Atherosclerosis is a modern human disease caused by genetic, environmental, and degenerative (i.e., senescence) factors. It is therefore likely that a unique set of factors operate within Virchow's triad to promote thrombosis when a coronary plaque ruptures or when an internal carotid artery continues to narrow beyond a 60 percent stenosis. If we can identify these factors and rank their importance in the patho-genesis of heart attack or stroke, we might be provided with the opportunity to develop drugs that target these factors. An ideal drug will inhibit thrombosis without inhibiting hemo-stasis. It will be "lesion-specific."
Differentiating molecular determinants of platelet GpIb-IX-V-mediated hemostasis from those regulating thrombosis is difficult and perhaps futile. It is difficult because there are few experimental systems that provide an examination of both hemostasis and thrombosis while also controlling for the important prothrombotic and antithrombotic variables simultaneously operating within Virchow's triad. This difficulty will likely be overcome because such experimental systems—both flow chambers and whole animal preparations—are being continually revised and optimized. It is perhaps futile because the evolutionary principles of conservation of function and functional redundancy must also apply to platelet GpIb-IX-V But such principles may relate mainly to physiology and not pathology, and it is reasonable to consider that they may not apply to GpIb-IX-V when it serves a pathological response.
Further experimentation will test the hypothesis that there are specific molecular determinants directing platelet GpIb-IX-V-mediated thrombosis but not hemostasis (i.e., "lesion-specific" determinants). If the hypothesis is validated, new drugs for heart attacks, strokes, and periph eral arterial diseases will be developed that have a therapeutic index superior to those currently in use. If the hypothesis is refuted, data generated during the process will inevitably contribute to our understanding of microvascular pathophysiology. Such a "win-win" situation reflects both the importance and the wonderfully mazelike complex heterogeneity of human microvascular circulation.
Andre, P., Delaney, S. M., LaRocca, T., Vincent, D., DeGuzman, F., Jurek, M., Koller, B., Phillips, D. R., and Conley, P. B. (2003). P2Y12 regulates platelet adhesion/activation, thrombus growth and thrombus stability in injured arteries. J. Clin. Invest. 112, 398-406. P2Y12 knockout mice had very elevated bleeding times. Provoked arterial thrombus formation was delayed and decreased. Platelet tethering to and translocation along the injured artery were unaffected. ADP-induced platelet activation resulting from a GpIb-IX-V initiated feedback loop that begins with dense granule release and terminates on the P2Y12 receptor is an essential component of both hemostasis and thrombosis. Eichorn, M. E., Ney, L., Massberg, S., and Goetz, A. E. (2002). Platelet kinetics in the pulmonary microcirculation in vivo assessed by intravital microscopy. J. Vasc. Res. 39, 330-339. This paper establishes experimental measurements of an entire microvascular circuit. The subject of their paper—the rabbit pulmonary microvasculature having a luminal diameter less than about 40 mm—is particularly useful and illuminating when considering platelet determinants of hemostasis and thrombosis. This is because the investigators specifically assayed platelet movement through the entire microvasculature and determined that red cell streams and vessel size determine platelet Gplb-IX-V-dependent hemostasis (an arteriolar response) while platelet activation (which does not affect GpIb-IX-V function) determines the magnitude of platelet deposition and thrombosis in the capillaries and venules. Feng, S., Resendiz, J. C., Lu, X., and Kroll, M. H. (2003). Filamin A binding to the cytoplasmic tail of glycoprotein Iba regulates von Willebrand factor-induced platelet activation. Blood 102, 2122-2129. Shear-induced binding of VWF to GpIb-IX-V may activate platelets and stimulate thrombosis by transducing the frictional shearing force generated by pathological blood flow through a cytoskeletal tether that links the cytoplasmic domains of GpIba and the 03 subunit of aIIb03. Such a tether is shown to operate at a shear stress that exceeds any within the microvasculature, suggesting that it could be a mechanism of platelet activation that develops only under conditions of pathological arterial blood flow.
Jackson, S. P., and Schoenwaelder, S. M. (2003). Antiplatelet therapy: In search of the "magic bullet." Nat. Rev. Drug Discov. 2, 775-789. A
review of clinically important platelet physiology, pathophysiology, and pharmacology. It emphasizes the feasibility and importance of hunting for platelet proteins that specifically direct thrombotic responses without affecting hemostasis. If one such protein were discovered and targeted pharmacologically, it would be an ideal drug for acute arterial occlusion.
Liu, L., and Kubes, P. (2003). Molecular mechanisms of leukocyte recruitment: Organ-specific mechanism of action. Thromb. Haemost. 89, 213-220. This review provides an important and unique perspective from which to examine the microvasculature. It describes our state-of-knowledge of organ-specific microvasculature function focusing on the liver (where capillaries are arranged in discontinuous sinusoids) and the brain (where capillaries are fused tightly together to form the "blood—brain barrier"). Although platelets are not emphasized, information is presented in support of the hypothesis that GpIb-IX-V is a "bridge for the endothelial—leukocyte—platelet interaction." Moake, J. L. (2002). Thrombotic microangiopathies. N. Engl. J. Med. 347, 589-600. This clear and beautifully illustrated review article describes the biology of VWF and ADAMTS13. It also breaks down the nosology of the "TMs" into a pathophysiological framework, with TTP a unique disease resulting from ADAMTS13 deficiency and HUS a separate disease resulting from an insult (e.g., an enterotoxin) to specific microvas-cular compartments (e.g., the renal glomerulus).
Nieswandt, B., and Watson, S. P. (2003). Platelet-collagen interaction: Is GpVI the central receptor? Blood 102, 449-461. This thorough review examines the question of platelet determinants of hemostasis versus thrombosis from a collagen receptor point of view. Based on an extensive body of work (much of it done in the authors' laboratories) they conclude that collagen binding to GpVI is more important than collagen binding to integrin a201, and that GpVI is an important co-receptor mediating hemostasis and thrombosis.
Sadler, J. E. Contact—how platelets touch von Willebrand factor. Science 297, 1128-1129. This is a small review based on an accompanying paper by Huizinga et al. presenting the crystal structure of the VWF/GpIba interaction. In summary, the model of platelet adhesion emphasizes that first contact involves the N-terminal hairpin of GpIba's extracellular domain binding to VWF's A1 domain. This binding appears to be shear dependent, with elevated shear stress displacing an inhibitory N-terminal extension of the VWF A1 domain. Following this initial contact, GpIba's extracellular domain undergoes a 0-switch that directs a second contact between several of its leucine-rich repeats and another site on VWF's A1 domain. These primary and secondary contacts are probably transitory, as shear stress drives platelet rolling (or tumbling), implying that bonds between VWF and GpIba are being rapidly formed and broken. In order for stable adherence to develop, shear-dependent platelet capture and rolling must be followed by collagen binding to GpVI and a.201, and by VWF binding to activated aIIb03.
Wagner, D. D., and Burger, P. C. (2003). Platelets in inflammation and thrombosis. Arterioscler. Thromb. Vasc. Biol., 23, 2131-2137. This timely review presents experimental evidence of many different mechanisms by which platelets participate in the inflammatory response. It reminds us that vascular pathology should generally be considered within the context of Virchow's triad for the pathogenesis of thrombosis, even when thrombosis is an irrelevant or minor secondary response. Platelets, and platelet GpIb-IX-V, appear to be important components in the pathophysiology of many inflammatory processes in the low-shear microvasculature and may be critically important in the initiation of atherosclerosis in the high shear macrovasculature.
Ware, J., Russell, S., and Ruggeri, Z. M. (2000). Generation and rescue of a murine model of platelet dysfunction: The Bernard-Soulier syndrome. Proc. Natl. Acad. Sci. USA 97, 2803-2808. It is possible that all future knowledge about distinct mechanisms of GpIb-IX-V-mediated hemostasis versus thrombosis will be based on this or related mouse models. This paper shows that the deficiency of GpIba in mice recapitulates a human disease. In doing this, it raises the possibility that genetically engineered alterations of GpIba function in mice—both decreased or increased function—will someday pinpoint molecular interactions that are specifically prothrombotic or prohemostatic.
Dr. Kroll is a member of the Specialized Center for Research in Thrombosis and an Associate Professor of Medicine and Molecular Physiology and Biophysics at Baylor College of Medicine. He is also an Associate Professor of Bioengineering at Rice University, where he is a member of the Cox Laboratory for Biomedical Engineering. His research, which is funded by the National Institutes of Health and the Department of Veterans' Affairs, focuses on mechanisms by which rheological factors affect platelet adhesion-activation coupling.
Dr. Feng is an Assisaent Professor of Medicine in the Section of Hematology-Oncology. His research to identify unique prothronbotic pletelet signaling pathways is funded by the Amercian Heart Assocation.
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