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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1369.)
© 2002 American Heart Association, Inc.

Editorials

A Simple Experiment and a Weakening Paradigm

The Contribution of Blood to Propensity for Thrombus Formation

Yale Nemerson

From the Department of Molecular Medicine, Mount Sinai School of Medicine, Annenberg, New York.

Correspondence to Dr Yale Nemerson, Division of Thrombosis Research, Department of Medicine, Mount Sinai School of Medicine, 1 Gustave Levey Pl, Box 1269, Annenberg, NY 10029-6504. E-mail Yale.Nemerson{at}mssm.edu

For many years, arterial thrombosis was considered a result of vascular injury combined with a "normal" response of circulating coagulation factors and formed elements. Indeed, the original articles describing tissue factor in atherosclerotic lesions^1,2 implied that rupture or erosion of the plaque that results in contact of the circulating blood with plaque-bound tissue factor is sufficient to result in thrombus formation. These formulations ignore the fact that thrombi have been observed to occlude an artery within minutes of vascular perturbations.³ In retrospect, the role assigned to lesion-bound tissue factor is not physically realistic. The implied mechanism of thrombus growth is that surface-bound tissue factor rapidly binds circulating factor VII/VIIa, thereby forming the catalytic complex that proteolytically activates factors IX and X, thereby generating procoagulant intermediates that lead to thrombin production. This necessarily involves the diffusion of these intermediates from surface-bound tissue factor to platelets, where they form the catalytic complexes that directly generate thrombin from prothrombin. While on a microscopic level, these events are certainly accurate; occlusive thrombi are macroscopic structures that can rapidly grow to 3 mm. Consider that a protein of 50 kDa, typical of procoagulant intermediates, would, on average, take some 3 hours to diffuse 1 mm through water. In reality, the diffusion would be obstructed by adherent platelets and fibrin, which would reduce further the effective diffusion rate of these proteins.

See pages 1495

This reasoning led us to examine more closely the participation of blood components in thrombus propagation. Using ex vivo and in vitro techniques, we were able to demonstrate the participation of blood-borne tissue factor in the formation of thrombi on collagen-coated surfaces and on arterial media.⁴ The article by Karnicki and colleagues⁵ significantly expands the previous results inasmuch as they performed a simple but revealing quantitative experiment. The fundamental question they addressed is the relative contribution of blood elements and arterial surfaces to formation of thrombi on arterial segments perfused with heparinized blood. The experimental design enabled these investigators to conclude that, in an all-porcine system, the thrombotic mass was more regulated by the blood than by the particular arterial segment used. The experiments were straightforward: blood was obtained from 25 pigs and perfused over arterial segments derived from a single donor aorta. The obverse experiment in which blood derived from 8 different donors was perfused over segments obtained from 12 donors was also performed. Importantly, the thrombotic mass was much more influenced by the blood as compared with the arterial wall.

This interesting and important result clearly indicates the importance of circulating elements in thrombogenesis. Thus, the speculations arising from the identification of circulating tissue factor-containing microparticles⁶ and elevated levels of tissue factor antigen noted in patients with acute coronary syndromes⁷ now has experimental verification. The mechanism underlying this phenomenon has yet to be clearly elucidated. Karnicki et al⁵ unexpectedly found that thrombus mass correlated with the lymphocyte count. Although the leukocyte count has been suggested as a risk factor for myocardial infarction,⁸ the current data could be explained by an unknown mechanism, even viral infection, as suggested by these authors. Whatever the explanation, these studies warrant a considerable effort to establish the way in which blood regulates thrombus growth. While porcine thrombosis resembles the human condition, we note the obvious differences between pigs and man.

References

1. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989; 86: 2839–2843.[Abstract/Free Full Text]
2. Zeldis SM, Nemerson Y, Pitlick FA, Lentz TL. Tissue factor (thromboplastin): localization to plasma membranes by peroxidase-conjugated antibodies. Science. 1972; 175: 766–768.[Abstract/Free Full Text]
3. Ambrose JA, Almeida OD, Sharma SK, Dangas G, Ratner DE. Angiographic evolution of intracoronary thrombus and dissection following percutaneous transluminal coronary angioplasty (the Thrombolysis and Angioplasty in Unstable Angina [TAUSA] trial). Am J Cardiol. 1997; 79: 559–563.[CrossRef][Medline] [Order article via Infotrieve]
4. Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A. 1999; 96: 2311–2315.[Abstract/Free Full Text]
5. Karnicki K, Owen W, Miller R, McBane RDII. Factors contributing to individual propensity for arterial thrombosis. Arterioscler Thromb Vasc Biol. 2002; 22: 1495–1499.[Abstract/Free Full Text]
6. Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999; 99: 348–353.[Abstract/Free Full Text]
7. Suefuji H, Ogawa H, Yasue H, Kaikita K, Soejima H, Motoyama T, Mizuno Y, Oshima S, Saito T, Tsuji I, Kumeda K, Kamikubo Y, Nakamura S. Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J. 1997; 134: 253–259.[CrossRef][Medline] [Order article via Infotrieve]
8. Phillips AN, Neaton JD, Cook DG, Grimm RH, Shaper AG. Leukocyte count and risk of major coronary heart disease events. Am J Epidemiol. 1992; 136: 59–70.[Abstract/Free Full Text]

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