Polycythemia, or erythrocytosis, refers to an increase in the absolute red blood cell (RBC) mass in the body. In practice, this is reflected by an increase in hemoglobin levels, or hematocrit, over what is considered physiologic for that age and gender.
The standard RBC mass does not usually exceed 36 ml/kg in males and 32 ml/kg in females. The reference ranges for normal hemoglobin levels, and hematocrits, vary depending on altitude, from ethnicity to ethnicity, and country to country. However, as a frame of reference, the hemoglobin and hematocrit of a healthy adult male are 16% plus or minus 2 gm/dl and 47% plus or minus 6%, respectively. The hemoglobin and hematocrit of a menstruating adult female are usually 13% plus or minus 2 gm/dl and 40 plus or minus 6%, respectively.
Polycythemia vera is a sub-type of polycythemia. Often referred to colloquially as simply “ polycythemia,” it is an acquired, Philadelphia-chromosome negative,, myeloproliferative disorder. This condition is associated with overproduction of all 3 cell lines, but with a notable prominence of red blood cells.
The clinical significance of erythrocytosis, due to any cause, lies in the associated risk of thrombotic events due to hyperviscosity of blood. Additionally, the potential for progression to leukemia in cases of polycythemia vera also warrants attention.
This occurs due to volume contraction rather than an increase in true RBC mass.
Further stratified based on serum erythropoietin (EPO) levels as follows:
Low serum EPO levels (Primary polycythemia)
High serum EPO levels (Secondary polycythemia)
The prevalence of polycythaemia vera has been estimated to be approximately 22 cases per 100,000 population. It is believed to occur more frequently among Jews of Eastern European descent than other Europeans and Asians. Polycythemia vera shows a male preponderance in all races and ethnicities, with a male to female ratio of approximately 2:1. The median age of presentation of PV is 60 years, with patients seldom seen before the age of 40. Polycythemia due to hemoglobinopathies and congenital cyanotic heart diseases is likely to be detected in significantly younger patients.
The pathophysiology would vary, depending on the cause in consideration.
High EPO Levels
Cellular hypoxia can occur due to any cause triggers the release of erythropoietin from the renal peritubular lining capillary cells. A small amount of EPO is produced by the liver as well. EPO, in turn, acts on erythroid progenitor cells and stimulates erythropoiesis.
Low EPO Levels
The primary defect in nearly 95% of cases of polycythemia vera is an acquired mutation in exon 14 of the tyrosine kinase JAK2 (V617F). Mutations have also been described in exon 12 of JAK2. These mutations result in a loss of the auto-inhibitory pseudo-kinase domain of JAK2, resulting in its constitutive activation. This constitutive activation results in both hypersensitivity to EPO and EPO-independent erythroid colony formation.
Bone marrow examination is not routinely employed. Its utility largely remains restricted to cases where the clinical suspicion of polycythemia vera is high, despite the absence of a JAK2 (V617F) mutation, or if facilities to test for the mutation are unavailable. Classical findings, when coexistent with other suggestive hematologic parameters, help support a diagnosis of polycythemia vera.
Strongly suggestive findings include a hypercellular marrow with erythroid hyperplasia and subtle megakaryocytic atypia. Tri-lineage hyperproliferation is also an expected feature.
Common presenting symptoms, usually non-specific, include fatigue, headache, dizziness, transient blurring of vision, amaurosis fugax and other symptoms suggestive of transient ischemic attacks (TIAs).
Infrequently, patients may complain of pruritus after a warm water shower, particularly over the back.
A history of epistaxis, gastrointestinal (GI) bleed or easy bruising may be forthcoming.
Peptic ulcer disease commonly co-exists, and patients may present with non-specific abdominal pain. Left, hypochondrial pain and early satiety should arouse the suspicion of splenomegaly.
Rarely, patients may present with a history of unexplained thrombotic complications, such as Budd-Chiari syndrome or digital infarcts.
It is vital to try and elicit etiology-specific history such as a history of smoking, an extended stay at high altitudes, congenital cardiac disease, among others. A significant family history may be elicited in patients with hemoglobinopathies.
Abnormal facial ruddiness may be prominent.
Cyanosis and clubbing, along with the presence of a murmur on auscultation, provide strong evidence favoring a congenital cyanotic heart disease.
Nicotine staining of the nails and teeth provide presumptive evidence of smoking, even in a non-forthcoming patient.
The presence of morbid obesity could raise the possibility of Pickwickian syndrome; whereas, a barrel chest could suggest an obstructive lung disease.
Examination of the abdomen may lead to finding a palpable spleen or eliciting the bruit of renal arterial stenosis.
An evaluation must proceed sequentially. Due to the broad array of potential causes, it is vital to consider the appropriate investigation in that specific clinical context. However, the following may provide a frame of reference:
Based on the WHO 2017 criteria, hematocrit levels above 49% in males and 48% in females, at sea level, are to be considered suggestive of polycythemia vera. In cases of polycythemia vera, there could be a concurrent increase in platelet and leucocyte counts as well. The leucocyte count is usually between 10,000 to 20,000/microliter and may show eosinophilia and basophilia. Platelet counts may rarely exceed 100,000/microliter.
Radioisotope studies using Cr-labeled autologous RBC transfusions accurately determine the true RBC mass and conclusively exclude spurious polycythemia.
Serum EPO Levels
The presence of either high or low EPO levels directs the further plan of evaluation.
Low EPO levels indicate primary polycythemia. Subsequent evaluation should be targeted toward the detection of polycythemia vera.
JAK2 mutation studies are virtually diagnostic for polycythemia vera (95% cases). Mutations may occur either in exon 14 (more commonly) or in exon 12.
High EPO levels indicate secondary polycythemia. Subsequent evaluation should be aimed at determining the cause. This should include, but not be limited to, the following:
Serum Ferritin, Vitamin B12, and Folate Levels
Low serum ferritin and low folate levels have been associated more with primary polycythemia. Raised vitamin B12 levels, often striking, may be observed. This occurs due to increased transcobalamin III secretion by leucocytes.
Assessment of Renal Function
Renal function abnormalities indicate a higher likelihood of secondary polycythemia. Uric acid levels are often raised, due to increased cell proliferation and subsequent turnover.
Assessment of Hepatic Status
Liver cirrhosis and inflammatory liver disease have been associated with secondary polycythemia and increased RBC proliferation.
An ultrasound and Doppler study of the abdomen would help identify a secondary cause.
In cases of suspected secondary polycythemia, the utility of additional investigations such as a chest radiograph, lung function tests, sleep studies, and an echocardiograph are to be considered as appropriate.
The treatment of secondary polycythemia is directed at correcting the cause.
For polycythemia vera, available treatment modalities include:
Phlebotomy was established as the backbone of therapy, primarily based on the trial conducted by the Polycythemia Vera Study Group (PVSG). The study found that, compared to the use of chlorambucil or radioactive phosphorous, treatment with phlebotomy alone was associated with a longer median survival.
The rationale behind repeated phlebotomies was that cytoreduction would reduce hyper-viscosity. Additionally, it would induce a state of iron-deficiency that would help retard red-cell proliferation.
In practice, weekly sessions are conducted, during which approximately 500 mL of blood is removed, provided the hemodynamic status permits this.
This is continued weekly until a target hematocrit of under 45% is obtained. This target was determined based on the findings of the CYTO-PV trial conducted in Italy. Investigators observed significantly lower rates of cardiovascular deaths and major thrombotic episodes in patients kept under this threshold.
For secondary polycythemias, phlebotomy is usually reserved for the following conditions:
Hydroxyurea is usually considered a second-line therapy. Evidence of benefit came from, among others, a study by the Polycythemia Vera Study Group (PVSG) that showed lower rates of thrombosis compared to a historical cohort treated with phlebotomy alone. Despite theoretical concerns, studies have not found a significant association between the use of hydroxyurea and an increased risk of leukemic transformation. Indications for use include:
The standard daily doses range from 500 to 1500 mg per day.
Doses are adjusted to target platelet counts below 500,000/mcL. However, it is necessary to adjust doses such that the absolute neutrophil count remains above 2000/microliters.
The JAK2 inhibitor ruxolitinib is used when patients are intolerant or unresponsive to hydroxyurea.
Evidence supporting the use of Ruxolitinib in myeloproliferative disorders came from the COMFORT trials. The COMFORT-I study compared the efficacy of Ruxolitinib with placebo therapy, whereas COMFORT-II compared it with “best available therapy.” Both trials showed a significant reduction in splenomegaly, improvement in symptoms, and better survival.
However, despite this enhanced benefit, the use of ruxolitinib was associated with increased risks of anemia, often dose-limiting, and thrombocytopenia.
The standard recommended dose for polycythemia vera is 10 mg, twice a day.
Dose reduction is required if hemoglobin drops to below 12 gm/dl.
A fall in hemoglobin to below 8 gm/dl is an indication for dosing is to be temporarily interrupted.
The original PVSG trial showed that, despite greater longevity, patients treated with phlebotomy alone were at a greater risk of developing thrombosis during the first 3 years of therapy. This seemed to suggest a potential benefit to the use of antiplatelet or anticoagulant agents concurrently. Initial trials using higher doses of aspirin or dipyridamole showed unsatisfactory gastrointestinal hemorrhage. However, subsequent studies found that lower doses of aspirin could be safely used.
Currently, aspirin is indicated when there is inadequate control of microvascular symptoms after achieving the target hematocrit, or in the presence of other cardiovascular risk factors.
Aspirin, when indicated, is recommended to be used at low doses, ranging from 40 to 100 mg daily.
Agents such as allopurinol and febuxostat may be required in cases with significant hyperuricemia. Recent studies indicate that, between them, allopurinol may be a safer alternative with respect to all-cause and cardiovascular mortality.
Management of Pruritus
Depending on the severity of pruritus and the clinical response to therapy, therapeutic modalities available for symptomatic relief include antihistamines and selective serotonin reuptake inhibitors (SSRIs).
Management of Polycythemia Vera in Pregnancy
The standard therapeutic measures of phlebotomy and low dose aspirin are appropriate in most cases. Certain high-risk women may require the addition of pegylated interferon (IFN)-alpha.
Studies estimate the median survival in cases diagnosed with polycythemia vera to be approximately 14.1 years.
Factors that were found to correlate with better prognosis included:
Factors associated with worse outcomes included:
Secondary polycythemia is associated primarily with complications arising from hyperviscosity. Polycythemia vera is associated with progression to malignant conditions.
Commonly encountered complications include:
Progression to leukemia, particularly acute myeloid leukemia (AML) is seen in approximately 5% of cases and is often refractory to treatment. Studies have implicated the use of chlorambucil, pipobroman, or radioactive phosphorous as factors that increase the likelihood of progression.
A hematologist consultation should be sought in all cases of suspected primary polycythemia.
Patients must be encouraged to stop smoking. Genetic counseling must be offered to the families of those with hemoglobinopathies. Patients with polycythemia vera must be discouraged from donating blood. Because this is a myeloproliferative disorder, blood from donors with polycythemia vera is not considered appropriate for donation in most countries.
Polycythemia can affect every organ in the body, and the symptoms are primarily related to impaired oxygen delivery and hyperviscosity of blood. The condition is primarily managed by the hematologist, but the management of complications requires a multidisciplinary team. Patients need to be educated about the potential complications and when to seek medical assistance. While survival has been improved over the past three decades, the aim is to also improve the quality of life. Two threats to life include bleeding and infection complications. Most patients require red cells transfusions to help improve fatigue. Finally, patients should be told that they need lifelong follow up as there is a risk of progression to acute leukemia or a myelodysplastic syndrome. (Level V)
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