Definition“Polycythemia is defined as an increase in thecirculating red blood cells above normal.”Erythrocytosis-?
When should I be worried?• When the haemoglobin level is at 18.5g/dL in men or 17g/dL in women it MAY be abnormal.• Hct levels >60% in men and >55% in women is almost INVARIABLY associated with an increased cell mass.
Pathophysiologic ClassificationRELATIVE Reduced plasma volume (hemoconcentration)ABSOLUTEPrimary (Erythropoietin normal or low) Polycythemia vera Inherited erythropoietin receptor mutationsSecondary (High erythropoietin) Compensatory Lung disease High-altitude living Cyanotic heart disease Paraneoplastic Erthropoietin secreting tumors Haemoglobin mutants with high O2 affinity Inherited defects that stabilize HIF-α Chuvash Polycythemia (homozygous VHL mutations) Prolyl hydroxylase mutations
• Historic features: – Smoking history, – living at a high altitude, – congenital heard disease, – peptic ulcer disease(?), – sleep apnea, – chronic lung disease, – renal disease.
POLYCYTHEMIA VERA• “A myeloproliferative disease arising from a clonal HSC and resulting in uncontrolled division of RBC’s.”• Granulocytes and platelets ↑sed
Clinical Features• Most symptoms are related to an increased red cell mass and elevated haematocrit• Hyperviscocity hence there is sluggish blood flow which mainly affects the _______ system?• Organomegaly.• Increased risk of bleeding and thrombotic disorders. – MI, DVT, Stroke, BCS, Bowel infarct – Epistaxis, Bleeding gums. Life threatening(5-10%)• Plethoric and cyanotic.• Intense pruritis and Peptic Ulceration(?)• Symptomatic gout(5-10%)?
• Bone Marrow: – Hypercellular. – ↑sed red cell progenitors(Mild), also granulocyte precursors and megakaryocytes. – Extensive marrow fibrosis(Later stages) Displacement of HC’s Extramedullary Haematopoiesis.• Peripheral Smear: – Hb: 14-28 g/dL; Increase in absolute red cell mas Cr labelling method – Hct: >60% – Iron deficiency?! – Microcytic erthrocytosis? – TLC: 12,000 – 50,000 cells/. ↑sed Basophils(?) – Platelets: >5,00,000/mm3 (Giant forms, qualitatively poor)
MOLECULAR PATHOGENESIS1. JAK 2: ?(97%)2. Important kinase for EPO and Thrombopoietin3. Obligate chaperone for the EPO and TPO receptor4. After binding autophosphorylation, receptor phosphorylation and phosphorylation of proteins involved in cell differentiation, proliferation and resistance to apoptosis.5. What if there was no JAK2?6. Constitutive activation?7. AML clones don’t have JAK2 mutations?
• Without treatment: Death within months of diagnosis from bleeding or thrombosis.• Treatment: – Periodic Phlebotomies – Anagralide(Hydroxyurea?) – INF-α
Gaisbock syndrome (Spurious polycythemia orstress polycythemia):1.Seen in middle aged persons, overweight,hypertensive chronic smokers2.Due to a combination of plasma volumedepletion and increased red cell production.3.Nicotine?4.Carbon Monoxide?