A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high–titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)–deficient dog and controlled bleeding in rabbits with antibody–induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.

1.
Mann KG, Jenny RJ, Krishnaswamy S: Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Ann Rev Biochem 1988;57:915–956.
2.
Giesen PL, Willems GM, Hemker HC, Hermens WT: Membrane–mediated assembly of the prothrombinase complex. J Biol Chem 1991;266:18720–18725.
3.
Mann KG, Krishnaswamy S, Lawson J: Surface–dependent hemostasis. Semin Hematol 1992;29:213–226.
4.
Yolken RH, Hilgartner MW: Prothrombin complex concentrates, use in treatment of hemophiliacs with factor VIII inhibitors. Am J Dis Child 1978;132:291–293.
5.
Macik BG: Treatment of factor VIII inhibitors: products and strategies. Semin Thromb Hemost 1993;19:13–24.
6.
Lusher JM: Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors – benefits and limitations. Semin Hematol 1994;31:49–52.
7.
Sander W, Wilms K: Ein Beitrag zum Mechanismus der ‘Factor Eight Bypassing Activity’ (FEIBA)–Wirkung. Folia Haematol 1990;117: 581–587.
8.
Hedner U, Bjoern S, Bernvil SS, Tengborn L, Stigendahl L: Clinical experience with human plasma–derived factor VIIa in patients with hemophilia A and high–titer inhibitors. Haemostasis 1989;19:335–343.
9.
Telgt DSC, Macik BG, McCord DM, Monroe DM, Roberts HR: Mechanism by which recombinant factor VIIa shortens the aPTT: Activation of factor X in the absence of tissue factor. Thromb Res 1989;56:603–609.
10.
Monroe DM, Hoffman M, Oliver JA, Roberts HR: Platelet activity of high–dose factor VIIa is independent of tissue factor. Br J Haematol 1997;99:542–547.
11.
Turecek PL, Varadi K, Gritsch H, Schwarz HP: Activated prothrombin complex concentrates induce hemostasis by a balanced effect at multiple sites of the coagulation pathway. Haemophilia 1998;4:197.
12.
Morrissey JH, Macik BG, Neuenschwander PF, Comp PC: Quantitation of activated factor VII levels in plasma using tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81:734–744.
13.
Brummelhuis HGJ: Preparation of the prothrombin complex; in Curling JM (ed.): Methods of Plasma Protein Fractionation. New York, Academic Press, 1980, pp 117–128.
14.
Preiss DU, Eberspächer B, Abdullah D, Rosner I: Safety of vapour heated prothrombin complex concentrate (PCC) Prothromplex S–TIM 4. Thromb Res 1991;63:651–659.
15.
Di Scipio RG, Hermodson MA, Davie EW: Activation of human factor X (Stuart factor) by a protease from Russell’s viper venom. Biochemistry 1977;16:5253–5260.
16.
Hemker HC, Wielders S, Kessels H, Beguin S: Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993;70:617–624.
17.
Gill JC, Schwarz HP, Wentz MA, Montgomery RR: Platelet prothrombinase activity may predict successful activated prothrombin complex concentrate (FEIBA) treatment. Blood 1990; 76(Suppl.1):399a.
18.
Sultan Y, Loyer F: In vitro evaluation of factor VIII bypassing activity of activated prothrombin complex concentrate, and factor VIIa in the plasma of patients with factor VIII inhibitors: Thrombin generation test in the presence of collagen–activated platelets. J Lab Clin Med 1993;121:444–452.
19.
Turecek PL, Gritsch H, Pichler L, Auer W, Fisher B, Mitterer A, Mundt W, Schlokat U, Dorner F, Brinkman HJM, Van Mourik JA, Schwarz HP: In vivo characterization of recombinant von Willebrand factor in dogs with von Willebrand disease. Blood 1997;90:3555– 3567.
20.
Rieger M, Schwarz HP, Turecek PL, Dorner F, Van Mourik JA, Mannhalter C: Identification of mutations in the canine von Willebrand factor gene causing type III von Willebrand disease. Thromb Haemost 1998;80:332–337.
21.
Giles AR, Tinlin S, Brosseau L, Hoogendoorn H: In vivo studies of the role of factor VII in hemostasis. Blood 1985;65:1197–1200.
22.
Giles AR, Tinlin S, Greenwood R: A canine model of hemophilic (factor VIII:C deficiency) bleeding. Blood 1982;60:727–730.
23.
Turecek PL, Gritsch H, Richter G, Auer W, Pichler L, Schwarz HP: Assessment of bleeding for the evaluation of therapeutic preparations in small animal models of antibody–induced hemophilia and von Willebrand disease. Thromb Haemost 1997;77:591–599.
24.
Dunn OJ: Multiple comparisons using rank sums. Technometrics 1964;6:241–252.
25.
Hemker HC, Beguin S: Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995;74: 134–138.
26.
Varadi K, Siekmann J, Turecek PL, Schwarz HP: The role of prothrombinase in the function of activated prothrombin complex concentrates. Ann Hematol 1997;74(Suppl. II):A144.
27.
Giles AR, Mann KG, Nesheim ME: A combination of factor Xa and phosphatidylcholine–phosphatidylserine vesicles bypasses factor VIII in vivo. Br J Haematol 1988;69:491–497.
28.
Baglia FA, Walsh PN: Prothrombin is a cofactor for the binding of factor XI to the platelet surface and for platelet–mediated factor XI activation by thrombin. Biochemistry 1998;37: 2271–2281.
1999
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