Polycythaemia

Definition/classification

↑Red cell mass. 3 types: primary (polycythaemia vera, clonal) · secondary (identifiable stimulus) · relative/spurious (plasma volume ↓, not true RBC excess).

Secondary polycythaemia

Appropriate (hypoxic drive): high altitude, cardiovascular disease, pulmonary disease w/ hypoventilation, heavy smoking. Inappropriate (↑EPO): renal cell carcinoma, hydronephrosis, HCC, cerebellar haemangioblastoma, uterine leiomyoma.

Key point: NO splenomegaly, NO leucocytosis/thrombocytosis in secondary — unlike PV.

Relative/spurious polycythaemia

Plasma loss (burns, dehydration from vomiting/water deprivation) — not true erythrocytosis.

Polycythaemia Vera (PV)

Clonal myeloproliferative disorder — ↑ALL myeloid elements (RBC+granulocytes+platelets = panmyelosis), no identifiable cause. MOST COMMON myeloproliferative disorder. ~1/3 have chromosomal abnormalities (20q, trisomy 8, 9p). Main mechanism: JAK2 mutation — removes autoinhibition, constitutive kinase activation, EPO-independent proliferation. Serum/urine EPO ↓ in PV (opposite of secondary).

Clinical features (late middle life, slight male predominance, chronic slow course; from hyperviscosity+hypervolaemia+hypermetabolism+↓cerebral perfusion):

• Headache, vertigo, tinnitus, visual disturbance, syncope, coma
• ↑Thrombosis risk (accelerated atherosclerosis)
• ↑Haemorrhage risk (↑blood volume + platelet dysfunction) — epistaxis, PUD
• Splenomegaly (absent in secondary polycythaemia)
• Pruritus (worse after hot bath)
• Hyperuricaemia → urate stones, gout

Labs: Hb>17.5(M)/15.5(F) g/dl · RBC>6(M)/5.5(F) million/µl · PCV>55%(M)/47%(F) · mild-mod leucocytosis (15-25k) + basophilia + ↑NAP score · thrombocytosis (dysfunctional platelets) · marrow: erythroid/panhyperplasia · cytogenetics 20q/tri8/9p in 30% · EPO REDUCED (key discriminator vs secondary).

Rx: Phlebotomy = mainstay (↓cell mass, induces mild iron deficiency) · anticoagulation if thrombosis · chemo for myelosuppression · uricosurics for hyperuricaemia · Interferon-α (↓JAK2 expression).

Prognosis: phlebotomy alone → survival 10-12yr. ~25% → myelofibrosis. Small % → AML/NHL/myeloma. Vascular thrombosis = major cause of death.

Clinical relevance

Splenomegaly+leucocytosis+thrombocytosis WITH erythrocytosis = PV bedside pattern vs secondary (RBC rise alone). EPO level = the test that resolves ambiguity: ↓ in PV (EPO-independent JAK2 drive), normal/↑ in secondary (EPO-driven by definition). Death mainly from thrombosis (not leukaemic/myelofibrotic transformation, though both occur) → explains why simple phlebotomy, not aggressive cytoreduction, is first-line.

Definition and Classification

Polycythaemia (erythrocytosis) is an increase in red cell mass above normal. It is classified as primary (polycythaemia vera) — a clonal myeloproliferative disorder — or secondary, driven by an identifiable external stimulus to erythropoiesis, or relative/spurious, from plasma volume contraction rather than true red cell excess.

Secondary Polycythaemia

Occurs from an appropriate or inappropriate rise in erythropoietin drive:

• Appropriate (physiological hypoxic drive): high altitude, cardiovascular disease, pulmonary disease with alveolar hypoventilation, heavy smoking.
• Inappropriate erythropoietin excess: renal cell carcinoma, hydronephrosis, hepatocellular carcinoma, cerebellar haemangioblastoma, massive uterine leiomyoma.

A key discriminating feature: none of the secondary causes produces splenomegaly or the accompanying leucocytosis/thrombocytosis that are typical of polycythaemia vera — because secondary polycythaemia reflects an isolated erythroid response to a signal, not a clonal proliferation of the whole myeloid lineage.

Relative (Spurious) Polycythaemia

From plasma loss rather than true erythrocytosis — seen in burns, or dehydration from vomiting or water deprivation.

Polycythaemia Vera (PV)

Definition and Pathophysiology

PV is a clonal myeloproliferative disorder characterised by increased production of all myeloid elements — red cells, granulocytes, and platelets (panmyelosis) — in the absence of any identifiable secondary cause. It is the most common of the myeloproliferative disorders. Exact aetiology is unknown, though about a third of cases show chromosomal abnormalities (20q, trisomy 8, 9p). The major pathogenetic mechanism is a JAK2 tyrosine kinase mutation, which removes normal autoinhibitory control and constitutively activates the kinase — driving unregulated proliferation independent of erythropoietin. Consequently, serum and urinary erythropoietin levels are reduced in PV, the opposite of secondary polycythaemia.

Clinical Features

A disease of late middle life, slightly more common in males, running a chronic, slowly progressive course. Manifestations reflect hyperviscosity, hypervolaemia, hypermetabolism, and reduced cerebral perfusion:

• Headache, vertigo, tinnitus, visual disturbance, syncope, occasionally coma.
• Increased thrombosis risk — from accelerated atherosclerosis and hyperviscosity.
• Increased haemorrhage risk — from expanded blood volume combined with intrinsic platelet dysfunction (epistaxis, peptic ulcer bleeding).
• Splenomegaly — producing abdominal fullness; a feature specifically absent in secondary polycythaemia.
• Pruritus, classically worse after a hot bath.
• Hyperuricaemia — increased risk of urate stones and gout.

Laboratory Findings

• Raised haemoglobin (>17.5 g/dL males, >15.5 g/dL females).
• Erythrocytosis (>6 million/µL males, >5.5 million/µL females).
• Raised haematocrit/PCV (>55% males, >47% females).
• Mild-moderate leucocytosis (15,000–25,000/µL) with basophilia and raised neutrophil alkaline phosphatase.
• Thrombocytosis with defective platelet function.
• Bone marrow: erythroid hyperplasia or full panhyperplasia.
• Cytogenetic abnormalities (20q, trisomy 8, 9p) in about 30%.
• Erythropoietin reduced — the key discriminator from secondary polycythaemia, where erythropoietin is normal or elevated.

Treatment and Prognosis

• Phlebotomy (venesection) at regular intervals — the mainstay, reducing total red cell mass and inducing a mild, deliberate state of iron deficiency to limit further erythropoiesis.
• Anticoagulation if thrombosis has occurred.
• Chemotherapy for myelosuppression when indicated.
• Uricosuric drugs for hyperuricaemia.
• Interferon-α — effective because it reduces JAK2 expression, targeting the underlying molecular abnormality.

With phlebotomy alone, survival of 10–12 years is typical. About 25% of patients progress to myelofibrosis; a smaller proportion develop secondary haematologic malignancy (AML, non-Hodgkin lymphoma, multiple myeloma). Vascular thrombosis is the major complication and leading cause of death.

Clinical Relevance

• Splenomegaly with leucocytosis and thrombocytosis alongside erythrocytosis is the clinical pattern that distinguishes PV from every secondary cause of polycythaemia at the bedside, before any laboratory testing is done — secondary causes raise red cells alone.
• The reciprocal erythropoietin pattern (low in PV, normal/high in secondary polycythaemia) is the single laboratory test that resolves genuine diagnostic ambiguity between the two, and follows directly from the underlying mechanism: PV proliferates independently of erythropoietin signalling (via JAK2), while secondary polycythaemia is erythropoietin-driven by definition.
• Recognising that PV’s major cause of death is vascular thrombosis (not the malignant transformation to myelofibrosis or leukaemia, though both occur) is what makes phlebotomy — a mechanically simple intervention — the appropriate first-line therapy rather than aggressive cytoreduction from the outset.

No Rendered Diagram for This Topic

Polycythaemia is fundamentally a classification-and-discrimination topic — separating primary (PV) from secondary from spurious causes by clinical pattern and laboratory values (chiefly erythropoietin level, splenomegaly, and leucocyte/platelet counts) — rather than a multi-step pathogenic mechanism. The JAK2 mutation’s effect (loss of autoinhibition → constitutive kinase activation) is a single molecular event, not a cascade that benefits from a rendered flowchart beyond the sentence already given under Pathogenesis.

Hand-draw suggestion (optional, not a rendered requirement): a simple three-column comparison — PV vs secondary vs spurious polycythaemia, rows for splenomegaly / leucocyte-platelet counts / erythropoietin level — is the most efficient hand-drawn revision aid, since discriminating these three is the actual tested skill in this topic.