clotting cascade

**Overview** - Primary hemostasis: vessel injury leads to vasoconstriction, then platelet adhesion (GPIb binds vWF), activation, and aggregation (GPIIb/IIIa binds fibrinogen). This forms a weak platelet plug. - Secondary hemostasis (the clotting cascade): coagulation factors stabilize the plug with cross-linked fibrin.

**Classic pathways** - Extrinsic pathway: Tissue factor (TF, factor III) released from damaged subendothelium binds factor VII, giving TF-VIIa, which activates X. It is measured by **PT/INR**. Factor VII has the shortest half-life, so PT/INR rises first with warfarin or early liver disease. - Intrinsic pathway: Contact activation of XII (on negatively charged surfaces) activates XI, then IX. IXa with VIIIa (the tenase complex) activates X. It is measured by **aPTT**. Heparin monitoring uses aPTT. - Common pathway: Xa with Va (the prothrombinase complex) converts prothrombin (II) to thrombin (IIa). Thrombin converts fibrinogen (I) to fibrin and activates XIII, which cross-links fibrin. Thrombin also activates V, VIII, XI, and platelets (positive feedback). - Modern cell-based model: In vivo, TF-VIIa initiates a small amount of thrombin. Thrombin then amplifies the process on the platelet surface through factors XI, VIII, and V. This is why hemophilia (VIII or IX deficiency) causes severe bleeding even though the extrinsic pathway is intact.

**Vitamin K-dependent factors** - Factors II, VII, IX, X, and proteins C and S require gamma-carboxylation (by gamma-glutamyl carboxylase, using vitamin K as a cofactor) to bind Ca²⁺ and phospholipid surfaces. - Warfarin inhibits vitamin K epoxide reductase (VKORC1). It is metabolized by CYP2C9. - Protein C and factor VII have the shortest half-lives. This explains warfarin-induced skin necrosis, a transient hypercoagulable state in the first days of therapy. Bridge with heparin.

**Natural anticoagulants (regulation)** - Antithrombin (ATIII) inhibits thrombin, Xa, IXa, XIa, and XIIa. Heparin potentiates it. Deficiency causes heparin resistance and thrombosis. - Protein C and S, with thrombomodulin, inactivate Va and VIIIa. Factor V Leiden is a mutation that makes factor V resistant to cleavage by activated protein C (APC resistance) and is the most common inherited thrombophilia. - TFPI inhibits the TF-VIIa-Xa complex. - Fibrinolysis: tPA converts plasminogen to plasmin, which cleaves fibrin and produces D-dimer. It is inhibited by α2-antiplasmin and PAI-1.

**Lab interpretation (high-yield)** - ↑PT, normal PTT: factor VII deficiency, early warfarin, early liver disease, or early vitamin K deficiency. - Normal PT, ↑PTT: hemophilia A (VIII), hemophilia B (IX), factor XI deficiency, or heparin. vWF disease can also raise PTT because vWF stabilizes VIII. - Both ↑: common pathway defect (X, V, II, fibrinogen), DIC, severe liver disease, heavy warfarin, or direct Xa or thrombin inhibitors. - Factor XII deficiency: ↑PTT in vitro but no bleeding (may even be prothrombotic). - Normal PT/PTT with bleeding: platelet disorder, factor XIII deficiency (delayed bleeding, poor wound healing, umbilical stump bleeding), or mild vWD. - Mixing study: correction of a prolonged PTT means factor deficiency. Failure to correct means an inhibitor (e.g., lupus anticoagulant, factor VIII inhibitor).

**Clinical correlations** - Hemophilia A/B: X-linked recessive. Presents with hemarthroses and deep-tissue bleeding, with normal bleeding time and ↑PTT. Treat with factor replacement or desmopressin (mild hemophilia A). - DIC: widespread activation with consumption of factors and platelets. Findings are ↑PT, ↑PTT, ↓fibrinogen, ↑D-dimer, and schistocytes. Triggers include sepsis, obstetric complications, malignancy (APL), and trauma. - Liver disease: decreased synthesis of all factors except VIII (made by endothelium). PT rises first. - Vitamin K deficiency: newborns (sterile gut, low stores; give vitamin K at birth), fat malabsorption, or antibiotics. - Antiphospholipid syndrome: ↑PTT in vitro that does not correct on mixing, yet causes thrombosis in vivo. - Anticoagulant targets: Heparin/LMWH (via antithrombin: Xa and IIa), fondaparinux (Xa), rivaroxaban/apixaban (direct Xa), dabigatran/argatroban/bivalirudin (direct thrombin), warfarin (II, VII, IX, X, C, S). Reversal agents are protamine (heparin), vitamin K, PCC or FFP (warfarin), idarucizumab (dabigatran), and andexanet alfa or PCC (Xa inhibitors).