Polycythemia

Etiology

Classification

Spurious Polycythemia

This occurs due to volume contraction rather than an increase in true RBC mass.

Causes include

• Severe dehydration due to isolated fluid loss: potentially seen in diarrhea and severe vomiting
• Gaisbock syndrome: Usually seen amongst obese, hypertensive males. Smoking, excessive alcohol, and use of diuretics are contributory.[4]

True Polycythemia

Further stratified based on serum erythropoietin (EPO) levels as follows:

Low serum EPO levels (Primary polycythemia)

• Polycythemia vera
• Primary familial and congenital polycythemia

High serum EPO levels (Secondary polycythemia)

• High altitude
• Respiratory disorders: Chronic obstructive pulmonary disease (COPD), Pickwickian syndrome, uncontrolled asthma
• Cyanotic heart diseases with right-to-left shunts
• Renal disorders: Renal cysts, kidney cancer, renal artery stenosis, Bartter syndrome, focal sclerosing glomerulonephritis
• Elevated carboxyhemoglobin: Usually seen in smokers, people working on cars in closed spaces, or people working in boiler rooms
• Hemoglobinopathies: High-affinity hemoglobins such as Hb Yakima, methemoglobinemia
• EPO-secreting tumors: sources include hepatomas, uterine leiomyomas, and cerebellar hemangiomas
• Iatrogenic causes: Including erythropoietin analog administration, anabolic steroids, and testosterone replacement therapy

Neonatal Polycythemia

• The increase in hematocrit is a normal compensatory mechanism in infants due to the relative tissue-level hypoxia in the intrauterine environment. It is exacerbated by the high affinity of fetal hemoglobin for oxygen.

Epidemiology

The prevalence of polycythemia vera has been estimated to be approximately 22 cases per 100,000 population[5]. It is believed to occur more frequently among Jewish patients 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 to 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.

Pathophysiology

The pathophysiology would vary, depending on the cause in consideration.

High EPO Levels

Cellular hypoxia can occur due to any cause that 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.[6]

Histopathology

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.[7]

Strongly suggestive findings include a hypercellular marrow with erythroid hyperplasia and subtle megakaryocytic atypia.[8] Tri-lineage hyperproliferation is also an expected feature.

History and Physical

History

• Common presenting symptoms, usually non-specific, include fatigue, headache, dizziness, transient blurry 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) bleeding, or easy bruising may be forthcoming.
• Peptic ulcer disease commonly coexists, and patients may present with non-specific abdominal pain. Left hypochondrial pain and early satiety should raise 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, and congenital cardiac disease, among others. Significant family history may be noted in patients with hemoglobinopathies.

Physical Examination

• 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 provides presumptive evidence of smoking, even in a non-forthcoming patient.
• Morbid obesity could raise the possibility of Pickwickian syndrome, whereas a barrel chest could suggest obstructive lung disease.
• Examining the abdomen may lead to finding a palpable spleen or eliciting the bruit of renal arterial stenosis in a thin-built individual.

Evaluation

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:

Hemogram

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 leukocyte 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 1,000,000/microliter.

Radioisotope Studies

Radioisotope studies using chromium-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

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

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:

• Measurement of arterial oxygen saturation levels using a pulse-oximeter: low levels would likely indicate a pulmonary or cardiac cause.
• Normal saturation levels could require further evaluation, such as:
  • The use of a co-oximeter to rule out methemoglobinemia
  • Measurement of carboxyhemoglobin levels for smokers
  • Measurement of the P50 of Hb to detect high-affinity hemoglobinopathies
  • Relevant investigations to detect a possible EPO-secreting tumor

Serum Ferritin, Vitamin B12, and Folate Levels

Low serum ferritin and low folate levels have been associated more with primary polycythemia.[4] Raised vitamin B12 levels, often striking, may be observed. This occurs due to increased transcobalamin III secretion by leukocytes. 

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.[4]

Ultrasound

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.

Treatment / Management

The treatment of secondary polycythemia is directed at correcting the cause.

For polycythemia vera, available treatment modalities include:

Phlebotomy

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 chlorambucil or radioactive phosphorous treatment, treatment with phlebotomy alone was associated with longer median survival.[9](A1)

The rationale behind repeated phlebotomies was that cytoreduction would reduce hyperviscosity. 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.[10]

For secondary polycythemias, phlebotomy is usually reserved for the following conditions:[11]

• Chronic lung diseases
• Cyanotic heart diseases
• Post-renal transplant patients with hypertension and erythrocytosis, not responding to optimal doses of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)

Hydroxyurea

Hydroxyurea is usually considered 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.[12] Despite theoretical concerns, studies have not found a significant association between the use of hydroxyurea and an increased risk of leukemic transformation.[13] Indications for use include:(B2)

• Poor venous access
• High phlebotomy requirement
• When phlebotomy is not possible due to logistic reasons
• Severe thrombocytosis
• Intractable pruritus

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.

Ruxolitinib

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 the “best available therapy.” Both trials showed a significant reduction in splenomegaly, improvement in symptoms, and better survival.[14][13][14](A1)

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 indicates that dosing is to be temporarily interrupted.

Low-Dose Aspirin

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 three years of therapy. This seemed to suggest a potential benefit to concurrently using antiplatelet or anticoagulant agents. 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.[15](A1)

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.

Hypouricemic Agents

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.[16]

Management of Pruritus

Depending on the severity of pruritus and the clinical response to therapy, therapeutic modalities available for symptomatic relief include antihistamines[17] and selective serotonin reuptake inhibitors (SSRIs).[18](B3)

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.[19]

Management of Neonatal Polycythemia

Most patients do not need treatment. Exchange transfusion is occasionally required due to hyperviscosity.

Differential Diagnosis

• Primary myelofibrosis
• Chronic myeloid leukemia
• Essential thrombocythemia
• EPO receptor mutations

Prognosis

Studies estimate the median survival in cases diagnosed with polycythemia vera to be approximately 14.1 years.[13]

Factors that were found to correlate with better prognosis included:

• Thrombocytosis
• Pruritus: The reason for the correlation of pruritus with a better prognosis was unclear. This could be attributed to the following:
  • Lead-time bias: patients with significant pruritus were likely to seek medical attention earlier.
  • Lower risk of arterial thrombosis[20]

Factors associated with worse outcomes included:

• Higher leucocyte counts
• Venous thrombosis
• Leukoerythroblastic blood smear

Complications

Secondary polycythemia is associated primarily with complications arising from hyperviscosity. Polycythemia vera is associated with complications associated with an increased risk of thrombosis and progression to malignant conditions.

Commonly encountered complications include:

1. Bleeding: Recurrent epistaxis or GI bleeding is often seen, which may lead to iron deficiency anemia, potentially confounding clinical findings, including bone marrow appearance.
2. Thrombosis: Due to hyperviscosity, there is a preponderance of both arterial and venous thrombosis. Manifestations of arterial thrombosis include digital infarcts, and cerebral ischemic infarcts, particularly in watershed territories. Venous thrombosis, such as Budd-Chiari syndrome, is also seen.

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.