Polycythemia vera

Introduction and Facts

Polycythemia vera (PV) in the WHO classification system belongs to the myeloproliferative neoplasm group; the group also includes essential thrombocytemia (ET), primary myelofibrosis (PMF), and prefibrotic PMF. Polycythemia is a state of increased levels of red blood cells which is characterized by increased concentrations of hemoglobin and hematocrit. An increase in hemoglobin and hematocrit that occurs due to a decrease in plasma volume without an increase in the number of red blood cells is called relative polycythemia.

Pathophysiology

Polycythemia vera is a chronic myeloproliferative neoplasm with a negative Philadelphia chromosome that causes a clonal disorder of myeloproliferation in the spinal cord. Myeloid cell proliferation is replaced by an abnormal monoclonal proliferation process that causes red blood cell overproduction in PV, platelet overproduction in essential thrombocytosis, and spinal cord fibrosis in primary myelofibrosis. In 2005, researchers discovered a somatic mutation in the Janus kinase 2 (JAK2) gene.6 The JAK2 gene provides instructions for making proteins that play a role in cell proliferation.6 This protein has an important role in controlling the production of erythrocytes, leukocytes, and platelets in stem cells. hematopoietic cells in the spinal cord.7 The JAK2 gene mutation most commonly associated with myeloproliferative neoplasms is located in exon 14 of JAK2. This mutation in exon 14 is called JAK2V617F. JAK2V617F can be found in more than 90% of PV, as well as 50-60% of ET and PMF.6 A small proportion of PV patients have JAK2 mutations in exon 12.8 JAK2V617F mutations cause genetic instability in gene expression by triggering changes in chromatin structure and by reducing apoptotic responses on DNA damage.9 The occurrence of mutations in JAK2 causes erythropoietin hypersensitivity which results in increased production of red blood cells

Polycythemia vera naturally tends to develop into myelofibrosis, called post-polycythemia vera myelofibrosis (PPVMF). 10 This transformation occurs in 25% of PV patients and reduces life expectancy. There are no risk factors for the evolution of PV to PPV-MF. In PPV-MF, an increase in JAK2V617F was found as well as in PV, and CD34+ cells in peripheral blood.

Clinical Symptoms and Complications

Clinical symptoms of PV may include mild to moderate splenomegaly, followed by fatigue, pruritus, signs of hyperviscosity such as bleeding into the skin and mucosa, visual disturbances and focal neurological deficits. In addition, microvascular symptoms such as headache, spinning dizziness, visual disturbances, paresthesias, and erythromelalgia also appear. Erythromelalgia is a syndrome of recurrent pain in the distal extremities, the skin becomes erythematous and warm, due to tissue hyperperfusion. In 40% of patients, symptoms of aquagenic pruritus are characterized by itching and burning of the skin, especially after contact with water without visible changes in the skin.

Symptoms of thrombosis were seen in 33% of patients with PV in the form of stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis. The incidence of thrombogenesis is closely related to mutations in JAK2; This mutation not only increases the production of erythrocytes, but also increases the production and performance of platelets so that thrombosis is easy to occur. Bleeding is found in 25% of patients due to platelet dysfunction. Platelet dysfunction occurs not only in PV, but also in essential thrombocytemic patients, with the majority of patients having acquired von Willebrand syndrome and a decreased number of platelet glycoprotein receptors. Bleeding can also be exacerbated by the use of aspirin.

Diagnosis

Initial diagnosis is based on history, physical examination, and laboratory. In the anamnesis, it is necessary to know a history of tumor or malignancy, cardiovascular and cerebrovascular disorders, and a family history of diseases associated with myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia, or primary myelofibrosis. On physical examination can be found splenomegaly and hepatomegaly, ruddy cyanosis (swelling of the mucosa and skin with cyanosis), conjunctival plethora, and skin plethora (accumulation of fluid and blood in the conjunctiva and mucosa).

On examination of the peripheral blood can be found an increase in the number of red blood cells, hematocrit, and red blood cell mass. According to WHO 2016 criteria, hemoglobin increases if it is more than 16.5 g/dL in men and 16 g/dL in women. The hematocrit increases if it is more than 49% in men and more than 48% in women. An increase also occurred in the mass of red blood cells as much as 25% above the average value. Erythropoietin serum levels below normal can also help the diagnosis and become a minor criterion in the WHO diagnostic criteria for PV.

Bone marrow aspiration is also helpful in diagnosis, especially in predicting the occurrence of myelofibrosis, and is useful in differentiating PV from essential thrombocythemia caused by JAK2 mutations.

The diagnosis of polycythemia vera requires 3 major criteria, or the first 2 major criteria plus the minor criteria. Bone marrow biopsy is not necessary if absolute erythrocytosis persists: Hb >18.5 g/dL in men (hematocrit 55.5%) or >16.5 g/dL in women (hematocrit 49.5%) and if there is mutation criteria number 3 plus minor criteria. However, myelofibrosis (MF) can only be detected by bone marrow biopsy; hypercellularity can predict faster progression to MF (post-PV MF), so a bone marrow biopsy should be performed if post-polycythemia vera myelofibrosis is suspected.

Management and Care

Current PV therapy cannot prevent the natural evolution of diseases such as post-PV myelofibrosis, but it can reduce the risk of thromboembolism and bleeding, based on the classification of risk factors.1 Classification of risk factors for patients with PV plays an important role in determining treatment.

Initial therapy was phlebotomy and aspirin administration in all patients, both male and female, regardless of risk factor classification. A plebotomi is performed until the hematocrit is below 45%, and aspirin is given at a dose of 40-100 mg once a day. In low-risk PV patients with microvascular symptoms not controlled with once-daily aspirin, the aspirin dose was increased to twice daily. This dose is also given to low-risk PV patients with cardiovascular symptoms such as hypertension or leukocytosis, because leukocytosis increases the risk of thrombosis, especially in patients with uncontrolled hematocrit.

Patients at high risk can be given a cytoreductive drug such as hydroxyurea as a first line with an initial dose of 500 mg twice daily.15 In patients with a history of arterial thrombosis, aspirin is given twice daily. If a history of venous thrombosis is found, systemic anticoagulation should be added. If there is intolerance or resistance to hydroxyurea, it is necessary to consider giving second-line drugs, namely pegylated interferon , busulfan, and ruxolutinib.

Reference:

Wijaya W. Diagnosis dan tatalaksana polisitemia vera. Cermin Dunia Kedokteran 2020;286:47(5):346-50.