At a Glance
Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by a proliferation of megakaryocytes, granulocytes, and erythrocytes in the bone marrow, leading to thrombocytosis, leukocytosis, and erythrocytosis in the peripheral blood. Patients are often asymptomatic, and it is detected only when routine blood work shows increased hematocrit or hemoglobin. If symptomatic, patients may present with symptoms of hyperviscosity due to the polycythemia (i.e., due to the increased red cell mass within the patient).
Hyperviscosity symptoms include:
myocardial ischemia or ischemia in other organs
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
To confirm the diagnosis of PV, a complete blood count (CBC) showing polycythemia (as measured with Hct/Hgb), JAK2V617F mutation testing, and bone marrow biopsy are typically sufficient.
The diagnosis of PV requires meeting two major and one minor criterion or the first major criteria with all three minor criteria. Although the PV Study Group previously encouraged the evaluation of red cell mass to define polycythemia, the challenges in accurate red cell mass measurement have favored alternative methods to define polycythemia based on hematocrit and hemoglobin measured by CBC. Of course, demonstration of a red cell mass (RCM) greater than 25% increased over mean normal would suffice for Major Criterion 1 (Table 1).
The JAK2V617F mutation is present in more than 95% of PV patients, with various mutations in JAK2 exon 12 found in an additional 3% of PV patients. These lead to the constitutive activation of the JAK2 protein, which is an intracellular nonreceptor tyrosine kinase associated with several cytokine and growth factor receptors, including the erythropoietin receptor. For that reason, there is an expansion of the red cell compartment in the marrow, leading to an increase in hematocrit and hemoglobin values in the CBC. The physiologic response by the juxtaglomerular apparatus is to decrease endogenous EPO production. The stimulation of the erythropoietin receptor in the marrow stem cells also allows for increased EEC formation in vitro.
|Major Criteria||Minor Criteria|
|Hgb >18.5g/dl in men, >16.5 g/dl in women|
|>99th percentile for age, sex, or altitude of residence||Hypercellular marrow with panmyelosis (increase in all three lineages, megakaryocytes, granulocyte, and erythrocytes)|
|OR >2g/dL rise above the patient’s previous normal range, unless associated with correction of nutritional deficiency|
|JAK2 V617F or exon 12 mutation||Decreased serum erythropoietin (EPO)|
|Increased endogenous erythroid colony (EEC) formation in vitro|
Are There Any Factors That Might Affect the Lab Results?
JAK2 mutations have been described in nearly 50% of primary myelofibrosis (PMF), essential thrombocythemia (ET), and refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) cases.
Secondary causes of polycythemia may be caused by drugs, particularly androgens and erythropoietin itself. Smoking can lead to polycythemia by decreasing the oxygen carrying capacity of blood. Any drug inhibiting renal blood flow, oxygen dissociation from red cells, or oxygen absorption in the lungs can theoretically lead to a secondary polycythemia but should not cause mutations in JAK2 or decreased EPO levels.
What Lab Results Are Absolutely Confirmatory?
There is no single laboratory test that is absolutely confirmatory. Testing for JAK2V617F, CBC, and bone marrow biopsy usually suffice to make the diagnosis.
Although nearly all PV patients have the JAK2V617F mutation (>95%), JAK2 mutations in exon 12 (about 3%) have also been described. Of note, other myeloproliferative disorders, such as primary myelofibrosis and essential thrombocythemia may also have JAK2 mutations, thus, the mutation testing is not specific for PV.
A polycythemic patient with evidence of JAK2V617F mutation most likely has PV. This can be confirmed with a bone marrow biopsy. Even if EPO levels are normal in a JAK2V617F patient, PV is still likely and bone marrow biopsy should be performed to confirm the diagnosis. In those patients with polycythemia, but lacking a JAK2V617F mutation, if the serum EPO level is low, PV is still possible and a bone marrow biopsy is recommended in combination with exon 12 mutation screening.
Furthermore, there is a wide range of causes for secondary polycythemia, including smoking, sleep apnea, and hemoglobinopathies. These typically lead to increased serum EPO, since these causes all lead to decreased oxygen sensed at the juxtaglomerular apparatus that produces EPO to compensate for the relative decrease in oxygen carrying capacity in the blood.
What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
Typically, the diagnosis can be confirmed based on hematocrit/ hemoglobin values, JAK2V617F testing, and bone marrow examination by a pathologist. In the 5% of cases in which JAK2V617F is not detected, follow-up testing for the other JAK2 mutations in exon 12 may be useful to definitively diagnose PV if serum EPO levels are low. Unfortunately, endogenous EEC formation is rarely performed outside of academic research laboratories.
What is the long-term prognosis?
If hyperviscosity associated morbidity can be controlled, the long-term prognosis for PV patients is generally good. High-risk patients have either a history of thrombosis OR are 60 years of age or older. Low risk patients have neither of these and have platelet counts less than 1,000/ microliter. Once platelets increase past that level, the risk of bleeding increases because of an acquired von Willebrand’s deficiency. Typically, low-risk patients can be treated solely with low-dose aspirin and phlebotomy, whereas high-risk patients may require hydroxyurea or busulfan for cytoreduction.
Overall, the risk for leukemic transformation in PV is low (<5%), as is the risk of progressive fibrosis (10%). The mean overall survival in PV patients is estimated to be at least 15 years.
Errors in Interpretion
JAK2 mutations have been described in nearly 50% of PMF, ET, and RARS-T cases. Therefore, detecting a JAK2 mutation is not definitive for PV.
Secondary causes of polycythemia must be ruled out before considering the first major criterion as met. Secondary polycythemia may be caused by exogenous agents or endogenous agents. Commonly, smoking can lead to polycythemia by decreasing the oxygen carrying capacity of blood due to carbon monoxide poisoning (carboxyhemoglobin formation), as well as leading to chronic obstructive pulmonary disease (COPD), which decreases oxygenation of blood.
Other causes of pulmonary and cardiac disease can also lead to hypoxia-associated polycythemia. Decreased renal blood flow due to arteriosclerosis, aortic or renal artery aneurysms, or renal artery stenosis can lead to secondary polycythemia. Focal glomerulonephritis has been associated with increased EPO production, as has the post-renal transplant state.
Familial polycythemias can be caused by hemoglobinopathies with high-oxygen affinities leading to less oxygen release from the hemoglobin as it transits the juxtaglomerular apparatus. Other causes of familial polycythemias include EPO receptor mutations and von Hippel Lindau protein mutations. Androgen administration can lead to polycythemia as can exogenous EPO administration.
Finally, EPO secretion by solid tumors has also been shown to lead to erythrocytosis. In almost all of these cases, the increased Hct/ Hgb occurs in the presence of increased EPO. Only in the case of EPO receptor mutations could the serum EPO levels be low, and, in those cases, there is an increase in bone marrow erythroids without a true polycythemia of all three lineages. Also, these are unassociated with JAK2 mutations.
Hyperviscosity may also be caused by monoclonal gammopathies, most commonly Waldenström’s macroglobulinemia, but also myeloma and more rarely leukocytoses associated with leukemias or myeloproliferative disorders.
All chronic myeloproliferative disorders may initially present with similar bone marrow findings. Although it is rare for chronic myelogenous leukemia (CML) to present with an increased Hct or Hgb, it is important to note that the presence of a BCRABL fusion precludes the diagnosis of PV and is definitive for CML. Often, prefibrotic PMF can be difficult to distinguish from PV; however, if there is progression to fibrosis or pancytopenia develops in a PV patient, consideration should be given to the reclassification of the disease to PMF versus spent-phase PV. Megakaryocyte morphology may be useful in this distinction but is by no means definitive.
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- At a Glance
- What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
- Are There Any Factors That Might Affect the Lab Results?
- What Lab Results Are Absolutely Confirmatory?
- What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
- What is the long-term prognosis?
- Errors in Interpretion