most often associated with hypoxia, and oxygen deficiency can occur both in utero and after birth. We talk about intrauterine hypoxia when the following conditions develop:

• fetoplacental insufficiency;
• pathologies of placental vessels;
• affected by tuberculosis;
• smoking during pregnancy;
• heart defects in a pregnant woman;
• late tying of the umbilical cord, which leads to hypervolemia of the child.

The pathology is often congenital

After the baby is born, cases of the development of polycythemia may be recorded due to disruption of the heart and blood vessels, pulmonary apparatus, and kidney and liver diseases.

Important! Sometimes the causes of illness in infants remain unclear. In such cases, treatment is aimed at restoring the functioning of the red bone marrow and improving hematopoiesis.

Oncology or not

Erythremia is a rather rare condition that mainly affects older men; it is diagnosed in patients of various age groups and even in newborns. More often we are talking about a secondary type of pathology, provoked by various reasons.

When most patients hear the diagnosis of leukemia, they understand it as a blood cancer. Is it so? The fact is that polycythemia has a benign course, and only over the years it turns into malignant, but that’s not all. Cancers involve neoplasms of epithelial tissue, and erythremia is a tumor of hematopoietic tissue.

The progression of the condition always depends on the treatment provided and the individual characteristics of the body.

How does the pathology proceed?

Vaquez's disease is characterized by such a main symptom as “plethora syndrome”. This concept implies a condition in which the amount of all formed elements in the blood increases. As a result, the patient experiences the following symptoms:

• headaches alternating with dizziness;
• itchy skin that occurs due to increased synthesis of histamine and prostaglandins produced by mast cells. Sometimes the itching is very strong, it is quite difficult to endure, scratches appear on the body, and a bacterial infection is often associated. Often, itching intensifies upon contact with water or other irritants;
• erythromelalgia - burning acute pain in the area of ​​the fingertips, accompanied by severe redness of the hands or their blueness, swelling;
• soreness in the arms and legs;
• periodic rashes on the body in the form of urticaria.

In addition, a person suffers from chronic fatigue, decreased quality of sleep, increased sweating, decreased concentration of memory and attention, hearing and visual disorders.

With the further development of pathology, the development of new signs is noted. Due to the expansion of capillaries, redness of the skin of the face and mucous membrane of the mouth appears. Often there are pain sensations in the heart area, which are similar to the symptoms of angina pectoris. This happens due to an increase in the size of the spleen due to the increased load on the organ. After all, it serves as a depot for platelets and red blood cells. In addition to the spleen, there is an increase in the size of the liver.

Itchy skin is a common symptom of polycythemia.

Another characteristic symptom is difficulty urinating and pain in the lumbar region. This is explained by the development of urolithiasis, which occurs due to a violation of the composition of the blood.

Due to the proliferation of bone marrow, patients often complain of joint pain, and gout is diagnosed. Manifestations of the disease also include intestinal and nosebleeds.

On the part of the blood vessels, there is a tendency to thrombosis, varicose veins, and thrombophlebitis. Less common is thrombosis of the coronary arteries and such a serious complication as myocardial infarction.

In almost 50% of cases, persistent arterial hypertension is observed. The patient suffers from frequent viral and bacterial infections, which is explained by the suppression of immunological reactions by red blood cells, which begin to behave as suppressors.

Important! The main danger of erythremia is the disruption of cerebral circulation, which often leads to strokes.

Diagnostics

Polycythemia vera is diagnosed in the laboratory using various tests. These include:

• general blood analysis. In this case, a significant increase in the concentration of red blood cells and hemoglobin is detected. Sometimes the number of red blood cells reaches 500-1000 x 10 9/l. The erythrocyte sedimentation rate in the true form of pathology is always reduced, often reduced to zero;
• blood chemistry. This test allows you to determine the level of uric acid and phosphatase. Vaquez disease is characterized by an increase in uric acid, which indicates the development of gout, which develops as a complication of erythremia;
• radiological examination method. This technique uses radioactive chromium to detect an increase in the number of circulating red blood cells;
• trepanobiopsy or histological evaluation of the ilium material. The method is highly informative and often confirms the diagnosis of polycythemia;
• sternal puncture. This test is done by examining bone marrow from the breastbone. In this case, hyperplasia of all germs is detected, megakaryocyte and red ones predominate.

A blood test can help make a diagnosis.

During diagnosis, the normal size of red blood cells is often discovered, that is, they do not change their shape and size. The severity of the pathology is determined by the concentration of platelets in the blood. It is believed that the more there are, the more severe the disease.

Important! In addition to laboratory tests of blood and bone marrow, to make a diagnosis, the patient must undergo an ultrasound of the abdominal organs, where the subject of the study is the presence of an enlarged liver and spleen.

Treatment methods

To choose a treatment strategy for erythremia, it is necessary to accurately determine which disease acted as the root cause. In addition, it is important to find out whether polycythemia is primary or secondary. For this purpose, the necessary laboratory tests are carried out.

True erythremia requires treatment of tumors in the bone marrow, and the secondary type requires getting rid of the root cause, that is, the disease that provoked a violation of the blood composition.

With true erythremia, treatment requires a lot of effort from doctors, which includes eliminating tumors in the bone marrow and preventing their reappearance. Here, an important role is played by the patient’s age, his individual characteristics, and concomitant pathologies. Not all medications are approved for older people, which significantly complicates the therapy process.

Bloodletting is considered an effective method of treatment. During the session, the blood volume decreases by approximately 500 ml. This allows you to reduce the concentration of platelets and thin the blood.

Cytopheresis is often used for treatment. This method allows you to filter the blood. The patient is given 2 catheters in one and the other arm, through one the blood enters a special device, and through the second it returns in a purified state. Sessions are held every other day.

The method of treatment is selected taking into account the type of disease and the severity of its course.

Secondary Vaquez disease is treated by getting rid of the pathology that caused polycythemia. This is, as a rule, a violation of the functioning of the lungs, heart, dehydration, etc.

The role of diet

Normalization of physical activity and diet are important aspects during the treatment of bone marrow disease. The patient should give up intense physical activity and ensure quality rest and sleep.

At the initial stage, the patient is prescribed a diet that excludes foods that promote hematopoiesis. These include:

• liver;
• sea ​​fish of fatty varieties;
• broccoli;
• citrus;
• apples;
• beets;
• pomegranate;
• avocado;
• nuts.

With further development of the disease, the doctor usually prescribes table No. 6 to the patient. This diet consists of a complete abstinence from fish, meat, legumes and dishes containing oxalic acid. Usually this table is indicated for gout and some other diseases.

Important! After undergoing therapy in a hospital setting, a person must follow the specialist’s instructions at home and undergo regular medical examinations.

Prevention

Prevention does not affect the development of true erythremia, since the pathology is congenital. To prevent a secondary type of disease, you should adhere to the following measures:

• to refuse from bad habits;
• drink plenty of fluids to prevent dehydration;
• promptly treat acute and chronic diseases;
• control body weight and avoid excess weight;
• devote enough time to physical activity, which will ensure normal metabolic processes;
• take medications only as prescribed by a specialist;
• Eat right, avoid junk food.

The best prevention is a healthy lifestyle

These simple rules will help keep the body in good shape, prevent many dangerous complications and the development of Vaquez disease.

Does folk treatment help?

Many patients with polycythemia are interested in the question of whether it is possible to improve blood composition using folk recipes? The fact is that Vaquez’s disease is a serious pathology, and without timely drug treatment, traditional methods will be absolutely ineffective. The main goal of drug therapy is to maximize the period of remission and delay the transition of erythremia to the third stage.

Even if there is a lull, the patient must remember that the pathology can recur at any time and make every effort to prevent this process. Throughout his life, he must be under medical supervision, discuss his condition with his attending physician, and undergo all necessary tests.

In folk medicine, indeed, there are a lot of recipes designed to improve blood composition, but they should not be used to increase hemoglobin and thin the blood. To date, no medicinal herbs that could slow down the progression of the pathology have been found. Therefore, you should not risk your health and self-medicate.

Prognosis for the patient

Vaquez disease is a complex disease, and in order to restore the function of the red bone marrow, it is necessary to have certain knowledge that only doctors possess. It is necessary to influence the hematopoietic system competently, only with the help of the correct choice of medications. If all the rules are followed and timely treatment, the prognosis for the patient is quite favorable, and the third stage can be postponed for many years.

Abdulkadyrov K. M., Shuvaev V. A., Martynkevich I. S., Shikhbabaeva D. I.

Federal State Budgetary Institution "Russian Research Institute of Hematology and Transfusiology of the Federal Medical and Biological Agency", St. Petersburg

MODERN CONCEPTS ABOUT DIAGNOSTICS AND TREATMENT OF POLYCYTHEMIA vera

Abdulkadyrov K. M., Shuvaev V. A., Martynkevich I. S., Shikhbabaeva D. I.

Russian Research Institution of Hematology and Transfusiology, St. Petersburg, Russian Federation

MODERN CONCEPTS OF DIAGNOSIS AND TREATMENT OF POLYCYTHEMIA VERA

Polycythemia vera (PV) is a rare disease, the number of newly diagnosed patients per year is about 1 per 100,000 population. Synonyms previously used to describe this disease: true erythremia, red erythremia, Vaquez disease, etc.

The pathogenesis of IP is based on a defect in the hematopoietic stem cell followed by a somatic mutation in the Janus kinase gene for cytokine receptors, leading to the proliferation of myeloid hematopoietic lineages, mostly erythrocytes, with the risk of developing vascular thrombosis and thromboembolism. Long-term proliferation of hematopoietic cells leads to fibrosis and replacement of active bone marrow with collagen fibers - the development of secondary post-polycythemic myelofibrosis. In some patients, further progression of the disease into the blast transformation phase may occur.

Thanks to the progress achieved in recent years in deciphering the molecular genetic mechanisms of IP, diagnostics have significantly improved and a new class of drugs with pathogenetic effects has been created.

The article presents a systematized algorithm for the management of patients with polycythemia vera, taking into account the most current information about advances in diagnosis and treatment, with a description of all stages of diagnosis and therapy.

KEY WORDS: polycythemia vera, algorithm, thrombosis risk prediction score, ruxolitinib.

Polycythemia vera (PV) - rare disease with incidence about 1 per 100,000 inhabitints yearly. Synonyms that had been used for PV previously are Erythremia vera, Red erythremia, Vaquez disease etc.

The PV pathogenesis based on stem cell defect with subsequent somatic mutation in Janus kinase gene of cytokine receptor that led to myeloid cell line proliferation, especially erythroid, with vascular thrombotic and thromboembolic complications risk. Long-term stem cells ptoliferation result to fibrosis and bone marrow substitution with collagen fibers - postpolycythemic myelofibrosis. Some patients can get disease progression with blastic transformation.

Through to recent success in molecular-genetic PV mechanisms decryption, PV diagnostic had been significantly improved; also new class of drugs with pathogenic action had been developed.

The article contains a thorough PV management algorithm that had been systemized with information of latest advances in PV diagnostic and treatment.

KEY WORDS: polycythemia vera, algorithm, thrombosis risk scale, ruxolitinib.

INTRODUCTION

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by damage to stem cells. The disease is accompanied by a somatic mutation in the Janus kinase gene (JAK2) for cytokine receptors and is manifested by proliferation of the myeloid hematopoietic lineage with the possible development of extramedullary hematopoiesis, thrombotic complications and outcome in postpolycythaemic myelofibrosis or blast transformation.

Synonyms previously used to describe this disease: true erythremia, red erythremia, Vaquez disease, etc. The most common name is polycythemia vera (PV), which indicates the need for differential diagnosis with secondary erythrocytoses.

IP was first described as an independent disease by Louis Henri Vaquez in 1892, who, while studying heart disease, described a form of cyanosis with constant erythrocytosis. In 1903, William Osler suggested that the cause of the disease in the group of patients he described was an increase in the activity of the bone marrow. In 1951, William Dameshek identified a group of myeloproliferative diseases with a similar pathogenesis, including IP and characterized the classic course of IP with the outcome in myelofibrosis. Since 1967, the Polycythemia Vera Study Group (PVSG) has been organized, which is an international methodological center for the development of diagnostic criteria and systematization of treatment results. Accumulation of data led to clarification of the criteria for the diagnosis of IP by an expert group of the World Health Organization (WHO) in 2000 and 2008. The discovery in 2005 of the role of the JAK2V617F mutation in the pathogenesis of myeloproliferative neoplasms led to significant progress in understanding the mechanisms of disease development and the creation of targeted drugs that have already proven their effectiveness and safety in clinical trials.

IP is a rare (orphan) disease. There are no domestic population epidemiological data on incidence and prevalence. Literary data about the

incidence rates reported from foreign registries are approximately 1-1.9: 100,000 population. Classic ideas about the median age at the onset of the disease of 60-70 years are currently being revised. The discovery of the involvement of molecular genetic defects in the pathogenesis of the disease (mutations in the JAK2 genes) has significantly improved the quality of diagnosis and makes it possible to identify the disease in young patients.

Traditionally, the incidence of PV is more frequent among men compared to women (1.5-2.0: 1).

When analyzing the ten-year dynamics of incidence, the annual primary incidence of IP in St. Petersburg ranged from 0.5 to 1.15 and averaged 0.83 per 100,000 population per year; median age at diagnosis was 59 years (range 20 to 86 years); The gender ratio was 145 women and 107 men (1.4:1).

Pathogenetically, IP is a clonal myeloproliferative process that develops as a result of malignant transformation in early hematopoietic precursors followed by a somatic mutation in the Janus kinase gene for cytokine receptors. Increased proliferation of myeloid hematopoietic lineages, mostly erythrocyte, gradually leads to the development of foci of extramedullary hematopoiesis (splenomegaly), the risk of developing vascular thrombosis and thromboembolism. Long-term proliferation of pathological hematopoietic cells is accompanied by fibrosis and replacement of active bone marrow with collagen fibers - the development of secondary post-polycythemic myelofibrosis. In some patients, the accumulation of damage in the genome and further progression of the disease ends in the blast transformation phase.

The determining factor for PV is the detection of a point mutation in the Janus kinase gene of the erythropoietin receptor JAK2V617F or other genetic disorders in the 1AK-8TAT signaling pathway (exon 12 of the JAK2 gene, the JIK gene, BOS genes, etc.).

Overall survival for PV averages about 20 years, thus not leading to a significant limitation in life expectancy in most patients. In young patients (with the onset of the disease

<50 years of age) with a median overall survival of 23 years, overall life expectancy is reduced due to the development of thrombosis, progression to myelofibrosis and blastic transformation. The main reason leading to disability and reduced life expectancy of patients with IP is the tendency to thrombosis and thromboembolism. The probability of developing clinically significant thrombosis occurs in 1.8% - 10.9% of patients per year, depending on risk factors. Moreover, even in young patients, the cumulative risk of developing thrombosis is 14% with a duration of PV of ten years. With a long course of the disease, secondary postpolycythemia myelofibrosis develops in about 0.5% per year. The probability of progression of the disease to the blast phase is 0.34% per year during the first 5 years of the disease, increasing to 1.1% per year if the disease lasts more than 10 years.

In recent years, significant progress has been made in deciphering the molecular genetic mechanisms of the development of IP, which has made it possible to create a new class of drugs - Janus kinase inhibitors, which have a pathogenetic effect that has shown good efficacy and safety in clinical studies.

The goal of modern therapy for IP is currently the prevention of vascular accidents, curbing the progression of the disease and relieving its symptoms with improving the quality of life of patients.

Accurate and timely diagnosis and regular monitoring of treatment using clinical, morphological and molecular genetic research methods are a condition for correctly predicting the course of the disease and achieving maximum effectiveness of therapy.

When writing this work, the results of research by domestic and foreign authors were used. We summarized our own experience in the diagnosis and treatment of 252 patients with polycythemia vera observed at the Russian Research Institute of Hematology and Transfusiology.

This work presents an algorithm for the diagnosis and treatment of patients with IP, based on our own many years of experience in managing patients with IP, the latest recommendations of WHO and the European Organization for the Treatment of Leukemia (ELN). It also covers issues related to the adequate use of various methods of treating IP in order to improve the quality of life of patients, increase life expectancy, and their social and labor rehabilitation.

ETIOLOGY AND PATHOGENESIS

The cause of IP currently remains unknown. The most likely complex genesis of the disease is when the predisposition to the disease is realized under the influence of external factors affecting the intact genome and leading to malignancy of the cell. Hereditary predisposition to the disease may occur in the presence of relatives of patients with chronic myeloproliferative neoplasms (CMPN). The relative risk of developing PV in relatives of patients with CMPN is 5.7 (95% CI 3.5-9.1) and can be associated with carriage of the 46/1 ha-lotype of the JAK2 gene. One of the key points in the pathogenesis of IP is considered to be the activation of the 1AK-8TAT signaling pathway, caused by the presence of a mutation in the Janus kinase gene for cytokine receptors JAK2 at position 617, leading to the replacement of phenylalanine with valine - JAK2V617F

Or more rarely in exon 12 of JAK2, even more rarely, activation of the JAKSTAT signaling pathway is observed, associated with loss of inhibition of Janus kinase phosphorylation due to a mutation in the LNK gene SH2B3 protein, between codons 208 and 234, or mutations in the genes of the SOC family of cytokine signal suppressors, most often SOC3 or hypermethylation of CpG sites in the SOC1 and SOC3 genes. Subsequently, mutations in other genes may occur: EZH2 and TET2, including epigenetic mechanisms.

Currently, there is no clear explanation for the development of different nosological forms upon activation of the same JAK-STAT signaling pathway: polycythemia vera (PV), primary myelofibrosis (PMF) or essential thrombocythemia (ET). Several pathogenetic hypotheses have been proposed to explain this phenomenon:

The carriers of mutations are various stem cells for different diseases;

Different levels of activity of the mutant JAK2V617F determine a special phenotype of the disease - theory of mutational load;

The specific genotype of the patient is a hereditary predisposition;

Molecular events preceding the occurrence of a mutation in the 1AK2 gene;

The contribution of non-mutational factors is epigenetic mechanisms, pathological expression of microRNAs, etc.

The primary genomic damage leading to malignancy in PV is unknown, although the vast majority (95%) of patients with PV have the JAK2V617F point mutation in the signal transducer kinase gene (JAK2) with cytokine receptors or, more rarely, in exon 12 of JAK2 (4%) . These mutations, although specific to IP, have a secondary genesis in the chain of genetic events.

1aphin kinase is a member of the family of non-receptor tyrosine kinases. The mutation causes a substitution of 1849 nucleotide O^T, which

For the first time in evolutionary terms, Ianhin kinases appear in primitive chordates. In mammals, the 1AK kinase family is represented by four proteins: 1AK1, 1AK2, 1AK3, and TYK2. Currently, the JAK2V617F mutation has been described not only in PV, but also in other myeloid neoplasms. However, she never

in turn, leads to the replacement of phenylalanine with valine in exon 14 of the JAK2 gene at codon 617. The molecules contain about 1100 amino acids with a total mass of 120-140 kDa (Fig. 1). Structurally, they consist of seven homologous regions that form four domains: kinase (JH1), pseudokinase (JH2), domain with Sarc oncoprotein homology (SH2), FERM domain. The first domain (JH1) from the carbohydrate end of the molecule is a typical tyrosine kinase with catalytic activity and is very similar to the catalytic domain of epidermal growth factor tyrosine kinases, the next domain (JH2) is structurally similar to the tyrosine kinase domain, but lacks catalytic activity and performs activity regulatory functions. This feature in the form of two similar areas gave the name to the entire family, dedicated to the ancient Roman god Janus, who had two faces. The SH2 domain facilitates the binding of other proteins to JAK, the FERM domain is located at the amino acid end of the molecule and interacts with transmembrane proteins - receptors of some cytokines, regulating the activity of JAK kinase.

Carboxyl terminus

was not determined in patients with tumors of lymphatic tissue, epithelial tumors and sarcomas. The localization of genes encoding the corresponding proteins and the participation of specific cytokines in signaling pathways are given in Table. 1.

Figure 1. Structure of JAK2 and location of point mutations that cause its independent gene activation.

Table 1.

Gene localization and cytokine signaling pathways involving Janus kinases

Name of Janus kinase Gene localization (chromosome/arm/region) Cytokines interacting with Janus kinase

JAK1 1p31.3 IL-1, IL-4, IL-6, IL-7, IL-9, IL-11, IL-15, IL-21, oncostatin M, leukemia inhibitory factor (LIF), ciliary neutrotrophic factor ( CNF), G-CSF, interferons

JAK2 9p24 IL-3, IL-6, IL-11, oncostatin M, leukemia inhibitory factor (LIF), ciliary neutrotrophic factor (CNF), interferon-gamma hormone-like cytokines (erythropoietin, growth hormone, prolactin, thrombopoietin)

JAK3 19p13.1 IL-1, IL-4, IL-7, IL-9, IL-15, IL-21

TYK2 19p13.2 IL-12, bacterial lipopolysaccharides

At the cellular level, 1amsh kinases are located in the cytosol and are localized near endosomes and the cell membrane near cytokine receptors. Proteins of the IR kinase family are involved in the regulation of many processes. One of the most significant is the transmission of a cytokine signal into the nucleus in order to stimulate proliferation through the 1AK-8TAT signaling pathway, schematically presented in Fig. 2. When the cytokine receptor is activated, a change in its conformational structure occurs, which causes auto- and/or transphosphorylation of two 1AA kinases. In turn, α-kinases phosphorylate the intracellular part of the cytokine receptor. 8TAT proteins bind to the phosphorylated parts of cytokine receptors and are also phosphorylated by 1Am kinases. The binding of 8TAT proteins to phosphorus allows them to form active dimers, which, penetrating into the nucleus, regulate gene expression. It is assumed that it is precisely this pathway that underlies signal transmission from cytokine receptors through 1AK2-kinase in myelopoiesis precursor cells and determines the general pathogenesis of chronic myeloproliferative neoplasms. One of the key moments of pathogenesis is often the occurrence of a point mutation at position 1849 of the JAK2 gene in the form of a replacement of guanine by thymine, resulting in the transformation of phenylalanine to valine in codon 617 of the regulatory domain of the III2-pseudokinase protein 1AK2. This results in independent activation of Janus kinase and phosphorylation of second messengers in the absence of receptor stimulation. These changes lead to activation

1AK-8TAT signaling pathway and increased proliferation of myeloid lineage.

The JAK2V617F mutation is found in pluripotent stem cells - common precursors of myelo- and lymphopoiesis, however, to activate proliferation through the 1AK-8TAT signaling pathway, co-expression with type I cytokine receptors is required: erythropoietin, granulocyte colony-stimulating factor and thrombopoietin. This fact explains that in the presence of JAK2V617F, isolated hyperplasia of the myeloid series occurs in the absence of changes in lymphopoiesis, despite the presence of the same JAK2 gene mutation in lymphoid cells.

When comparing the characteristics of JAK2V617F-mutant clones in patients with polycythemia vera (PV), primary myelofibrosis (PMF) and ET, it was found that the frequency of homozygous carriage of JAK2V617F mutations was 30% in PV and PMF compared to 2-4% in ET. Moreover, the frequency of heterozygotes for JAK2V617F, according to another study, is 67.8% in PV and 57.6% in ET. When studying the allelic load of JAK2V617F using quantitative real-time PCR in a group of patients with chronic myeloproliferative neoplasms (CMPN), it turned out that the highest load was in patients with PV (48±26%), intermediate in PMF (72±24%), the lowest in ET (26 ±15%). The results obtained formed the basis for the theory of “mutational load” of the development of CMPN: different phenotypes of the nosological variant of CMPN: PV, PMF or ET are determined by varying degrees of allelic

load JAK2V617F and, as a result, different activation of the 1AK-8TAT signaling pathway.

Mutations in the genes EZH2 (gene for the catalytic unit of histone methyltransferase) and TET2 (TET enzyme is involved in the conversion of 5-methylcytosine to 5-hydroxymethylcytosine), accompanying JAK2 mutations in PV in 3% and 16% of cases, respectively, introduce epigenetic disturbances in transcription regulation . The addition of these and other (ASXL1, CBL, GON1/2, IKZF1, etc.) disease-transforming mutations can lead to blast transformation (Fig. 5). The morphological substrate of the disease (blasts) in different types of blast crisis after transformation may or may not contain mutations of the JAK2 gene. Hyperplasia of hematopoiesis in PV may be accompanied by pathological production of cytokines, leading to secondary inflammation and changes in the bone stroma.

no brain. Cytokines involved in this mechanism are transforming growth factor beta myeloid progenitors (TGF-P), platelet-derived growth factor (PDGFR), and vascular endothelial growth factor (VEGF), which can lead to the development of secondary myelofibrosis, osteosclerosis and angiogenesis. Pathological production of cytokines, chemokines and metalloproteinases can participate in the perverse intercellular interaction of neutrophils, monocytes and megakaryocytes, leading to the release of CD34+ myeloid precursors and endothelial cells into the peripheral blood with the development of foci of extramedullary hematopoiesis, primarily myeloid metaplasia of the spleen. The result of the long-term influence of these changes may be the transition of the disease to the phase of post-polycythemia myelofibrosis.

Figure 2. Diagram of the JAK-STAT signaling pathway.

Figure 3. Molecular genetic pathogenesis of CMPN (adapted to PV).

Molecular genetic events in PV lead to activation of the JAK-STAT signaling pathway, independent of the influence of external stimuli, manifested by the proliferation of myeloid lineages (erythrocyte, granulocyte, megakaryocyte). The result of this is an increase in the number of red blood cells, granulocytes, platelets, and peripheral blood hemoglobin levels, which leads to blood thickening and increases the risk of thrombosis and bleeding. The most significant factors in the pathogenesis of thrombosis in PV are the following: erythrocytosis, thrombocytosis, disturbances in the structure and function of platelets, activation of leukocytes.

The relationship between erythrocytosis and increased hematocrit with the risk of thrombosis is not so clear. It has been shown in vitro that the hematocrit level is the main determinant of blood viscosity. However, in vivo, blood flow velocity and arterial oxygen saturation are of significant importance. With an increased hematocrit, as expected, the velocity of blood flow in the cerebral vessels is reduced; in PV this is associated not only with increased blood viscosity, but also with a reduced velocity of blood flow in the cerebral vessels, in accordance with the increased oxygen tension. For example, in pulmonary diseases and hypoxia, the vessels are dilated due to hypercapnia and, as a result, cerebral blood flow is reduced less than in PV. Moving

red blood cells in the vessel occurs along the axis of the blood flow with a displacement of platelets into the plasma wall zone with the maximum effect of lateral hemodynamic pressure. As hematocrit increases, the plasma zone of blood flow narrows, which leads to more platelet interactions with both the endothelium and other blood cells. The highest lateral hemodynamic pressure, comparable to axial pressure, is observed in arterioles and capillaries, while in the venous system it is much lower. At high lateral pressure, platelet receptors change, which leads to increased binding of glycoprotein Ib receptors to von Willebrand factor and, after platelet activation, to glycoprotein IIb/IIIA receptor. With a high hematocrit and a small size of the plasma zone, increased interaction of activated platelets with each other leads to thrombosis against the background of previous vascular pathology.

The platelet level itself does not have a direct statistically significant correlation with the incidence of thrombosis.

However, in high-risk patients, reducing platelet levels to less than 400 x 109/L with drug therapy may lead to a reduction in the incidence of thrombosis. However, it remains unclear whether this is due only to a decrease in platelet levels or to myelosuppression.

To assess qualitative and structural changes in platelets in PV, platelet aggregation studies are most often performed in routine clinical practice. Unfortunately, despite the frequent abnormal findings of these studies (decreased or increased aggregation), the clinical correlation of these results with the risk of thrombosis or bleeding is negligible. Most often, a decrease in primary or secondary aggregation with adrenaline and/or ADP and a reduced response to collagen are observed, although aggregation with arachidonic acid remains intact. Spontaneous platelet aggregation may also be observed. Deficiency of storage granules is a characteristic feature of platelets in all CIPN. The difference with hereditary deficiency is that the cause of the deficiency is not due to decreased production, but due to increased consumption - degranulation as a result of constant activation of platelets. Signs of platelet activation in CIPN are an increase in the concentration of arachidonic acid metabolites in plasma and urine, alpha granule proteins and activation markers on the platelet membrane (p-selectin, thrombospondin, fibrinogen receptors, glycoprotein IIb/IIIa). Impaired metabolism of arachidonic acid in chronic MPN leads to a constant increase in the concentration of thromboxane A2, which is a powerful vasoconstrictor and stimulator of platelet aggregation. This is confirmed by the effectiveness of the use of small doses of acetylsalicylic acid, which reduces the clinical manifestations of microcirculation disorders and the risk of thrombosis in PV. In CMPN, multiple disturbances in the expression of proteins and receptors on the platelet membrane are observed: a decrease in the number of adrenergic receptors, glycoproteins Ib and IIb/IIIa, while the expression of glycoprotein IV is increased, especially in patients who have suffered thrombosis.

The role of activation of a clone of pathological leukocytes in the pathogenesis of thrombosis in PV has been empirically proven to reduce the risk of thrombosis

when using myelosuppressive agents. Studies have shown frequent activation of neutrophils in PV, evidenced by high levels of markers of endothelial damage and coagulation activation. Also, in PV, a greater number of circulating leukocyte and platelet aggregates were found compared to controls. The number of these aggregates correlated with platelet levels, percentage of platelets positive for p-selectin and thrombospondin, and glycoprotein IV expression. The presence of microcirculation disorders or thrombosis is also associated with a higher number of leukocyte-platelet aggregates.

The pathogenesis of bleeding in PV involves a combination of causes: disturbances in the structure and function of platelets and acquired secondary von Willebrand syndrome. Disturbances in the structure and function of platelets, caused by the proliferation of a pathological clone of transformed cells in PV, most often manifest themselves in changes in the absolute quantity and relative ratio of the expression of proteins and receptors on the membrane, as well as a deficiency of storage granules associated with their depletion against the background of permanent activation of platelets. The causes of secondary von Willebrand syndrome are a decrease in the concentration of von Willebrand factor, caused by its binding to an excess number of platelets. A relationship has been established between platelet levels and a decrease in large multimers of von Willebrand factor, which is a more accurate indicator than measuring its antigen or the level of factor eight

Despite the different causes, the clinical manifestations of the secondary syndrome are similar to those of von Willebrand disease. Secondary von Willebrand syndrome is also observed with reactive hyperthrombocytosis

The leading role of hyperthrombocytosis in the pathogenesis of secondary von Willebrand syndrome both in CMPN and in reactive conditions is confirmed by the relief of its manifestations during cytoreductive therapy.

CLINICAL MANIFESTATIONS

Some patients, especially in the initial stages of the disease, may not have any complaints. The main symptoms of IP are associated with manifestations of plethora (plethora) and disorders

blood circulation (microcirculation disorders and thrombosis). The most common complaints of 252 patients observed in RosNI-IGT are given in table. 2.

table 2

Clinical manifestations of polycythemia vera at the time of diagnosis of the disease

Symptom Frequency, % of the total number of patients (n) (n=252)

Plethora 85% (215)

Headaches 60% (151)

Weakness 27%(68)

Itchy skin 21% (55)

Joint pain 7% (18)

Erythromelalgia 5% (13)

Thrombosis 11%(28)

No symptoms 3% (8)

The most common symptoms of the disease:

Dilation of the saphenous veins and changes in skin color. The characteristic shade of the skin and mucous membranes occurs due to the overflow of the superficial vessels with blood and a slowdown in the speed of its flow. As a result, most of the hemoglobin has time to transform into a reduced form. Protruding, dilated, swollen veins are clearly visible on the patient’s skin, especially in the neck area. With polycythemia, the skin has a red-cherry color, especially pronounced on open parts of the body - on the face, neck, hands. The tongue and lips are bluish-red, the eyes seem to be bloodshot (the conjunctiva of the eyes is hyperemic). The color of the soft palate is changed while the normal color of the hard palate is preserved (Cooperman's symptom).

Headache, impaired concentration, dizziness, weakness are manifestations of microcirculation disorders in the cerebrovascular vessels. Deterioration of blood circulation in the organs leads to patient complaints of fatigue, headache, dizziness, tinnitus, rush of blood to the head, fatigue, shortness of breath, flashing spots before the eyes, blurred vision. Patients may notice their intensification in hot weather and during physical activity - conditions leading to dehydration. A positive effect is observed when drinking water (for which patients often carry it with them), acetylsalicylic acid.

An increase in blood pressure is a compensatory reaction of the vascular bed

to increase blood viscosity. There is a manifestation or worsening of the course of a previous cardiac pathology (hypertension, coronary heart disease). The rate of progression of heart failure and cardiosclerosis is increasing.

Skin itching. Skin itching is observed in a significant proportion of patients and is a characteristic sign of IP. Itching worsens after swimming in warm water, which is thought to be due to the release of histamine, serotonin and prostaglandins.

Erythromelalgia is unbearable burning pain in the tips of the fingers and toes, accompanied by redness of the skin and the appearance of purple cyanotic spots. The occurrence of erythromelagias is explained by impaired microcirculation against the background of increased hematocrit and platelet count and, as a consequence, the appearance of microthrombi in the capillaries. This assumption is confirmed by the good effect of using acetylsalicylic acid.

Arthralgia - up to 20% of patients complain of persistent pain in the joints. Joint pain can be caused by impaired microcirculation due to increased blood viscosity, but can also be a symptom of secondary gout. An increase in the level of uric acid in PV occurs as a result of the destruction of excess amounts of cell mass, and as a result, an increase in the exchange of purine bases - products of DNA degradation.

The resulting hyperuricemia can manifest itself with a typical clinical picture of gout - joint pain with arthritis, urolithiasis, extra-articular deposition of uric acid (tophi).

Pain in the lower extremities. Patients with IP may complain of persistent pain in the legs, the cause of which is vascular insufficiency against the background of increased blood viscosity and a decrease in blood flow speed, worsening of the course of concomitant vascular diseases of the lower extremities against the background of IP (varicose veins, obliterating endarteritis, etc.).

Splenomegaly and hepatomegaly, manifested by heaviness in the hypochondrium and rapid satiety after eating, are a common symptom of IP. In contrast to liver diseases, the spleen in PV is enlarged significantly more than the liver. In the initial phase of the disease, the enlargement of the liver and spleen is caused by excessive blood supply. Subsequently, with the development of foci of extramedullary hematopoiesis (myeloid metaplasia), the severity of splenomegaly progressively increases.

Development of ulcers in the duodenum and stomach. In 10-15% of patients, the presence of ulcers of the duodenum, less often the stomach, may be observed, which is associated with thrombosis of small vessels and trophic disorders in the mucous membrane, leading to a decrease in the strength of the mucous barrier and the penetration of Helicobacter pylori.

The occurrence of blood clots in blood vessels. During the first years of the disease, the main risks for IP are thrombosis and thromboembolism against the background of existing cardiovascular pathology and atherosclerosis. Previously, vascular thrombosis and embolism were the main causes of death in PV. Patients have a tendency to form blood clots due to increased

blood viscosity, thrombocytosis and changes in the vascular wall. This leads to circulatory disorders in the veins of the lower extremities, cerebral, coronary and splenic vessels. Leukocytosis and thrombocytosis can lead to microcirculation disorders and the development of thrombosis. The occurrence of thrombosis in PV is always the result of the interaction of disease manifestations and multiple risk factors for thrombosis (Fig. 4). Factors contributing to the development of thrombosis can be divided into two groups:

Factors caused by the disease: thrombocytosis, leukocytosis, activation of leukocytes and platelets, interaction between leukocytes and platelets, biochemical and functional abnormalities in platelets, activation of blood coagulation factors, the presence of JAK2V617F mutation and high allelic load;

Individual patient factors: age, history of thrombosis, risk of developing cardiovascular complications, hereditary genetic factors (thrombophilia).

Despite the decrease in the activity of stimulated platelet aggregation in PV, there is a significant increase in their number, which causes their multiple interactions with each other and leukocytes, which leads to spontaneous aggregation. When the diagnosis is made, the presence of thrombosis is noted in 12-39% of patients with PV. Subsequently, during the course of IP, thrombosis develops in another 10.3% -25% of patients. The probability of developing clinically significant thrombosis ranges from 1.8% to 10.9% of patients per year, depending on risk factors. Moreover, even in young patients, the cumulative risk of thrombosis is 14% with a duration of PV of ten years. At the same time, the proportion of deaths in patients with PV with thrombosis ranges from 11% to 70%.

Figure 4. Risk factors for thrombosis in PV.

In PV, arterial thrombosis occurs more often than venous thrombosis. Compared with essential thrombocythemia (ET), thrombosis in PV more often occurs in the cerebrovascular system, coronary or abdominal vessels, while in ET, disturbances in the microcirculation occur more often. Thrombosis of large vessels, which are the leading causes of disability and death, according to the decreasing frequency of occurrence, are distributed as follows: the most common disorders occur in the cerebrovascular system (strokes and transient ischemic attacks), then myocardial infarction and occlusion of peripheral arteries. Most venous thrombosis in PV occurs in the venous systems of the lower extremities or lungs. Also, compared to the population with PV, thrombosis of the abdominal vessels (portal and hepatic veins) occurs much more often (up to 10%) in the structure of venous thrombosis, the symptoms of which are difficult to diagnose, especially when this thrombosis is the first clinical manifestation of undiagnosed PV.

In the group of patients with thrombosis of the portal and hepatic veins without an obvious preceding cause, CMPN as the cause of thrombosis is detected in 31-53% of patients, and this occurs more often in young patients. In the absence of a clear cause (liver carcinoma or cirrhosis) of abdominal vein thrombosis, screening for the JAK2V617F mutation is necessary.

Age is a repeatedly proven risk factor for thrombosis. Frequency

The incidence of thrombosis in PV patients under 40 years of age is 1.8% per year; in those over 70 years of age, it increases to 5.1% per year. Another study showed that the relative risk of thrombosis in PV patients over 60 years of age is 8 .6 times higher than in patients under 60 years of age. A history of thrombosis is an independent prognostic factor for the development of recurrent thrombosis and, together with age, determines the indications for starting cytoreductive therapy. In patients with PV who had a history of thrombosis, their recurrence developed in 26.5% of cases, while for the first time thrombosis occurred only in 17.3% of patients. The combination of a history of thrombosis and age over 60 years increases the risk of thrombosis to 17.3.

The presence of risk factors for cardiovascular pathology (smoking, diabetes, signs of heart failure) also has a statistically significant effect on the likelihood of developing thrombosis in PV. Hereditary and acquired thrombophilic conditions as risk factors for thrombosis in PV have been extensively studied over the past years. The effect of natural anticoagulants (antithrombin, protein C, protein 8) was studied; polymorphism in the genes of factor V, prothrombin, methylenetetrahydrofolate reductase; acquired conditions (anti-cardiolipin antibodies (lupus anticoagulant), homocysteine, etc.). It has been shown that in patients with venous thrombosis, factor V Leiden mutation is detected significantly more often (16%) compared to patients without thrombosis (3%). The frequency of carriage of this mutation also correlated with the number of thromboses suffered: 3.6% in patients without thrombosis, 6.9% in patients with one episode of thrombosis and 18.1% in patients with recurrent thrombosis. Several studies have shown that patients with CMPN have elevated homocysteine ​​levels. However, the relationship between arterial thrombosis and increased homocysteine ​​levels was shown in only one study.

Bleeding. Along with increased blood clotting and thrombus formation in PV, 1.7-20% of patients may experience bleeding from the gums and dilated veins of the esophagus. Hemorrhagic syndrome can be the cause of death in 3.1 to 11% of deaths in PV. Moreover, if over the past years, due to the expansion of therapeutic options, mortality in PV from thrombosis has been gradual-

but decreases, the mortality associated with bleeding remains stable. The probability of developing massive bleeding and death with them is 0.8% and 0.15% per year, respectively. Hemorrhagic syndrome in IP primarily affects the skin and mucous membranes and can manifest itself in the form of ecchymosis, nasal and gingival bleeding, and menorrhagia. Gastrointestinal bleeding is often associated with taking acetylsalicylic acid, occurs less frequently, but is massive and requires hospitalization and transfusions of blood components. This type of bleeding is associated with quantitative or qualitative platelet defects as a result of proliferation of a defective clone and/or secondary von Willebrand syndrome. Despite the fact that hemorrhagic syndrome in PV is observed with significant hyperthrombocytosis, a direct correlation

there is no relationship between platelet count and bleeding risk. In some cases, bleeding in PV is associated with thrombotic complications, varicose veins with portal hypertension. Also, hemorrhagic syndrome can be caused by the use of antiplatelet agents and anticoagulants.

The most common clinical manifestations in 252 patients with IP, the diagnosis of which was established in RosNIIGT, were: plethora (85%), headache and dizziness (60%), weakness (27%), itching (21%), joint pain (7%), erythromelalgia (5%) (Table 2). Thrombotic complications in the study group of patients were recorded in 11.1% of patients (16 arterial and 13 venous thromboses). Myocardial infarctions were observed in 3.6% of patients and acute cerebrovascular accidents in 5.2% of patients. Bleeding of varying intensity was observed in 2.4% of patients.

MORPHOLOGICAL AND LABORATORY MANIFESTATIONS

At the onset of the disease, in a clinical blood test, the number of red blood cells and the level of hemoglobin are moderately increased with normal levels of white blood cells and platelets. When analyzing our own experience, isolated erythrocytosis was observed in 19.0% of patients with PV. The hemoglobin level at the onset of PV, more often in women, may remain within normal limits, being masked by concomitant iron deficiency. We observed this situation in 3.2% of patients with IP.

Subsequently, the mass of circulating erythrocytes progressively increases (the number of erythrocytes, hemoglobin level and hematocrit increase). In the blood, due to an increase in the number of leukocytes, the concentration of transcobalamin-1 contained in them, associated with vitamin B12, increases. In the bone marrow, there is a change in the ratio of active and fatty bone marrow towards the expansion of all sprouts of myeloid hematopoiesis. When studying the colony-forming ability of myelokaryocytes, spontaneous growth of cell colonies in a medium without the addition of growth factors is observed - the implementation of independent activation of the JAK-STAT signaling pathway of cell proliferation. Cytochemical examination showed normal levels of neutrophil alkaline phosphatase activity. Acute phase indicators (fibrinogen,

C-reactive protein, etc.) and LDH, as a rule, remain within normal values. Indicators of a coagulogram can often indicate plasma hypocoagulation - a decrease in fibrinogen, the level of von Willebrand factor, which can be either compensatory in nature or be caused by the sorption of plasma coagulation factors on platelets in the vascular bed. Instrumental research methods (Doppler ultrasound, computed tomography and magnetic resonance imaging, scintigraphy) can indicate the consequences of thrombosis and thromboembolism, some of which may occur subclinically. With the subsequent development of the disease in the peripheral blood, the number of leukocytes increases due to neutrophils with a gradually increasing shift to the left, thrombocytosis increases, and ESR slows down. In the bone marrow, total three-line hyperplasia is called panmyelosis. The size of the spleen and liver increases, initially due to the accumulation of excess cell mass, and then due to their myeloid metaplasia.

With the development of foci of extramedullary hematopoiesis, immature granulocytic cells, erythroblasts, appear in the peripheral blood; immunophenotyping reveals CD34-positive cells.

The development of reticulin and collagen fibrosis of the bone marrow leads to the transition of the disease to the stage of postpolycythaemic myelofibrosis. In a blood test, the hemoglobin level decreases to normal, and then anemia develops. The level of leukocytes may increase or, conversely, decrease; in the leukocyte formula, a shift to the left increases until blast forms appear. The platelet count may also increase, but subsequently decrease with the development of thrombocytopenia and the risk of hemorrhagic complications. LDH levels increase as a marker of tumor progression. A change in the profile of cytokine secretion leads to an increase in their pro-inflammatory fraction (tumor necrosis factor alpha, interleukin-6, etc.) with the appearance of symptoms of tumor intoxication. The severity of hepatosplenomegaly increases with the formation of portal hypertension with its clinical and laboratory manifestations - hepatorenal insufficiency.

In PV, no specific cytogenetic markers have been identified; chromosomal abnormalities are detected in a small proportion of patients. The most common deletions of the long arm of chromosome 20 and trisomy 9 are detected. When IP transitions to the stage of post-polycythemic myelofibrosis, the frequency of karyotype aberrations increases - partial or complete trisomy of the long arm of chromosome 1 is detected in 70% of patients, and it can be formed by genetic material 1, 6, 7, 9, 13, 14 , 15, 16, 19 and Y chromosomes. It is assumed that these changes are interconnected with the leukemic effect of long-term exposure to cytostatics.

Molecular genetic markers are highly specific for PV: the JAK2V617F mutation is detected in 95% of patients with PV, more rarely (4%) mutations are present in exon 12

JAK2 gene. In rare cases, mutations in the LNK protein 8H2B3 gene, between codons 208 and 234, or mutations in the genes of the BOS cytokine signal suppressor family, most often BOS3, or hypermethylation of CpG sites in the BOS1 and BOS3 genes are observed. With the progression of the disease and the formation of post-polycythemic myelofibrosis, mutations may appear in other genes: EZH2 in 3% and TET2 in 16% of patients, including epigenetic mechanisms.

The typical histological appearance of bone marrow in PV is proliferation of all three myeloid lineages with a significant increase in the number of megakaryocytes. Immunohistochemical staining reveals acidophilic-stained neutropoiesis cells, basophilic nucleated erythropoiesis precursors, and scattered clusters of megakaryocytes of various sizes. With the development of postpolycythaemic myelofibrosis, a decrease in cellularity is observed with a few scattered islands of erythropoiesis, pathological megakaryocytes and a significant expansion of the structures of the bone marrow stroma. Specific staining shows the formation of collagen and reticulin bundles with the formation of osteosclerosis and single scattered megakaryocytes (Fig. 5).

One of the main methods for diagnosing CMPN is histological assessment of the degree of fibrosis in the bone marrow according to the standard scale of the European consensus of pathologists for assessing bone marrow cellularity and fibrosis. Microphotographs of bone marrow corresponding to different degrees of the scale are presented in Fig. 6. In the chronic phase of PV, unlike post-polycythemic myelofibrosis and PMF, the degree of fibrosis should not be more than MB-1.

Figure 5. Microphotographs of bone marrow in polycythemia vera (A, B-chronic phase of PV; C, D-post-polycythaemic myelofibrosis).

MF-0 rare reticulin fibers without intersections, corresponding to normal bone marrow;

MF-1 is a loose reticulin network with many intersections, especially in perivascular areas;

MF-2 diffuse increase in reticulin density with excessive crossings

Figure 6. Micrographs of bone marrow, European consensus (A - N¥-0; B

occasionally with focal collagen formations and/or focal osteosclerosis;

MF-3 diffuse increase in reticulin density with excessive intersections with collagen bundles, often associated with significant osteosclerosis.

corresponding to various degrees of the scale > - Ш-1; V - Sh-2; G - Sh-3).

CLASSIFICATION OF POLYCYTHEMIA VUE

In domestic hematology, there are four clinical stages of IP development associated with the pathogenesis of the disease.

Stage I - initial. At this stage, bone marrow hyperplasia occurs without any signs of fibrosis; in the peripheral blood, there is predominantly an increase in the mass of circulating red blood cells. Clinical manifestations are plethora, acrocyanosis, erythromelalgia, skin itching after water procedures (hand washing, shower, bath). An increase in blood viscosity leads to an increase in blood pressure - a worsening of the course of hypertension with a decrease in the effectiveness of antihypertensive drugs or the occurrence of symptomatic arterial hypertension. The course of coronary heart disease, cerebrovascular disease and other pathological conditions associated with impaired microcirculation is also aggravated. The reason for examination by a hematologist at this stage is often an increase in hemoglobin levels and the number of red blood cells during a clinical blood test performed for other diseases or a preventive examination.

Stage 11A - erythremic (expanded) without myeloid metaplasia of the spleen. In the peripheral blood, in addition to erythrocytosis, significant neutrophilia is observed, sometimes with a shift in the leukocyte formula to single myelocytes, basophilia, and thrombocytosis. In the bone marrow there is total hyperplasia of all three myeloid lineages with pronounced megakaryocytosis, and the presence of initial reticulin fibrosis is possible. At this stage, there are no foci of extramedullary hematopoiesis, and hepatosplenomegaly is caused by sequestration of excess cell mass. Due to more pronounced deviations in blood parameters, the frequency of thrombosis is higher, and their nature is more severe compared to the previous stage. Often the diagnosis of IP at this stage is established after thrombotic complications have occurred.

Stage II B - erythremic (expanded) with myeloid metaplasia of the spleen. At this stage, foci of extramedullary hematopoiesis appear in the liver and spleen, their progressive increase occurs against the background of stable peripheral blood counts or even a slight decrease in the amount

red blood cells and platelets as a result of secondary hypersplenism. In the leukocyte formula, the shift to the left gradually increases and the proportion of immature cells of the granulocyte series increases. In the bone marrow, fibrosis increases to pronounced reticulin and collagen fibrosis. A gradual decrease in blood counts, regardless of the influence of medications, indicates a transition to stage III IP.

Stage III - post-polycythemic myelofibrosis (anemic). Collagen fibrosis increases in the bone marrow with the development of osteosclerosis. Depression of myelopoiesis leads to a progressive decrease in hemoglobin, leukopenia, and thrombocytopenia. The clinical picture is dominated by anemic and hemorrhagic syndromes, accompanied by infectious complications and symptoms of tumor intoxication.

Another variant of the outcome of IP is blast transformation of the disease and the development of blast crisis. The use of chemotherapy as a restraining therapy, according to some authors, may increase the risk of this transformation. Blast crisis in PV can either develop de novo or after the development of secondary myelodysplastic syndrome.

With a long course of the disease, secondary postpolycythemic myelofibrosis may occur. The probability of progression of the disease to the blast phase is 0.34% per year during the first 5 years of the disease, increasing to 1.1% per year if the disease lasts more than 10 years. In patients with PV observed in RosNIIGT, the incidence of post-polycythaemic myelofibrosis was 5.7% over 10 years.

DIAGNOSIS OF POLYCYTHEMIA VUE

The diagnosis of IP is established based on the presence of:

Complaints about changes in the color of the skin and mucous membranes, dilation of the saphenous veins, burning, paresthesia in the fingers and toes, itching after taking water procedures, headaches, increased blood pressure, pain in the joints and lower extremities, feelings of heaviness in the left and right hypochondrium , bleeding with minimal trauma, tooth extraction;

Anamnestic data: a gradual increase in the level of red blood cells and hemoglobin, leukocytes, platelets in blood tests over several years, previous thrombosis, especially in unusual locations in young people, recurrent peptic ulcer, hemorrhagic syndrome with minimal surgical interventions or tooth extraction;

Results of clinical and laboratory studies: persistent erythrocytosis, leukocytosis, thrombocytosis, expansion of the myeloid lineage with hyperplasia of megakaryocytes in the myelogram and histological examination of the bone marrow, detection of a point mutation JAK2V617F or ex-zone 12 of the Janus kinase erythropolytic receptor gene

ethin, absence of causes of secondary erythrocytosis.

A reliable diagnosis of the disease can only be established with a full examination, the parameters of which are presented below. A particular difficulty is the differential diagnosis between polycythemia vera and the prefibrotic stage of primary myelofibrosis, secondary erythrocytosis in other diseases and conditions of hereditary (familial) nature.

Mandatory studies:

Initial appointment and examination by a hematologist with the collection of complaints, medical history (symptoms of tumor intoxication), examination of the patient’s objective status with mandatory determination of the size of the liver and spleen;

General (clinical) blood test, detailed with visual examination of a smear for the morphological characteristics of the myeloid germ (impaired maturation of neutrophils with a shift of the formula to the left, pathology of the size and shape of platelets, erythrocytes, the presence of intracellular inclusions, normoblasts);

Biochemical blood markers: total bilirubin, AST, ALT, LDH, uric acid

lota, urea, creatinine, total protein, albumin, LDH, alkaline phosphatase, electrolytes (potassium, sodium, calcium, phosphorus), serum iron, ferritin, trans-ferrin, vitamin B12, erythropoietin;

Oxygen saturation of arterial blood (using a pulse oximeter or by measuring partial oxygen tension on a gas analyzer);

Sternal puncture with myelogram calculation, determination of the ratio of myeloid and erythroid lineage, quantitative and qualitative characteristics of myelokaryocytes;

Cytogenetic study of bone marrow cells;

Molecular genetic study of peripheral blood: qualitative PCR for the presence of the JAK2V617F mutation; if the result is positive, determination of the allelic load of the mutant JAK2V617F and “wild” types of the JAK2 gene using real-time PCR;

Trephine biopsy of the bone marrow with determination of cellularity, three-color staining (van Gieson, silver impregnation, Perls), assessment of the degree of fibrosis using a standard scale;

Ultrasound of the abdominal organs (size and density of the liver and spleen, diameter of the portal vein);

Research according to indications:

Determination of mutations in exon 12 of the JAK2 gene, LNK, CALR, MPL genes (W515L; W515K) in JAK2V617F negative patients;

Determination of mutations in the genes CBL, TET2, ASXL1, IDH, IKZF1, EZH2 - in PV in the stage of postpolycythemic myelofibrosis;

Coagulogram (activated partial thromboplastin time (APTT), thrombin time (TT), international normalized ratio (INR), fibrinogen) if there is a risk of thrombotic or hemorrhagic complications;

Molecular genetic screening of markers of hereditary thrombophilia, homocysteine, consultation with a vascular surgeon in the presence of previous thrombosis and thromboembolism to determine the indications and scope of anticoagulant therapy;

Determination of alkaline phosphatase activity of neutrophils;

Cytochemical (myeloperoxidase, lipids, PA8 reaction, alpha-naphthylesterase) and immunophenotypic study of blast cells (in the blast crisis phase);

Determination of blood group (AB0, Rh factor) if hemocomponent therapy is necessary (in the phases of post-polycythemic myelofibrosis and blast crisis);

Blood test for HBsAg, antibodies to HCV-β, HIV types 1 and 2 Wasserman reaction;

Rehberg test for signs of kidney pathology;

Fibrogastroduodenoscopy to exclude secondary thrombocytosis against the background of gastrointestinal pathology and with signs of portal hypertension to exclude varicose veins of the esophagus and stomach in the post-thrombocythemic myelofibrosis phase;

Standard 12-lead ECG in the presence of cardiac pathology;

X-ray of tubular bones for indirect assessment of osteosclerosis if the patient refuses trepanobiopsy (in the post-polycythemic myelofibrosis phase);

X-ray of the chest organs to exclude secondary thrombocytosis due to chronic diseases and lung tumors;

Consultations with medical specialists (neurologist, cardiologist, ophthalmologist, endocrinologist, gynecologist, gastroenterologist, etc.) in the presence of complications and concomitant pathologies to optimize therapy.

DIAGNOSTIC CRITERIA AND DIFFERENTIAL DIAGNOSIS OF POLYCYTHEMIA VUE

To verify the diagnosis, the international working group on the diagnosis and treatment of IP developed diagnostic criteria, which were subsequently adopted by WHO in 2001. Thanks to the accumulation of data on the molecular genetic basis of the pathogenesis of IP, primarily information on the role of the JAK2V617F mutation, the diagnostic criteria were revised in 2007. Their significant simplification was achieved with improved sensitivity and specificity, which made it possible to recommend them to WHO in 2008 use in clinical practice.

The criteria are divided into two groups: large and small.

Large criteria:

Hemoglobin level more than 185 g/l in men and 165 g/l in women or other signs of an increase in the mass of circulating red blood cells1;

Determination of the JAK2V617F mutation or other functionally similar mutations, for example, in the 12th exon of the JAK2 gene.

Minor criteria:

Trilinear (erythroid, granulocytic, megakaryocyte lineages) bone marrow hyperplasia according to trepanobiopsy;

Erythropoietin levels are below the upper limit of normal;

Spontaneous growth of erythroid colonies of hematopoietic cells in a medium without the addition of growth factors.

The diagnosis of IP is reliable in the presence of two major criteria and one minor or the first major criterion and two minor ones.

Currently, a new edition of the criteria, developed in 2014, has been submitted to WHO for consideration. Just like the previous version, the criteria are divided into large and small.

Large criteria:

Hemoglobin level more than 165 g/l in men and 160 g/l in women or hematocrit more than 49% in men and more than 48% in women;

Detection of the JAK2V617F mutation or other functionally similar mutations, for example, in the 12th exon of the JAK2^ gene;

Trilinear (erythroid, granulocytic, megakaryocyte lineages) hyperplasia of the bone marrow with pleomorphic megakaryocytes according to trephine biopsy.

Minor criteria:

Erythropoietin levels are below the upper limit of normal.

The differences from the previous edition are: the transfer of histological features to the group of major criteria and the exclusion of spontaneous colony growth from the list. The diagnosis of IP in this version is verified if three major criteria or the first two major and minor criteria are present.

When diagnosing IP, it is often necessary to conduct a differential diagnosis with many conditions characterized by erythrocytosis, both hereditary and acquired. Some help in this can be provided by the use of the diagnostic algorithm presented in Fig. 7. The most common causes of secondary erythrocytosis are listed in Table. 3.

A hemoglobin or hematocrit level above the 99th percentile or above normal values ​​for age, sex, altitude, or an increase in the red blood cell count of more than 25% or a hemoglobin level of more than 170 g/L in men and 150 g/L in women if this is accompanied by an increase in hemoglobin levels by more than 20 g/l compared to anamnestic data and is not associated with the correction of iron deficiency.

Figure 7. Algorithm for differential diagnosis with an increase in the number of red blood cells and/or hemoglobin levels.

Causes of secondary erythrocytosis

Table 3.

Decreased plasma volume (relative erythrocytosis) Acute - Prolonged vomiting or diarrhea - Severe burns - Prolonged fever - Diabetic ketoacidosis Chronic - Prolonged inappropriate use of diuretics - Gaisbeck syndrome (moderate increase in hematocrit without erythrocytosis in middle-aged male smokers with obesity and hypertension)

DETERMINING THE PROGNOSIS OF THROMBOTIC COMPLICATIONS (RISK GROUP FOR DEVELOPMENT OF THROMBOSIS)

Mechanism of occurrence Condition

Reactive increase in erythropoietin levels Chronic obstructive pulmonary disease Cardiovascular diseases with circulatory failure Smoking Living in high altitudes Sleep apnea Obesity combined with sleep apnea Side effects of drugs (androgens and corticosteroids) Doping (administration of erythropoietin drugs) Professional activity or sports activity under hypoxic conditions (flight crew, submariners, scuba divers, divers, climbers, skiers, stokers, cryobank personnel, etc.)

Pathological increase in erythropoietin levels Renal carcinoma Non-neoplastic kidney diseases (cysts, hydronephrosis, severe renal artery stenosis) Hepatocellular carcinoma Uterine fibroids Meningioma Cerebellar hemangioblastoma Other tumors (Wilms tumor, ovarian cancer, carcinoid, pituitary adenoma)

Traditionally, age and a history of thrombosis are identified as risk factors for the development of thrombosis in PV. Also, information has now been accumulated on the effect on the incidence of thrombosis in patients with PV of the allelic load JAK2V617F, leukocytosis more than 15 x 109/l, female gender, risk factors for cardiovascular diseases (diabetes mellitus, arterial hypertension, smoking), increased acute phase markers inflammation, activation of leukocytes and platelets,

resistance to protein C, circulating microparticles.

In clinical practice, the thrombosis risk prediction scale developed by Marchioli R. e tal is simple and easy to use. in an international multicenter prospective study of cardiovascular events in 1638 patients with IP. The scale includes two statistically significant factors: age over 65 years and a history of thrombosis, which determine the risk of thrombosis from 2.5% to 10.9% per year (Table 4).

Table 4.

Predictive risk scale for thrombosis in PV

Factors Risk of thrombosis Development of thrombosis, % per year

Age under 65 years No history of thrombosis low 2.S %

Age 65 years and older No history of thrombosis intermediate 4.9%

Age under 65 years History of thrombosis S,0%

Age 65 years and older History of thrombosis high 10.9%

The use of this scale allows you to choose an adequate strategy for the prevention of thrombotic complications, which constitute the main risks of disability and death in IP.

According to the results of a survey of 252 patients with PV, during the initial examination, all patients had a simultaneous increase in hematocrit and erythrocytosis, a leukocyte level of more than 9.0 x 109/l was recorded in 66% (166) patients, thrombocytosis above 400 x 109/l was detected in 61.1% (154) patients. Histological examination of the bone marrow revealed no signs of fibrosis (MF-0) in 91.4% of patients, the first degree of reticulin fibrosis (MF-1) was determined at the time of diagnosis in 2.9% of patients and the second degree of reticulin fibrosis (MF-2 ) in 5.7% of patients.

A cytogenetic study of bone marrow cells was performed in 18 patients. Chromosomal aberrations were not detected in any of the patients.

The JAK2V617F mutation was detected in 97.7% of patients, JAK2 mutations in exon 12 were detected in 2.3% of patients.

The proportion of patients who suffered thrombosis was 11.1%, including myocardial infarction 3.6%, acute cerebrovascular accident 5.2%. The frequency of thrombosis differed statistically significantly (p=0.0004) in risk groups according to the prognosis scale for thrombosis in PV: in the low-risk group 2.6% (2/78), intermediate risk 7.8% (6/77) and 20. 6% (20/97) with a high risk of thrombosis (Table 5).

Table 5

The incidence of thrombosis in polycythemia vera

Frequency of thrombosis in risk groups (p = 0.0004)

low intermediate high

Thrombosis, overall frequency 2.6% 7.8% 20.6%

The overall ten-year survival rate of patients with PV was 77.7%, the estimated median overall survival was 20.2 years (Fig. 8). In the analyzed group, 56 patients had registered

we have deaths. Progression to the phase of secondary myelofibrosis occurred in 12 (5.0%) patients.

Overall survival - 77.7% Estimated median overall survival - 20.2 years

%Progression into the phase of secondary myelofibrosis 5.0%

ALIVE DIE

1 - - - - - - - - 1 - - . . > .

duration of observation, pet

Figure 8. Overall survival of patients with PV.

THERAPY OF POLYCYTHEMIA REAU

The goal of IP therapy currently is to prevent thrombotic complications of the disease and relieve its symptoms to improve quality of life. The ability to control disease progression using standard therapy has not yet been proven. The results of using targeted drugs for this purpose - Janus kinase inhibitors - will be clear after the completion of clinical trials.

IP therapy is primarily aimed at reducing the risks of microcirculation disorders, for which angioplatelet agents and vascular drugs are used. Another important component of thrombosis prevention is the control of risk factors: the course of concomitant diseases (hypertension, diabetes), normalization of body weight, smoking cessation.

Cytoreductive therapy is prescribed for clinically significant deviations in parameters

blood, causing the risk of thrombotic complications. There are no exact levels to be corrected. Typically, it is advisable to adjust blood counts when the hematocrit increases by more than 50% (the risk of cardiovascular complications has been proven to decrease when the hematocrit level is less than 45%), leukocytes more than 15 x 109/l, platelets more than 1000 x 109/l. Drug cytoreduction for PV is carried out in the form of monochemotherapy, interferon therapy, or their combined use. In some patients, most often young with a low risk of vascular complications, correction of blood parameters can be carried out using physical removal of excess cell mass (hemoexfusion, erythrocytapheresis). In the blast transformation (BC) phase, treatment can be carried out according to acute leukemia treatment programs, taking into account the age and comorbidity of patients.

DEFINITION OF THERAPEUTIC TACTICS

To determine therapeutic tactics, it is advisable to collect the following information about the various factors that determine risk:

ski and allowing individualization of treatment tactics, which are presented in table. 6.

Table 6

Individual factors determining treatment tactics

Symptoms of the disease Symptoms of tumor intoxication (constitutional) profuse night sweats loss of body weight more than 10% unexplained febrile fever Skin itching (localization, duration of occurrence, treatment result) Vasomotor symptoms (headache, dizziness, ringing in the ears, paresthesia of the extremities, erythromelalgia, redness of the skin integument and mucous membranes, problems concentrating) Myalgia, arthralgia, bone pain Abdominal discomfort, early satiety Fatigue, weakness, their impact on daily activities

Life history Concomitant pathology (hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, hyperuricemia/gout) Previous diseases Surgical interventions Previous cardiovascular episodes and bleeding Presence and characteristics of the menstrual cycle in women Altitude of residence above sea level

Life history Smoking Dietary habits Sleep apnea Physical activity Occupational hazards Willingness to change lifestyle in accordance with recommendations

Taking medications Antihypertensive drugs, including diuretics Androgens Glucocorticoid hormones Antiplatelet agents or anticoagulants Contraceptives Adherence to constant use of prescribed therapy

Pregnancy Previous pregnancies, abortions and/or miscarriages Planning future pregnancies

Family history Relatives with a diagnosis of myeloproliferative neoplasms, with other diseases of the blood system Relatives with erythrocytosis of unknown etiology Relatives with thrombosis of unusual locations and/or at a young age

During the examination period, until the final diagnosis is established, the patient is given symptomatic therapy aimed at controlling the most severe symptoms, preventing thrombosis with the help of angioaggregants and relieving the manifestations of concomitant diseases (normalization of blood pressure, blood glucose levels, etc.). If there are clinical signs of microcirculation disorders (encephalopathy, decreased vision, renal failure, circulatory failure of the extremities), mechanical removal of excess red blood cells (hemoexfusion, erythrocytepheresis) can be performed for symptomatic purposes until the hematocrit level is normalized.

To correct high erythrocytosis, leukocytosis and thrombocytosis during the examination period until the final confirmation of the diagnosis of PV, Hydroxycarbamide (Hy-

drea®, Hydroxycarbamide medak®, Hydroxyu-rea®) at an initial dose of 15 mg/kg/day with subsequent adjustment depending on the dynamics of the level of hemoglobin, leukocytes and platelets.

After confirmation of the diagnosis, the tactics of further therapy should be determined and the issue of the need and type of cytoreductive therapy should be resolved. The use of risk-adapted therapeutic tactics seems justified.

The main factors influencing the choice of treatment option are the following:

The presence and severity of symptoms of the disease;

Age of the patient;

Risk of developing thrombosis;

Concomitant diseases and the need for their constant therapy;

Lifestyle, etc.

CHARACTERISTICS AND PRINCIPLES OF CHOOSING A TREATMENT METHOD

IP therapy methods

Despite the variety of methods currently used to treat IP, they can all be divided into several groups:

Prevention of thrombotic complications;

Mechanical removal of excess cell mass (hemoexfusion, erythrocyte pheresis);

Cytoreductive drug therapy;

Targeted therapy;

Treatment of complications of the disease (thrombosis, thromboembolism);

Prevention of thrombotic complications

Efforts to prevent thrombosis and thromboembolism in PV should be aimed primarily at reducing the significance of cardiovascular risks: arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia.

lesterolemia, obesity, normalization of lifestyle, physical activity, etc. The use of highly effective cholesterol-lowering drugs can significantly reduce the manifestations of atherosclerosis, which is one of the main factors in thrombus formation.

Reducing the activity of platelet aggregation in most patients is traditionally carried out with the help of constant intake of arachidonic acid cascade inhibitors - non-steroidal anti-inflammatory drugs. The most common drug used for this purpose is acetylsalicylic acid in small doses. Currently, there are many drugs on the pharmaceutical market with different trade names and in different forms, including enteric-rima, to minimize the side effects of long-term use. The optimal dosage of the drug to achieve an antiplatelet effect is in the range of 75-100 mg/day. Lower doses are not effective enough, and higher doses are accompanied by significant side effects (development of stomach and duodenal ulcers, inhibition of prostacyclin synthesis, etc.). The use of acetylsalicylic acid in PV has received evidence of effectiveness in multicenter placebo-controlled randomized clinical trials (ECLAP), both for a significant reduction in the incidence of thrombosis (hazard ratio 0.4 compared with placebo) and a reduction in overall mortality (46% ) and mortality from cardiovascular diseases (59%), also the use of acetylsalicylic acid led to relief of erythromelalgia and vasomotor symptoms. If there are contraindications or intolerance to acetylsalicylic acid, antiplatelet therapy can be carried out using its substitutes - clopidogrel (75 mg/day) and ticlopidine (500-750 mg/day). A certain problem, especially with hyperthrombocytosis more than 1000 x 109/L, may be the risk of bleeding due to acquired von Willebrand syndrome. In practice, the risk of hemorrhages can be assessed by studying the activity of ristocetin; if its value is more than 30%, the use of acetylsalicylic acid is safe.

Mechanical removal of excess cell mass

Reducing and maintaining hematocrit within normal limits is easily achieved through the use of hemoexfusion and erythrocytepheresis. These procedures can be used as the main treatment method in low-risk PV patients, predominantly young, or in combination with cytoreductive therapy in all PV patients. Reducing the hematocrit level from 60% to normal reduces the incidence of cardiovascular complications by 38 times. In the Cy1;o-RU study, it was proven that in patients with PV, whose hematocrit was maintained within normal values, the incidence of thrombosis was significantly lower. The main advantage of hemoexfusion and erythrocytepheresis is the rapid decrease in hematocrit and relief of microcirculation disorders. The disadvantages are the stimulation of the coagulation system during the procedure, which increases the risk of vascular complications and loss of blood plasma with red blood cells, protein and other components. These negative aspects are much less pronounced when performing manual, and even more so, hardware erythrocytepheresis, which allows it to be widely used in outpatient settings.

The most common method of hemoexfusion is the following: while taking antiplatelet drugs (acetylsalicylic acid, clopidogrel), immediately before bloodletting, 400 ml of rheopolyglucin solution or saline is administered, as well as 5000 U of heparin intravenously, after which up to 500 ml is removed (250 ml during the first procedures) blood. The volume of bloodletting and their frequency are selected individually depending on the patient’s age, concomitant pathology and tolerability of the procedures. In the case of erythrocytapheresis, the same rules are followed. Most often, 2-3 sessions are performed per week. After one procedure, the hematocrit decreases by 3-5%. The target level for hematocrit reduction is its normal (below 45% for men and 42% for women) level. As a rule, one course of hemoexfusion or erythrocytepheresis is enough to normalize hematocrit for 2-3 months. Frequent hemoexfusions and erythrocytepheresis lead to reflex hyperthrombocytosis; in order to correct it, it may be useful to prescribe

anagrelide or hydroxyurea. Another side effect is an iron deficiency state, the correction of which with the help of iron supplements is necessary only in the presence of sideropenic syndrome - tissue iron deficiency, manifested in the form of muscle weakness, impaired trophism of the skin, hair, mucous membranes, taste perversion, and swallowing disorders.

Cytoreductive therapy

Drugs are currently the main means of reducing excess cell mass in PV. This therapy does not lead to a cure, but, with the right approach, it can relieve symptoms and maintain the quality of life of patients. Traditional drugs used for the purpose of cytoreduction are the following:

Cytostatics: Hydroxyurea (Hydrea®, Hydroxyurea medak®, Hydroxyurea®); Cytarabine (Alexan®, Cytarabine-LENS, Cytosar®, Cytostadin®); Mercaptopurine (Mercaptopurine, Puri-Netol®) used, as a rule, as monochemotherapy in low doses (Hydroxyurea 10-30 mg/kg/day; Mercaptopurine 1-2 mg/kg/day; Cytarabine 10-20 mg/m2/day 10-14 days every month). The purpose of using cytostatics is to inhibit tumor proliferation and control blood counts in order to prevent complications. There are no generally accepted standard application regimens. Preferred is continuous daily or intermittent (in the case of cytarabine) dosage in doses selected taking into account individual tolerance, allowing control of blood counts. The most commonly used treatment for PV is hydroxyurea (hydroxyurea, hydrea). Hydroxyurea is a highly effective drug for the prevention of thrombosis in all patients with PV, especially in the high-risk group. The antithrombotic effect of Hydrea is associated with the normalization of not only hematocrit, but also the level of leukocytes and platelets. When comparing hydroxyurea monotherapy with treatment with hemoexfusions for 15 years (study RU8v-01), the effectiveness of preventing thrombosis was approximately the same. Differences were observed in a higher frequency of blast transformation (9.8% for hydrea and 3.7% for hemoexfusion), lower frequency

those of post-polycythemic myelofibrosis (7.8% for the treatment of hydrea and 12.7% for hemoexfusions) and better overall survival (60.8% for hydrea and 44.8% for hemoexfusions). A 17-year randomized comparison study of pipobromane and hydroxyurea also showed hydrea to be highly effective in preventing thrombosis and maintaining survival comparable to pipobromane. The initial dose of hydroxyurea is 15-20 mg/kg/day (1000-1500 mg/day) with a gradual increase to a dose that allows you to achieve a normal hematocrit level and a leukocyte level of more than 3.0 x 109/l or the maximum tolerated. Monitoring the number of leukocytes and other hemogram indicators (hemoglobin + platelets + blood count) while taking hydroxycarbamide should be carried out weekly during the first 1-2 months of treatment, then monthly. To prevent complications associated with tumor lysis syndrome during the period of cytoreduction, it is mandatory to prescribe an adequate volume of fluid (up to 2-2.5 l/m2 per day in the absence of heart failure), allopurinol at a dose of 300-600 mg/day due to sufficient Hyperuricemia often developing at the beginning of therapy, it is also advisable to periodically monitor blood uric acid levels. The most common side effects of hydroxyurea are leukopenia and thrombocytopenia, their control is achieved by individual dose selection under the control of blood counts. Less frequent, but more difficult to correct, adverse events are ulcers of the legs and mouth, skin changes, pulmonitis.

Interferon-alpha (IFN-a) (Altevir®, Alfarona®, Interferal®, Intron A®, Realdiron®, Roferon-A®, Reaferon-ES®) in PV suppresses the proliferation of myeloid progenitor cells and also has a direct has an inhibitory effect on bone marrow fibroblasts and is an antagonist of cytokines (growth factor produced by platelets; transforming growth factor B, etc.) involved in the formation of myelofibrosis. The use of IFN-a in PV has a history of more than twenty years and has been well studied in several clinical studies. IFN-a allows one to achieve control of blood counts without the use of hemoexfusion in 50% of patients; in 77% of patients, the size of the spleen decreases

and in 75% a decrease in the severity of skin itching. In some patients with PV, the use of IFN-a leads to a decrease in the allelic load of JAK2V617F. The most justified use of IFN-a is in patients under 40-50 years of age, in whom the possible leukemic effect of long-term use of hydroxyurea should be taken into account. Also, the use of IFN-a is relevant especially for women of childbearing age who are planning pregnancy or do not want to use adequate methods of contraception. Interferon is contraindicated in diseases of the thyroid gland and mental illness. The initial dose is 1 million IU 3 times a week, increasing with satisfactory tolerability to 3 million IU 3 times a week or daily. Once hematocrit control is achieved within normal limits, the dose can be gradually reduced to the lowest dose that allows hematocrit control to be maintained. Pegylated interferons are much better tolerated than simple IFN, but have not yet received official approval for use in IP. However, their effect has been studied in clinical studies. The initial dose of peg-IFN is 0.5 mcg/kg per week, increased if necessary to 0.5 mcg/kg per week. A complete hematological response using pegIFN was observed in 76% of patients, and 13% also achieved a complete molecular response (no JAK2Y617F mutation). The advantages of IFN-a are the absence of leukemic and teratogenic effects and the likelihood of obtaining molecular responses. The greatest disadvantages are the side effects of its use: flu-like syndrome, weakness, muscle pain, weight loss, hair loss, depression, gastrointestinal and cardiovascular disorders, the occurrence of which forces the cancellation of therapy in a third of patients. In case of insufficient effectiveness or poor tolerability, combined administration of IFN-a with hydroxyurea is possible. This combination may increase efficacy and allow dose reduction of each drug with improved tolerability.

Anagrelide is a specific agent that causes a dose-dependent and reversible decrease in the number of platelets in peripheral blood. The mechanism of action is not fully understood. Research data indicate that anagrelide inhibits hypermaturation of megakaryocytes in a dose-dependent manner. Application

anagrelide does not lead to a significant change in parameters such as blood clotting time and platelet lifespan, and the morphology of the bone marrow does not change. The drug does not significantly affect the level of hemoglobin and leukocytes, but significantly reduces platelets. In PV, anagrelide is a good option for combination treatment together with hemoexfusions or hydroxyurea, when thrombocytosis cannot be controlled with monotherapy. The recommended starting dose of anagrelide is 0.5 mg 4 times a day or 1.0 mg 2 times a day. The maximum single dose is 2.5 mg, the daily dose is 10 mg. At the optimal dose, the platelet count begins to decrease after 7-14 days. The minimum effective dose should be used that will be sufficient to maintain the platelet count below 600,000/µl, and ideally to the normal level. In most patients, an adequate response is achieved with anagrelide at a dose of 1.5-5.0 mg/day. Most side effects are dose-dependent, mild and transient and do not require therapeutic measures to eliminate them. The most common adverse events are vasodilatory and positive inotropic effects, headache, diarrhea, fluid retention, heart failure, and arrhythmias. The frequency and severity of adverse reactions decreases with continued therapy.

Janus kinase inhibitors are medications that block the activity of 1AK2 kinases, the first targeted drugs aimed at the key link in the pathogenesis of IP - the 1AK-8TAT signaling pathway. It should be taken into account that these drugs affect both the mutant (JAK2V617F) and the “wild” type of 1AK kinases, and therefore can be effective in the treatment of patients negative for the presence of the JAK2Y617F mutation. The following drugs are currently being evaluated in clinical trials: WDSV018424, TG101348, CEP-701, CYT387, AZD1480, 8B1518 and LY2784544. At the moment, only the drug ShSV018424 (Kiho1Shshb, Iakau1® (Ruxolitinib, Jakavi®), manufactured by Ho-vartis Pharma AG, Switzerland) has received a trade name and approval for use in PV. Currently, ruxolitinib is indicated for patients with PV with insufficient response or intolerance to hydroxyurea. Maximum transferability

the dose of the drug is 25 mg twice a day, therapeutic doses for PV are from 10 to 25 mg twice a day. According to the RESPONSE study comparing ruxolitinib and standard therapy in 222 patients who were resistant to treatment or intolerant to hydroxyurea, ruxolitinib showed significant superiority in both efficacy and tolerability. Hematocrit control during ruxolitinib treatment was achieved in 97% of patients after 48 weeks and in 86% after 80 weeks. Also, in most patients, reduction of the spleen was achieved. As a result, 84% of patients in the standard therapy group were switched to ruxolitinib. The severity of PV symptoms, especially skin itching, weakness and sweating, decreased by 49%-100% during treatment with ruxolitinib, while there was no change in symptoms with standard therapy (-2%-4%). Adverse effects of ruxolitinib in PV are well tolerated and easily controlled with dose modification. Ruxolitinib resulted in a significant reduction in JAK2V617F allelic load by 8% after 48 weeks, 14% after 96 weeks, and 22% after 144 weeks of treatment. To achieve deeper molecular responses, it is attractive to investigate the effectiveness of combination therapy with ruxolitinib and interferon.

Telomerase inhibitors are promising drugs that block the activity of enzymes that shorten the length of telomeres - the end sections of chromosomes, thus normalizing the proliferation of myeloid precursors. Currently, there is only one representative of this new class - the drug Imetelstat (Imetelstat, GRN163L), which has undergone phase II studies for use in PV. Due to hepatotoxicity, the study was temporarily suspended, but in November 2014, restrictions were lifted.

Treatment of the majority of 252 patients with PV who underwent examination and treatment at our institute was carried out using hydroxyurea and its analogues - 205 patients (81.8%), average dose of 0.7 g/day. Interferon preparations were used in 43 patients (17.1%), the average dose was 8.5 million/week; mercaptopurine in 25 (10.1%). Erythrocytapheresis was performed in 221 patients (88.9%) with an average frequency of 1 to 8 procedures per year (average 2.84). Surgical treatment was used

1 patient had splenectomy due to splenic infarction. As a result of therapy, 7.5% achieved a complete response; 72.6% had a partial response and 19.8% had no response to treatment.

Principles for choosing a treatment method

The basis for choosing a treatment method is the patient’s age and the presence of cardiovascular diseases, which determine the risk of thrombosis, the life expectancy of patients and the likelihood of disability.

Patients under the age of 50 years. Most often, these patients have a low risk of thrombosis. Often such patients do not have pronounced clinical symptoms and are referred to a hematologist based on the results of a clinical analysis performed during medical examination or during examination for other diseases. Patients with PV in this group have the greatest likelihood of maintaining life expectancy, preventing the development of thrombosis and maintaining quality of life. The use of cytoreductive therapy in such patients is associated with a greater risk of developing long-term side effects than the risks of disease progression. In this group, especially in patients under the age of 40, the use of only methods of mechanical removal of excess cell mass (hemoexfusion, erythrocytapheresis) and the prevention of vascular complications by taking antiplatelet agents is often justified. Cytoreductive therapy should be started if patients have cardiovascular pathology or a history of thrombosis, as well as with insufficient effect or poor tolerability of hemoexfusion/erythrocytapheresis, with the appearance of symptoms of vascular complications (transient ischemia, thrombophlebitis of the veins of the lower extremities, etc.), a significant increase in the level platelets (to a level of more than 1,000 x 109/L or more than 300 x 109/L within three months). If it is necessary to prescribe cytoreductive therapy under the age of 50 years, it is advisable to use IFN-a preparations as the first line of therapy, taking into account the possible leukemic effect of cytostatics with long-term use. To correct hyperthrombocytosis in such patients, the administration of anagrelide is indicated, the administration of which is rarely accompanied by significant side effects in young patients. In this group of patients, the question of planning pregnancy often arises, which also

makes the choice of IFN-a drugs more reasonable. In case of resistance and/or intolerance to IFN-a drugs, it is advisable to use hydroxyurea as a second line of therapy. If hydroxyurea is insufficiently effective and/or poorly tolerated, therapy with Janus kinase inhibitors (ruxolitinib) seems adequate. Prospects for clinical studies, taking into account the life expectancy and long course of IP, the prevention of the development of blast transformation and post-polycythaemic myelofibrosis, may be the use of targeted therapy drugs, primarily Janus kinase inhibitors (ruxolitinib, etc.).

Patients aged 50-70 years. Patients in this group most often have an intermediate or high risk of developing thrombosis, which, accordingly, determines the choice in favor of continuous cytoreductive therapy, most often hydroxyurea, which is better tolerated compared to IFN-a drugs. In the absence of cardiovascular pathology and a history of thrombosis, drug therapy can be combined with hemoexfusion/erythrocytapheresis. In patients with cardiac pathology and/or who have suffered thrombosis, mechanical removal of excess cell mass may be associated with the risk of thrombotic complications. With resistance and/

or intolerance to hydroxyurea, IFN-α drugs or Janus kinase inhibitors (ruxolitinib) can be used.

Patients over 70 years of age. Patients in this group most often have a high risk of developing thrombosis. The life expectancy of patients in this group may be limited both by the presence of IP and the associated high frequency of repeated thrombosis, and by the residual consequences of thrombosis (chronic heart failure after a heart attack, encephalopathy after strokes, etc.). It is vitally important, given the pronounced vascular atherosclerosis at this age, to control blood counts (hematocrit, leukocytes, platelets) within normal limits (less than 400 x 109/l) using cytoreductive drugs. The most preferred treatment option is the use of hydroxyurea. If its effect is insufficient or is poorly tolerated, targeted drugs (ruxolitinib) may be prescribed. Hydroxyurea can also be combined or replaced with other cytostatics (mercaptopurine, busulfan, cytosar). In some patients, the possibility of administering radioactive phosphorus or using low doses of IFN-a drugs may be considered. In graphical form, the recommended treatment algorithm for patients with IP, depending on age and concomitant pathology, is presented in Fig. 9.

Figure 9. Algorithm of treatment tactics for IP.

MONITORING AND EVALUATION OF TREATMENT EFFECTIVENESS

For adequate and timely correction of therapy in order to achieve maximum effectiveness and control toxicity, it is necessary to conduct timely monitoring of hematological and biochemical, and, if necessary, cytogenetic and molecular genetic parameters.

Timely assessment of the effectiveness of therapy using standardized methods allows us to obtain accurate data on the results of using various treatment methods and systematize therapy tactics with the aim of individualizing it.

the presence of complications, etc.) the frequency of clinical and laboratory monitoring may be more intensive. The results of therapy in patients with IP are assessed according to clinical assessment, hematological and molecular genetic studies. Currently, promising methods for assessing the effect of PV treatment in clinical trials include patient assessment of symptoms and histological method. Depending on the methods of assessment and the degree of suppression of the tumor clone, different types of response are distinguished: clinical-hematological, cytogenetic and histological.

Table 7.

Frequency of dynamic examination of patients with IP

Study Monitoring Frequency

General (clinical) blood test detailed At the time of diagnosis, then at least once every three months or more often depending on blood counts

Biochemical parameters (bilirubin, AST, ALT, LDH, uric acid) At the time of diagnosis, then at least once every three months during cytoreductive therapy

Coagulogram (APTT, TV, INR, fibrinogen) At the time of diagnosis, in the presence of thrombosis and anticoagulant therapy at least once every three months

Ultrasound of the abdominal cavity with determination of the size of the liver, spleen, assessment of portal blood flow At the time of diagnosis, then at least once a year

Sternal puncture with myelogram counting and cytogenetic examination Bone marrow trepanobiopsy with histological examination and assessment of the degree of fibrosis Upon diagnosis, then with the development of leukocytosis, a shift in the leukoformula, cytopenia

The clinical and hematological response is assessed by the level of hematocrit, the presence or absence of symptoms of circulatory failure, ischemia, splenomegaly, and blood counts. It can be complete or partial, or absent. The criteria for determining the clinical and hematological response are given in Table. 8. A complete clinical and hematological response is determined by complete normalization of blood parameters (hematocrit, leukocytes, platelets), normal size of the spleen and the absence of clinical symptoms of the disease.

nia. A partial response is established when the criteria for a complete response are not fully met, but in this case it is necessary to either normalize the hematocrit without the need for hemoexfusion (erythrocytapheresis) or the presence of three or more criteria (normalization of leukocytes, platelets), the absence of splenomegaly and other symptoms of PV. Lack of response to treatment is stated when the assessment does not correspond to a complete or partial clinical and hematological response.

BULLETIN OF HEMATOLOGY, volume XI, No. 1, 2015

Table 8.

Criteria for clinical and hematological response in the treatment of PV

Response Type Definition

Full answer Hematocrit<45 % без необходимости гемоэксфузий (эритроцитафереза) Тромбоциты < 400 х 109/л Лейкоциты < 10 х 109/л Нормальные размеры селезенки Нет симптомов заболевания*

Partial response Does not meet full response criteria Hematocrit<45 % без необходимости гемоэксфузий (эритроцитафереза) ИЛИ ответ по трем или более критериям (лейкоциты, тромбоциты, размеры селезенки, симптомы заболевания)

No answer Any answer that does not correspond to a partial answer

* microcirculation disorders, skin itching, headache

The molecular response is assessed by molecular genetic study of peripheral blood over time. Response rate may

to be big and small. Molecular response criteria are given in Table. 9 .

Table 9

Assessing molecular response in PV treatment

Response Type Definition

Complete response Reduction of the allelic load of a molecular marker (JAK2V617F, etc.) to a level undetectable

Partial response* Reduction >50% from the level at the initial study in patients with an allelic load level< 50 % при первоначальном исследовании ИЛИ Снижение >25% of the level at the initial study in patients with an allelic load level > 50% at the initial study

No response Any response that does not correspond to a full or partial response

*can only be used for patients with an allelic load level > 10% during the initial study

Carrying out trepanobiopsy with histological examination of the bone marrow allows us to evaluate the histological response, the achievement of which has become possible with the use of new methods of treatment of IP-targeted drugs. The presence of a histological response is stated in the absence of trilineage bone marrow hyperplasia and cellularity corresponding to the patient’s age.

Hydroxyurea is the most widely used drug for the treatment of PV. At the same time, as literature data and our own experience show, therapy with hydroxyurea rarely (7-10%) allows achieving complete clinical and hematological relief.

veta. An effective alternative in case of insufficient effectiveness and/or intolerance to hydroxyurea are Janus kinase inhibitors (ruxolitinib), which allow achieving independence from hemoexfusions in the vast majority of patients. In order to determine the indications for the need to transfer patients with PV from hydroxyurea to therapy with Janus kinase inhibitors, the European Organization for the Diagnosis and Treatment of Leukemia (ELN) developed criteria for determining the ineffectiveness (resistance) and intolerance of hydroxyurea in patients with PV, presented in Table. 10 .

Table 10

Criteria for ineffectiveness (resistance) and intolerance of hydroxyurea in patients with PV

No. Definition

1. The need for hemoexfusion (erythrocytepheresis) to maintain hematocrit level< 45 % после 3 месяцев терапии гидроксимочевиной в дозе не менее 2 г/сут ИЛИ

2. Uncontrolled myeloproliferation (platelets > 400 x 109/L, white blood cells > 10 x 109/L) after 3 months of hydroxyurea therapy at a dose of at least 2 g/day OR

3. Inability to reduce massive splenomegaly by more than 50% when measured by palpation OR inability to completely relieve symptoms associated with splenomegaly after 3 months of therapy with hydroxyurea at a dose of at least 2 g/day OR

4. Absolute number of neutrophils< 0,5 х 109/л ИЛИ тромбоцитов <100 х 109/л ИЛИ гемоглобина < 100 г/л при приеме наименьшей дозе гидроксимочевины, позволяющей достичь полного или частичного клинико-гематологического ответа ИЛИ

5. Presence of leg ulcers or other unacceptable nonhematologic toxicities associated with hydroxyurea, such as mucocutaneous lesions, gastrointestinal symptoms, pneumonitis, or fever with any dose of hydroxyurea

COMPLICATIONS IN POLYCYTHEMIA VEREA AND THEIR THERAPY TACTICS

The course of IP can be complicated by: the development of thrombosis and thromboembolism, bleeding, secondary postpolycythaemic myelofibrosis,

THROMBOSIS AND THROMBOEMBOLISM

The main risks of PV are associated with the accumulation of excess blood cell mass, which leads to a significant increase in the risks of developing thrombosis and manifestations of cardiac pathology. Clinically significant thrombosis develops in 1.8%-10.9% of patients with PV annually. Statistically significant risk factors for thrombosis in PV are increased levels of hematocrit and leukocytes, age over 60 years, and a history of thrombosis. Prevention of thrombus formation by prescribing antiplatelet agents - acetylsalicylic acid or its analogues is indicated for all patients with IP in the presence of at least one risk factor. An effective way to reduce the risk of thrombosis in PV is the use of Janus kinase inhibitors, in particular ruxolitinib. In the RESPONSE trial, ruxolitinib reduced the likelihood of major thrombosis and death from cardiovascular events by 45% compared with usual clinical practice. Secondary prevention after thrombosis has already occurred comes down to normalizing blood counts using

cytoreductive therapy and prescription of anticoagulant therapy with direct and indirect anticoagulants according to indications with the achievement of target parameters of the coagulation system. As a rule, in the acute period of thrombotic complications, low molecular weight heparins are prescribed, which can subsequently be replaced by warfarin in combination with antiplatelet agents, maintaining a therapeutic INR level within 2.0-3.0.

Thrombosis of abdominal veins. The development of thrombosis in unusual places, in particular the abdominal veins, can often be the first manifestation of PV, which requires a screening study to exclude CMPN in such patients. These thromboses can lead to serious consequences, including the development of hepatic vein occlusion with Bud-Chiari syndrome and subhepatic jaundice. Emergency therapy may include the application of a transjugular portosystemic vascular shunt, angioplasty with stenting, the application of portocaval vascular shunts-anastomoses, and in exceptional cases transplantation.

tation of the liver. In the presence of abdominal thrombosis in the acute phase, the administration of heparin or its low molecular weight analogues is required. Subsequently, lifelong therapy is indicated

anticoagulants in combination with cytoreduction with hydroxyurea while maintaining the target hematocrit level within the normal range and platelets less than 400 x 109/l.

BLEEDING

Hemorrhagic syndrome can complicate the course of PV with severe thrombocytosis, more often with more than 1500 x 109/l, and may be caused by secondary von Willebrand syndrome. This phenomenon is due to the consumption of von Willebrand factor multimers due to their sorption on an excess number of platelets. When platelet levels are normalized, the concentration of free factor is restored and the hemorrhagic syndrome is relieved. Bleeding in patients with PV with hyperthrombocytosis may be more pronounced when taking antiplatelet agents and/or anticoagulants. If patients with IP have a history of bleeding or conditions with a risk of hemorrhagic syndrome (peptic ulcer of the stomach and duodenum, varicose veins of the esophagus) for the prevention of hemorrhagic

syndrome, it is advisable to refrain from prescribing antiplatelet agents and anticoagulants against the background of thrombocytosis and to reduce the risks of thrombosis and bleeding by normalizing blood counts using cytoreductive therapy. Treatment of hemorrhagic episodes in PV primarily involves discontinuation of antiplatelet and anticoagulant medications and reduction of platelet counts, most commonly with hydroxyurea. As a hemostatic agent, it is possible to prescribe tranexamic acid (1 g every 6-8 hours) and desmopressin (0.3 mcg/kg/day). To compensate for the functional deficiency of von Willebrand factor, transfusions of hemocomponents containing it (cry-oprecipitate, fresh frozen plasma) or synthetic coagulation factors (von Willebrand factor in combination with factor VII, etc.) are carried out.

ITCHY SKIN

Itching, which worsens after skin contact with water, is a typical symptom of IP. In some patients, the severity of itching can be painful, causing serious concern, reducing the quality of life. The pathogenesis of skin itching is not entirely clear; it is believed that its occurrence is associated with the activation and release of inflammatory mediators by tissue basophils of the skin. Correcting itching in PV is often challenging. Antihistamines are used for symptomatic purposes.

sedatives such as cyproheptadine (Peritol®) or hydroxyzine (Atarax®), antidepressants (paroxetine - Rexetine®) or psoralen with ultraviolet irradiation of the skin. IFN-a preparations, including pegylated ones, can have a pathogenetic effect on skin itching. A significant reduction in the severity of skin itching in almost all (97%) patients was noted when using ruk-solitinib in the RESPONSE study.

SECONDARY POSTPOLYCYTHEMIC MYELOFIBROSIS

Long-term proliferation of hematopoietic cells in IP after total bone marrow hyperplasia leads to fibrosis and replacement of active bone marrow with reticulin and collagen fibers, and subsequently osteosclerosis - the development of secondary post-polycythemic myelofibrosis. The probability of outcome in postpolycythaemic myelofibrosis is about 0.5% per year. During development

secondary myelofibrosis, the addition of new syndromes may be observed: tumor intoxication, extramedullary proliferation, anemia, infectious complications, hemorrhagic syndrome.

Tumor intoxication. Symptoms of tumor intoxication (fever, heavy sweats and weight loss) cause restrictions in daily activities and worsening

improving the quality of life of patients. Traditional therapy, in the form of hydroxyurea, as a rule, leads to a slight decrease in the severity of tumor intoxication, but does not completely stop it. The use of glucocorticoids and immunomodulators, as well as their combinations, which in a significant proportion of patients lead to a reduction in disturbances in the secretion of cytokines and an improvement in their condition, has a great effect. The most effective drugs that influence the level of pro-inflammatory cytokines are currently Janus kinase inhibitors, as confirmed by the COMFORT-II study, which compared the effect of treatment with ruxolitinib and standard therapies. In the ruxolitinib group, a statistically significant reduction in the severity of intoxication symptoms and an improvement in quality of life indicators was obtained, while standard therapy did not significantly affect these indicators.

Extramedullary proliferation. With myelofibrosis, foci of hematopoiesis may develop outside the hematopoietic organs. In addition to the liver and spleen, extramedullary foci of hematopoiesis can appear in the peritoneum with the development of ascites, the lungs with the formation of pulmonary hypertension and exudative pleurisy, lymph nodes with their enlargement and compression of the underlying organs and vessels, the thoracic and lumbar spine with possible compression of the spinal cord, the extremities with compression nerve trunks and neuropathic pain. The emergence of areas of extra-bone marrow hematopoiesis is accompanied by damage to the organ structure and disruption of vascular blood flow (portal hypertension, exudative pleurisy and ascites). The presence of asymptomatic foci of extramedullary hematopoiesis does not require the addition of systemic therapy. The most effective means of prevention and pathogenetic therapy of these complications may be immunomodulators in combination with glucocorticoids and Janus kinase inhibitors. The presence of local clinical symptoms associated with extramedullary lesions is an indication for local radiation therapy in low doses (single dose 1 Gy, course dose 10 Gy). If fluid accumulates in the cavities, it is possible to use pleural punctures and paracentesis with pleurodesis. Enlargement of the spleen due to extramedullary hematopoiesis

is one of the most common manifestations of myelofibrosis and can pose a significant problem in the treatment of patients. In addition to physical symptoms such as abdominal enlargement and bloating, early satiety, and abdominal pain, splenomegaly can lead to the development of splenic infarctions, compression of the abdominal organs, and portal hypertension. Hypersplenism syndrome due to sequestration of a significant amount of blood and the development of autoimmunization leads to increased severity of cytopenias. Splenomegaly can be treated with medications or surgery. The most commonly used is hydroxyurea, which can lead to a reduction in the size of the spleen, but much more effective is the use of Janus kinase inhibitors (ruxolitinib), which leads to a significant and lasting reduction in splenomegaly in almost all patients. Splenectomy is an alternative to drug treatment when drug therapy is ineffective or poorly tolerated. Indications for removal of the spleen are massive splenomegaly, cachexia, portal hypertension with the presence of varicose veins of the esophagus and stomach, anemia with transfusion dependence. However, an enlarged spleen, the presence of portal hypertension, concomitant cytopenias and hemostasis disorders cause significant difficulties during the operation and lead to postoperative complications in 3050% of patients, and to death in 5-10% of patients. Radiation therapy to the spleen area can moderately reduce the clinical symptoms and size of the spleen in patients and is used when drug therapy is ineffective and splenectomy is impossible or refused. The therapeutic effect of radiation therapy does not lead to complete elimination of pathological symptoms, is unstable and lasts only a few months. Irradiation, as a rule, leads to increased cytopenias, which causes mortality in about 10-15% of patients. In this case, radiation therapy leads to the development of local fibrosis and the formation of adhesions with the peritoneum and adjacent organs, which subsequently makes splenectomy extremely difficult technically.

Anemia. One of the most common complications of myelofibrosis is anemia, which is often observed at the onset of the disease and serves as a reason for the patient to consult a hematologist and diagnose PMF. To correct anemia

In order to replace the deficiency and prevent life-threatening conditions, it is often necessary to resort to red blood cell transfusions. Anemia in PMF can be multi-etiological in nature and may be a consequence of a deficiency of vitamins and microelements, as well as concomitant pathology. In order to correct anemia, it is necessary to conduct a comprehensive examination and correct the deficiency of iron and vitamins, and administer erythropoietin preparations in case of insufficient production of erythropoietin. In the presence of splenomegaly and hypersplenism syndrome, a moderate increase in hemoglobin may be observed after splenectomy.

Infectious complications. Leukopenia and neutropenia, which are sometimes manifestations of secondary myelofibrosis, cause an increased incidence of infectious complications. Infectious processes in patients with myelofibrosis are caused by secondary immunodeficiency and often occur atypically. Diagnosis of infectious complications is based on a thorough history taking, identifying a possible source of infection with a thorough topical examination, including visualization (radiation diagnostic methods and endoscopy) of the organ structure and collection of material to identify the pathogen (washes, examination of biological fluids, etc.). Before identifying the pathogen, patients, due to the frequent presence of combined immunodeficiency, should be prescribed empirical antibacterial therapy using antibiotics that cover the entire spectrum of infectious pathogens in maximum doses. If the effect is insufficient, it is necessary to prescribe other antibiotics or their combination, taking into account clinical data and the results of microflora studies for sensitivity to antibiotics. After identifying the pathogen and determining its individual sensitivity, antibacterial therapy should be rationalized by choosing the most effective drug.

For infectious complications that arise against the background of neutropenia, it is possible to use

administration of G-CSF 5 mcg/kg/day, as well as human immunoglobulin in doses of 0.2-0.5 g/kg for 3-5 days and plasmapheresis for the purpose of detoxification and improving sensitivity to drugs.

Thrombocytopenia and hemorrhagic syndrome. Thrombocytopenia in post-platelet myelofibrosis can appear in the presence of severe bone marrow fibrosis and depletion of hematopoiesis. A certain contribution to the development of hemorrhages is made by secondary coa-gulopathy associated with impaired production of coagulation factors by the liver due to damage to the parenchyma by foci of extramedullary hematopoiesis and portal hypertension. Therapeutic tactics for thrombocytopenia should be aimed at eliminating the cause of thrombocytopenia and preventing hemorrhagic syndrome. The causes of thrombocytopenia may be a decrease in platelet production and their increased destruction. Prevention of complications should be aimed at improving the condition of the vascular wall by prescribing vitamin C, rutin, sodium ethamsylate and eliminating risk factors - normalizing venous pressure (reducing portal hypertension using beta blockers, calcium channel blockers, vascular bypass), preventing damage to the mucous membranes (moisturizing the nasal mucosa, secretolytics for the prevention of ulceration, local therapy of hemorrhoidal venous nodes). Transfusion of platelet concentrate has a short-term effect and is advisable only in the presence of hemorrhagic syndrome or with a high risk of bleeding; moreover, with repeated transfusions, resistance to transfusions may develop due to autoimmunization. To correct DIC syndrome and disorders of the plasma hemostasis, transfusions of fresh frozen plasma in adequate doses and the introduction of recombinant coagulation factors are also used.

BLAST TRANSFORMATION

Long-term proliferation of the IP tumor clone with genetic instability can lead to the accumulation of additional mutations and the development of the terminal stage of the disease - blast transformation. Progressive

The progression of the disease into the blast transformation phase is observed with a probability of 0.34% of the total number of patients per year during the first 5 years of the disease, with an increase to 1.1% annually when the disease lasts more than 10 years.

The time period from the onset of the disease to the development of transformation into a blast crisis can vary significantly from several to tens of years. The difference in the timing of development of blast transformation is due to the heterogeneity of the disease, as well as the inaccuracy in establishing the timing of the onset of the disease. Due to insufficient knowledge of the mechanisms of its occurrence, no proven means of preventing the blast crisis of the disease have been developed at present. Ruxolitinib, which has shown this effect in studies in the treatment of PMF, may be a possible promising means of reducing the frequency of blast transformation.

With the development of blast transformation, the prognosis is unfavorable, the median survival is several months. Treatment tactics are determined by the age of the patients and concomitant

existing pathology. In patients with intact general somatic status, an attempt can be made to conduct a course of chemotherapy according to the treatment regimens for acute leukemia, which brings a temporary effect in a small part of patients. When the effect of induction chemotherapy is achieved in order to increase life expectancy, allo-BMT can be performed. In elderly patients with significant comorbidity and thrombotic complications of PV, it is advisable to carry out restraining palliative monochemotherapy and prescribe small doses of glucocorticoids. These measures are aimed at inhibiting tumor growth and stopping complications (transfusion of blood components, treatment of infectious complications, etc.), in order to improve the patient’s quality of life.

SELECTED CLINICAL SITUATIONS IN PV

PREGNANCY

The introduction into widespread practice of determining molecular genetic markers (JAK2V611F) has made it possible to identify a significant proportion of young PV patients. Violation of blood rheology during PV leads to pathology of microcirculation of placental blood flow and complicates the course of pregnancy. Pregnancy in patients with PV is often complicated by miscarriage, early miscarriages, placental insufficiency, developmental delay, preeclampsia; venous thrombosis can also be observed, especially in the postpartum period, more often in patients with a history of thrombosis. The risk of developing thrombosis during pregnancy is 3-5%. During pregnancy in a patient with IP, it is first necessary to determine the risk of pregnancy complications, based on the presence or absence of a history of thrombosis and miscarriage of previous pregnancies.

The use of acetylsalicylic acid in pregnant women at risk of preeclampsia was analyzed in a large multicenter study and, according to its results, was found to be safe and recommended for its prevention. The use of heparin in unfractionated form and low molecular weight analogues

logs has a positive experience of use and is especially recommended during the last weeks of pregnancy and for 4-6 weeks after birth. In order to prevent increased blood loss during childbirth, it is recommended to interrupt heparin administration 12 hours before the expected birth and resume the day after birth.

Carrying out hemoexfusion (erythrocytapheresis) and cytoreductive therapy is recommended in the presence of a history of thrombosis, as well as in cases of recurrent miscarriage and fetal development delays. The use of hydroxyurea during pregnancy is not recommended due to the presence of a proven teratogenic effect. Anagrelide can cross the placenta; its effect on fetal development is unknown, so its use during pregnancy cannot be recommended. The safest drug option for cytoreduction in pregnant women with PV is IFN-a drugs. Its use has been reported in a small number of cases to reduce the risk of both PV complications and pregnancy complications. In general, recommendations for the management of pregnancy in patients with chronic MPN are given in Table. eleven .

Table 11

Pregnancy management strategy in patients with chronic MPN

Risk of pregnancy Therapy

Low risk Maintain hematocrit level less than 45% or at the hematocrit level of the second trimester of pregnancy; antiplatelet agents (low doses of acetylsalicylic acid or other drugs if intolerant); low molecular weight heparins after delivery for 6 weeks

High risk* Measures for low risk supplemented: If there is a history of serious thrombosis or severe complications of pregnancy: low molecular weight heparins throughout pregnancy. If the platelet level is more than 1500 x 109/l, interferon alpha is prescribed. If there is a history of bleeding: use interferon, avoid acetylsalicylic acid.

*signs of high risk pregnancy: a history of venous or arterial thrombosis, bleeding associated with chronic MPN, previous complications of pregnancy (recurrence of early miscarriage, intrauterine growth retardation, placental dysfunction, miscarriages, premature birth, severe preeclampsia, severe intrapartum or postpartum blood loss), hyperthrombocytosis more than 1500 x 109/l

SURGICAL INTERVENTIONS IN PATIENTS WITH IP

The presence of PV increases the risk of complications during surgical interventions: mortality due to thrombosis is 7.7%, mortality due to bleeding is 7.3%, and operative mortality is 1.6%. When planning surgical interventions in all patients with IP, it is advisable to preliminary normalize the hematocrit and platelet count using hemoexfusions (erythrocytapheresis and plateletpheresis) and/or cytoreductive therapy. 7-10 days before surgery, planned withdrawal of antiplatelet agents and cytoreductive drugs. For all patients with IP over 12

hours before surgery and in the postoperative period, prophylactic administration of low molecular weight heparins is recommended. Taking into account the fact that in PV there is an increased risk of both thrombotic and hemorrhagic complications, the use of antiplatelet agents and cytoreductive therapy is resumed as quickly as possible with stable hemostasis and after healing of surgical wounds. To eliminate risks and timely correction of complications in the postoperative period, it is advisable to inpatiently monitor the patient with daily monitoring of blood counts.

CONCLUSION

In recent years, significant progress has been made in deciphering the molecular genetic mechanisms of the pathogenesis of IP, and the role of the JAK-STAT signaling pathway has been established. The quality of diagnosis has significantly improved, new diagnostic criteria for the disease, monitoring and evaluation of response to treatment have been created. Currently, molecular targets for targeted pathogenetic therapy have been identified and evidence has been obtained.

research on the effectiveness and safety of a new class of targeted drugs for the treatment of PV.

The typical course of the disease is associated with the occurrence of symptoms of microcirculation disorders. The disease is identified when referred to a hematologist regarding abnormalities in a clinical blood test during a preventive examination or after thrombosis and thromboembolism have occurred.

The diagnosis of IP is established based on a combination of clinical data and the results of laboratory and instrumental studies. Deciphering the molecular genetic pathogenesis of the disease and introducing the detection of mutations in the JAK2 gene into practice has significantly improved the accuracy of diagnosis. To verify the diagnosis, the international working group on the diagnosis and treatment of IP has developed new diagnostic criteria aimed at approval by the WHO.

With timely diagnosis and adequate treatment with the prevention of vascular complications and hematocrit levels, the manifestations of the disease may not bother patients for many years. The main risk factors for thrombosis are age and a history of thrombosis. With a long course of the disease, some patients may develop into secondary postpolycythaemic myelofibrosis or progress to the blast transformation phase.

The current goal of PV therapy is to curb the progression of the disease and relieve its symptoms to improve the quality of life of patients. With the right approach to treatment and monitoring its results, the life expectancy of patients with IP should not differ from the population. Treatment of patients with IP should be carried out under the supervision of a hematologist with monitoring of its results in accordance with standard response assessment criteria. The choice of treatment method should be based on an assessment of the possible benefits and risks of side effects of therapy for a particular patient.

The new data obtained on the pathogenesis of IP served as the basis for the development and introduction into practice of treatment of new classes of drugs (Janus kinase inhibitors), which have shown high efficiency and safety even with resistance to previous treatment.

LITERATURE

1. Abdulkadyrov K. M., Shuvaev V. A., Martynkevich I. S. Diagnostic criteria and modern methods of treatment of primary myelofibrosis // Bulletin of Hematology. - 2013. - T. 9, No. 3. - P. 44-78.

2. Bessmeltsev S. S., Zamotina T. B. The influence of erythrocytepheresis on the condition of the left parts of the heart in patients with polycythemia vera according to echocardiography // Clinical Medicine. - 1995. - No. 4. - P. 80-82.

3. Guseva S. A., Bessmeltsev S. S., Abdulkadyrov K. M., Goncharov Y. P. True polycythemia. - Kiev, St. Petersburg: Logos, 2009. - 405 p.

4. Demidova A.V., Kotsyubinsky N.N., Mazurov V.I. Erythremia and secondary erythrocytosis. - St. Petersburg: Publishing House of St. Petersburg MAPO, 2001. - 228 p.

5. 2006 Update of ASCO Practice Guideline Recommendations for the Use of White Blood Cell Growth Factors: Guideline Summary // Journal of Oncology Practice.- 2006.- Vol. 2, N 4.- P. 196-201.

6. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425677.htm. [electronic resource] (date of access: 01/29/2015).

7. Amitrano L., Guardascione M. A., Ames P. R. J. et al. Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine ​​in myeloproliferative disorders: Relationship with splanchnic vein thrombosis and arterial disease // American Journal of Hematology.- 2003.- Vol. 72, N 2.- P. 75-81.

8. Andrieux J., Demory J. L., Caulier M. T. et al. Karyotypic abnormalities in myelofibrosis following polycythemia vera // Cancer Genetics and Cytogenetics.- Vol. 140, N 2.- P. 118-123.

9. Andrieux J. L., Demory J. L. Karyotype and molecular cytogenetic studies in polycythemia vera // Curr Hematol Rep. - 2005.- Vol. 4, N 3.- P. 224-229.

10. Anger B., Haug U., Seidler R. et al. Polycythemia vera. A clinical study of 141 patients // Blut.- 1989.- Vol. 59, N 6.- P. 493-500.

11. Anger B. R., Seifried E., Scheppach J. et al. Budd-chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases // Klinische Wochenschrift.- 1989.- Vol. 67, N 16.- P. 818-825.

12. Ania B. J., Suman V. J., Sobell J. L. et al. Trends in the incidence of polycythemia vera among olmsted county, Minnesota residents, 1935-1989 // American Journal of Hematology.- 1994.- Vol. 47, N 2.- P. 89-93.

13. Askie L.M., Duley L., Henderson-Smart D.J. et al. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data // The Lancet.- Vol. 369, N 9575.- P. 1791-1798.

14. Baden L. R. Prophylactic Antimicrobial Agents and the Importance of Fitness // New England Journal of Medicine 2005. 353: (10): 1052-1054.

15. Baerlocher G. M., Leibundgut E. O., Ayran C. et al. Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results // ASH Annual Meeting Abstracts.- 2012.- Vol. 120, N 21.- P. 179.

16. Barbui T., Barosi G., Birgegard G. et al. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet // Journal of Clinical Oncology.- 2011.- Vol. 29, N 6.- P. 761-770.

17. Barbui T., Carobbio A., Finazzi G. et al. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3 // Haematologica.- 2011.- Vol. 96, N 2.- P. 315-318.

18. Barbui T., Cortelazzo S., Viero P. et al. Thrombohaemorrhagic complications in 101 cases of myeloproliferative disorders: Relationship to platelet number and function // European Journal of Cancer and Clinical Oncology.- 1983.- Vol. 19, N 11.- P. 1593-1599.

19. Barbui T., Finazzi G. Indications for cytoreductive therapy in polycythemia vera and essential thrombocythemia // Hematology.- 2003.- P. 202-209.

20. Barosi G., Birgegard G., Finazzi G. et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference // Blood.- 2009.- Vol. 113, N 20.- P. 4829-4833.

21. Barosi G., Mesa R., Finazzi G. et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project // Blood.- 2013.- Vol. 121, N 23.- P. 4778-4781.

22. Baxter E. J., Scott L. M., Campbell P. J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders // The Lancet.- 2005.- Vol. 365, N 9464.- P. 1054-1061.

23. Bellucci S., Janvier M., Tobelem G. et al. Essential thrombocythemias. Clinical evolutionary and biological data // Cancer.- 1986.- Vol. 58, N 11.- P. 2440-2447.

24. Berk P. D., Goldberg J. D., Silverstein M. N. et al. Increased Incidence of Acute Leukemia in Polycythemia Vera Associated with Chlorambucil Therapy // New England Journal of Medicine.- 1981.- Vol. 304, N 8.- P. 441-447.

25. Berlin N. Diagnosis and classification of polycythemias // Semin Hematol.- 1975.- Vol. 12.- P. 339-351.

26. Besses C., Cervantes F., Pereira A., Florensa L. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients // Leukemia.- 1999.- Vol. 13.- P. 150-154.

27. Björn M. E., de Stricker K., Kjsr L. et al. Rapid Clearance Of JAK2 V617F Allele Burden In Patient With Advanced Polycythemia Vera (PV) During Combination Therapy With Ruxolitinib and Peg-Interferon Alpha-2a // Blood.- 2013.- Vol. 122, N 21.- P. 5241-5241.

28. Björn M. E., de Stricker K., Kjsr L. et al. Combination therapy with interferon and JAK1-2 inhibitor is feasible: Proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera // Leukemia Research Reports.- 2014.- Vol. 3, N 2.- P. 73-75.

29. Budde U., Van Genderen P. Acquired von Willebrand Disease in Patients with High Platelet Counts // Semin Thromb Hemost. - 1997. - Vol. 23, N 05.- P. 425-431.

30. Budde U., Scharf R. E., Franke P. et al. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma // Blood.- 1993.- Vol. 82, N6.- P. 1749-1757.

31. Cardin, F., Graffeo M., McCormick P.A. et al. Adult "idiopathic" extrahepatic venous thrombosis // Digestive Diseases and Sciences.- 1992.- Vol. 37, N 3.- P. 335-339.

32. Cervantes F., Passamonti F., Barosi G. Life expectancy and prognostic factors in the classic BCR// ABL-negative myeloproliferative disorders // Leukemia.- 2008.- Vol. 22, N 5.- P. 905-914.

33. Cervantes F., Vannucchi A. M., Kiladjian J.-J. et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis // Blood.- 2013.- Vol. 122, N 25.- P. 4047-4053.

34. Chan D., Koren-Michowitz M., Update on JAK2 inhibitors in myeloproliferative neoplasm // Therapeutic Advances in Hematology.- 2011.- Vol. 2, N2.- P. 61-71.

35. Cho S. Y., Xu M., Roboz J. et al. The Effect of CXCL12 Processing on CD34+ Cell Migration in Myeloproliferative Neoplasms // Cancer Research.- 2010.- Vol. 70, N 8.- P. 3402-3410.

36. Colombi M., Radaelli F., Zocchi L. et al. Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients // Cancer.- 1991.- Vol. 67, N 11.- P. 2926-2930.

37. Cools J., Peeters P., Voet T. et al. Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia // Cytogenetic and Genome Research.- 1999.- Vol. 85, N 3-4.- P. 260-266.

38. Cortelazzo S., Finazzi G., Ruggeri M. et al. Hydroxyurea for Patients with Essential Thrombocythemia and a High Risk of Thrombosis // New England Journal of Medicine.- 1995.- Vol. 332, N 17.- P. 1132-1137.

39. Dameshek W. Editorial: Some Speculations on the Myeloproliferative Syndromes // Blood.- 1951.- N 6.- P.372-375.

40. Delhommeau F., Dupont S., Valle V. D. et al. Mutation in TET2 in Myeloid Cancers // New England Journal of Medicine.- 2009.- Vol. 360, N22.- P. 2289-2301.

41. Denninger M.- H., Chai"t Y., Casadevall N. et al. Cause of portal or hepatic venous thrombosis in adults: The role of multiple concurrent factors // Hepatology.- 2000.- Vol. 31, N 3.- P. 587-591.

42. Elliott M.A., Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia // British Journal of Haematology. - 2005. - Vol. 128, N 3.- P. 275-290.

43. Ernst T., Chase A. J., Score J. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders // Nat Genet.- 2010.- Vol. 42, N 8.- P. 722-726.

44. Falanga A., Marchetti M., Evangelista V. et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera // Blood.- 2000.- Vol. 96, N 13.- P. 4261-4266.

45. Faurschou M., Nielsen O. J., Jensen M. K. et al. High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders // American Journal of Hematology.- 2000.- Vol. 65, N 2.- P. 136-140.

46. ​​Feener E. P., Rosario F., Dunn S. L. et al. Tyrosine Phosphorylation of Jak2 in the JH2 Domain Inhibits Cytokine Signaling // Molecular and Cellular Biology.- 2004.- Vol. 24, N 11.- P. 4968-4978.

47. Finazzi G., Barbui T. How I treat patients with polycythemia vera // Blood.- 2007.- Vol. 109, N 12.- P. 5104-5111.

48. Fruchtman S. M., Mack K., Kaplan M. E. et al. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera // Semin Hematol.- 1997.- Vol. 34, N 1.- P. 17-23.

49. Fruchtman S. M., Petitt R. M., Gilbert H. S. et al. Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders // Leukemia Research.- Vol. 29, N 5.- P. 481-491.

50. Gisslinger H., Rodeghiero F., Ruggeri M. et al. Homocysteine ​​levels in polycythaemia vera and essential thrombocythaemia // British Journal of Haematology.- 1999.- Vol. 105, N 2.- P. 551-555.

51. Greer I.A., Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy // Blood.- 2005.- Vol. 106, N 2.- P. 401-407.

52. Griesshammer M., Struve S., Barbui T. Management of Philadelphia chronic negative myeloproliferative disorders in pregnancy // Blood Reviews.- Vol. 22, N 5.- P. 235-245.

53. Gruppo Italiano Studio Policitemia. Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 Years // Annals of Internal Medicine.- 1995.- Vol. 123, N 9.- P. 656-664.

54. Guglielmelli P., Tozzi L., Bogani C. et al. Dysregulated Expression of MicroRNA-16 Contributes to Abnormal Erythropoiesis in Patients with Polycythemia Vera // 50th ASH Annual Meeting abstracts.- 2010.- P. 179.

55. Hoffman R, Bosswel S, Hematology. Basic Principles and Practice, in Hematology. Basic Principles and Practice / B. E. Hoffman R, Shattil SJ, Editor // Churchill Livingstone: New York.- 1995.- P. 1121-1142.

56. Huang P. Y., Heliums J. D. Aggregation and disaggregation kinetics of human blood platelets: Part III. The disaggregation under shear stress of platelet aggregates // Biophysical Journal.- Vol. 65, N 1.- P. 354-361.

57. Hunt B. J., Gattens M., Khamashta M. et al. Thromboprophylaxis with unmonitored intermediate-dose low molecular weight heparin in pregnancies with a previous arterial or venous thrombotic event // Blood Coagulation & Fibrinolysis.- 2003.- Vol. 14, N 8.- P. 735-739.

58. Izaguirre-Avila R., Penia-Diaz A., De la Barinagarrementeria-Aldatz F. et al. Effect of Clopidogrel on Platelet Aggregation and Plasma Concentration of Fibrinogen in Subjects with Cerebral or Coronary Atherosclerotic Disease // Clinical and Applied Thrombosis/Hemostasis.- 2002.- Vol. 8, N 2.- P. 169-177.

59. Jessler C. M., Klein H. G., Havlik R. J. Uncontrolled thrombocytosis in chronic myeloproliferative disorders // British journal of haematology.- 1982.- Vol. 50, N 1.- P. 157-167.

60. Ackson N., Burt D., Crocker J. et al. Skin mast cells in polycythaemia vera relationship to the pathogenesis and treatment of pruritus // British Journal of Dermatology.- 1987.- Vol. 116, N 1.- P. 21-29.

61. James C., Ugo V., Le Couedic J.-P. et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera // Nature.- 2005.- Vol. 434, N 7037.- P. 1144-1148.

62. Jensen M. K., De Nully Brown P., Lund B. V. et al. Increased circulating platelet-leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet count // European Journal of Haematology.- 2001.- Vol. 66, N 3.- P. 143-151.

63. Jensen M. K., De Nully Brown P., Lund B. V. et al. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders // British Journal of Haematology.- 2000.- Vol. 110, N 1.- P. 116-124.

64. Jones A. V., Chase A., Silver R. T. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms // Nat Genet.- 2009.- Vol. 41, N4.- P. 446-449.

65. Jones A. V., Kreil S., Zoi K. et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders // Blood.- 2005.- Vol. 106, N 6.- P. 2162-2168.

66. Jost E., Do O N., Dahl E. et al. Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR//ABL-negative myeloproliferative disorders. // Leukemia.- 2007.- Vol. 21, N3.- P. 505-510.

67. Kassum D., Thomas E. J. Morbidity and mortality of incidental splenectomy // Canadian Journal of Surgery.- 1977.- Vol. 20.- P. 209-214.

68. Kiladjian J.-J., Rain J.-D., Bernard J.-F. et al. Long-Term Incidence of Hematological Evolution in Three French Prospective Studies of Hydroxyurea and Pipobroman in Polycythemia Vera and Essential Thrombocythemia // Semin Thromb Hemost.- 2006.- Vol. 32, N 04.- P. 417-421.

69. Koch C.A., Li C.-Y., Mesa R.A. et al. Nonhepatosplenic Extramedullary Hematopoiesis: Associated Diseases, Pathology, Clinical Course, and Treatment // Mayo Clinic Proceedings.- Vol. 78, N 10.- P. 1223-1233.

70. Kralovics R., Teo S.-S., Buser A. S. et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2 // Blood.- 2005.- Vol. 106.- P. 3374-3376.

71. Landgren O., Goldin L. R., Kristinsson S. Y. et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden // Blood.- 2008.- Vol. 112, N 6.- P. 2199-2204.

72. Landolfi R., Cipriani M. C., Novarese L. Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: Pathogenetic mechanisms and prevention // Best Practice & Research Clinical Haematology.- Vol. 19, N 3.- P. 617-633.

73. Landolfi R., Di Gennaro L., Barbui T. et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera // Blood.- 2006.- Vol. 109, N 6.- P. 2446-2452.

74. Landolfi R., Marchioli R. European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP): A Randomized Trial // Semin Thromb Hemost. - 1997. - Vol. 23, N05.- P. 473-478.

75. Landolfi R., Marchioli R., Kutti J. et al. Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera // New England Journal of Medicine.- 2004.- Vol. 350, N 2.- P. 114-124.

76. Landolfi R., Rocca B., Patrono C. Bleeding and thrombosis in myeloproliferative disorders:

mechanisms and treatment // Critical Reviews in Oncology / Hematology.- Vol. 20, N 3.- P. 203222.

77. Landolfi R., Ciabattoni G., Patrignani P. et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo // Blood.- 1992.- Vol. 80, N 8.- P. 1965-1971.

78. Lasho T. L., Pardanani A., Tefferi A. LNK Mutations in JAK2 Mutation-Negative Erythrocytosis // New England Journal of Medicine.- 2010.- Vol. 363, N 12.- P. 1189-1190.

79. Lengfelder E., Berger U., Hehlmann R. Interferon in the treatment of polycythemia vera // Annals of Hematology.- 2000.- Vol. 79, N 3.- P. 103-109.

80. Levine R. L., Wadleigh R., Cools J. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis // Cancer Cell.- Vol. 7, N 4.- P. 387-397.

81. Liebelt E. L., Balk S. J., Faber W. et al. NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of hydroxyurea. Birth Defects Research Part B // Developmental and Reproductive.- Toxicology.- 2007.- Vol. 80, N 4.- P. 259-366.

82. Lu X., Levine R., Tong W. et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation // Proceedings of the National Academy of Sciences of the United States of America.- 2005.- Vol. 102, N 52.- P. 18962-18967.

83. Mandi M. L. Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases) // Journal of medicine.- 1991.- Vol. 22, N 4-5.- P. 213-223.

84. Marchioli R., Finazzi G., Landolfi R. et al. Vascular and Neoplastic Risk in a Large Cohort of Patients With Polycythemia Vera // Journal of Clinical Oncology.- 2005.- Vol. 23, N 10.- P. 2224-2232.

85. Marchioli R., Finazzi G., Specchia G. et al. Cardiovascular Events and Intensity of Treatment in Polycythemia Vera // New England Journal of Medicine.- 2013.- Vol. 368, N 1.- P. 22-33.

86. Massa M., Rosti V., Ramajoli I. et al. Circulating CD34+, CD133+, and Vascular Endothelial Growth Factor Receptor 2-Positive Endothelial Progenitor Cells in Myelofibrosis With Myeloid Metaplasia // Journal of Clinical Oncology.- 2005.- Vol. 23, N24.- P. 5688-5695.

87. Mavrogianni D., Viniou N., Michali E. et al. Leukemogenic risk of hydroxyurea therapy as a single agent in polycythemia vera and essential thrombocythemia: N- and K-ras mutations and microsatellite instability in chromosomes 5 and 7 in 69 patients // Int J Hematol.- 2002.-Vol. 75, N 4.- P. 394-400.

88. Martyre M. C. Critical review of pathogenetic mechanisms in myelofibrosis with myeloid metaplasia // Curr Hematol Rep. - 2003.- Vol. 2, N 3.- P. 257-263.

89. Mesa R. A. How I treat symptomatic splenomegaly in patients with myelofibrosis // Blood.- 2009.- Vol. 113, N 22.- P. 5394-5400.

90. Michiels J. J., Budde U., van der Planken M. et al. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management // Best Practice & Research Clinical Haematology.- Vol. 14, N 2.- P. 401-436.

91. Najean Y., Rain J.-D. Treatment of Polycythemia Vera: The Use of Hydroxyurea and Pipobroman in 292 Patients Under the Age of 65 Years // Blood.- 1997.- Vol. 90, N 9.- P. 3370-3377.

92. Nielsen I., Hasselbalch H. C. Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan // American Journal of Hematology.- 2003.- Vol. 74, N 1.- P. 26-31.

93. Osler W. Chronic cyanosis, with polycythaemia and enlarged spleen: a new clinical entity // The American Journal of the Medical Sciences.- 1903.- Vol. 126, N 2.- P. 187-201.

94. Passamonti F. How I treat polycythemia vera // Blood.- 2012.- Vol. 120.- P. 275-284.

95. Passamonti F., Elena C., Schnittger S. et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations // Blood.- 2011.- Vol. 117.- P. 2813-2816.

96. Passamonti F., Malabarba L., Orlandi E. et al. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia // Blood.- 2003.- Vol. 88.- P. 13-18.

97. Passamonti F., Malabarba L., Orlandi E. et al. Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis // British Journal of Haematology.- 2002.- Vol. 116, N 4.- P. 855-861.

98. Passamonti F., Rumi E., Pungolino E. et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia // The American Journal of Medicine.- Vol. 117, N 10.- P. 755-761.

99. Pearson T. C. Hemorheologic Considerations in the Pathogenesis of Vascular Occlusive Events in Polycythemia Vera // Semin Thromb Hemost. - 1997. - Vol. 23, N 05.- P. 433-439.

100. Pieri L., Bogani C., Guglielmelli P. et al. The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera // Haematologica.- 2009.- Vol. 94, N 11.- P. 1537-1545.

101. Polycythemia Treatment. A Panel Discussion // Blood.- 1968.- Vol. 32, N 3.- P. 483-506.

102. Quintas-Cardama A., Abdel-Wahab O., Manshouri T. et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon a-2a // Blood.- 2013.- Vol. 122, N 6.- P. 893-901.

103. Quintas-Cardama A., Kantarjian H. M., Giles F. et al. Pegylated Interferon Therapy for Patients with Philadelphia Chromosome-Negative Myeloproliferative Disorders // Semin Thromb Hemost. - 2006. - Vol. 32, N 04.- P. 409-416.

104. Quintas-Cardama A., Verstovsek S. Spleen deflation and beyond: The pros and cons of Janus kinase 2 inhibitor therapy for patients with myeloproliferative neoplasms // Cancer.- 2012.- Vol. 118, N 4.- P. 870-877.

105. Rosendaal F. R. Risk factors for venous thrombosis: prevalence, risk, and interaction // Seminars in hematology.- 1997.- Vol. 34, N 3.- P. 171-187.

106. Rortaglia A. P., Goldberg J. D., Berk P. D., Wasserman L. R. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera // Seminars in hematology.- 1986.- Vol. 23, N 3.- P. 172-176.

107. Ruggeri M., Gisslinger H., Tosetto A. et al. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia // American Journal of Hematology.- 2002.- Vol. 71, N 1.- P. 1-6.

108. Ruggeri M., Rodeghiero F., Tosetto A. et al. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey // Blood.- 2007.- Vol. 111, N 2. P. 666-671.

109. Saini K. S., Patnaik M. M., Tefferi A. Polycythemia vera-associated pruritus and its management // European Journal of Clinical Investigation.- 2010.- Vol. 40, N 9.- P. 828-834.

110. Santos F. P. S., Verstovsek S. JAK2 Inhibitors: Are They the Solution? // Clinical Lymphoma Myeloma and Leukemia.- 2011.- Vol. 11.- P. S28-S36.

111. Schafer A. I. Bleeding and thrombosis in the myeloproliferative disorders // Blood.- 1984.- Vol. 64, N 1.- P. 1-12.

112. Schmitt Alain J. H., Guichard J., Wendling F. et al. Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis // Blood.- 2000.- Vol. 96, N 4.- P. 13421347.

113. Scott L. M., Tong W., Levine R. L. et al. JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis // New England Journal of Medicine.- 2007.- Vol. 356, N 5.- P. 459-468.

114. Shikhbabaeva D., Shuvaev V., Martynkevich I. et al. Polycythemia Vera - Analysis of Diagnostic and Treatment Results on Population Level // ELN Frontiers Meeting October 16-19, 2014, Berlin, Germany.- 2014.- P. 36.

115. Silvennoinen O., Ihle J. N., Schlessinger J. et al., Interferon-induced nuclear signaling by Jak protein tyrosine kinases // Nature.- 1993.- Vol. 366, N 6455. P. 583-585.

116. Solberg L. A. Jr, Tefferi A., Oles K. J. et al. The effects of anagrelide on human megakaryocytopoiesis // Br J Haematol.- 1997.- Vol. 99, N 1.- P. 174-180.

117. Stein B. L., Rademaker A., ​​Spivak J. L. et al. Gender and Vascular Complications in the JAK2 V617F-Positive Myeloproliferative Neoplasms // Thrombosis.- 2011.- P. 8.

118. Steinman H. K., Kobza-Black A., Greaves W. et al. Polycythaemia rubra vera and water-induced pruritus: blood histamine levels and cutaneous fibrinolytic activity before and after water challenge // British Journal of Dermatology.- 1987.- Vol. 116, N 3.- P. 329-333.

119. Storen E. C., Tefferi A., Long-term use of anagrelide in young patients with essential thrombocythemia // Blood.- 2001.- Vol. 97, N 4.- P. 863-866.

120. Suessmuth Y., Elliott J., Percy M. J. et al. A new polycythaemia vera-associated SOCS3 SH2 mutant (SOCS3F136L) cannot regulate erythropoietin responses // British Journal of Haematology.- 2009.- Vol. 147, N 4.- P. 450-458.

121. Tan X., Shi J., Fu Y. et al. Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation // Thrombosis and Haemostasis.- 2013.- Vol. 109, N 6.- P. 1025-1032.

122. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 // Leukemia. - 2010. - Vol. 24, N 6.- P. 11281138.

123. Tefferi A. Pathogenesis of Myelofibrosis With Myeloid Metaplasia // Journal of Clinical Oncology.- 2005.- Vol. 23, N 33.- P. 8520-8530.

124. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management // American Journal of Hematology.- 2013.- Vol. 88, N 6.- P. 507-516.

125. Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management // American Journal of Hematology.- 2013.- Vol. 88, N 2.- P. 141-150.

126. Tefferi A., Pardanani A., Lim K. H. et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis // Leukemia.- 2009.- Vol. 23, N 5.- P. 905-911.

127. Tefferi A., Thiele J., Orazi A. et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel // Blood.- 2007.- Vol. 110, N 4.- P. 1092-1097.

128. Tefferi A., Thiele J., Vannucchi A. M., Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms // Leukemia.- 2014.- Vol. 28, N 7.- P. 1407-1413.

129. Tefferi A., Vardiman J. W. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms // Leukemia.- 2007.- Vol. 22, N 1.- P. 14-22.

130. Thiele J., Kvasnicka H. M. A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders // Leukemia & Lymphoma.- 2006.- Vol. 47, N 3.- P. 381-396.

131. Thiele J., Kvasnicka H. M., Facchetti F. et al. European consensus on grading bone marrow fibrosis and assessment of cellularity // Haematologica.- 2005.- Vol. 90, N 8.- P. 1128-1132.

132. Tibes R., Mesa R. A. Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the impact of JAK2 inhibitor therapy? // Leukemia & Lymphoma.- 2011.- Vol. 52, N 7.- P. 1178-1187.

133. Torgano G., Mandelli C., Massaro P. et al. Gastroduodenal lesions in polycythaemia vera: frequency and role of Helicobacter pylori // British Journal of Haematology.- 2002.- Vol. 117, N1.- P. 198-202.

134. Turitto V. T., Weiss H. J. Platelet and red cell involvement in mural thrombogenesis // Annals of the New York Academy of Sciences. - 1983. - Vol. 416, N 1.- P. 363-376.

135. Van Cott E. M., Laposata M., Prins M. H. Laboratory Evaluation of Hypercoagulability With Venous or Arterial Thrombosis // Archives of Pathology & Laboratory Medicine.-2002.-Vol. 126, N 11.- P. 1281-1295.

136. Van Genderen, Perry J. J., Michiels J. J. Erythromelalgia: A Pathognomonic Microvascular Thrombotic Complication in Essential Thrombocythemia and Polycythemia Vera // Semin Thromb Hemost. - 1997. - Vol. 23, N 04.- P. 357-363.

137. Vannucchi A. M. How I treat polycythemia vera // Blood.- 2014.-Vol. 124, N 22.- P. 3212-3220.

138. Vannucchi A. M. Management of Myelofibrosis // ASH Education Program Book 2011.- 2011.- P. 222-230.

139. Vannucchi A. M., Antonioli E., Guglielmelli P. et al. Prospective identification of high-risk polycythemia vera patients based on JAK2V617F allele burden // Leukemia.- 2007.- Vol. 21, N 9.- P. 1952-1959.

140. Vannucchi A. M., Antonioli E., Guglielmelli P. et al. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal // Leukemia.- 2008.- Vol. 22, N 7.- P. 1299-1307.

141. Vannucchi A. M., Guglielmelli P. Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations // Haematologica.- 2008.- Vol. 93, N 7.- P. 972-976.

142. Vannucchi A. M., Guglielmelli P., Rambaldi A. et al. Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives // Journal of Cellular and Molecular Medicine.- 2009.- Vol. 13, N 8a.- P. 1437-1450.

143. Vannucchi A. M., Antonioli E., Guglielmelli P. et al. Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia // Blood.- 2007.- Vol. 110, N 3.- P. 840-846.

144. Vaquez L. Sur une forme spéciale de cyanose s "accompagnant d" hyperglobulie excessive et persistante // C R Soc Biol (Paris). - 1892. - N 44. - P. 384-388.

145. Vardiman J. W., Harris N. L., Brunning R. D. The World Health Organization (WHO) classification of the myeloid neoplasms. - 2002. - Vol. 100.- P. 2292-2302.

146. Vardiman J. W., Thiele J., Arber D. A. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes // Blood.- 2009.- Vol. 114, N 5.- P. 937-951.

147. Verstovsek S., Kiladjian J.-J., Mesa R. et al. Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial // Blood.- 2014.- Vol. 124, N 21.- P. 3201.

148. Verstovsek S., Passamonti F., Rambaldi A. et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea // Cancer.- 2014.- Vol. 120, N 4.- P. 513-520.

149. Verstovsek S., Kiladjian J.-J., Griesshammer M., Masszi T. Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): the RESPONSE trial // J Clin Oncol.- 2014.- Vol. 32, N 5s.- abstr. 7026.

150. Wade J. P., Pearson T. C., Russell R. W., Wetherley-Mein G. Cerebral blood flow and blood viscosity in patients with polycythaemia secondary to hypoxic lung disease // BMJ - 1981.- Vol. 283, N 6293.- P. 689-692.

151. Wehmeier A., ​​Fricke S., Scharf R. E. et al. A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders // European Journal of Haematology.- 1990.- Vol. 45, N 4.- P. 191-197.

152. Weiss H., Witte L., Kaplan K. et al. Heterogeneity in storage pool deficiency: studies on granule-bound substances in 18 patients including variants deficient in alpha-granules, platelet factor 4, beta-thromboglobulin, and platelet-derived growth factor // Blood.-1979.- Vol. 54.- P. 1296-1319.

153. Yacoub A., Odenike O., Verstovsek S. Ruxolitinib: Long-Term Management of Patients with Myelofibrosis and Future Directions in the Treatment of Myeloproliferative Neoplasms // Current Hematologic Malignancy Reports.- 2014.- Vol. 9, N 4.- P. 350-359.

154. Yamaoka K., Saharinen P., Pesu M. et al. The Janus kinases (Jaks) // Genome Biology.- 2004.- Vol. 5, N 12.- P. 253.

155. Zhou Y.-J., Chen M., Cusack N. A. et al. Unexpected Effects of FERM Domain Mutations on Catalytic Activity of Jak3 // Molecular Cell.- 2002.- Vol. 8, N 5.- P. 959-969.

Polycythemia is a chronic disease in which there is an increase in the number of red cells or red blood cells in the blood. Middle-aged and older people are susceptible to the disease - men are affected several times more often than women. More than half of people experience an increase in the number of platelets and white blood cells.

The occurrence of a disease can be due to several reasons, which separate its types. Primary or polycythemia vera is caused mainly by genetic abnormalities or bone marrow tumors, while secondary polycythemia is caused by external or internal influences. Without proper treatment, it leads to serious complications, the prognosis of which is not always comforting. Thus, the primary form, if therapy is not started in a timely manner, can lead to death over several years of progression, and the outcome of the secondary form depends on the cause of its occurrence.

The main symptoms of the disease are attacks of severe dizziness and tinnitus; the person feels as if he is losing consciousness. Treatment uses bloodletting and chemotherapy.

A distinctive feature of this disorder is that it cannot disappear spontaneously and it is also impossible to completely recover from it. The person will need to undergo regular blood tests and be under the supervision of doctors for the rest of his life.

Etiology

The causes of the disease depend on its form and can be caused by various factors. Polycythemia vera occurs when:

• hereditary predisposition to production disorders;
• genetic failures;
• malignant neoplasms in the bone marrow;
• the effects of hypoxia (oxygen deficiency) on red cells in the blood.

Secondary polycythemia is caused by:

• chronic heart failure;
• insufficient supply of blood and oxygen to the kidneys;
• climatic conditions. People living in high mountain areas are most susceptible;
• oncological tumors of internal organs;
• various infectious diseases that cause intoxication of the body;
• harmful working conditions, for example, in a mine or at height;
• living in polluted cities or near factories;
• long-term nicotine abuse;
• nation. According to statistics, polycythemia occurs in people of Jewish origin, this is due to genetics.

The disease itself is rare, but polycythemia in newborns is even rarer. The main method of transmission of the disease is through the mother's placenta. The baby's place does not provide sufficient oxygen to the fetus (poor blood circulation).

Varieties

As mentioned above, the disease is divided into several types, which directly depend on the causes of occurrence:

• primary or true polycythemia - caused by blood pathologies;
• secondary polycythemia, which can be called relative - caused by external and internal pathogens.

Polycythemia vera, in turn, can occur in several stages:

• initial, which is characterized by a slight manifestation of symptoms or their complete absence. May last for five years;
• expanded. It is divided into two forms - without a malignant effect on the spleen and with its presence. The stage lasts one or two decades;
• severe - the formation of cancerous tumors on internal organs, including the liver and spleen, and malignant blood lesions is observed.

Relative polycythemia occurs:

• stressful - based on the name, it becomes clear that it occurs when the body is affected by prolonged overexertion, unfavorable working conditions and an unhealthy lifestyle;
• false - in which the level of red blood cells and in the blood is within normal limits.

The prognosis of polycythemia vera is considered unfavorable; life expectancy with this disease does not exceed two years, but the chances of a long life increase when used in the treatment of bloodletting. In this case, a person will be able to live fifteen or more years. The prognosis of secondary polycythemia completely depends on the course of the disease, which triggered the process of increasing the number of red cells in the blood.

Symptoms

At the initial stage, polycythemia occurs with virtually no symptoms. It is usually discovered during a random examination or during preventive blood tests. The first symptoms may be mistaken for a common cold or indicate a normal condition in older people. These include:

• decreased visual acuity;
• severe dizziness and headaches;
• noise in ears;
• sleep disturbance;
• cold tips of the fingers of the extremities.

In the advanced stage, the following symptoms may be observed:

• muscle and bone pain;
• an increase in the size of the spleen, the volume of the liver changes slightly less frequently;
• bleeding gums;
• continuous bleeding for quite a long time after tooth extraction;
• the appearance of bruises on the skin, the nature of which a person cannot explain.

In addition, specific symptoms of this disease are:

• severe itching of the skin, which is characterized by an increase in intensity after taking a bath or shower;
• painful burning sensations in the tips of the fingers and toes;
• manifestation of veins that were not previously noticeable;
• the skin of the neck, hands and face takes on a bright red color;
• lips and tongue acquire a bluish tint;
• the whites of the eyes become bloodshot;
• general weakness of the patient's body.

In newborns, especially twins, symptoms of polycythemia begin to appear within a week after birth. These include:

• redness of the baby's skin. The child begins to cry and scream when touched;
• significant reduction in body weight;
• a large number of red blood cells, leukocytes and platelets are found in the blood;
• The volumes of the liver and spleen increase.

These signs can lead to the death of the baby.

Complications

The consequences of ineffective or untimely treatment can be:

• release of large quantities of uric acid. Urine becomes concentrated and acquires an unpleasant odor;
• education ;
• chronic;
• occurrence and;
• poor circulation, which leads to trophic ulcers on the skin;
• hemorrhages in various locations, for example, nose, gums, gastrointestinal tract, etc.

And they are considered the most common causes of death for patients with this disease.

Diagnostics

Polycythemia is very often discovered accidentally during a blood test for completely different reasons. When diagnosing, the doctor must:

• carefully review the medical history of the patient and his immediate family;
• conduct a thorough examination of the patient;
• find out the cause of the disease.

The patient, in turn, must undergo the following examinations:

Treatment of the primary disease is a rather labor-intensive process, which includes influencing tumors and preventing their activity. In drug therapy, the age of the patient plays an important role, because those substances that will help people under fifty years of age will be strictly prohibited for treating patients over seventy.

If the content of red blood cells in the blood is high, the best treatment is bloodletting - during one procedure, the blood volume is reduced by approximately 500 milliliters. Cytopheresis is considered a more modern method of treating polycythemia. The procedure involves filtering the blood. To do this, catheters are inserted into the veins of both arms of the patient, blood enters the machine through one, and after filtration, the purified blood is returned to the other vein. This procedure must be carried out every other day.

For secondary polycythemia, treatment will depend on the underlying disease and the severity of its symptoms.

Prevention

Most causes of polycythemia cannot be prevented, but despite this, there are several preventive measures:

• completely stop smoking;
• change place of work or residence;
• promptly treat diseases that can cause this disorder;
• undergo regular preventive examinations at the clinic and take blood tests.

Polycythemia vera (erythremia, Vaquez disease or primary polycythemia) is a progressive malignant disease belonging to the group of leukemias, which is associated with hyperplasia of the cellular elements of the bone marrow (myeloproliferation). The pathological process primarily affects the erythroblastic germ, so an excess number of red blood cells is detected in the blood. An increase in the number of neutrophilic leukocytes and platelets is also observed.

An increased number of red blood cells increases blood viscosity, increases its mass, causes a slowdown in blood flow in the vessels and the formation of blood clots. As a result, patients develop impaired blood supply and hypoxia.

General information

Polycythemia vera was first described in 1892 by French and Vaquez. Vaquez suggested that the hepatosplenomegaly and erythrocytosis detected in his patient arose as a result of increased proliferation of hematopoietic cells, and identified erythremia as a separate nosological form.

In 1903, W. Osler used the term “Vaquez disease” to describe patients with splenomegaly (enlarged spleen) and severe erythrocytosis and gave a detailed description of the disease.

Turk (W. Turk) in 1902-1904 suggested that in this disease the disorder of hematopoiesis is hyperplastic in nature, and called the disease erythremia by analogy with leukemia.

The clonal neoplastic nature of myeloproliferation, which is observed in polycythemia, was proven in 1980 by P. J. Fialkov. He discovered one type of enzyme, glucose-6-phosphate dehydrogenase, in red blood cells, granulocytes and platelets. In addition, both types of this enzyme were detected in the lymphocytes of two patients heterozygous for this enzyme. Thanks to Fialkov's research, it became clear that the target of the neoplastic process is the precursor cell of myelopoiesis.

In 1980, a number of researchers managed to separate the neoplastic clone from normal cells. It has been experimentally proven that polycythemia produces a population of erythroid committed precursors that are pathologically highly sensitive to even small amounts of erythropoietin (a kidney hormone). According to scientists, this contributes to increased formation of red blood cells in polycythemia vera.

In 1981, L. D. Sidorova and co-authors conducted studies that made it possible to detect qualitative and quantitative changes in the platelet component of hemostasis, which play a major role in the development of hemorrhagic and thrombotic complications in polycythemia.

Polycythemia vera is detected mainly in older people, but can be observed in young people and children. In young people, the disease is more severe. The average age of patients varies from 50 to 70 years. The average age of those who become ill for the first time is gradually increasing (in 1912 it was 44 years, and in 1964 - 60 years). The number of patients under 40 years of age is about 5%, and erythremia in children and patients under 20 years of age is detected in 0.1% of all cases of the disease.

Erythremia is slightly less common in women than in men (1: 1.2-1.5).

It is the most common disease in the group of chronic myeloproliferative diseases. It is quite rare - according to various sources, from 5 to 29 cases per 100,000 population.

There is isolated data on the influence of racial factors (above the average among Jews and below the average among representatives of the Negroid race), but at the moment this assumption has not been confirmed.

Forms

Polycythemia vera is divided into:

• Primary (not a consequence of other diseases).
• Secondary. It can be triggered by chronic lung disease, hydronephrosis, the presence of tumors (uterine fibroids, etc.), the presence of abnormal hemoglobins and other factors associated with tissue hypoxia.

An absolute increase in erythrocyte mass is observed in all patients, but only in 2/3 the number of leukocytes and platelets also increases.

Reasons for development

The causes of polycythemia vera have not been definitively established. Currently, there is no single theory that would explain the occurrence of hemoblastoses (blood tumors), to which this disease belongs.

Based on epidemiological observations, a theory was put forward about the connection of erythremia with the transformation of stem cells, which occurs under the influence of gene mutations.

It has been established that most patients have a mutation in the enzyme Janus kinase-tyrosine kinase, synthesized in the liver, which is involved in the transcription of certain genes by phosphorylating many tyrosines in the cytoplasmic part of the receptors.

The most common mutation, discovered in 2005, is in exon 14 JAK2V617F (detected in 96% of all cases of the disease). In 2% of cases, the mutation affects exon 12 of the JAK2 gene.

Patients with polycythemia vera also have:

• In some cases, mutations in the thrombopoietin receptor gene MPL. These mutations are of secondary origin and are not strictly specific for this disease. They are detected in older people (mainly women) with low levels of hemoglobin and platelets.
• Loss of function of the LNK gene protein SH2B3, which reduces the activity of the JAK2 gene.

Elderly patients with a high JAK2V617F allelic load are characterized by elevated hemoglobin levels, leukocytosis and thrombocytopenia.

With a mutation of the JAK2 gene in exon 12, erythremia is accompanied by a subnormal serum level of the hormone erythropoietin. Patients with this mutation are younger.
In polycythemia vera, mutations of TET2, IDH, ASXL1, DNMT3A, etc. are also often detected, but their pathogenetic significance has not yet been studied.

There were no differences in survival of patients with different types of mutations.

As a result of molecular genetic disorders, the JAK-STAT signaling pathway is activated, which is manifested by proliferation (cell production) of the myeloid lineage. At the same time, proliferation and an increase in the number of red blood cells in the peripheral blood increase (an increase in the number of leukocytes and platelets is also possible).

The identified mutations are inherited in an autosomal recessive manner.

There is also a hypothesis according to which the cause of erythremia may be viruses (15 types of such viruses have been identified), which, in the presence of predisposing factors and weakened immunity, penetrate into immature bone marrow cells or lymph nodes. Cells affected by the virus begin to actively divide instead of maturing, thus starting the pathological process.

Factors that provoke the disease include:

• X-ray irradiation, ionizing radiation;
• paints, varnishes and other toxic substances that penetrate the human body;
• long-term use of certain medications for medicinal purposes (gold salts for rheumatoid arthritis, etc.);
• viral and intestinal infections, tuberculosis;
• surgical interventions;
• stressful situations.

Secondary erythremia develops under the influence of favorable factors when:

• high innate affinity of hemoglobin for oxygen;
• low levels of 2,3-diphosphoglycerate;
• autonomous production of erythropoietin;
• arterial hypoxemia of a physiological and pathological nature (“blue” heart defects, smoking, adaptation to high altitude conditions and chronic lung diseases);
• kidney diseases (cystic lesions, hydronephrosis, renal artery stenosis and diffuse diseases of the renal parenchyma);
• the presence of tumors (possibly influenced by bronchial carcinoma, cerebellar hemangioblastoma, uterine fibroids);
• endocrine diseases associated with adrenal tumors;
• liver diseases (cirrhosis, hepatitis, hepatoma, Budd-Chiari syndrome);
• tuberculosis.

Pathogenesis

The pathogenesis of polycythemia vera is associated with a disruption of the process of hematopoiesis (hematopoiesis) at the level of the progenitor cell. Hematopoiesis acquires the unlimited proliferation of progenitor cells characteristic of a tumor, the descendants of which form a specialized phenotype in all hematopoietic lineages.

Polycythemia vera is characterized by the formation of erythroid colonies in the absence of exogenous erythropoietin (the appearance of endogenous erythropoietin-independent colonies is a sign that distinguishes erythremia from secondary erythrocytosis).

The formation of erythroid colonies indicates a disruption in the implementation of regulatory signals that the myeloid cell receives from the external environment.

The basis of the pathogenesis of polycythemia vera is defects in genes encoding proteins that are responsible for maintaining myelopoiesis within the normal range.

A decrease in oxygen concentration in the blood causes a reaction in the interstitial cells of the kidneys that synthesize erythropoietin. The process occurring in interstitial cells concerns the work of many genes. The main regulation of this process is carried out by factor-1 (HIF-1), which is a heterodimeric protein consisting of two subunits (HIF-1alpha and HIF-1beta).

If the oxygen concentration in the blood is within normal limits, proline residues (the heterocyclic amino acid of the freely existing HIF-1 molecule) are hydroxylated under the influence of the regulatory enzyme PHD2 (molecular oxygen sensor). Thanks to hydroxylation, the HIF-1 subunit acquires the ability to bind to the VHL protein, which provides tumor prevention.

The VHL protein forms a complex with a number of E3 ubiquitin ligase proteins, which, after forming covalent bonds with other proteins, are sent to the proteasome and destroyed there.

During hypoxia, hydroxylation of the HIF-1 molecule does not occur; the subunits of this protein combine and form the heterodimeric HIF-1 protein, which travels from the cytoplasm to the nucleus. Once in the nucleus, the protein binds to special DNA sequences in the promoter regions of genes (the conversion of genes into protein or RNA is induced by hypoxia). As a result of these transformations, erythropoietin is released into the bloodstream by the interstitial cells of the kidneys.

By myelopoiesis precursor cells, the genetic program embedded in them is carried out as a result of the stimulating effect of cytokines (these small peptide control (signal) molecules bind to the corresponding receptors on the surface of the precursor cells).

When erythropoietin binds to the erythropoietin receptor EPO-R, dimerization of this receptor occurs, which activates Jak2, a kinase associated with the intracellular domains of EPO-R.

Jak2 kinase is responsible for signal transmission from erythropoietin, thrombopoietin and G-CSF (granulocyte colony-stimulating factor).

Due to the activation of Jak2-kinase, phospholation of a number of cytoplasmic target proteins occurs, which includes adapter proteins of the STAT family.

Erythremia was detected in 30% of patients with constitutive activation of the STAT3 gene.

Also, with erythremia, in some cases, a reduced level of expression of the thrombopoietin receptor MPL is detected, which is compensatory in nature. The reduction in MPL expression is secondary and is caused by a genetic defect responsible for the development of polycythemia vera.

A decrease in degradation and an increase in the level of the HIF-1 factor is caused by defects in the VHL gene (for example, representatives of the population of Chuvashia are characterized by a homozygous mutation 598C>T of this gene).

Polycythemia vera can be caused by abnormalities of chromosome 9, but the most common is a deletion of the long arm of chromosome 20.

In 2005, a point mutation in exon 14 of the Jak2 kinase gene (mutation JAK2V617F) was identified, which causes the replacement of the amino acid valine with phenylalanine in the pseudokinase domain JH2 of the JAK2 protein at position 617.

The JAK2V617F mutation in hematopoietic precursor cells in erythremia is presented in a homozygous form (the formation of the homozygous form is affected by mitotic recombination and duplication of the mutant allele).

When JAK2V617F and STAT5 are active, the level of reactive oxygen species increases, resulting in a transition of the cell cycle from the G1 to S phase. The adapter protein STAT5 and reactive oxygen species transmit a regulatory signal from JAK2V617F to the cyclin D2 and p27kip genes, which causes an accelerated transition of the cell cycle from phase G1 to S. As a result, the proliferation of erythroid cells that carry a mutant form of the JAK2 gene increases.

In JAK2V617F-positive patients, this mutation is detected in myeloid cells, B- and T-lymphocytes and natural killer cells, which proves the proliferative advantage of defective cells compared to the norm.

Polycythemia vera in most cases is characterized by a fairly low ratio of mutant to normal allele in mature myeloid cells and early precursors. In the presence of clonal dominance, patients have a more severe clinical picture compared to patients without this defect.

Symptoms

Symptoms of polycythemia vera are associated with excess production of red blood cells, which increase blood viscosity. In most patients, the level of platelets, which cause vascular thrombosis, also increases.

The disease develops very slowly and is asymptomatic at the initial stage.
At later stages, polycythemia vera manifests itself:

• plethoric syndrome, which is associated with increased blood supply to organs;
• myeloproliferative syndrome, which occurs with increased production of red blood cells, platelets and leukocytes.

Plethoric syndrome is accompanied by:

• Headaches.
• Feeling of heaviness in the head;
• Dizziness.
• Attacks of pressing, squeezing pain behind the sternum, which occurs during physical activity.
• Erythrocyanosis (redness of the skin to a cherry tint and a bluish tint of the tongue and lips).
• Redness of the eyes, which occurs as a result of dilation of blood vessels in them.
• A feeling of heaviness in the upper abdomen (left), which occurs as a result of an enlarged spleen.
• Skin itching, which is observed in 40% of patients (a specific sign of the disease). It intensifies after water procedures and occurs as a result of irritation by the breakdown products of red blood cells of the nerve endings.
• An increase in blood pressure, which decreases well with bloodletting and decreases slightly with standard treatment.
• Erythromelalgia (sharp, burning pain in the fingertips that is relieved by taking blood thinners, or painful swelling and redness of the foot or lower third of the leg).

Myeloproliferative syndrome manifests itself:

• soreness in flat bones and joint pain;
• a feeling of heaviness in the right upper abdomen as a result of an enlarged liver;
• general weakness and increased fatigue;
• increase in body temperature.

Varicose veins are also observed, especially noticeable in the neck area, Cooperman's sign (change in color of the soft palate with normal coloration of the hard palate), duodenal ulcer and, in some cases, stomach, bleeding of the gums and esophagus, and increased uric acid levels. The development of heart failure and cardiosclerosis is possible.

Stages of the disease

Polycythemia vera is characterized by three stages of development:

• Initial, stage I, which lasts about 5 years (a longer period is possible). It is characterized by moderate manifestations of plethoric syndrome, the size of the spleen does not exceed the norm. A general blood test reveals a moderate increase in the number of red blood cells; increased formation of red blood cells is observed in the bone marrow (an increase in the number of all blood cells, with the exception of lymphocytes, is also possible). At this stage, complications practically do not arise.
• The second stage, which can be polycythemic (II A) and polycythemic with myeloid metaplasia of the spleen (II B). Form II A, lasting from 5 to 15 years, is accompanied by severe plethoric syndrome, enlargement of the liver and spleen, the presence of thrombosis, and bleeding. Tumor growth in the spleen is not detected. Possible iron deficiency due to frequent bleeding. A general blood test reveals an increase in the number of red blood cells, platelets and leukocytes. Scar changes are observed in the bone marrow. Form II B is characterized by progressive enlargement of the liver and spleen, the presence of tumor growth in the spleen, thrombosis, general exhaustion, and bleeding. A complete blood count can detect an increase in the number of all blood cells, with the exception of lymphocytes. Red blood cells take on different sizes and shapes, and immature blood cells appear. Scar changes in the bone marrow gradually increase.
• Anemic, stage III, which develops 15-20 years after the onset of the disease and is accompanied by a pronounced enlargement of the liver and spleen, extensive scar changes in the bone marrow, circulatory disorders, a decrease in the number of red blood cells, platelets and leukocytes. Transformation into acute or chronic leukemia is possible.

Diagnostics

Erythremia is diagnosed based on:

• Analysis of complaints, medical history and family history, during which the doctor clarifies when the symptoms of the disease appeared, what chronic diseases the patient has, whether there was contact with toxic substances, etc.
• Data from a physical examination, which pays attention to the color of the skin. During palpation and with the help of percussion (tapping), the size of the liver and spleen is determined, pulse and blood pressure are also measured (may be elevated).
• A blood test that determines the number of red blood cells (the norm is 4.0-5.5x109 g/l), leukocytes (can be normal, increased or decreased), platelets (at the initial stage does not deviate from the norm, then an increase in the level is observed, and then a decrease ), hemoglobin level, color indicator (usually the norm is 0.86-1.05). ESR (erythrocyte sedimentation rate) is reduced in most cases.
• Urinalysis, which allows you to identify concomitant diseases or the presence of renal bleeding.
• A biochemical blood test that reveals the increased level of uric acid characteristic of many cases of the disease. To identify organ damage accompanying the disease, the level of cholesterol, glucose, etc. is also determined.
• Data from a bone marrow study, which is performed using a puncture in the sternum and reveals increased production of red blood cells, platelets and leukocytes, as well as the formation of scar tissue in the bone marrow.
• Trepanobiopsy data, which most fully reflect the condition of the bone marrow. For examination, using a special trephine device, a column of bone marrow is taken from the wing of the ilium along with the bone and periosteum.

A coagulogram, iron metabolism studies are also performed, and the level of erythropoietin in the blood serum is determined.

Since chronic erythremia is accompanied by an enlargement of the liver and spleen, an ultrasound of the internal organs is performed. Ultrasound also detects the presence of hemorrhages.

To assess the extent of the tumor process, SCT (spiral computed tomography) and MRI (magnetic resonance imaging) are performed.

To identify genetic abnormalities, a molecular genetic study of peripheral blood is performed.

Treatment

The goals of treatment for polycythemia vera are:

• prevention and treatment of thrombohemorrhagic complications;
• elimination of symptoms of the disease;
• reducing the risk of complications and development of acute leukemia.

Erythremia is treated with:

• Bloodletting, in which 200-400 ml of blood is removed to reduce blood viscosity in young people and 100 ml of blood in case of concomitant heart diseases or in the elderly. The course consists of 3 procedures, which are carried out at intervals of 2-3 days. Before the procedure, the patient takes medications that reduce blood clotting. Bloodletting is not performed in the presence of recent thrombosis.
• Hardware treatment methods (erythrocytapheresis), which remove excess red blood cells and platelets. The procedure is carried out at intervals of 5-7 days.
• Chemotherapy, which is used at stage II B, in the presence of an increase in the number of all blood cells, poor tolerance to bloodletting, or the presence of complications from internal organs or blood vessels. Chemotherapy is carried out according to a special regimen.
• Symptomatic therapy, including antihypertensive drugs for high blood pressure (ACE inhibitors are usually prescribed), antihistamines to reduce skin itching, antiplatelet agents that reduce blood clotting, hemostatic drugs for bleeding.

To prevent thrombosis, anticoagulants are used (usually acetylsalicylic acid is prescribed at 40-325 mg/day).

Nutrition for erythremia must meet the requirements of the treatment table according to Pevzner No. 6 (the amount of protein foods is reduced, red fruits and vegetables and foods containing dyes are excluded).

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