Trombos

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The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Mechanisms of Disease

Mechanisms of Thrombus Formation
Bruce Furie, M.D., and Barbara C. Furie, Ph.D.

From the Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, and Harvard Medical School — both in Boston. N Engl J Med 2008;359:938-49.
Copyright © 2008 Massachusetts Medical Society.H

emostasis is the process that maintains the integrity of a closed, high-pressure circulatory system after vascular damage. Vessel-wall injury and the extravasation of blood from the circulation rapidly initiate events in the vessel wall and in blood that seal the breach. Circulating platelets are recruited to the site of injury, where they become a major component of the developingthrombus; blood coagulation, initiated by tissue factor, culminates in the generation of thrombin and fibrin. These events occur concomitantly (Fig. 1A; also see Video, available with the full text of this article at www.nejm.org), and under normal conditions, regulatory mechanisms contain thrombus formation temporally and spatially. When pathologic processes overwhelm the regulatory mechanisms ofhemostasis, excessive quantities of thrombin form, initiating thrombosis (Fig. 1B; and Video, Chap. 2). Thrombosis is a critical event in the arterial diseases associated with myocardial infarction and stroke, and venous thromboembolic disorders account for considerable morbidity and mortality. Moreover, venous thrombosis is the second leading cause of death in patients with cancer. Our understandingof the molecular and cellular basis of thrombus formation has advanced greatly through the use of novel techniques for studying mouse models of thrombosis. In this article, we review recent advances in knowledge about thrombus formation. We also offer new hypotheses and some speculations about thrombus formation and the prevention and treatment of thrombosis.
Figure 1 (facing page). ThrombusFormation In Vivo. The developing thrombus in a living mouse after vessel-wall injury (Panel A) is characterized by the deposition of platelets (red), tissue factor (green), and fibrin (blue). Platelet thrombus formation and fibrin deposition occur concomitantly. Platelets and tissue factor appear yellow; tissue factor and fibrin, turquoise; platelets and fibrin, magenta; and platelets, fibrin, andtissue factor, white. A three-dimensional, confocal optical reconstruction of a thrombus in the lumen of an arteriole (Panel B) shows the platelet thrombus (red and yellow) being formed in the vessel wall, which is lined with the endothelium (labeled green with antibodies to platelet-endothelial cell-adhesion molecule [PECAM-1]). Platelets are labeled red using antibodies to CD41; platelets stainedwith both CD41 and PECAM-1 appear yellow. Calcium is mobilized during platelet activation. Panel C shows platelets loaded with a calcium-sensitive dye during thrombus formation; resting platelets appear green, and activated platelets appear yellow. Labeled microparticles bearing tissue factor (Panel D, green) infused into a recipient mouse accumulate in the developing thrombus. In Panel E,expression of protein disulfide isomerase (PDI, green) is shown during thrombus formation. Panel F shows fibrin (green) and platelets (red), which appear rapidly after vessel-wall injury and form a thrombus; yellow indicates colocalization of fibrin and platelets. In Panel G, inhibition of PDI blocks platelet accumulation and the generation of fibrin, and neither is observed. A video showing the processof thrombus formation in live mice is available with the full text of this article at www.nejm.org.

938

n engl j med 359;9

www.nejm.org

august 28, 2008

Downloaded from www.nejm.org at UNIVERSIDAD DE CHILE on August 11, 2009 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.

mechanisms of disease

For m at ion of a Pl atel e t Thrombus
The vessel wall,...
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