Overview

Classical pathways (as used in laboratory tests). The extrinsic pathway begins when tissue factor binds factor VIIa. This complex activates factor X, and also factor IX. In the intrinsic (contact) pathway, factor XII activates XI, XIa activates IX, and IXa with VIIIa forms the "tenase" complex that activates X. Both pathways feed into the common pathway. There, factor Xa with Va forms the "prothrombinase" complex, which converts prothrombin (II) into thrombin (IIa). Thrombin cleaves fibrinogen (I) into fibrin, which polymerises. Factor XIIIa then cross-links the fibrin. Ca²⁺ (once called factor IV) and phospholipid surfaces are needed at several steps. This is why citrate or EDTA, which bind Ca²⁺, stop blood samples from clotting.

Cell-based model (what happens in the body). Clotting happens on cell surfaces in three phases. Initiation: small amounts of thrombin form on cells that carry tissue factor. Amplification: this thrombin activates platelets and factors V, VIII and XI. Propagation: tenase and prothrombinase on activated platelets generate a large burst of thrombin. Factor XII is not needed for normal haemostasis. A deficiency prolongs the aPTT but does not cause bleeding.

Vitamin K-dependent proteins. Factors II, VII, IX and X, and the anticoagulant proteins C and S, need vitamin K-dependent γ-carboxylation to work. Warfarin blocks this by inhibiting VKORC1.

Natural anticoagulants. Antithrombin inactivates thrombin, Xa and IXa, and heparin strongly enhances its action. Protein C, once activated by thrombin bound to thrombomodulin, and its cofactor protein S inactivate factors Va and VIIIa. Tissue factor pathway inhibitor blocks the TF–VIIa–Xa complex.

Fibrinolysis. Tissue plasminogen activator (tPA) and urokinase convert plasminogen into plasmin, which breaks down fibrin into fibrin degradation products, including D-dimer. PAI-1 and α2-antiplasmin restrain this process, and tranexamic acid blocks it.

Parts & subdivisions

Extrinsic pathway
Tissue factor and factor VIIa. Measured by the PT/INR.
Intrinsic pathway
Factors XII, XI, IX and VIII. Measured by the aPTT.
Common pathway
Factors X, V, II (prothrombin) and I (fibrinogen), plus XIII.
Natural anticoagulants
Antithrombin, protein C and protein S, and tissue factor pathway inhibitor.
Fibrinolytic system
Plasminogen, tPA, plasmin and D-dimer. Inhibited by PAI-1 and α2-antiplasmin.

Function

Converts the loose platelet plug into a stable fibrin clot.
Amplifies a small trigger into a large but localised thrombin burst.
Is balanced by anticoagulant and fibrinolytic systems to prevent clotting from spreading.

Clinical significance

Haemophilias

Haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) are X-linked recessive disorders. They cause bleeding into joints (haemarthroses) and muscles. The aPTT is prolonged while the PT is normal.

Anticoagulant drugs

Unfractionated heparin works through antithrombin and is monitored with the aPTT. Low-molecular-weight heparin acts mainly on factor Xa. Warfarin blocks vitamin K-dependent factors and is monitored with the INR, usually aiming for 2–3. Direct oral anticoagulants inhibit factor Xa (apixaban, rivaroxaban, edoxaban) or thrombin (dabigatran).

Each has a reversal agent: protamine for heparin, vitamin K with prothrombin complex concentrate for warfarin, idarucizumab for dabigatran and andexanet alfa for the factor Xa inhibitors.

Thrombophilia

Factor V Leiden, the commonest inherited thrombophilia in people of European descent, makes factor V resistant to activated protein C. Other causes include the prothrombin G20210A mutation, deficiencies of protein C, protein S or antithrombin, and antiphospholipid syndrome. When warfarin is started, protein C falls quickly, which can briefly make the blood more likely to clot. This is why heparin is given alongside warfarin at first, and why warfarin can rarely cause skin necrosis.

Mnemonics

Vitamin K-dependent factors

"1972": factors 10, 9, 7, 2, plus proteins C and S.

PT versus aPTT

"PT is a WET game": the PT monitors Warfarin and the Extrinsic pathway. "HIP" for the aPTT: it monitors Heparin and the Intrinsic Pathway.

Test yourself

Which clotting factors require vitamin K for their synthesis in active form?

II, VII, IX and X
I, V, VIII and XIII
VIII, IX, XI and XII
III, IV, V and VII

Answer: II, VII, IX and X

Factors II, VII, IX and X (mnemonic "1972"), together with proteins C and S, need vitamin K-dependent γ-carboxylation. Warfarin blocks vitamin K epoxide reductase (VKORC1). Factor VII has the shortest half-life, which is why the INR rises first when warfarin is started.