Injection of recombinant activated factor VII can induce transient increase in circulating procoagulant microparticles

Valérie Proulle; Bénédicte Hugel; Benoit Guillet; Catherine Trichet; Anne Rafowicz; Thierry Lambert; Jean-Marie Freyssinet; Marie Dreyfus

doi:10.1160/TH03-05-0301

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(05): 873-878
DOI: 10.1160/TH03-05-0301

Rapid and Short Communication

Schattauer GmbH

Injection of recombinant activated factor VII can induce transient increase in circulating procoagulant microparticles

Valérie Proulle

¹INSERM Unit 143, Hôpital Bicêtre, Le Kremlin Bicêtre

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

,

Bénédicte Hugel

¹INSERM Unit 143, Hôpital Bicêtre, Le Kremlin Bicêtre

³Institut d’Hématologie et d’Immunologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France

,

Benoit Guillet

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

,

Catherine Trichet

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

,

Anne Rafowicz

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

,

Thierry Lambert

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

,

Jean-Marie Freyssinet

¹INSERM Unit 143, Hôpital Bicêtre, Le Kremlin Bicêtre

³Institut d’Hématologie et d’Immunologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France

,

Marie Dreyfus

¹INSERM Unit 143, Hôpital Bicêtre, Le Kremlin Bicêtre

²Laboratoire d’Hématologie, AP-HP, Faculté de Médecine, Paris XI, Hôpital Bicêtre, Le Kremlin Bicêtre

› Author Affiliations

Abstract

Summary

Recombinant activated factor VII (rFVIIa) is an effective haemostatic treatment in haemophiliacs with inhibitors. In vitro, FVIIa concentrations corresponding to those obtained with therapeutic doses of rFVIIa have been shown to induce normal thrombin generation and platelet activation in the absence of factors VIII or IX. To further study the in vivo haemostatic changes induced by rFVIIa, circulating procoagulant microparticles (MP) were measured in patients treated with discontinuous injections of Novoseven®. In 6 out of 15 patients, a transient peak of procoagulant MP was observed after injection, occurring 15 min to 2 h after infusion. It was composed primarily of platelet-derived MP and was of very short duration. This peak was not observed in haemophiliacs without inhibitor, who were treated with conventional replacement therapies. Our results provide further in vivo evidence that rFVIIa specifically activates platelets, either directly or as a consequence of a burst of thrombin generation that could account for its haemostatic efficacy.

Keywords

Microparticle - platelet activation - haemophilia therapy

Full Text

References

References
1 Butenas S, Brummel KE, Branda RF. et al. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood 2002; 99: 923-30.
2 Hoffman M, Monroe DM, 3rd Roberts HR. Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagul Fibrinolysis 1998; 09 (Suppl. 01) S61-65.
3 Hoffman M, Monroe DM. 3rd The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Semin Hematol 2001; 38: 6-9.
4 Butenas S, Brummel KE, Bouchard BA. et al. How factor VIIa works in hemophilia. J Thromb Haemost 2003; 01: 1158-60.
5 Hugel B, Socie G, Vu T. et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 1999; 93: 3451-6.
6 Lee DH, Warkentin TE, Denomme GA. et al. A diagnostic test for heparin-induced thrombocytopenia: detection of platelet microparticles using flow cytometry. Br J Haematol 1996; 95: 724-31.
7 Mallat Z, Benamer H, Hugel B. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101: 841-3.
8 Kasper CK, Aledort L, Aronson D. et al. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 612.
9 Aupeix K, Hugel B, Martin T. et al. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J Clin Invest 1997; 99: 1546-54.
10 Key NS, Slungaard A, Dandelet L. et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998; 91: 4216-23.
11 Sumner WT, Monroe DM, Hoffman M. Variability in platelet procoagulant activity in healthy volunteers. Thromb Res 1996; 81: 533-43.
12 Butenas S, van’t Veer C, Mann KG. “Normal” thrombin generation. Blood 1999; 94: 2169-78.
13 Blann AD, Lanza F, Galajda P. et al. Increased platelet glycoprotein V levels in patients with coronary and peripheral atherosclerosis. Thromb Haemost 2001; 86: 777-83.
14 Ravanat C, Freund M, Mangin P. et al. GPV is a marker of in vivo platelet activation study in a rat thrombosis model. Thromb Haemost 2000; 83: 327-33.
15 Hrachovinova I, Cambien B, Hafezi-Moghadam A. et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 2003; 09: 1020-5.