Blood Clotting: Intrinsic Activity

 
Blood clotting is initiated by the extrinsic activity which is localized to the surfaces of tissue factor (TF) bearing cells. These cells are located at the site of injury [Blood Clotting: Extrinsic Activity and Platelet Activation]. The initial steps result in activation of some blood coagulation factors and activation of platelets.

The next step in coagulation requires an amplification of thrombin production so that clotting can proceed rapidly. The amplification stage is referred to as intrinsic activity, or the intrinsic pathway. These reactions take place on the surface of activated platelets. Activated platelets aggregate at the site of injury [Blood Clotting: Platelets].

The ultimate goal in the amplification stage is to create a prothrombinase activity on platelet surfaces. Prothrombinase will cleave prothrombin to make thrombin and thrombin is the enzyme that cuts fibrinogen to make fibrin for clot formation [Blood Clotting: The Basics]. The platelet prothrombinase activity is the same as the activity on TP-bearing cells: it’s formed from Xa and membrane-bound Va. The difference between the two pathways (extrinsic and intrinsic) is the way in which factor X (ten) is activated to form Xa. The platelet enzyme is called “tenase” (cleaves factor “ten”) and it’s formed from Factor VIIIa and Factor IXa.

The final steps are shown in the figure below. Large amounts of thrombin are generated and large amounts of fibrin are produced.


Tenase activity is formed when VIIIa binds to the platelet membrane. VIIIa is produced by thrombin cleavage of factor VIII in the extrinsic part of the pathway. Factor VIII is the factor that associates with von Willebrand factor (vWF). The most common hereditary bleeding disorder is caused by a deficiency of von Willebrand factor (von Willebrand diseases). In the absence of vWF, factor VIII is unstable and platelets cannot form the tenase enzyme. Hemophilia A is the X-linked form of hemophilia that was common in European royal families descending from Queen Victoria. It is caused by a deficiency of Factor VIII.

IXa, the active component of tenase, is produced when XIa cleaves the precursor factor IX. Deficiencies in factor IX cause hemophilia B. IX is another factor that contains a γ-carboxyglutamyl residue that chelates a Ca⁺⁺ ion.

A little bit of IXa is made in the extrinsic pathway but the major amplification on platelet cell surfaces requires XIa. The pathway leading to formation of XIa is shown on the left. HMWK stands for “high molecular weight kininogen.” It binds to and stabilizes XIa and kallikren.

Thanks to my colleague Marion Packham for answering some questions about platelets. I recommend the Hemostasis & Thrombosis chapter in Harper's Illustrated Biochemistry 27th ed. written by my colleagues Marg Rand and Bob Murray.

Devlin, T.H. (ed.) (2006) Textbook of Biochemistry with Clinical Correlations 6th ed., Wiley-Liss, Hoboken, N.J. (USA)

Rand, M.L. and Murray, R.K. (2006) Hemostasis & Thrombosis in Harper's Illustrated Biochemistry 27th ed., R.K. Murray, D.K. Granner, and V.W. Rodwell eds. McGraw Hill Lange, Toronto Canada.

Wolberg, A.S. (2007) Thrombin generation and fibrin clot structure. Blood Reviews Jan. 5 2007. [PubMed]