Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (818 page)

   Clotting factors are circulating plasma proteins. The final coagulation product, the clot, results from the interaction of clotting factors through an enzymatic cascade. In vivo, many of these interactions take place on lipid surfaces, the most abundant of which are provided by platelets. In contrast, in vitro, the cascade can be dissected into three pathways: intrinsic, extrinsic, and common. Although to some extent artificial, this distinction remains useful for performing and understanding the tests of coagulation. For instance, PT reflects the extrinsic and common pathway, whereas PTT reflects the intrinsic and common pathway. Fibrinogen, the penultimate step in the generation of clots, is the target of the common pathway, being changed by thrombin into fibrin; finally, fibrin is consolidated by factor XIII to generate a stable clot, essential for achieving hemostasis through clotting. (Primary hemostasis through activation of platelets and the von Willebrand factor is discussed separately.)

   
Properties of individual clotting factors:

   
Factor II
(prothrombin): Synthesized in the liver; becomes active only after carboxylation by vitamin K. It is converted to thrombin (factor IIa). Its deficiency results in prolonged PT and PTT.

   
Thrombin
(factor IIa): A major coagulant that converts fibrinogen into fibrin; has multiple functions, including as an anticoagulant, by binding to thrombomodulin on endothelial cell surfaces to convert protein C into its active form.

   
Factor V
: Synthesized in the liver; 20% is released from platelets. Cofactor in the conversion of factor II to IIa. Vitamin K has no effect on its activity. Proteolyzed by the protein C/S complex.

   
Factor VII
: Synthesized in the liver. Becomes activated in a complex with tissue factor. Factor VII requires carboxylation by vitamin K for its activity. Shortest half-life of all clotting factors (4 hours) reflected in the initial rapid elongation in PT (elevation of INR) in patients started on vitamin K antagonists. Recombinant factor VIIa is used therapeutically.

   
Factor VIII
(antihemophilic factor): Synthesized in the liver and endothelial cells of others organs (principally the spleen). It is unaffected by liver failure or vitamin K deficiency. Principal cofactor in the intrinsic pathway of coagulation. PT (INR) not affected by deficiency of factor VIII. PTT becomes prolonged when factor VIII decreases to <40%. Serves as substrate for proteolysis by the protein C/S complex. Purified or recombinant factor VIII preparations are used therapeutically.

   
Factor IX
(also known as Christmas factor): Synthesized in the liver. Requires vitamin K to become active in coagulation. Principal factor in the intrinsic pathway of coagulation. PT (INR) not affected by deficiency of factor IX. PTT becomes prolonged when factor IX decreases to <40%. Purified and recombinant factor IX are used therapeutically.

   
Factor X
: Synthesized in the liver. Requires vitamin K to become active in coagulation. Principal factor in the common pathway of coagulation where it converts factor II into IIA (thrombin). Both PT (INR) and PTT affected in marked deficiencies.

   
Factor XI
: Synthesized in the liver and megakaryocytes. Activates factors XII and IX in the intrinsic pathway. If markedly decreased, it may prolong PTT but not PT.

   
Factor XII
(Hageman factor): Synthesized in the liver. Activated by collagen, disrupted basement membranes, activated platelets, and high molecular weight kininogen and prekallikrein in conjunction with factor XI. PTT (but not PT) is prolonged in severe deficiency. No bleeding diathesis associated with its congenital deficiency.