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Blood Coagulation in Hemophilia A and Hemophilia C
Kevin M. Cawthern,
Cornelis van `t Veer,
Jennifer B. Lock,
Maria E. DiLorenzo,
Richard F. Branda, and
Kenneth G. Mann
From the Department of Biochemistry, College of Medicine, and the
Department of Medicine, University of Vermont, Burlington, VT.
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 quenched samples by immunoassay and immunoblotting for
fibrinopeptide A (FPA), thrombin-antithrombin (TAT), factor V
activation, and osteonectin. In hemophilia A blood (factor VIII:C <1%) treated with 25 pmol/L TF, clotting was significantly delayed versus normal, whereas replacement with recombinant factor VIII (1 U/mL) restored the clot time near normal values. Fibrinopeptide A
release was slower over the course of the experiment than in normal
blood or hemophilic blood with factor VIII replaced, but significant
release was observed by the end of the experiment. Factor V activation
was significantly impaired, with both the heavy and light chains
presenting more slowly than in the normal or replacement cases.
Differences in platelet activation (osteonectin release) between normal
and factor VIII-deficient blood were small, with the midpoint of the
profiles observed within 1 minute of each other. Thrombin generation
during the propagation phase (subsequent to clotting) was greatly
impaired in factor VIII deficiency, being depressed to less than 1/29
(<1.9 nmol TAT/L/min) the rate in normal blood (55 nmol TAT/L/min).
Replacement with recombinant factor VIII normalized the rate of TAT
generation. Thus, coagulation in hemophilia A blood at 25 pmol/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 platelet
activation. At the same level of TF in factor XI-deficient blood (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. The
maximum thrombin generation rate observed (~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, factor V
activation, and release of platelet osteonectin were slower in factor
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 propagation
phase after formation of the initial clot in hemophilia C blood.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4581-4592
© 1998 by The American Society of Hematology.
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