Medicine & USMLE

Intrinsic Pathway of Coagulation

  1. Common Pathway of Coagulation
  2. Extrinsic Pathway of Coagulation
  3. Intrinsic Pathway of Coagulation
  4. Hemophilia A
  5. Hemophilia B
  6. Hemophilia C
  7. Factor V Leiden
  8. Antithrombin-3 Deficiency


The intrinsic pathway of coagulation, also known as the contact activation pathway, is one of 2 starting pathways that eventually leads to the formation of a blood clot. This pathway is started by the exposure of collagen, basement membrane components, or activated platelets to flowing blood. These are components of the inner layers of blood vessels that usually make contact with blood in the context of a vessel injury. Upon contact with these components, activation of Factor 12 or Hageman factor occurs by way of cleavage. Activated Factor 12 then goes onto cleave and activate Factor 11. Factor 12 and 11 are both inhibited by the actions of C1 esterase inhibitor. Factor 11 specifically is deficient in the bleeding disorder Hemophilia C. Next, activated factor 11 goes on to cleave and activate factor 9, in a process that requires calcium ions, phospholipid membranes, and vitamin K. Factor 9 is deficient in Hemophilia B, another bleeding disorder caused by insufficient clotting factors. In an independent process, factor 8 is activated by factor 2, in a process that is inhibited by C and S. In particular, factor 8 is stabilized by von willebrand factor or VWF in the blood. Factor 8 may also be deficient in patients with the bleeding disorder Hemophilia A. Next, the activated forms of factor 9 and 8 combine to form a complex that cleaves and activates factor 10, signifying the end of the intrinsic pathway and the beginning of the common pathway of coagulation. Finally, the function of the intrinsic pathway can be monitored using the PTT lab test.

Key Points

  • Intrinsic Pathway of Coagulation
    • Also known as the contact activation pathway
    • Pathway
      • Starts with contact with a damaged vessel surface
        • Collagen
          • Usually sub-endothelial collagen exposed by vessel injury
        • Basement membrane
          • This is made of type 4 collagen, so this is effectively the same thing as the above
        • Activated platelets
          • via polyphosphate
        • Activating lab compounds (above)
      • Activates Factor XII (Hageman Factor) by cleavage → XIIa
        • Inhibited by C1-esterase inhibitor
      • Factor XIIa cleaves Factor XI → XIa
        • Also inhibited by C1-esterase inhibitor
        • Factor XI is deficient in Hemophilia C
      • Factor XIa cleaves Factor IX → IXa
        • Requires calcium (Ca2+), phospholipid
        • Vitamin K-dependent clotting factor
          • Inhibited by Warfarin
        • Stimulated by Factor IIa (downstream)
        • Factor IX is deficient in Hemophilia B
      • Independent cleavage of Factor VIII → VIIIa
        • Activated by IIa (thrombin)
          • Does not rely on factor IXa, activated in an independent fashion by thrombin
        • Factor VIII is deficient in Hemophilia A
        • Factor VIII is stabilized by vWF
          • vWF is a protective carrier protein for Factor VIII; without which it is quickly cleared from the bloodstream
          • Factor VIII activity may be deficient in von Willebrand disease
        • Blocked by proteins C & S
      • Factors VIIIa + IXa stimulates cleavage of Factor X → Xa
        • Entry into common coagulation pathway
    • Monitoring
      • PTT / aPTT (activated partial thromboplastin time)
        • Measures intrinsic and common pathway (time to clot) after adding an intrinsic activator (silica, celite, kaolin, or ellagic acid)
        • Usually used to monitor therapeutic effect of heparin, although warfarin use may also increase PTT levels (however, vitamin K-dependent clotting factor with the shortest half-life is factor VII, which is not involved in intrinsic pathway)
        • Mnemonic: “play table tennis inside” = PTT inside