Local tissue factor pathway inhibitor release in the human forearm

Michiel J. B. Kemme; Jacobus Burggraaf; Rik C. Schoemaker; Adam F. Cohen; Cornelis Kluft; Stanley Chia; David J. Webb; David E. Newby

doi:10.1055/s-0037-1613371

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 89(03): 438-445
DOI: 10.1055/s-0037-1613371

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Local tissue factor pathway inhibitor release in the human forearm

Michiel J. B. Kemme

³Centre for Human Drug Research, Leiden, The Netherlands

,

Jacobus Burggraaf

³Centre for Human Drug Research, Leiden, The Netherlands

,

Rik C. Schoemaker

³Centre for Human Drug Research, Leiden, The Netherlands

,

Adam F. Cohen

³Centre for Human Drug Research, Leiden, The Netherlands

,

Cornelis Kluft

¹Gaubius Laboratory, TNO-PG, Leiden, The Netherlands

,

Stanley Chia

²Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK

,

David J. Webb

²Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK

,

David E. Newby

²Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK

› Author Affiliations

Abstract

Summary

Nineteen healthy men received unilateral brachial artery infusions of either unfractioned heparin (0.3-100 IU/min), saline or the endothelium-dependent vasodilators substance P (2-8 pmol/min) and bradykinin (100-1000 pmol/min), and the endothelium-independent vasodilator sodium nitroprusside (2-8 µg/min). Heparin caused a dose-dependent increase in plasma TFPI concentrations in both arms (ANOVA, p <0.0001). Estimated net forearm TFPI release was 7 ± 16, 29 ± 20 and 138 ± 72 ng/100 mL tissue/min during 10, 30 and 100 IU/min of heparin respectively (ANOVA, p <0.0001). Compared to the systemic circulation, the forearm sensitivity to heparin induced TFPI release was 3.6-fold lower (166 ± 67 ng/IU vs. 596 ± 252 ng/IU: t-test, p = 0.004). Substance P, bradykinin and sodium nitroprusside all caused substantial dose-dependent increases in blood flow (ANOVA, p <0.001 for all) without affecting plasma TFPI concentrations. There are important regional differences in endothelial TFPI release, with the forearm circulation being relatively insensitive to heparin.

Keywords

Tissue factor pathway inhibitor - haemostasis - heparin - substance P - bradykinin

Full Text

References

References
1 Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects. Arterioscler Thromb Vasc Biol 2002; 22: 539-48.
2 Crawley J. et al Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20: 1362-73.
3 Broze Jr. GJ. et al Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5: 551-9.
4 Soejima H. et al Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999; 99: 2908-13.
5 Taubman MB. et al Tissue factor in the pathogenesis of atherosclerosis. Thromb Haemost 1997; 78: 200-4.
6 Wilcox JN. et al Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
7 Abendschein DR. et al Maintenance of coronary patency after fibrinolysis with tissue factor pathway inhibitor. Circulation 1995; 92: 944-9.
8 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 28: S31-S33.
9 Rao AK. et al Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 1999; 48: 1156-61.
10 Idell S. Extravascular coagulation and fibrin deposition in acute lung injury. New Horiz 1994; 2: 566-74.
11 Tipping PG. et al Glomerular tissue factor expression in crescentic glomerulonephritis. Correlations between antigen, activity, and mRNA. Am J Pathol 1995; 147: 1736-48.
12 Sakkinen PA. et al Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. Thromb Haemost 1998; 80: 134-9.
13 Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78: 471-7.
14 Kojima T. et al Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001; 15: 60-4.
15 Badimon JJ. et al Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-7.
16 Roque M. et al Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-10.
17 Carr C. et al Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock 1994; 44: 126-37.
18 Westmuckett AD. et al Fluid flow induces upregulation of synthesis and release of tissue factor pathway inhibitor in vitro. Arterioscler Thromb Vasc Biol 2000; 20: 2474-82.
19 Grabowski EF. et al Shear stress decreases endothelial cell tissue factor activity by augmenting secretion of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2001; 21: 157-62.
20 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-13.
21 Giraux JL, Tapon-Bretaudiere J, Matou S, Fischer AM. Fucoidan, as heparin, induces tissue factor pathway inhibitor release from cultured human endothelial cells. Thromb Haemost 1998; 80: 692-5.
22 Kemme MJ, Burggraaf J, Schoemaker RC. et al The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor. Clin Pharmacol Ther 2000; 67: 504-11.
23 Webb DJ. The pharmacology of human blood vessels in vivo. J Vasc Res 1995; 32: 2-15.
24 Newby DE. et al An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium. Thromb Haemost 1997; 78: 1242-8.
25 Alban S, Gastpar R. Plasma levels of total and free tissue factor pathway inhibitor (TFPI) as individual pharmacological parameters of various heparins. Thromb Haemost 2001; 85: 824-9.
26 Labinjoh C. et al Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. J Am Coll Cardiol 2001; 38: 1402-8.
27 Labinjoh C. et al Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man. Cardiovasc Res 2000; 47: 707-14.
28 Kemme MJ. et al Quantification of heparin induced TFPI release: a maximum release at low heparin dose. Br J Clin Pharmacol 2002; 54: 627-34.
29 Stein CM. et al Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent ago-nists in human vasculature. J Am Coll Cardiol 1998; 32: 117-22.
30 Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev 2001; 81: 1415-59.
31 de Boer A. et al Influence of heparin and a low molecular weight heparinoid on specific endogenous and exogenous fibrinolytic factors during rest and exercise. Thromb Haemost 1992; 68: 550-5.
32 Piatti PM. et al Effects of low-dose heparin infusion on arterial endothelin-1 release in humans. Circulation 1996; 94: 2703-7.
33 Tangphao O. et al Heparin-induced vasodilation in human hand veins. Clin Pharmacol Ther 1999; 66: 232-8.
34 Yokokawa K, Tahara H, Kohno M. et al Heparin regulates endothelin production through endothelium-derived nitric oxide in human endothelial cells. J Clin Invest 1993; 92: 2080-5.