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The polycythaemias 

The polycythaemias

The polycythaemias

Stefan O. Ciurea

and Ronald Hoffman

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date: 30 March 2017

Polycythaemia or erythrocytosis is characterized by an abnormal increase in the numbers of red blood cells, leading to an elevation in the haemoglobin concentration and haematocrit (>52% in men and >48% in women). The cause may be either (1) primary—due to an intrinsic defect of haemopoietic stem cells; or (2) secondary—due to extrinsic stimulation of progenitor erythroid cells by circulating growth factors; and the condition needs to be distinguished from (3) pseudopolycythaemia—in which haematocrit is raised because the plasma volume is decreased.

Normal erythropoiesis

The primary controlling factor for erythropoiesis is the glycoprotein hormone erythropoietin. This is produced by the kidney in response to hypoxia, which leads to the accumulation of a transcriptional factor, hypoxia-inducible factor-1 (HIF-1), the principal regulator of numerous genes that participate in the hypoxic response. Mutation in genes encoding for proteins involved in the oxygen sensing mechanism, in the erythropoietin receptor, or in pathways downstream of the receptor, can all (rarely) lead to polycythaemia.

Secondary polycythaemias

Associated with appropriate erythropoietin secretion—conditions that are ultimately the result of tissue hypoxia and subsequent excessive erythropoietin production include (1) living at high altitude, (2) chronic lung disease, (3) cyanotic congenital heart disease with right-to-left shunting, (4) carbon monoxide intoxication—as occurs in heavy smokers, (5) haemoglobin variants with increased oxygen affinity, (6) mutations in genes involved in the oxygen sensing pathway—e.g. von Hippel–Lindau gene (Chuvash polycythaemia), prolyl hydroxylases.

Associated with inappropriate erythropoietin secretion—in the absence of tissue hypoxia, inappropriate erythropoietin production commonly originates from the kidney and many renal disorders are associated with erythrocytosis, e.g. renal artery stenosis, polycystic kidney disease, tumours. Tumour-associated polycythaemia may also result from cerebellar haemangioblastoma, hepatocellular carcinoma, phaeochromocytoma, and other adrenal tumours.

Primary polycythaemia—polycythaemia vera

This is a clonal, chronic progressive haematological malignancy characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic elements in the bone marrow.

Aetiology—up to 95% of cases are caused by somatic mutation in the pluripotential haemopoietic stem cells leading to replacement of a key valine residue by phenylalanine at position 617 of the JAK2 kinase (V617F), which releases it from autoinhibition.

Clinical features—may be detected on a ‘routine’ full blood count in asymptomatic patients, or present with a wide range of nonspecific symptoms (notably including pruritus). Signs include those directly related to polycythaemia (e.g. ruddy complexion), also splenomegaly and hepatomegaly. Complications of particular note include (1) thrombotic tendency—deep venous thrombosis/pulmonary embolism, hepatic or portal venous thrombosis, venous thrombosis in unusual sites, transient ischaemic attack/stroke; (2) other neurological syndromes—a wide variety are described; (3) haemorrhagic tendency—due to abnormalities of platelet function; (4) gout—associated with hyperuricaemia. Myelofibrosis with marrow failure develops in about half with polycythaemia vera for 20 years.

Diagnosis—major criteria are (1) evidence of elevated red blood cell mass, and (2) presence of JAK2(V617F) or similar mutation. Minor criteria are (1) trilineage myeloproliferation in the bone marrow, (2) a low serum erythropoietin level, and (3) abnormal marrow proliferative capacity as manifested by the formation of erythroid colonies in the absence of exogenous erythropoietin. Diagnosis requires the presence of both major criteria and one minor criterion, or the first major criterion and two minor criteria.

Treatment—patients should be strongly advised to stop smoking. Phlebotomy should be initiated as soon as the diagnosis is established to reduce and maintain the haematocrit to at less than 45% in men and less than 42% in women. Low-dose aspirin should be given. Myelosuppressive therapy with hydroxycarbamide (hydroxyurea) or other agents should be considered in older patients intolerant of phlebotomies and in those with repeated thrombotic episodes and/or high platelet counts. Haematopoietic stem-cell transplantation is a potentially curative option for myelofibrosis. The use of tyrosine kinase inhibitors to control the downstream effects of the mutant JAK-2 protein hold much promise for future management.

Prognosis—survival is about 18 months in untreated patients, whereas with appropriate management survival of over 10 years is now common. Patients previously treated with alkylating agents and/or radioactive phosphorous have an increased long-term risk of leukaemia.

Rare causes of primary polycythaemia

These include primary familial and congenital polycythaemia—caused by germ-line mutations in the erythropoietin receptor gene and genes encoding components of the JAK2-STAT pathway; may be suggested by family history (autosomal dominant).

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