Tissue Factor Reduction and Tissue Factor Pathway Inhibitor Release after Heparin Administration

Summary

Elevated plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and large amounts of monocyte procoagulant activity (PCA) have been documented in unstable angina (UA) patients. In in vitro experiments heparin is able to blunt monocyte TF production by inhibiting TF and cytokine gene expression by stimulated cells and after in vivo administration it reduces adverse ischemic outcomes in UA patients. TF and TFPI plasma levels and monocyte PCA have been investigated in 28 refractory UA patients before and during anticoagulant subcutaneous heparin administration (thrice daily weight- and PTT-adjusted for 3 days) followed by 5000 IU × 3 for 5 days. After 2-day treatment, immediately prior to the heparin injection, TF and TFPI plasma levels [(median and range): 239 pg/ml, 130-385 pg/ ml and 120 ng/ml, 80-287 ng/ml] were lower in comparison to baseline samples (254.5 pg/ml, 134.6-380 pg/ml and 135.5 ng/ml, 74-306 ng/ml). Four h after the heparin injection TF furtherly decreased (176.5 pg/ml, 87.5-321 pg/ml; -32.5%, p<0.001) and TFPI increased (240.5 ng/ml, 140-450 ng/ml; +67%, p<0.0001).

After 7-day treatment, before the injection of heparin, TF and TFPI plasma levels (200 pg/ml, 128-325 pg/ml and 115 ng/ml, 70-252 ng/ml) significantly decreased (p<0.05) in comparison to the pre-treatment values. On the morning of the 8th day, 4 h after the injection of heparin TF plasma levels and monocytes PCA significantly decreased (156.5 pg/ml, 74-259 pg/ml and from 180 U/10⁵ monocytes, 109-582 U/10⁵ monocytes to 86.1 U/10⁵ monocytes, 28-320 U/10⁵ monocytes; - 38% and -55% respectively) and TFPI increased (235.6 ng/ml, 152-423 ng/ ml; +70%, p<0.001). In conclusion, heparin treatment is associated with a decrease of high TF plasma levels and monocyte procoagulant activity in UA patients. These actions of heparin may play a role in determining the antithrombotic and antiinflammatory properties of this drug.

• References

• 1 Schecter AD, Giesen PLA, Taby O, Rosenfield CL, Rossikhina M, Fyfe BS, Kohtz DS, Fallon JT, Nemerson Y, Taubman MB. Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation. J Clin Invest 1997; 100: 2276-85.
• 2 Sandset PM, Abildgaard U. Extrinsic pathway inhibitor: the key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemostasis 1991; 21: 219-39.
• 3 Rao LVM, Rapaport I S. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 1987; 69: 645-51.
• 4 Broze Jr GJ, Warren LA, Novotny WF, Higughi DA, Girar JJ, Miletich JP. The lipoprotein-associated coagulation inhibitor that inhibit the factor VII-tissue factor complex, also inhibits factor Xa: insight into possible mechanism of action. Blood 1988; 71: 335-43.
• 5 Lindhal AK. Tissue factor pathway inhibitor: from unknown coagulation inhibitor to major antithrombotic principle. Cardiovasc Res 1997; 33: 286-91.
• 6 Ameri A, Kuppuswamy MN, Basu S, Bajaj SP. Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators. Blood 1992; 79: 3219-26.
• 7 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor. Evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA 1990; 87: 8869-73.
• 8 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.
• 9 McGee MP, Foster S, Wang X. Simultaneous expression of tissue factor and tissue factor pathway inhibitor by human monocytes: a potential mechanism for localized control of blood coagulation. J Exp Med 1994; 179: 1847-54.
• 10 Van der Logt CPE, Dirven RJ, Reitsma PH, Bertina RM. Expression of tissue factor and tissue factor pathway inhibitor in monocytes in response to bacterial lipopolysaccharide and phorbolester. Blood Coagul Fibrinolysis 1994; 5: 211-20.
• 11 Østerud B, Bajaj MS, Bajaj SP. Sites of tissue factor pathway inhibitor (-TFPI) and tissue factor expression under physiologic and pathologic conditions. Thromb Haemost 1995; 73: 873-5.
• 12 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-13.
• 13 Bara L, Bloch MF, Zitoun D, Samama M, Collignon F, Frydman A, Uzan A, Bouthier J. Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin comsumption in whole blood during coagulation, and release of tissue factor pathway inhibitor. Thromb Res 1993; 69: 443-52.
• 14 Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1978; 12: 773-82.
• 15 Vannucchi S, Pasquali F, Porciatti F, Chiarugi V, Magnelli L, Bianchini P. Binding, internalization and degradation of heparin and heparin fragments by cultured endothelial cells. Thromb Res 1988; 49: 373-83.
• 16 Leung L, Saigo K, Grant D. Heparin binds to human monocytes and modulates their pro-coagulant activities and secretory phenotypes. Effect of histidine-rich glycoprotein. Blood 1989; 73: 177-82.
• 17 Pepe G, Giusti B, Attanasio M, Gori AM, Comeglio P, Martini F, Gensini GF, Abbate R, Neri Serneri GG. Tissue factor and plasminogen activator inhibitor type 2 expression in human stimulated monocytes is inhibited by heparin. Semin Thromb Haemost 1997; 23: 135-41.
• 18 Attanasio M, Gori AM, Giusti B, Pepe G, Comeglio P, Brunelli T, Prisco D, Abbate R, Gensini GF, Neri Serneri GG. Cytokine gene expression in human stimulated monocytes is inhibited by heparin. Thromb Haemost 1998; 79: 959-62.
• 19 Neri Serneri GG, Abbate R, Gori AM, Attanasio M, Martini F, Giusti B, Dabizzi RP, Poggesi L, Modesti PA, Trotta F, Rostagno C, Boddi M, Gensini GF. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation 1992; 86: 790-7.
• 20 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. Thromb Haemost 1998; 79: 495-499.
• 21 Théroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88: 2045-8.
• 22 Neri Serneri GG, Modesti PA, Gensini GF, Branzi A, Melandri G, Poggesi L, Rostagno C, Tamburini C, Carnovali M, Magnani B. Randomised comparison of subcutaneous heparin, intravenous heparin and aspirin in unstable angina. Lancet 1995; 345: 1201-4.
• 23 Braunwald E. Unstable angina: a classification. Circulation 1989; 80: 410-4.
• 24 Hansen JB, Sandset PM, Huseby KR, Huseby NE, Nordoy A. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man. Thromb Haemost 1996; 76: 703-9.
• 25 Lindhal AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1992; 3: 439-49.
• 26 Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I, Fossati G, Pasotti D, Bramucci E, Angoli L, Marsico F, Specchia G, Notario A. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation 1993; 88: 358-63.
• 27 Jang Y, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994; 24: 1591-601.
• 28 Morisaki N, Saito I, Tamura K, Tashiro J, Masuda M, Kanzaki T, Watanabe S, Masuda Y, Saito Y. New indices of ischaemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischaemic heart disease. Atherosclerosis 1997; 131: 43-8.
• 29 Ghaisas NK, Shahi CN, Foley B, Goggins M, Crean P, Kelly A, Kelleher D, Walsh M. Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina. Am J Cardiol 1997; 80: 617-9.
• 30 Moreno PR, Bernardi VH, Lopez-Cuellar J, Murcia AM, Palacios IF, Gold HK, Mehran R, Sharma SK, Nemerson Y, Fuster V, Fallon JT. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 1996; 94: 3090-7.
• 31 Cadroy Y, Gaspin D, Dupouy D, Lormeau JC, Boneu B, Sié P. Heparin reverses the procoagulant properties of stimulated endothelial cells. Thromb Haemost 1996; 75: 190-5.
• 32 Nelson RM, Cecconi O, Roberts WG, Aruffo A, Linhardt RJ, Bevilacqua MP. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 1993; 82: 3253-8.
• 33 Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 1994; 81: 8767-71.
• 34 Matzner Y, Marx G, Drexler R, Eldor A. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb Haemost 1984; 52: 134-7.
• 35 Bazzoni GF, Nunez AB, Mascellani G, Bianchini P, Dejana E, Del Maschio A. Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions. J Lab Clin Med 1993; 121: 268-75.
• 36 Kamikura Y, Wada H, Yamada A, Shimura M, Hiyoyama K, Shiku H, Tanigawa M, Nishikawa H, Yamada N, Isaka N, Nakano T, Kumeda K, Kato H. Increased tissue factor pathway inhibitor in patients with acute myocardial infarction. Am J Hematol 1997; 55: 183-7.
• 37 Théroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Eng J Med 1992; 327: 141-5.
• 38 Granger CB, Miller JM, Bovill EG, Gruber A, Tracy RP, Krucoff MW, Green C, Berrios E, Harrington RA, Ohman M, Califf RM. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 1995; 91: 1929-35.
• 39 Neri Serneri GG, Prisco D, Martini F, Gori AM, Brunelli T, Poggesi L, Rostagno C, Gensini GF, Abbate R. Acute T-cell activation is detectable in unstable angina. Circulation 1997; 95: 1806-12.