fibrin clot

**Formation (secondary hemostasis):** - Tissue injury exposes tissue factor (TF), which activates factor VII (extrinsic pathway). The intrinsic pathway (XII, XI, IX, VIII) amplifies the response. Both converge on the common pathway: factor Xa (with Va, Ca2+, and phospholipid, forming prothrombinase) converts prothrombin (II) to thrombin (IIa). - Thrombin cleaves fibrinopeptides A and B from fibrinogen (factor I), producing soluble fibrin monomers. The monomers spontaneously polymerize into a loose, non-covalent fibrin mesh. - Thrombin also activates factor XIII to XIIIa (a transglutaminase, Ca2+-dependent). XIIIa forms covalent cross-links between fibrin strands, making the clot stable and insoluble. - Thrombin also amplifies its own production by activating factors V, VIII, and XI, and it activates platelets (via PAR receptors). - Vitamin K-dependent factors are II, VII, IX, and X, plus proteins C and S. They require gamma-carboxylation, which warfarin inhibits.

**Primary versus secondary hemostasis:** - Primary hemostasis: the platelet plug forms through vWF, GpIb adhesion, and GpIIb/IIIa aggregation via fibrinogen. This is a weak, temporary plug. - Secondary hemostasis: the coagulation cascade produces the fibrin mesh, which stabilizes the platelet plug into a definitive clot.

**Regulation and breakdown (fibrinolysis):** - Endothelial cells release tPA, which converts plasminogen to plasmin. Plasmin cleaves fibrin and fibrinogen. - Fibrin degradation products include D-dimer (cross-linked fibrin fragments). D-dimer is elevated in DVT/PE, DIC, and recent surgery or trauma. It has high negative predictive value for excluding VTE in low-risk patients. - Inhibitors include alpha-2 antiplasmin and PAI-1 (which inhibits tPA). - Natural anticoagulants: antithrombin (activated by heparin) inhibits thrombin and Xa. Proteins C and S inactivate Va and VIIIa. Factor V Leiden resists inactivation by protein C.

**Clinical significance:** - Lab tests: PT (extrinsic and common pathways; monitors warfarin as INR). aPTT (intrinsic and common pathways; monitors unfractionated heparin). Thrombin time and fibrinogen level assess the final step. - Hereditary deficiencies: hemophilia A (factor VIII), hemophilia B (factor IX), and hemophilia C (factor XI) all prolong the aPTT. Hemarthrosis is characteristic of hemophilia A and B. Factor XIII deficiency gives normal PT and aPTT but delayed bleeding, poor wound healing, and umbilical stump bleeding. It is diagnosed by a clot solubility test in urea. - Afibrinogenemia/hypofibrinogenemia: bleeding with prolonged PT, aPTT, and thrombin time. - DIC: widespread activation of coagulation causes microthrombi and consumption of platelets and clotting factors. Findings are low fibrinogen, high D-dimer, schistocytes, and prolonged PT/aPTT. Causes include sepsis, obstetric complications, malignancy (e.g., APL), and trauma. - Thrombosis: Virchow triad (stasis, endothelial injury, hypercoagulability). Venous thrombi are fibrin- and RBC-rich ("red clots"). Arterial thrombi are platelet-rich ("white clots"). - Pharmacology: heparin and LMWH (activate antithrombin), direct thrombin inhibitors (argatroban, bivalirudin, dabigatran), factor Xa inhibitors (rivaroxaban, apixaban), and warfarin all reduce fibrin formation. Thrombolytics (alteplase, tenecteplase, reteplase) activate plasminogen to lyse fibrin. Aminocaproic acid and tranexamic acid inhibit plasmin activation and are used for fibrinolytic bleeding. - Pathology: a postmortem clot (currant jelly/chicken fat) differs from an antemortem thrombus, which shows lines of Zahn (alternating layers of platelets/fibrin and RBCs) and is firmly attached to the vessel wall.

**High-yield pearls:** - Thrombin is the central enzyme: it cleaves fibrinogen, activates XIII, and activates V, VIII, XI, and platelets. - Factor XIIIa cross-linking is not measured by PT or aPTT. - D-dimer indicates both fibrin formation and fibrinolysis. Fibrinogen split products without D-dimer suggest primary fibrinogenolysis.