Polycythemia vera is an uncommon neoplasm or blood cancer where the bone marrow produces too many erythrocytes, megakaryocytes, and granulocytes, resulting in panmyelosis. The cancer is caused by a mutation in the JAK2 gene. Janus Kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a role in signaling in the type II cytokine receptor family. Members of that family include interferon receptors, GM-CSF receptor family, gp130 receptors, and the single chain receptors (EPO-R, etc). The function of those receptors are not important. The most important receptor for this article is the EPO-R receptor. The erythropoietin receptor (EPO-R) is a protein encoded by the EPOR gene that pre-exists in a dimerized state. When the ligand erythropoietin binds to the EPO-R receptor it induces a conformational change that results in the autophosphorylation of the JAK2 kinases. This establishes the function of EPO-R which is to promote proliferation and the rescue of erythroid progenitors from apoptosis. EPO-R induces JAK2-STAT5 signaling and with help from the transcription factor GATA-1 induces the transcription of the protein BCL-XL which is anti-apoptotic and promotes red cell survival.
In polycythemia vera (PV) there is a JAK2V617F mutation that causes independent continuous expression of the JAK2 kinase without erythropoietin (EPO) that acts on signaling pathways involving the EPO-R or hyperexpression in the presence of EPO. This causes increased gene expression for erythroid precursor cell proliferation and differentiation. It up regulates BCL-XL, which as mentioned above is an anti-apoptotic. This causes an abnormal accumulation of red cells in the peripheral blood. Its important to note that the accumulation of the red cells is due to lack of apoptosis, NOT because they are dividing quicker. Also there is a difference between primary PV and secondary PV. In primary PV there is a decreased expression of EPO, this is a compensation method for the body. As there is autophosphorylation of the EPO-Receptor, the body tries to reverse the process by down regulating the expression of erythropoietin (EPO). In secondary PV, there is normal to increased expression of EPO.
Diagnosis of PV according to the World Heath Organization (WHO) has to satisfy both major and minor criteria. The major criteria that has to be observed is a hemoglobin higher than 18.5 g/dL in men, and greater than 16.5 g/dL in women. There also has to be the presence of the JAK2 mutation. Minor criteria include presence of bone marrow hypercellularity demonstrating panmyelosis, serum EPO levels decreased, and a demonstration of endogenous erythroid colony growth in vitro. Meaning that there is presence of red cell growth in the laboratory using EPO from the patient, which assumes there is an issue with the downstream signaling of EPO, not EPO itself.
Laboratory results illustrate an increased hemoglobin, hematocrit, and MCV. There is an increased red cell count, platelet count, and white blood cell count. The leukocyte alkaline phosphatase is also increased. Its important to know that although the platelet count is increased, there is also an altered function of the platelets. The erythrocyte sedimentation rate will be decreased due to the decrease in the zeta potential. The zeta potential is the electrokinetic potential between the red cells that stops them from stacking or from sticking to one another. One classic characteristic of PV is erythromelalgia. This is a burning sensation in the pain and feet, with a reddish or bluish discoloration. This is caused by an increased platelet agglutination, from being dysfunctional that results in microvascular blood clots.
If untreated, PV can be fatal. Although the disease can’t be cured, it can be controlled and the life expectancy has risen with modern advances in medicine. Phlebotomy is recommended to reduce the hemoglobin and hematocrit levels, but can induce iron deficiency anemia if not monitored. Low dose aspirin is prescribed to reduce the risk of thrombotic events. The accumulation of the red cells increases the risk for the patient to develop thrombotic events because the blood is “thick”. Chemotherapy can be used, but is not normally indicated, unless therapeutic phlebotomy is unable to maintain a normal hemoglobin or hematocrit or when there is significant thrombocytosis. It is dangerous because of the risk for transformation to acute myeloid leukemia (AML).
To recap; its important to know the mutation in the JAK2 kinase that induces polycythemia vera. Although this mutation is demonstrated in 90% of cases, its possible that its absent. Panmyelosis and elevation of RBC indices is a diagnostic finding. Its important to know the major and minor criteria for the diagnosis of PV. Treatment is therapeutic phlebotomy and chemotherapy in rare cases, only when prior treatment has failed.