True polycythemia: causes, symptoms, diagnosis, treatment

True polycythemia (primary polycythemia) is an idiopathic chronic myeloproliferative disease characterized by an increase in the number of red blood cells (erythrocytosis), an increase in hematocrit and blood viscosity, which can lead to the development of thrombosis. Hepatosplenomegaly can develop with this disease. In order to establish a diagnosis, it is necessary to determine the number of red blood cells and exclude other causes of erythrocytosis. Treatment consists of periodic bloodletting, in some cases myelosuppressive drugs are used.

Epidemiology

Polycythemia vera (PV) is the most common myeloproliferative disorder; the incidence is 5 cases per 1,000,000 people, and men are more often affected (ratio of about 1.4:1). The average age of patients at diagnosis is 60 years (range: 15–90 years, rare in children); 5% of patients are under 40 years of age at disease onset.

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Causes true polycythemia

Type	Cause
Primary	Polycythemia vera
Secondary	Reduced tissue oxygenation: lung disease, high altitudes, intracardiac shunts, hypoventilation syndromes, hemoglobinopathies, carboxyhemoglobinemia in smokers. Aberrant erythropoietin production: tumors, cysts
Relative (false or Gaisbeck syndrome)	Hemoconcentration: diuretics, burns, diarrhea, stress

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Pathogenesis

Polycythemia vera is characterized by increased proliferation of all cell lines, including the erythrocyte, leukocyte, and platelet lineages. Isolated increase in erythrocyte proliferation is termed primary erythrocytosis. In polycythemia vera, increased red blood cell production occurs independently of erythropoietin (EPO). Extramedullary hematopoiesis occurs in the spleen, liver, and other sites with hematopoietic potential. The life cycle of peripheral blood cells is shortened. In the late stages of the disease, approximately 25% of patients have a decreased red blood cell survival and inadequate hematopoiesis. Anemia, thrombocytopenia, and myelofibrosis may develop; red blood cell and leukocyte precursors may be released into the systemic circulation. Depending on the treatment, the incidence of transformation of the disease to acute leukemia varies from 1.5 to 10%.

In true polycythemia, the volume and viscosity of the blood increase, which creates a predisposition to thrombosis. Since the function of platelets is impaired, the risk of bleeding increases. A sharp intensification of metabolism is possible. A reduction in the life cycle of cells leads to hyperuricemia.

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Symptoms true polycythemia

True polycythemia is often asymptomatic. Sometimes increased blood volume and viscosity are accompanied by weakness, headaches, dizziness, visual disturbances, fatigue and shortness of breath. Itching is common, especially after a hot shower/bath. Facial hyperemia and retinal vein plethora may be observed. The lower extremities may be hyperemic, hot to the touch and painful, sometimes there is ischemia of the fingers (erythromelalgia). Liver enlargement is characteristic, and 75% of patients also have splenomegaly, which can be very pronounced.

Thrombosis can occur in various vessels, resulting in strokes, transient ischemic attacks, deep vein thrombosis, myocardial infarction, retinal artery or vein occlusion, splenic infarction, or Budd-Chiari syndrome.

Bleeding (usually in the gastrointestinal tract) occurs in 10-20% of patients.

Complications and consequences

Complications of hyperuricemia (eg, gout, kidney stones) are usually seen in later stages of polycythemia vera. Hypermetabolism may cause low-grade fever and weight loss.

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Diagnostics true polycythemia

PV should be excluded in patients with characteristic symptoms (especially in the presence of Budd-Chiari syndrome), but the first suspicion of this disease often arises when abnormalities are detected in the general blood test (for example, with Ht> 54% in men and> 49% in women). The number of neutrophils and platelets may be increased, while the morphological structure of these cells may be disrupted. Since PV is a panmyelosis, the diagnosis is clear in the case of proliferation of all 3 peripheral blood lineages in combination with splenomegaly in the absence of causes for secondary erythrocytosis. However, not all of the above changes are always present. In the presence of myelofibrosis, anemia and thrombocytopenia, as well as massive splenomegaly, may develop. Precursors of leukocytes and erythrocytes are found in the peripheral blood, pronounced anisocytosis and poikilocytosis are observed, microcytes, elliptocytes and teardrop-shaped cells are present. Bone marrow examination is usually performed and reveals panmyelosis, enlarged and aggregated megakaryocytes, and (sometimes) reticulin fibers. Cytogenetic analysis of bone marrow sometimes reveals the abnormal clone characteristic of myeloproliferative syndrome.

Since Ht reflects the proportion of red blood cells per unit volume of whole blood, an increase in Ht levels can also be caused by a decrease in plasma volume (relative or false erythrocytosis, also called stress polycythemia or Gaisbeck's syndrome). As one of the first tests that helps to differentiate true polycythemia from hematocrit increased due to hypovolemia, it was proposed to determine the number of red blood cells. It should be taken into account that with true polycythemia, the plasma volume can also be increased, especially in the presence of splenomegaly, which makes Ht falsely normal, despite the presence of erythrocytosis. Thus, an increase in red blood cell mass is necessary for the diagnosis of true erythrocytosis. When determining the erythrocyte mass using erythrocytes labeled with radioactive chromium ( ^51Cr ), an erythrocyte mass greater than 36 ml/kg in men (normal 28.3 ± 2.8 ml/kg) and greater than 32 ml/kg in women (normal 25.4 + 2.6 ml/kg) is considered pathological. Unfortunately, many laboratories do not conduct blood volume studies.

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Diagnostic criteria for polycythemia vera

Erythrocytosis, absence of secondary polycythemia and characteristic changes in the bone marrow (panmyelosis, enlarged megakaryocytes with the presence of aggregates) in combination with any of the following factors:

• Splenomegaly.
• Plasma erythropoietin level < 4 mIU/ml.
• Platelet count > 400,000/µl.
• Positive endogenous colonies.
• Neutrophil count > 10,000/µL in the absence of infection.
• Clonal cytogenetic abnormalities in bone marrow

It is necessary to think about the causes of erythrocytosis (of which there are many). The most common are secondary erythrocytosis due to hypoxia (HbO2 concentration _in arterial blood < 92%), smoker's polycythemia caused by elevated carboxyhemoglobin levels, and tumors that produce erythropoietin and erythropoietin-like substances. It is necessary to determine the arterial oxygen saturation, serum EPO levels, and P (partial pressure of O2, at which hemoglobin saturation reaches 50%). A P study allows one to determine the affinity of hemoglobin for O2 and excludes the presence of increased hemoglobin affinity (hereditary disorder) as a cause of erythrocytosis. An alternative diagnostic approach can also be used - searching for the cause of erythrocytosis before determining the red blood cell mass: with Ht greater than 53% in men or greater than 46% in women in the absence of a cause for secondary erythrocytosis, the probability of true polycythemia is greater than 99%; however, there is currently no consensus on the justification of this approach.

Serum EPO levels are usually low or normal in patients with polycythemia vera, elevated in hypoxia-associated erythrocytosis, and normal or elevated in tumor-associated erythrocytosis. Patients with elevated EPO levels or microhematuria should be evaluated with CT to detect renal pathology or other tumors that secrete EPO, leading to secondary erythrocytosis. Unlike bone marrow from healthy individuals, bone marrow culture from patients with polycythemia vera can form erythrocyte colonies without the addition of EPO (i.e., positive endogenous colonies).

Although other laboratory tests may be abnormal in polycythemia vera, most are unnecessary: vitamin B12 levels and B12-binding capacity are often elevated, but these tests are not cost-effective. Bone marrow biopsy is also usually unnecessary: it typically reveals hyperplasia of all blood cell lines, megakaryocyte clusters, decreased iron stores (best assessed by bone marrow aspirate), and elevated reticulin levels. Hyperuricemia and hyperuricosuria occur in more than 30% of patients. New diagnostic tests have recently been proposed: increased PRV-1 gene expression in leukocytes and decreased C-Mpl (thrombopoietin receptor) expression on megakaryocytes and platelets.

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Treatment true polycythemia

Since polycythemia vera is the only form of erythrocytosis for which myelosuppressive therapy may be indicated, it is very important to establish an accurate diagnosis. Therapy should be individualized taking into account the patient's age, sex, general condition, clinical manifestations of the disease, and hematological parameters.

Phlebotomy. Phlebotomy reduces the risk of thrombosis, improves symptoms and may be the only method of therapy. Bloodletting is the therapy of choice in women of childbearing age and patients under 40 years of age, since it does not have a mutagenic effect. As a rule, an indication for phlebotomy is an Ht level above 45% in men and above 42% in women. At the beginning of therapy, 300-500 ml of blood is exfused every other day. A smaller volume of exfusions (200-300 ml twice a week) is performed in elderly patients, as well as patients with concomitant cardiac and cerebrovascular pathology. After the hematocrit has been reduced below the threshold value, it should be determined once a month and maintained at this level using additional bloodletting (as needed). Before performing planned surgical interventions, the number of red blood cells should be reduced using phlebotomies. If necessary, intravascular volume can be maintained by infusions of crystal or colloid solutions.

Aspirin (81–100 mg orally once daily) reduces the incidence of thrombotic complications. Patients undergoing phlebotomy alone or phlebotomy in combination with myelosuppressive therapy should take aspirin unless contraindicated.

Myelosuppressive therapy. Myelosuppressive therapy may be indicated for patients with platelet counts greater than 1/μl, discomfort due to enlarged visceral organs, thrombosis despite Ht less than 45%, symptoms of hypermetabolism or uncontrolled itching, as well as for patients over 60 years of age or patients with cardiovascular disease who do not tolerate bloodletting.

Radioactive phosphorus ( ^32P ) is effective in 80-90% of cases. The duration of remission ranges from 6 months to several years. P is well tolerated, and if the disease is stable, the number of visits to the clinic can be reduced. However, P therapy is associated with an increased incidence of leukemic transformation, and if leukemia develops after treatment with phosphorus, it is often resistant to induction chemotherapy. Thus, P therapy requires careful patient selection (e.g., it is performed only in patients with a high probability of death due to other disorders within 5 years).

Hydroxyurea, an inhibitor of the enzyme ribonucleoside diphosphate reductase, has long been used for myelosuppression; its leukemogenic potential continues to be studied. Ht is reduced to less than 45% by bloodletting, after which patients receive hydroxyurea at a dose of 20-30 mg/kg orally once a day. Patients are monitored weekly with a complete blood count. Upon reaching a stable condition, the interval between control blood tests is extended to 2 weeks, and then to 4 weeks. When the leukocyte level decreases to less than 4000/μl or platelets to less than 100,000/μl, hydroxyurea intake is suspended; when the indicators return to normal, it is resumed at a 50% reduced dose. In patients with poor disease control, requiring frequent phlebotomies, or with thrombocytosis (platelet count > 600,000/μL), the dose may be increased by 5 mg/kg monthly. Acute toxicity is rare, but may include rash, gastrointestinal symptoms, fever, nail changes, and skin ulceration, which may require discontinuation of hydroxyurea.

Interferon a2b was used when hydroxyurea failed to control blood cell counts or when the drug was poorly tolerated. The usual starting dose is 3 U subcutaneously 3 times per week.

Anagrelide is a new drug that has a more specific effect on megakaryocyte proliferation compared to other drugs and is used to reduce platelet levels in patients with myeloproliferative diseases. The safety of this drug during long-term use is currently being studied, but according to available data, it does not contribute to the transition of the disease to acute leukemia. Vasodilation with headaches, palpitations, and fluid retention may develop with the use of the drug. To minimize the indicated side effects, the drug is started at an initial dose of 0.5 mg twice daily, then the dose is increased weekly by 0.5 mg until the platelet count decreases to less than 450,000/mcL or until the dose is 5 mg twice daily. The average dose of the drug is 2 mg/day.

Most alkylating agents and to a lesser extent radioactive phosphorus (which were previously used for myelosuppression) have a leukemoid effect and should be avoided.

Treatment of complications of polycythemia vera

In case of hyperuricemia, if it is accompanied by symptoms or if the patient is receiving myelosuppressive therapy, allopurinol 300 mg orally once a day is necessary. Itching may be relieved by taking antihistamines, but this is not always the case; myelosuppressive therapy is often the most effective treatment for this complication. Cholestyramine 4 g orally three times a day, cyproheptadine 4 mg orally 3-4 times a day, cimetidine 300 mg orally 4 times a day, paroxetine 20-40 mg orally once a day can also be used to relieve itching. After a bath, the skin should be dried gently. Aspirin relieves the symptoms of erythromelalgia. Elective surgical interventions in polycythemia vera should be performed only after the Ht level has decreased to < 42% and the platelet count is less than 600,000/μl.

Forecast

Without treatment, 50% of patients with symptoms of the disease die within 18 months of diagnosis. With treatment, the median survival exceeds 10 years, and young patients can live for several decades. The most common cause of death in patients is thrombosis, followed by complications of myeloid metaplasia and the transition of the disease to leukemia.

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