HAEMATOLOGY AND BLOOD TRANSFUSION — NOTE 1 MBML 3223 Semester 3 Mount Kenya University Topic: Haemostasis, Coagulation and Bleeding Disorders --- SECTION 1: HAE
HAEMATOLOGY AND BLOOD TRANSFUSION — NOTE 1 MBML 3223 Semester 3 Mount Kenya University Topic: Haemostasis, Coagulation and Bleeding Disorders --- SECTION 1: HAEMOSTASIS Definition Haemostasis is the physiological process by which bleeding is arrested following damage to a blood vessel wall. It involves a coordinated interaction between the blood vessel wall, platelets, and the coagulation system. Too little activity causes haemorrhage; too much causes pathological thrombosis. The Four Physiologic Events of Haemostasis These occur in sequence following vessel injury: - Step 1 — Vascular Spasm: Immediate reflex vasoconstriction mediated by local myogenic responses, neural reflexes, and chemical mediators including endothelin and thromboxane A2. This is always the first response to vessel injury. - Step 2 — Primary Haemostasis (Platelet Plug Formation): Platelets adhere to exposed subendothelial collagen via von Willebrand factor, then activate and aggregate to form a loose primary plug. - Step 3 — Secondary Haemostasis (Coagulation Cascade): Coagulation factors are sequentially activated, generating thrombin, which converts fibrinogen to fibrin. Factor XIII cross-links fibrin strands to form a stable, firm clot. - Step 4 — Fibrinolysis: Tissue plasminogen activator (tPA) converts plasminogen to plasmin, which degrades the fibrin clot after vessel repair. D-dimer and fibrin degradation products (FDPs) are released. Fibrinolysis is an integral part of haemostasis — it is not a separate process. Essential Cofactors Cofactor Role --- --- Calcium (Ca²⁺) Required at multiple steps in the coagulation cascade Vitamin K Required for hepatic synthesis of Factors II, VII, IX, X and Proteins C and S Phospholipid Provided by activated platelets; forms the surface for coagulation complex assembly --- SECTION 2: PLATELETS AND PRIMARY HAEMOSTASIS Structure and Origin Platelets are small, anucleate cell fragments derived from megakaryocytes in the bone marrow. The primary growth factor driving platelet production is thrombopoietin . Normal platelet count is 150,000 – 450,000 per µL. Sequence of Platelet Plug Formation - Vascular injury exposes subendothelial collagen - Von Willebrand factor (vWF) binds to the exposed collagen - Platelets bind vWF via glycoprotein Ib (GPIb) — this is platelet adhesion - Adhered platelets activate and change shape from disc to spiny sphere - Activated platelets release granule contents: ADP, serotonin, thromboxane A2, and platelet factor 4 - ADP recruits additional platelets; thromboxane A2 causes vasoconstriction and further aggregation - GPIIb/IIIa receptors activate and bind fibrinogen, cross-linking platelets together — this is platelet aggregation - A loose primary platelet plug forms, later reinforced by fibrin from the coagulation cascade Platelets do NOT release urea, calcium ions, or antibodies. Their primary role is plug formation, not oxygen transport. Von Willebrand Factor (vWF) vWF is a large glycoprotein synthesised in endothelial cells and megakaryocytes. It has two critical functions: - Bridges platelets to exposed subendothelial collagen at sites of vascular injury - Carries and protects Factor VIII in circulation from premature degradation Deficiency or dysfunction of vWF causes Von Willebrand Disease — the most common inherited bleeding disorder. --- SECTION 3: THE COAGULATION CASCADE Overview The coagulation cascade is a series of enzymatic reactions in which inactive zymogens are sequentially activated. The end result is generation of thrombin, which converts fibrinogen to fibrin, forming a stable clot. The cascade has three interconnected pathways: intrinsic, extrinsic, and common. Coagulation Factors Factor Name Pathway Key Clinical Point --- --- --- --- I Fibrinogen Common Converted to fibrin — end product of coagulation II Prothrombin Common Converted to thrombin by Factor Xa III Tissue Factor (Thromboplastin) Extrinsic Initiates extrinsic pathway IV Calcium (Ca²⁺) All Essential mineral cofactor throughout cascade V Labile Factor Common Cofactor for Factor Xa in prothrombinase complex VII Proconvertin Extrinsic Shortest half-life; first affected by warfarin VIII Antihemophilic Factor A Intrinsic Deficient in Haemophilia A IX Christmas Factor Intrinsic Deficient in Haemophilia B X Stuart-Prower Factor Common Convergence point of intrinsic and extrinsic pathways XI Plasma Thromboplastin Antecedent Intrinsic — XII Hageman Factor Intrinsic Initiates intrinsic (contact activation) pathway XIII Fibrin-Stabilising Factor Common Cross-links fibrin; stabilises the clot vWF Von Willebrand Factor — Platelet adhesion; Factor VIII carrier Key name associations to memorise: - Fibrinogen = Factor I - Christmas factor = Factor IX — deficient in Haemophilia B - Stuart-Prower factor = Factor X - Hageman factor = Factor XII — initiates intrinsic pathway - Factor VIII deficiency = Haemophilia A The Three Pathways Intrinsic Pathway (Contact Activation) - Initiated when Factor XII (Hageman factor) contacts a damaged surface - Sequence: Factor XII → XI → IX → joins with Factor VIII - Factor IXa and Factor VIIIa form a complex on the platelet phospholipid surface with calcium - This complex activates Factor X, entering the common pathway Extrinsic Pathway (Tissue Damage) - Initiated when tissue factor (Factor III) is released from damaged tissue - Tissue factor combines with Factor VII to form the Factor VIIa-tissue factor complex - This complex activates Factor X directly, entering the common pathway - Factor VII belongs exclusively to the extrinsic pathway Common Pathway - Begins at Factor X activation - Factor Xa combines with Factor Va, calcium, and phospholipid to form the prothrombinase complex - Prothrombinase complex converts prothrombin (Factor II) to thrombin (Factor IIa) - Thrombin converts fibrinogen (Factor I) to fibrin monomers - Factor XIII cross-links fibrin monomers into a stable, insoluble fibrin clot Pathway Summary Table Pathway Key Factors Laboratory Test --- --- --- Intrinsic XII, XI, IX, VIII aPTT Extrinsic III (Tissue Factor), VII PT (Prothrombin Time) Common X, V, II, I, XIII Both PT and aPTT --- SECTION 4: NATURAL ANTICOAGULANTS The body prevents excessive clotting through a system of natural anticoagulants that act as checkpoints in the cascade. Anticoagulant Mechanism Clinical Note --- --- --- Antithrombin III Inhibits thrombin and Factor Xa Activity enhanced by heparin; deficiency causes thrombosis Protein C Inactivates Factors Va and VIIIa Requires Protein S as cofactor; activated by thrombin-thrombomodulin complex Protein S Cofactor for Protein C Deficiency causes thrombotic tendency Tissue Factor Pathway Inhibitor (TFPI) Inhibits Factor VIIa-tissue factor complex Limits extrinsic pathway activation Prostacyclin (PGI₂) Inhibits platelet aggregation Released by intact, healthy endothelium - Antithrombin III deficiency predisposes to thrombotic disorders, not bleeding - Protein S is a cofactor for Protein C — not for antithrombin and not for Factor VIII - When thrombin binds thrombomodulin on endothelial cells, it activates Protein C — this is a negative feedback mechanism --- SECTION 5: COAGULATION TESTS Laboratory Tests Test Pathway Assessed Collection Tube Normal Range Clinical Use --- --- --- --- --- PT (Prothrombin Time) Extrinsic + Common Light blue 10–14 seconds Monitor warfarin; assess liver function aPTT Intrinsic + Common Light blue 25–35 seconds Monitor heparin; diagnose Haemophilia Bleeding Time Platelet function + vessel wall — 2–9 minutes Platelet dysfunction, vWD D-dimer Fibrinolysis marker — Below 0.5 mg/L Most sensitive test for DIC Thrombin Time Fibrinogen to fibrin conversion — 10–14 seconds Fibrinogen defects, heparin effect Platelet Count — Purple (EDTA) 150,000–450,000/µL Thrombocytopenia Fibrinogen Level — Light blue 2–4 g/L DIC, liver disease - All coagulation studies are collected in light blue tubes containing sodium citrate anticoagulant - PT and aPTT are both reported in seconds