Microparticles in Thrombosis and Hemostasis

Microparticles are submicron-size cellular fragments released by eukaryocytic cells following activation or apoptosis. First described as products of platelet activation in the late 1960s,[1] a limited number of laboratories continued to focus on the mechanism of formation of microparticles from platelets through the mid-1990s. The virtually exclusive focus on platelet-derived microparticles appeared to be vindicated by the realization that platelets from patients with Scott syndrome, a rare hemorrhagic disorder, failed to generate microparticles when activated.[2] In addition to their role in thrombin generation, in 1997 platelet microparticles were shown to act as transcellular activators of endothelial cells and other platelets.[3] At about the same time, reports characterizing the cellular origin and number of microparticles using quantitative flow cytometry protocols began to appear. By the end of the last millennium, microparticles had been described in normal human plasma and in other tissues such as atherosclerotic plaques,[4] [5] [6] [7] and with the possible exception of the early studies of Dvorak and colleagues on cancer cell–derived microparticles,[8] [9] a new focus on microparticles derived from cells other than platelets, possessing other pro- and anticoagulant activities, began to emerge. In the past decade, the number of microparticle publications has ballooned. The scope of reported activities has expanded beyond hemostasis and thrombosis to other areas of cancer and cardiovascular biology to include tumor growth and spread, angiogenesis, vascular reactivity, immune response and inflammation, and various types of transcellular activation.

The study of microparticles is thus a relatively new science that offers potential insights into novel mechanisms by which cells communicate with one another and with humoral mediators. As potential disease biomarkers, microparticle measurement and characterization in plasma could reveal otherwise enigmatic diagnostic and/or prognostic information in human disease, ranging from early diagnosis of cancer and cardiovascular disease to detection of subclinical organ rejection. However, before the full promise of microparticle analysis can be realized, it is clear that more accurate and reproducible technologies will be required.

With this background, this issue of Seminars in Thrombosis and Hemostasis, “The Role of Microparticles in Plasma in Hemostasis and Thrombosis” is presented in three sections. In the first section, the focus is on detection methodologies and includes a review of developments in conventional flow cytometry, as well as novel technologies such as impedance-based cytometry and several candidate light scattering approaches. The second section focuses on the formation and composition of microparticles from several cellular sources and discusses approaches to the measurement of procoagulant activity on microparticles. The final section examines the role of microparticles in various disease states, highlighting some of the insights that have been gained into the pathophysiology of coagulation disorders that occur in these disorders.

This comprehensive series of articles by a distinguished group of authors represents a state-of-the-art review of the current literature that we trust will be of educational and reference value to our readers.

REFERENCES

• 1 Wolf P. The nature and significance of platelet products in human plasma.  Br J Haematol. 1967;  13(3) 269-288
• 2 Sims P J, Wiedmer T, Esmon C T, Weiss H J, Shattil S J. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity.  J Biol Chem. 1989;  264(29) 17049-17057
• 3 Barry O P, Pratico D, Lawson J A, FitzGerald G A. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles.  J Clin Invest. 1997;  99(9) 2118-2127
• 4 Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet J M, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity.  Circulation. 1999;  99(3) 348-353
• 5 Nieuwland R, Berckmans R J, Rotteveel-Eijkman R C et al.. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant.  Circulation. 1997;  96(10) 3534-3541
• 6 Combes V, Dignat-George F, Mutin M, Sampol J. A new flow cytometry method of platelet-derived microvesicle quantitation in plasma.  Thromb Haemost. 1997;  77(1) 220
• 7 Abrams C S, Ellison N, Budzynski A Z, Shattil S J. Direct detection of activated platelets and platelet-derived microparticles in humans.  Blood. 1990;  75(1) 128-138
• 8 Carr J M, Dvorak A M, Dvorak H F. Circulating membrane vesicles in leukemic blood.  Cancer Res. 1985;  45(11 Pt 2) 5944-5951
• 9 Dvorak H F, Van DeWater L, Bitzer A M et al.. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells.  Cancer Res. 1983;  43(9) 4434-4442