Acute Release of Tissue Factor Pathway Inhibitor after In Vivo Thrombin Generation in Baboons

Cristina Lupu; Egbert K. O. Kruithof; Vijay V. Kakkar; Florea Lupu

doi:10.1055/s-0037-1614895

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(06): 1652-1658
DOI: 10.1055/s-0037-1614895

Rapid Communication

Schattauer GmbH

Acute Release of Tissue Factor Pathway Inhibitor after In Vivo Thrombin Generation in Baboons

Cristina Lupu

¹From the Vascular Biology Laboratory, Weston Centre for Experimental Research, Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, United Kingdom

,

Egbert K. O. Kruithof

²Division of Angiology and Hemostasis, University Hospital, Geneva, Switzerland

,

Vijay V. Kakkar

¹From the Vascular Biology Laboratory, Weston Centre for Experimental Research, Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, United Kingdom

,

Florea Lupu

¹From the Vascular Biology Laboratory, Weston Centre for Experimental Research, Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, United Kingdom

› Author Affiliations

Abstract

Summary

Tissue factor pathway inhibitor (TFPI), the major downregulator of the procoagulant activity of tissue factor (TF), is synthesised by endothelial cells (EC) and acutely released in vitro after thrombin stimulation. Expression of TF on EC and subsequent thrombin generation occurs in vivo during sepsis or malignancy, inducing disseminated intravascular coagulation (DIC). The present study investigates the changes in plasma TFPI in relation to markers of in vivo thrombin generation induced by injection of factor Xa (FXa)/phospholipids in baboons at dosages leading to partial (48%) or complete fibrinogen depletion. The plasma concentrations of thrombin-antithrombin III (TAT) and fibrinopeptide A (FpA), as markers of in vivo generation of thrombin, were strongly enhanced after injection of FXa/phospholipids. TFPI levels, whether measured as antigen or activity, increased significantly in both treatment groups within few minutes, and were dependent on the dose of FXa/phospholipids. Significant positive correlations between plasma levels of TFPI and of TAT or FpA were observed. Altogether, our results indicate that experimentally induced in vivo generation of thrombin causes the acute release of TFPI, high-lighting a possible novel function of thrombin in downregulation of the coagulation process, potentially relevant for the outcome of DIC.

Keywords

TFPI - thrombin - DIC - non-human primate - animal model

Full Text

References

References
1 Colucci M, Balconi G, Lorenzet R, Pietra A, Locati D, Donati MB, Semeraro N. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest 1983; 71: 1893-6.
2 Hara S, Asada Y, Hatakeyama K, Marutsuka K, Sato Y, Kisanuki A, Sumiyoshi A. Expression of tissue factor and tissue factor pathway inhibitor in rat lungs with lipopolysaccharide-induced disseminated intravascular coagulation. Lab Invest 1997; 77: 581-9.
3 Kruithof EKO, Mestries JC, Gascon M-P, Ythier A. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation – effect of Interleukin 6. Thromb Haemost 1997; 77: 905-10.
4 Broze Jr. GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990; 29: 7539-46.
5 Takahashi H, Sato N, Shibata A. Plasma tissue factor pathway inhibitor in disseminated intravascular coagulation: comparison of its behavior with plasma tissue factor. Thromb Res 1995; 80: 339-48.
6 Shimura M, Wada H, Wakita Y, Nakase T, Hiyoyama K, Nagaya S, Mori Y, Shiku H. Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation. Am J Hematol 1996; 52: 165-70.
7 van 't Veer C, Hackeng TM, Delahaye C, Sixma JJ, Bouma BN. Activated factor X and thrombin formation triggered by tissue factor on endothelial cell matrix in a flow model: effect of the tissue factor pathway inhibitor. Blood 1994; 84: 1132-42.
8 Falciani M, Gori AM, Fedi S, Chiarugi L, Simonetti I, Dabizzi RP, Prisco D, Pepe G, Abbate R, Gensini GF, Neri Serneri GG. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischaemic heart disease patients. Thromb Haemost 1998; 79: 495-9.
9 Sandset PM, Sirnes PA, Abildgaard U. Factor VII and extrinsic pathway inhibitor in acute coronary disease. Br J Haematol 1989; 72: 391-6.
10 Mestries JC, Kruithof EKO, Gascon M-P, Herodin F, Agay D, Ythier A. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 5: 275-81.
11 Lupu C, Lupu F, Dennehy U, Kakkar VV, Scully MF. Thrombin induces the redistribution and acute release of tissue factor pathway inhibitor from specific granules within human endothelial cells in culture. Arterioscler Thromb Vasc Biol 1995; 15: 2055-62.
12 Giles AR, Nesheim ME, Herring SW, Hoogendoorn H, Stump DC, Heldebrant CM. The fibrinolytic potential of the normal primate following the generation of thrombin in vivo . Thromb Haemost 1990; 63: 476-81.
13 Kruithof EKO, Agay D, Mestries JC, Gascon M-P, Ythier A. The effect of Factor Xa/phospholipid infusion on the acute phase response in baboons. Thromb Haemost 1997; 77: 308-11.
14 Vischer UM, Ingerslev J, Wollheim CB, Mestries JC, Tsakiris DA, Haefeli WE, Kruithof EKO. Acute von Willebrand Factor secretion from the endothelium in vivo: assessment through plasma propeptide (vWf:AgII) levels. Thromb Haemost 1997; 77: 387-93.
15 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Büller HR, van Deventer SJH, Hack CE, ten Cate JW, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-20.
16 Giles AR, Hoogendoorn H, Tinlin S, Morrissey JH. Activation of FVII in vivo following the infusion of a combination of FXa and phosphatidylcholine/phosphatidylserine (PCPS) vesicles at a dosage that bypasses FVIII and normalizes hemostatic plug formation in hemophilic dogs. Thromb Haemost 1993; 69: 2739 (Abstract).
17 Warn-Cramer BJ, Rapaport SI. Evidence suggestive of activation of the intrinsic pathway of blood coagulation after injection of Factor Xa/phospholipid into rabbits. Arterioscler Thromb Vasc Biol 1995; 15: 133-9.
18 Rubin N, Colman RW. Disseminated intravascular coagulation. Approach to treatment. Drugs 1992; 150: 225-35.
19 Novotny WF, Girard TJ, Miletich JP, Broze Jr GJ. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988; 72: 2020-5.
20 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsch J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombinIII-independent inhibitors. J Clin Invest 1990; 86: 385-91.
21 Hogg PJ, Bock PE. Modulation of thrombin and heparin activities by fibrin. Thromb Haemost 1997; 77: 424-33.
22 Ornberg RL, Deune EG, Ozbek MR, Wun TC, Khouri RK. Localization of topically applied TFPI binding sites in an intimectomized microvessel. Thromb Haemost 1995; 73: 55-8.
23 Warn-Cramer BJ, Rapaport SI. Studies of factor Xa/phospholipid-induced intravascular coagulation in rabbits. Effects of immunodepletion of tissue factor pathway inhibitor. Arterioscler Thromb 1993; 13: 1551-7.