Polycythemia Rubra Vera
Polycythemia Rubra Vera (PRV) or Primary Polycythemia Vera is a chronic myeloproliferative disorder characterized by an increase in RBC mass, which often manifests as an increased hematocrit (Hct). There is a malignant transformation of the multipotential stem cell with excess production of red cells.
PRV involves increased production of all cell lines, including RBCs, WBCs, and platelets.
Polycythaemia Rubra Vera is characterized by overproduction of red cells in the bone marrow, without any identifiable cause. These cells accumulate in the bone marrow and in the blood stream where they increase the blood volume and cause the blood to become thicker, or more ‘viscous’ than normal. In many people with polycythemia rubra vera, too many platelets and white cells are also produced.
Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that have the potential for blood cell formation.
There is no Philadelphia chromosome.
PRV is the most common of the myeloproliferative disorders; with incidence increasing with age. PRV may be slightly more common in men. The mean age at diagnosis is around 60 years. The disease is very rare in children.
Develop gradually and include:
- Headaches, dizziness, tinnitus and visual problems.
- The face may be red (plethoric) and the retinal veins engorged. The palms and feet may be red, warm, and painful.
- Thrombotic episodes e.g. (neurologic deficits with stroke or transient ischemic attack, DVTs, unilateral vision loss with retinal vascular occlusion).
- Bleeding episodes especially peptic ulcers.
- Generalized pruritus, particularly after a hot bath.
- Hepatomegaly is common, and splenomegaly is present in 75% of cases.
- One-third of patients is hypertensive.
- Hypermetabolism can cause low-grade fevers and weight loss and suggests disease progression.
- Raised Hb.
- Raised red cell mass. This is essential for the diagnosis to differentiate it from pseudo- polycythemia due to a low plasma volume.
- White cell count is usually raised.
- Platelet count is often raised.
- NAP score is raised.
- JAK2 V617F mutation.
- JAK2 exon 12 mutation.
- Abdominal USS.
- In some cases, the diagnosis of PRV must be made by careful exclusion of Secondary Polycythemia. This includes a CXR, IV urogram, blood gases, Hb electrophoresis and O2 dissociation curve.
Diagnostic criteria for PRV as per the 2008 revised World Health Organization (WHO) guidelines include both major and minor criteria. Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria.
Major WHO criteria are as follows:
- Hemoglobin >18.5 g/dL in men and >16.5 g/dL in women, or other evidence of increased red blood cell volume.
- Presence of JAK2 V617F or other functionally similar mutation, such as JAK2 exon 12 mutation.
Minor WHO criteria are as follows:
- Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation.
- Serum erythropoietin level below the reference range for normal.
- Endogenous erythroid colony formation in vitro.
JAK2 V617F mutation and erythropoietin (Epo) level are key in the diagnosis of erythrocytosis. If the JAK2 V617F mutation is positive and Epo level is low, then it confirms the diagnosis of PRV (JAK2 V617F mutation is positive in 97% of PRV patients).
JAK2 mutations also occur in about 60% of patients with essential thrombocythemia. In patients who are positive for JAK2 and whose hemoglobin/hematocrit level is diagnostically equivocal, bone marrow examination is necessary to distinguish the two conditions.
If the JAK2 V617F mutation is absent but the Epo level is low, then testing for JAK2 exon 12 and 13 mutations would be helpful for making a diagnosis of PRV in the 2-3% of PRV patients who are negative for JAK2 V617F mutation.
Patients who are negative for JAK2 mutations and have a normal or high Epo level have secondary polycythemia.
Repeated phlebotomies (venesections) aiming to keep Hct < 0.45
Cytoreductive therapy e.g. hydroxyurea. In patients who are refractory to or intolerant of hydroxyurea, interferon-alpha can be used as an alternative. Busulfan is also an option for patients older than 65 years.
Aspirin, 75 mg daily, unless contraindicated by major bleeding or gastric intolerance.
Allopurinol to prevent gout.
JAK inhibitors: the JAK1/2 inhibitor ruxolitinib (Jakavi) is approved for treatment of PRV in patients who have had an inadequate response to or are intolerant of hydroxyurea.
Radioactive phosphorus (rarely used).
Control of blood pressure if raised.
Untreated PRV is fatal within several years. The long-term risks of PRV include acute leukemia and myelofibrosis transformation, which occurs in fewer than 5% and 10% of patients, respectively, at 10 years. Current treatment modalities do not change these outcomes. Instead, treatment for PRV is intended to decrease the risk of arterial and venous thrombotic events, which could be approximately 20%.
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