BLOOD-COAGULATION IN HEMOPHILIA-A AND HEMOPHILIA-C

Tissue factor (TF)-induced coagulation was compared in contact pathway suppressed human blood from normal, factor VIII-deficient, and factor XI-deficient donors. The progress of the reaction was analyzed in que nched samples by immunoassay and immunoblotting for fibrinopeptide A ( FPA), thrombin-antithrombin (TAT), factor V activation, and osteonecti n. In hemophilia A blood (factor VIII:C <1%) treated with 25 pmol/L TF , clotting was significantly delayed versus normal, whereas replacemen t with recombinant factor VIII (1 U/mL) restored the clot time near no rmal values. Fibrinopeptide A release was slower over the course of th e experiment than in normal blood or hemophilic blood with factor VIII replaced, but significant release was observed by the end of the expe riment. Factor V activation was significantly impaired, with both the heavy and light chains presenting more slowly than in the normal or re placement cases. Differences in platelet activation (osteonectin relea se) between normal and factor VIII-deficient blood were small, with th e midpoint of the profiles observed within 1 minute of each other. Thr ombin generation during the propagation phase (subsequent to clotting) was greatly impaired in factor VIII deficiency, being depressed to le ss than 1/29 (<1.9 nmol TAT/L/min) the rate in normal blood (55 nmol T AT/L/min). Replacement with recombinant factor VIII normalized the rat e of TAT generation. Thus, coagulation in hemophilia A blood at 25 pmo l/L TF is impaired, with significantly slower thrombin generation than normal during the propagation phase; this reduced thrombin appears to affect FPA production and factor V activation more profoundly than pl atelet activation. At the same level of TF in factor XI-deficient bloo d (XI:C <2%), only minor differences in clotting or product formation (FPA, osteonectin, and factor Va) were observed. Using reduced levels of initiator (5 pmol/L TF), the reaction was more strongly influenced by factor XI deficiency. Clot formation was delayed from 11.1 to 15.7 minutes, which shortened to 9.7 minutes with factor XI replacement. Th e maximum thrombin generation rate observed (similar to 37 nmol TAT/L/ min) was approximately one third that for normal (110 nmol/L TAT/min) or with factor XI replacement (119 nmol TAT/L/min). FPA release, facto r V activation, and release of platelet osteonectin were slower in fac tor XI-deficient blood than in normal blood. The data demonstrate that factor XI deficiency results in significantly delayed clot formation only at sufficiently low TF concentrations. However, even at these low TF concentrations, significant thrombin is generated in the propagati on phase after formation of the initial clot in hemophilia C blood. (C ) 1998 by The American Society of Hematology.