common pathway

**Note:** "Common pathway" most often refers to the coagulation cascade (covered here).

**Steps** 1. **Factor X activation:** Intrinsic tenase (VIIIa + IXa + Ca²⁺ + phospholipid) or extrinsic tenase (tissue factor + VIIa) converts X to Xa. 2. **Prothrombinase complex:** Xa + Va + Ca²⁺ on platelet phospholipid converts prothrombin (II) to thrombin (IIa). 3. **Thrombin (IIa):** Cleaves fibrinogen (I) to fibrin monomers, which polymerize into a loose clot. It activates XIII, which cross-links fibrin into a stable clot. It also provides positive feedback by activating V, VIII, XI, and platelets (via PAR receptors). With thrombomodulin, it activates protein C, which is anticoagulant.

**Lab correlates** - Common pathway factors: X, V, II, I (fibrinogen). XIII is the stabilizing step after the pathway. - Deficiency or inhibition of X, V, II, or fibrinogen gives prolonged PT and prolonged aPTT. - Factor XIII deficiency gives normal PT and aPTT, with delayed bleeding, umbilical stump bleeding, and poor wound healing. The clot solubility test (urea) is abnormal. - Factor VII deficiency prolongs only PT (extrinsic). Factor VIII, IX, XI, and XII deficiencies prolong only aPTT (intrinsic). - Thrombin time tests the final step (fibrinogen to fibrin). It is prolonged by heparin, hypofibrinogenemia, dysfibrinogenemia, and direct thrombin inhibitors.

**Clinical associations** - **Vitamin K-dependent factors:** II, VII, IX, X, protein C, and protein S. These need γ-carboxylation by γ-glutamyl carboxylase, which requires reduced vitamin K (regenerated by vitamin K epoxide reductase, VKORC1). Warfarin inhibits this. It causes early hypercoagulability because protein C and S have short half-lives, and it is monitored by PT/INR. Vitamin K deficiency (newborns, malabsorption, antibiotics) gives a similar picture. - **Liver disease, DIC, and massive transfusion:** Multiple factors are deficient, so PT and aPTT are both prolonged. In DIC, fibrinogen is low and D-dimer is high. - **Acquired factor X deficiency:** Seen in AL amyloidosis, where amyloid fibrils adsorb factor X. - **Rare inherited deficiencies:** Factor V (parahemophilia), factor X, prothrombin (II), and afibrinogenemia. These are autosomal recessive. - **Factor V Leiden:** Mutated factor V resists inactivation by activated protein C. This is the most common inherited thrombophilia and causes venous thrombosis (DVT, cerebral venous sinus thrombosis). Factor V levels are normal. - **Prothrombin G20210A mutation:** Increases prothrombin levels and thrombosis risk. - **Russell viper venom** directly activates factor X (used in the dilute Russell viper venom time to test for lupus anticoagulant).

**Pharmacology: drugs acting on the common pathway** - **Unfractionated heparin:** Binds antithrombin, which inactivates Xa and IIa (and also IXa, XIa, XIIa). Monitor with aPTT. Reverse with protamine. - **LMWH (enoxaparin):** Mainly anti-Xa. Less monitoring is needed, and it has a lower risk of HIT. - **Fondaparinux:** Indirect Xa inhibitor via antithrombin. - **Direct Xa inhibitors:** Rivaroxaban, apixaban, edoxaban. Reverse with andexanet alfa or 4-factor PCC. - **Direct thrombin inhibitors:** Dabigatran (reverse with idarucizumab), argatroban (used in HIT), bivalirudin.

**High-yield pearls** - Prolonged PT and aPTT with normal thrombin time suggests a factor deficiency in the common pathway (X, V, or II). - Prolonged PT and aPTT with prolonged thrombin time suggests a fibrinogen problem or heparin. - A mixing study that corrects the prolongation indicates a factor deficiency. Failure to correct indicates an inhibitor (for example, lupus anticoagulant or acquired factor inhibitors).