Effect of SR121566A, a Potent GP IIb-IIIa Antagonist, on the HIT Serum/heparin-Induced Platelet Mediated Activation of Human Endothelial Cells

Jean-Marc Herbert; Pierre Savi; Walter P. Jeske; Jeanine M. Walenga

doi:10.1055/s-0037-1615196

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1998; 80(02): 326-331
DOI: 10.1055/s-0037-1615196

Rapid Communication

Schattauer GmbH

Effect of SR121566A, a Potent GP IIb-IIIa Antagonist, on the HIT Serum/heparin-Induced Platelet Mediated Activation of Human Endothelial Cells

Jean-Marc Herbert

¹From the Haemobiology Research Department, Sanofi Recherche, Toulouse, France, Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

,

Pierre Savi

¹From the Haemobiology Research Department, Sanofi Recherche, Toulouse, France, Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

,

Walter P. Jeske

¹From the Haemobiology Research Department, Sanofi Recherche, Toulouse, France, Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

,

Jeanine M. Walenga

¹From the Haemobiology Research Department, Sanofi Recherche, Toulouse, France, Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

› Institutsangaben

Abstract

Summary

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of heparin therapy that carries a risk of serious thrombotic events. This condition is caused by platelet aggregation, which is mediated by anti-heparin/platelet factor 4 antibodies. Sera from patients with HIT in the presence of platelets, induced the expression of E-selectin, VCAM, ICAM-1 and tissue factor and the release of IL1β, IL6, TNFα and PAI-1 by human umbilical vein endothelial cells (HUVECs) in vitro and initiated platelet adhesion to activated HUVECs. These effects which occurred in a time-dependent manner were significant in the first 1-2 h of incubation and reached a maximum after 6 to 9 h. The GP IIb-IIIa receptor antagonist SR121566A which has been shown to block platelet aggregation induced by a wide variety of agonists including HIT serum/heparin, reduced in a dose-dependent manner the HIT serum/heparin-induced, platelet mediated expression and release of the above mentioned proteins. The IC50 for inhibition of HIT serum/ heparin-induced platelet dependent HUVEC activation by SR121566A was approximately 10-20 nM. ADP, but not serotonin release, also appeared to be involved as apyrase and ATPγS blocked platelet-dependent, HIT serum/heparin-induced cell surface protein expression and cytokine release by HUVECs. Increased platelet adherence to HIT serum/heparin-activated HUVECs was inhibited by SR121566A and, to a lesser extent, by apyrase and ATPγS, showing that platelet activation and release was at the origin of the HIT serum/heparin-induced expression of these proteins by HUVECs.

Thus, sera from patients with HIT induced the expression of adhesive and coagulation proteins and the release of cytokines by HUVECs through the activation of platelets which occurred in a GP IIb-IIIa-dependent manner, a process that could be selectively blocked by SR121566A.

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Referenzen

References
1 Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995; 89: 431-45.
2 Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: 247-51.
3 Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-40.
4 Kelton JG, Sheridan D, Santos A, Smith J. Heparin-induced thrombocytopenia: Laboratory studies. Blood 1988; 72: 925-30.
5 Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994; 93: 81-8.
6 Alberto MF, Bermejo EI, Lazzari MA. Fcγ receptors on human umbilical vein endothelial cells. Evaluation by flow cytometry. Thromb Haemost 1997; (Suppl. 01) abst. PS-581 142.
7 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-9.
8 Liem TK, Teel R, Shukla S, Silver D. The glycoprotein IIb/IIIa antagonist c7E3 inhibits platelet aggregation in the presence of heparin-associated antibodies. J Vasc Surg 1997; 25: 124-30.
9 Hérault JP, Lalé A, Savi P, Pflieger AM, Herbert JM. In vitro inhibition of heparin-induced platelet aggregation in plasma from patients with HIT by SR 121566, a newly developed GpIIb/IIIa antagonist. Blood Coag Fibrinol 1997; 8: 206-7.
10 Jeske WP, Walenga JM, Szatkowski E, Ero M, Herbert JM, Bakhos M. Effect of glycoprotein IIb/IIIa antagonists on the HIT serum induced activation of platelets. Thromb Res 1997; 88: 271-81.
11 Savi P, Badorc A, Lale A, Bordes MF, Bornia J, Labouret C, Bernat A, de Cointet P, Hoffmann P, Maffrand JP, Herbert JM. SR 121787, a new orally active fibrinogen receptor antagonist. Thromb Haemost, in press.
12 Lewis BE, Wallenga JM, Wallis DE. Anticoagulation with Novastan^® (Argatroban) in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. Semin Thromb Haemost 1997; 32: 197-202.
13 Surprenant YM, Zuckerman SH. A novel microtiter plate assay for the quantitation of procoagulant activity on adherent monocytes, macrophages and endothelial cells. Thromb Res 1989; 53: 339-42.
14 Rinaldi-Carmona M, Congy C, Santucci V, Simiand J, Gautret B, Neliat G, Labeeuw B, Le Fur G, Soubrie P, Brelière JC. Biochemical and pharmacological properties of SR 46349B a new potent and selective 5-HT₂ receptor antagonist. J Pharmacol Exp Ther 1992; 262: 759-68.
15 Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69: 344-50.
16 Slupsky JR, Cawley JC, Griffith LS, Shaw AR, Zuzel M. Role of FC gamma RII in platelet activation by monoclonal antibodies. J Immunol 1992; 48: 3189-204.
17 Bar RS, Dake BL, Spanheimer RG. Sulfated glycosaminoglycans in cultured endothelial cells from capillaries and large vessels of human and bovine origin. Atherosclerosis 1985; 56: 11-26.
18 Amirkhosravi A, Alexander M, May K, Francis DA, Warnes G, Biggerstaff J, Francis JL. The importance of platelets in the expression of monocyte tissue factor antigen measured by a new whole blood flow cytometric assay. Thromb Haemost 1996; 75: 87-95.
19 De Gaetano G, Vermylen J, Verstraete M. Platelet aggregation by specific human immunoglobulin preparation. Thromb Diath Haemorrh 1970; 24: 419-31.
20 De Clerck F, Somers Y, Van Grop L. Platelet-vessel wall interactions in hemostasis: implication of 5-hydroxytryptamine. Agents Actions 1984; 15: 627-35.
21 Li JM, Podolsky RS, Rohrer MJ, Cutler BS, Massie MT, Barnard MR, Michelson AD. Adhesion of activated platelets to venous endothelial cells is mediated via GPIIb/IIIa. J Surg Res 1996; 61: 543-8.