Polycythemia vera overview
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Primary polycythemia occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. Polycythemia vera is classified as a myeloproliferative neoplasm. Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue. The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. Common risk factors in the development of polycythemia vera are history of thrombosis and old age ( 65 year old and older). If left untreated, patients with polycythemia vera may progress to develop headache, fatigue, and dyspnea. Common complications of polycythemia vera include bleeding, thrombosis, tinnitus , and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years. People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, andthrombocytosis. The mainstay of therapy for polycythemia vera is phlebotomy, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil, and low-dose aspirin.
The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that hydroxyurea and interferon-alpha were effective in treating polycythemia vera. In 2005, a mutation in the JAK2 kinase (V617F) was found in multiple patients with myeloproliferative neoplasms (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.
Polycythemia vera is a subtype of myeloproliferative neoplasm. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic hypoxia). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.
Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis.
Polycythemia vera is caused by a mutation in the JAK2 gene (V617F mutation). This mutation occurs in more than 98% of cases of polycythemia vera. The JAK2 exon 12 mutation occurs in a small proportion of patients. There are no other causes of this disease.
Differentiating Polycythemia Vera from other Diseases
Polycythemia vera must be differentiated from other myeloproliferative neoplasms, such as chronic myelogenous leukemia, essential thrombocythemia, and primary myelofibrosis. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic hypoxia. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.
Epidemiology and Demographics
The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. The prevalence of polycythemia vera is 48 to 57 cases per 100,000 individuals in the United States. Males are more commonly affected than females. The life expectancy is variable but is typically more than 10 years for patients who have uncomplicated polycythemia vera and is significantly shorter in the case of post-PV myelofibrosis or post-PV acute myeloid leukemia.
Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and thrombotic history. The risk assessment for development of post-PV myelofibrosis or post-PV acute myeloid leukemia include a variety of factors.
Screening for polycythemia vera is not a routine clinical practice. However, assessment of a complete blood count (CBC), which is done routinely, usually gives the first indication for the presence of polycythemia vera in a patient.
Natural History, Complications and Prognosis
The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.
The diagnosis of polycythemia vera is based on the World Health Organization criteria, which was initially proposed in 2008 then revised in 2016. In general, the diagnosis of polycythemia vera requires a combination of elevated hemoglobin, which include high levels of hemoglobin, presence of JAK2 V617F mutation, hypercellularity on bone marrow biopsy, low serum erythropoietin level, and endogenous erythroid colony formation in vitro. The 2016 WHO criteria more accurately reflect the disease biology of polycythemia vera.
History and Symptoms
People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. The symptomatology is highly variable between patients. Some patients can present with a minimal symptom burden that does not result in any change in quality of life, and other patients can have severe symptom burden.
Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, and thrombocytosis. The most sensitive test for polycythemia vera is JAK2 V617F mutation testing in the peripheral blood. A specific finding in patients with polycythemia vera is low erythropoietin level.
Abdominal and chest CT scan may be helpful in the diagnosis of polycythemia vera. Findings on CT scan suggestive of polycythemia vera include enlarged lymph nodes, splenomegaly, and splanchnic venous thrombosis.
Brain MRI may be helpful in the detection of ischemic stroke in patients with polycythemia vera. Abdominal MRI can help with diagnosis of mesenteric thrombosis.
Abdominal ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of myeloproliferative neoplasm include splenomegaly, abdominal fluid, and hepatic lesions. Ultrasound of the extremities can assist with diagnosis of deep vein thrombosis, which is commonly associated with high-risk polycythemia vera.
Other Imaging Studies
Other imaging studies for polycythemia vera include PET scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.
Other Diagnostic Studies
The mainstay of therapy for polycythemia vera is phlebotomy, aspirin, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil. Some of these medications are targeted agents that work specifically in polycythemia vera, while others are non-specific therapies that can have numerous off-target adverse effects. Some of these treatments can modify the course of the disease, while others simply alleviate symptom burden.
Surgical intervention is a consideration in the management of polycythemia vera in case of splenomegaly, though surgery is not typically done.
There is no established method for primary prevention of polycythemia vera.
Secondary prevention strategy following polycythemia vera include low dose aspirin.