Biochemistry and physiology of blood coagulation.

The biochemical era of blood coagulation research begins toward the end of the 19th century, primarily with the work of Alexander Schmidt1 and Paul Morawitz,2 who hypothesized that the fundamental reactions involved in clotting included the activation of prothrombin to thrombin by thromboplastins and the conversion of fibrinogen to fibrin by thrombin. Throughout the first half of the twentieth century, the inventory of blood clotting, which focused principally on procoagulant components, was expanded by the evaluation of human pathology and by laboratory analysis. These studies were greatly advantaged by two factors: (a) blood is easily obtainable, and (b) mothers almost always note when a child is bleeding excessively. As a consequence of the observations of hemorrhagic disease, hemophilia A (factor VIII deficiency)3,4 hemophilia B, Christmas disease (factor IX deficiency),5-7 Stuart factor disease (factor X deficiency)8 SPCA (serum prothrombin conversion accelerator) deficiency (factor VII deficiency),9 hemophilia C (factor XI deficiency),10,11 and parahemophillia, factor V (proaccelerin)12 deficiency were identified. Paul Owren, the discoverer of parahemophilia, named the component missing in his patient as factor V, since it was the fifth component (in addition to prothrombin, calcium, thromboplastin, and fibrinogen) required to produce a clot. He, thus, presaged the subsequent adoption of the array of roman numeral identifications.13 The pioneering work of the Smith group in Iowa14 and the clinical pathology work of Armand J. Quick15 led to quantitative laboratory evaluations of blood clotting reactions. The length (11-15 seconds) of Quick’s prothrombin time assay was, in part, dictated by the fact that blood spontaneously clots, even when removed from the blood vessel under the most carefully controlled conditions. Studies of this “intrinsic” clotting reaction were advanced by the development of the partial thromboplastin time by Langdell et al.16 This latter assay, exploited in the laboratory as a diagnostic test, led to the identification of deficiencies of factor XII (Hagemann factor),17 prekallikrein,18 and high molecular weight kininogen,18,19 as agents which contributed to the intrinsic clotting potential of blood. However, the deficiency of these “activities” was not associated with clinical bleeding. Factor XIII (plasma transglutaminase) was discovered as the precursor of the agent that produces the insoluble fibrin clot.20 A number of the antithrombin elements were identified in these early tests, including fibrin (antithrombin I) and antithrombin III.21 The tissue factor pathway inhibitor, a relatively recent discovery, but an inhibitor of great significance, was initially identified using in vitro clotting assays.22 The discovery of gamma carboxylation23 provided another entre for the expansion of the inventory of blood clotting components and led to the discovery of protein C,24 protein S,25 and protein Z.26 The search for the function of protein C led to the discovery of thrombomodulin27 and the anticoagulant role of thrombin in the activated protein C pathway, a significant negative-feedback, dynamic regulator of the coagulation process. No function has yet been assigned to protein Z. The inventory of the molecules involved in blood clotting and its regulation, their genes, and plasma lifetimes are presented in Table 1.