True polycythemia: causes, symptoms, diagnosis, treatment

True polycythemia (primary polycythemia) is an idiopathic chronic myeloproliferative disease characterized by an increase in the number of erythrocytes (erythrocytosis), increased hematocrit and blood viscosity, which can lead to the development of thromboses. With this disease, hepatosplenomegaly can develop. In order to establish the diagnosis, it is necessary to determine the number of red blood cells and exclude other causes of erythrocytosis. Treatment consists in periodic bleeding, in some cases, using myelosuppressive drugs.

Epidemiology

True polycythemia (PI) occurs more often than other myeloproliferative diseases; the incidence is 5 cases per 1000 000 people, men are more likely to fall ill (the ratio is about 1.4: 1). The average age of patients at the time of diagnosis is 60 years (from 15 to 90 years, in children this disease is rare); at the time of onset of the disease 5% of patients younger than 40 years.

[1], [2]

Causes of the true polycythemia

A type	Cause
Primary	True polycythemia
Secondary	Reduced oxygenation of tissues: lung disease, stay at high altitudes (above sea level), intracardiac blood discharge, hypoventilation syndromes, hemoglobinopathies, carboxyhemoglobinemia in smokers. Aberrant production of erythropoietin: tumors, cysts
Relative (false or Gaysbek syndrome)	Hemoconcentration: diuretics, burns, diarrhea, stress

[3], [4], [5]

Pathogenesis

True polycythemia is characterized by increased proliferation of all cell lines, including erythrocyte, leukocyte and platelet sprouts. Isolated increase in erythrocyte proliferation is designated by the term "primary erythrocytosis". With true polycythemia, enhanced erythrocyte formation occurs independently of erythropoietin (EPO). Extramedullary hematopoiesis is observed in the spleen, liver and other places with the potential for hematopoiesis. The life cycle of peripheral blood cells is shortened. In the late stages of the disease, in approximately 25% of patients, the life span of erythrocytes decreases, and inadequate hematopoiesis takes place. Anemia, thrombocytopenia and myelofibrosis can develop; the precursors of erythrocytes and leukocytes can enter the systemic circulation. Depending on the ongoing treatment, the frequency of transformation of the disease into acute leukemia varies from 1.5 to 10%.

With true polycythemia, the volume increases and the viscosity of the blood increases, which creates a predisposition to thrombosis. Since the function of platelets is impaired, the risk of bleeding is increased. There is a sharp intensification of metabolism. Reducing the life cycle of cells leads to hyperuricemia.

[6], [7],

Symptoms of the true polycythemia

True polycythemia often occurs asymptomatically. Sometimes the increased volume and viscosity of the blood are accompanied by weakness, headaches, dizziness, visual disturbances, fatigue and shortness of breath. Frequent itching, especially after a hot shower / bath. There may be hyperemia of the face, fullness of the veins of the retina. Lower extremities can be hyperemic, hot to the touch and painful, sometimes ischemia of the fingers (erythromelalgia) is observed. Characteristic of the increase in the liver, in addition, 75% of patients also show splenomegaly, which can be very pronounced.

Thrombosis can occur in a variety of vessels, resulting in strokes, transient ischemic attacks, deep vein thrombosis, myocardial infarction, arterial or retinal vein occlusion, spleen infarction, or Budd Chiari syndrome.

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

Complications and consequences

Complications of hyperuricemia (for example, gout, kidney stones), as a rule, are observed at later stages of the true polycythemia. Hypermetabolism can be the reason for the development of subfebrile and weight loss.

[8], [9], [10], [11], [12]

Diagnostics of the true polycythemia

PI should be excluded in patients with characteristic symptoms (especially in the presence of Badda-Chiari syndrome), but the first suspicion of this disease is more likely to occur if there are abnormalities in a general blood test (for example, for Ht> 54% for men and> 49% for women ). The number of neutrophils and platelets can be increased, and the morphological structure of these cells can be disturbed. Since PI is panmyelosis, the diagnosis is not in doubt in the case of proliferation of all 3 peripheral blood sprouts in combination with splenomegaly in the absence of reasons for secondary erythrocytosis. However, all listed changes are not always present. In the presence of myelofibrosis, the development of anemia and thrombocytopenia, as well as massive splenomegaly, is possible. In the peripheral blood, precursors of leukocytes and erythrocytes are detected, pronounced anisocytosis and poikilocytosis are observed, microcytomas, ellipocytes and drop-shaped cells are present. Usually a bone marrow examination is performed, in which panmyelosis, enlarged and aggregated megakaryocytes, and (sometimes) reticulin fibers are detected. In cytogenetic analysis of the bone marrow, an abnormal clone, characteristic of the myeloproliferative syndrome, is sometimes found.

Since Ht reflects the proportion of red blood cells per unit volume of whole blood, an increase in Ht level may also be caused by a decrease in plasma volume (relative or false erythrocytosis, also referred to as stress polycythemia or Gaysbek syndrome). As one of the first tests to help distinguish the true polycythemia from increased hematocrit due to hypovolemia, it was suggested to determine the number of red blood cells. It should be borne in mind that with true polycythemia, the volume of plasma can also be increased, especially in the presence of splenomegaly, which makes Ht false-normal, despite the presence of erythrocytosis. Thus, for the diagnosis of true erythrocytosis, an increase in erythrocyte mass is necessary. In the determination of erythrocyte mass with the use of erythrocytes labeled with radioactive chromium ( ⁵¹ Cr), erythrocyte mass is more than 36 ml / kg in men (norm 28.3 ± 2.8 ml / kg) and more than 32 ml / kg in women (norm 25, 4 + 2.6 ml / kg) is considered pathological. Unfortunately, many laboratories do not conduct blood volume studies.

[13], [14], [15]

Diagnostic criteria of true polycythemia

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

• Splenomegaly.
• The plasma erythropoietin level is <4 mU / ml.
• The number of platelets is> 400,000 / μl.
• Positive endogenous colonies.
• The level of neutrophils> 10 000 / μL in the absence of infection.
• Clonal cytogenetic abnormalities in the bone marrow

It is necessary to think about the causes of erythrocytosis (which there are quite a lot). The most commonly encountered secondary erythrocytosis due to hypoxia (concentration NbO ₂ in the arterial blood <92%), polycythemia smokers, due to elevated levels of carboxyhemoglobin and tumor producing erythropoietin and eritropoetinpodobnye substance. It is necessary to determine the saturation of arterial blood with oxygen, serum EPO and P levels (partial pressure of O2, at which the saturation of hemoglobin reaches 50%). Study P allows to determine the affinity of hemoglobin for O2 and excludes the presence of increased affinity for hemoglobin (hereditary disorder) as the cause of erythrocytosis. Alternatively, an alternative diagnostic approach can be used-the search for the cause of erythrocytosis before the determination of erythrocyte mass: when Ht is greater than 53% in men or more 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 no consensus at this time about the justification of this approach.

The level of serum EPO in patients with true polycythemia is usually reduced or normal, with erythrocytosis due to hypoxia - increased, with tumor-associated erythrocytosis - normal or elevated. Patients with elevated levels of EPO or microhematuria should be examined with CT to search for renal pathology or other tumors secreting EPO, which leads to the development of secondary erythrocytosis. Unlike the bone marrow of healthy people, the bone marrow culture of patients with true polycythemia can form red blood cell colonies without the addition of EPO (ie, positive endogenous colonies).

Although the true polycythaemia may have different deviations in other laboratory tests, most of them are not necessary: the level of vitamin B12 and B12-binding capacity is often increased, but these analyzes are inexpedient from an economic point of view. In bone marrow biopsy, there is usually no need: when performed, as a rule, hyperplasia of all blood sprouts, megakaryocyte accumulation, decrease in iron stores (better estimated in bone marrow aspirate) and increased reticulin content are usually determined. Hyperuricemia and hyperuricosuria occur in more than 30% of patients. Recently, new diagnostic tests have been proposed: the determination of increased expression of the PRV-1 gene in leukocytes and reduced expression of C-Mpl (a receptor for thrombopoietin) on megakaryocytes and platelets.

[16], [17]

Treatment of the true polycythemia

Since true polycythemia is the only form of erythrocytosis at which myelosuppressive therapy can be shown, it is very important to make an accurate diagnosis. Therapy should be carried out in an individualized manner taking into account the age, sex, general condition of the patient, clinical manifestations of the disease and hematological parameters.

Phlebotomy. Phlebotomy reduces the risk of thrombosis, improves symptoms and can be the only method of therapy. Bleeding is a therapy of choice in women of childbearing age and patients younger than 40, since it does not have a mutagenic effect. Usually, the indication for phlebotomy is 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 produced in elderly patients, as well as patients who have concomitant cardiac and cerebrovascular pathologies. After the hematocrit was lowered below the threshold, it should be determined once a month and maintained at this level by additional bleeding (as needed). Before the planned surgical intervention should reduce the number of red blood cells with phlebotomies. If necessary, the intravascular volume may be supported by infusions of a crystal of oid or colloidal solutions.

Aspirin (in a dose of 81-100 mg orally once a day) reduces the incidence of thrombotic complications. Patients who are only phlebotomies or phlebotomies in combination with myelosuppressive therapy should take aspirin, if there are no contraindications.

Myelosuppressive therapy. Myelosuppressive therapy may be indicated to patients with a platelet count greater than 1 / μL, with discomfort due to an increase in visceral organs, with thrombosis despite Ht less than 45%, symptoms of hypermetabolism or uncontrolled pruritus, as well as patients over 60 years of age or patients with cardiovascular disease, vascular diseases that do not tolerate bloodletting.

Radioactive phosphorus ( ³² P) is effective in 80-90% of cases. The duration of remission is from 6 months to several years. P is well tolerated, and with a stable course of the disease, the number of visits to the clinic can be reduced. However, P therapy is associated with an increased incidence of leukemic transformation, and with the development of leukemia after treatment with phosphorus it is often resistant to induction chemotherapy. Thus, P therapy requires careful selection of patients (eg, 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 been used for a long time for myelosuppression, and its leukogenic potential continues to be studied. Ht reduce less than 45% by bleeding, after which patients receive hydroxyurea at a dose of 20-30 mg / kg orally once a day. Patients undergo weekly monitoring with a general blood test. When the stable state is reached, the interval between the control blood tests is extended to 2 weeks, then to 4 weeks. With a decrease in the white blood cell count of less than 4000 / μL or less than 100,000 / μL, the hydroxyurea is suspended, and when normalized, it resumes in a 50% reduced dose. In patients with unsatisfactory control of the disease, requiring frequent phlebotomies, or patients with thrombocytosis (platelet level> 600 000 / μL), the dose of the drug may be increased by 5 mg / kg monthly. Acute toxicity is rare, sometimes there may be a rash, symptoms of gastrointestinal damage, fever, nail changes and skin ulceration, which may require discontinuation of hydroxyurea.

Interferon a2b was used in cases when hydroxyurea failed to achieve control of blood cell level or when the drug was poorly tolerated. The usual starting dose is 3 units subcutaneously 3 times a week.

Anagrelide is a new drug that has a more specific effect on the proliferation of megakaryocytes compared to other drugs and is used to reduce platelet levels in patients with myeloproliferative diseases. The safety of this drug with prolonged use is currently being studied, but, according to available data, it does not contribute to the transition of the disease to acute leukemia. When using the drug, the development of vasodilation with headaches, palpitations and fluid retention is possible. To minimize the indicated side effects, the drug is taken at an initial dose of 0.5 mg twice a day, then the dose is increased weekly by 0.5 mg to reduce the platelet count to less than 450,000 / μL or until the dose is 5 mg twice a day. The average dose of the drug is 2 mg / day.

Most alkylating drugs and to a lesser extent radioactive phosphorus (previously used for myelosuppression) have a leukemoid effect, and their use should be avoided.

Treatment of complications of true polycythemia

With hyperuricemia, if it is accompanied by symptoms or if the patient simultaneously receives myelosuppressive therapy, allopurinol should be taken 300 mg orally once a day. Itching can be relieved after taking antihistamines, but this does not always happen; The most effective treatment for this complication is often myelosuppressive therapy. To alleviate the itching, cholestyramine 4 g orally may be used three times a day, cyproheptadine 4 mg 3-4 times a day, cime-tidine 300 mg orally 4 times a day, paroxetine 20-40 mg orally once a day. After the bath, the skin should be wiped gently. Aspirin alleviates the symptoms of erythromelalgia. Planned surgical interventions for true polycythemia should be performed only after a decrease in Ht <42% and a platelet count of less than 600 000 / μL.

Forecast

Without treatment, 50% of patients who have symptoms of the disease die within 18 months of the diagnosis. In the treatment, the median survival is more than 10 years, and young patients can survive several decades. The most common cause of death of patients is thrombosis, following the frequency of the cause of death - complications of myeloid metaplasia and the transition of the disease to leukemia.

[18],