Polycythemia Vera (PV) is a chronic, progressive blood cancer belonging to the group of myeloproliferative neoplasms (MPNs). PV is characterized by the overproduction of red blood cells in the bone marrow, often accompanied by elevated white blood cells and platelets. This excessive cell production thickens the blood, significantly increasing the risk of complications such as blood clots, heart attack, and stroke. The vast majority of PV cases are driven by a specific, acquired genetic change, which is the primary tool for diagnosis. This raises a fundamental question: Can a person genuinely have Polycythemia Vera without this dominant genetic signature?
The JAK2 Gene and its Mutational Role
The JAK2 gene provides instructions for making Janus Kinase 2, a signaling enzyme in blood-forming cells. This enzyme relays growth signals from receptors to the cell nucleus. When growth factors, such as erythropoietin, bind to the cell surface, JAK2 is activated, telling the cell to divide and mature.
The most common mutation in PV, found in over 95% of cases, is JAK2 V617F. This specific change causes the JAK2 enzyme to be constantly switched on, regardless of whether a growth factor is present. The consequence is an unregulated, independent proliferation of blood cells in the bone marrow, which is the hallmark of the disease.
A second, less common set of mutations involves JAK2 Exon 12, accounting for most remaining PV cases. These mutations also result in constitutive activation. While the JAK2 V617F mutation may be associated with increased white blood cell and platelet counts, the Exon 12 mutations often present as an isolated overproduction of only red blood cells.
Defining Polycythemia Vera Through Diagnostic Criteria
The diagnosis of Polycythemia Vera relies on comprehensive standards established by organizations like the World Health Organization (WHO). These criteria integrate clinical, laboratory, and molecular findings to confirm the presence of a clonal blood disorder. The criteria require evidence of high red blood cell parameters, such as elevated hemoglobin or hematocrit levels.
The presence of the JAK2 V617F or a functionally similar JAK2 Exon 12 mutation serves as a major criterion. For the vast majority of patients, a blood test confirming this mutation, combined with elevated red cell counts, is powerful evidence of PV, acting as a molecular fingerprint that points directly to the abnormal, unregulated signaling defining the disease. This mutation provides clear proof that the red blood cell overproduction is primary—originating from a defect in the bone marrow stem cell—rather than secondary to an external stimulus like chronic low oxygen.
Polycythemia Vera Without the JAK2 Mutation
Yes, Polycythemia Vera can exist without the JAK2 V617F or Exon 12 mutations, but this is an extremely rare occurrence, accounting for less than 5% of all PV diagnoses. When the primary genetic drivers are absent, the diagnostic process becomes significantly more challenging, requiring a stricter reliance on non-molecular evidence.
In these rare circumstances, the diagnosis must be established by fulfilling all the other major and minor criteria, proving a clonal disorder despite the negative genetic test. Physicians must screen for alternative genetic drivers, although no single common mutation has been identified to replace JAK2. A negative JAK2 test usually prompts a deeper search for a secondary cause, as the existence of JAK2-negative PV suggests that other, yet-to-be-discovered somatic mutations may result in the same pathological overproduction of blood cells.
Required Clinical and Bone Marrow Evidence
When the JAK2 mutation is not found, the diagnosis of PV hinges on two specific types of non-genetic evidence: very low serum erythropoietin (EPO) levels and characteristic bone marrow findings. EPO is the hormone that normally stimulates red blood cell production. In true PV, the abnormal bone marrow cells grow independently of it. This autonomy causes the body to suppress EPO production, resulting in levels below the normal reference range.
A significantly low serum EPO level is considered a minor criterion and is a strong indicator of a primary process. However, this finding alone is not enough to confirm the diagnosis. The other necessary component is a bone marrow biopsy and aspiration, which allows for a direct visual and cellular examination of the blood-forming tissue.
The bone marrow evidence must show panmyelosis, indicating hypercellularity for the patient’s age. This involves an abnormal increase in the production of all three blood cell lines: red cells, white cells, and platelets. The morphology is particularly characterized by prominent erythroid and megakaryocytic proliferation. The megakaryocytes often appear large, with unusual shapes and hyperlobulated nuclei, which helps distinguish PV from other conditions.
Distinguishing PV from Other Causes of High Red Blood Cell Count
When a patient presents with an elevated red blood cell count and a negative JAK2 test, the differential diagnosis begins by excluding common conditions that mimic PV, most notably secondary erythrocytosis. Unlike PV, secondary erythrocytosis is a reactive condition where the body overproduces red cells in response to an external stimulus, such as chronic oxygen deprivation or smoking.
A distinguishing factor is the EPO level: it is suppressed in true PV but typically elevated or high-normal in secondary erythrocytosis as the body attempts to compensate for low oxygen. Secondary erythrocytosis does not typically show the characteristic clonal findings on a bone marrow biopsy.
Another category to rule out is Idiopathic Erythrocytosis (unexplained high red blood cell count). Rigorous screening is also performed to ensure the patient does not have another myeloproliferative neoplasm, such as Essential Thrombocythemia or Primary Myelofibrosis. While these conditions can be JAK2 positive, their typical presentation and distinct bone marrow morphology help separate them from the rare JAK2-negative Polycythemia Vera.