The Two Pathways
The coagulation cascade has two initiation arms that converge on a common pathway. Extrinsic pathway (tissue factor pathway): activated by tissue factor (TF/factor III) released from damaged cells. TF binds factor VII → forms TF-VIIa complex → activates factor X. This is the primary physiologic pathway for hemostasis. Measured by PT (prothrombin time). Intrinsic pathway (contact activation): activated by exposed subendothelial collagen. Factors XII → XI → IX → VIII → X. Historically named 'intrinsic' because all components are in blood. Measured by aPTT. Common pathway: Factor X + Va → prothrombinase complex → prothrombin (II) → thrombin (IIa) → fibrinogen → fibrin.
PT vs aPTT: Which Test Measures What
PT (Prothrombin Time): measures extrinsic + common pathways (factors VII, X, V, II, fibrinogen). Reported as INR = patient PT / mean normal PT. Prolonged by warfarin (inhibits vitamin K-dependent factors: II, VII, IX, X + protein C, S). Factor VII has shortest half-life → PT elevates first with warfarin. aPTT (activated Partial Thromboplastin Time): measures intrinsic + common pathways (factors XII, XI, IX, VIII, X, V, II, fibrinogen). Prolonged by heparin (enhances antithrombin → inhibits IIa and Xa) and by hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency). Both prolonged: common pathway defect (factor X, V, II, fibrinogen) — seen in liver disease, DIC, vitamin K deficiency (if severe).
Hemophilias and Bleeding Disorders
Hemophilia A: factor VIII deficiency, X-linked recessive, most common hemophilia. Prolonged aPTT, normal PT. Treat with factor VIII concentrate or desmopressin (DDAVP) for mild cases (releases vWF + factor VIII from endothelium). Hemophilia B (Christmas disease): factor IX deficiency, X-linked recessive. Same lab pattern as A — distinguish only by factor assay. Treat with factor IX concentrate. Von Willebrand Disease: most common inherited bleeding disorder. Affects platelet adhesion (vWF binds collagen + GPIb) AND prolongs aPTT (vWF carries/protects factor VIII). Type 1 (most common): quantitative deficiency, treat with DDAVP. Type 3: absent vWF, treat with factor concentrates. Bernard-Soulier: GPIb deficiency → platelet count low, giant platelets on smear. Glanzmann thrombasthenia: GPIIb/IIIa deficiency → platelets cannot aggregate.
Anticoagulant Mechanisms
Warfarin: inhibits vitamin K epoxide reductase → prevents carboxylation of factors II, VII, IX, X and proteins C and S. Slow onset (days); monitored by INR; reversed by vitamin K (slow, 12-24h) or 4-factor PCC/FFP (immediate). Heparin (UFH): binds antithrombin → potentiates inhibition of IIa (thrombin) and Xa. Monitored by aPTT. Reversed by protamine sulfate. Complication: HIT (heparin-induced thrombocytopenia) — antibodies against PF4-heparin complexes → paradoxic thrombosis; treat by stopping heparin, starting argatroban (direct thrombin inhibitor). LMWH (enoxaparin): mainly anti-Xa activity, less anti-IIa. Monitored by anti-Xa level. DOACs: rivaroxaban/apixaban (factor Xa inhibitors), dabigatran (direct thrombin inhibitor). Monitored by anti-Xa (Xa inhibitors) or thrombin time/ecarin clotting time (dabigatran). Reversed by andexanet alfa (Xa inhibitors), idarucizumab (dabigatran).
DIC: Disseminated Intravascular Coagulation
DIC = pathologic simultaneous activation of coagulation and fibrinolysis. Causes: sepsis (most common), obstetric catastrophe (placental abruption, amniotic fluid embolism), trauma, APML (M3 AML — promyelocytes release tissue factor). Mechanism: massive TF release → thrombin generation → fibrin microthrombi (ischemia) + consumption of coagulation factors and platelets → bleeding. Labs: elevated PT + aPTT, low platelets, low fibrinogen, elevated D-dimer/fibrin split products, schistocytes on smear (MAHA). Treatment: treat underlying cause; replace with FFP (factors), cryoprecipitate (fibrinogen + VIII), and platelets as needed.