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THE EVOLUTION OF HEMOSTATIC MECHANISMS OSCAR D. RATNOFF* The survival of every living creature depends on the preservation of its internal environment. In mammals, complex mechanisms have evolved that limit blood loss after vascular damage, phenomena described generically as hemostasis. An almost immediate response is transient vasoconstriction, probably ofonly minor benefit. Two other devices are of much greater importance, adhesion and aggregation of circulating blood platelets and the coagulation of blood. In the specialized case of the uterus, contraction of the myometrium after delivery applies external pressure on the uterine blood vessels that cuts off the influx of blood and helps to control bleeding from the placental site. Analogous responses to injury are observed in even the lowest of creatures, that is, contraction of tissues, cellular aggregation, and the gelation ofbody fluids. Current evidence, however, suggests that, by and large, these defenses have arisen independently in invertebrates and vertebrates, for the phylogenetic chain from protozoans to mammals is as yet by no means apparent.1 Human Hemostasis A briefsynopsis of some of the reactions involved in the protection of human beings against blood loss may serve as a background against Dr. Georgia E. Lesh-Laurie, Cleveland State University, aided in my understanding of invertebrate evolution. Dr. Robert Good, Ms. Joanne Finstad, and the late Dr. Frank Belatnarich provided the plasmas of primitive fish and Dr. David A. Rickards, of seals. Supported in part by grant HL01661 from the National Heart, Lung, and Blood Institute, the National Institutes of Health, U.S. Public Health Service and, in part, by grants from the American Heart Association. ?Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio 44106. Career Investigator of the American Heart Association. 1TWs review makes no attempt to be all-inclusive. Rather, I have tried to summarize some striking features of the evolution of hemostasis. I offer a broad apology to those whose studies I have inadvertendy overlooked.© 1987 by The University of Chicago. AU rights reserved. 0031-5982/88/3101-0551$01.00 4 I Oscar D. Ratnoff ¦ Hemostatic Mechanisms which to compare similar devices that have evolved in both invertebrates and vertebrates. A normal constituent of human blood is a disk-shaped, anuclear cell, the platelet, that is derived from the cytoplasm of megakaryocytes , large cells found, in the adult, in bone marrow. When the endothelial lining of blood vessels is disrupted by injury, an almost immediate response is adhesion of platelets to exposed subendothelial structures, particularly collagen. The adherent platelets assume a more spherical shape and extrude pseudopods or spicules that spread like the legs of a spider along the subendothelial structures. At the same time, the platelets' cytoplasmic granules release agents through a canalicular system open to the surrounding milieu. The agents discharged during this release reaction, among them adenosine diphosphate (ADP) and the prostaglandin thromboxane A2, attract circulating platelets that stick both to those platelets that are adherent to the vascular wall and to each other, forming aggregates that halt the flow of blood from minor wounds. Soon, too, the blood trapped within the platelet aggregates coagulates, a phenomenon abetted by the platelets' own clot-enhancing properties; thrombin, a proteolytic enzyme generated during the process of blood coagulation, can bring about further aggregation of platelets. The clots solidify the platelet aggregates, enhancing their hemostatic properties. In the test tube, the blood clot normally shrinks, extruding serum; this phenomenon ofclot retraction is a function ofthe platelets within the clotted mass. As will be seen, the hemostatic behavior ofplatelets is superficially similar to reactions seen in the lowest metazoa. Larger wounds are sealed by clotting, that is, the gelation of plasma. The clot is made up of an insoluble network of protein fibers, fibrin, within whose meshes blood cells and plasma (more properly, serum) are entrapped. Fibrin is derived from a soluble plasma precursor, fibrinogen (factor I), a dimer, each half of which is composed of three nonidentical polypeptide chains, designated as Aa, Bß, and y. The conversion of fibrinogen to fibrin takes place in three steps (fig. 1). In the first, thrombin, a protease that is generated by earlier steps of the clotting process, cleaves two pairs ofsmall polypeptides...


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