July 25, 2002 CHAPEL HILL -- New research at the University of North Carolina at Chapel Hill has found that a fatty molecule on the surface of platelet cells is a regulator of blood coagulation. Besides its role in forming cell membranes, the lipid phosphatidylserine, or PS, also appears to activate the final step in the process of blood coagulation - the conversion of prothrombin to thrombin, the central enzyme of coagulation. Thrombin is needed both to encourage and then cut off clotting at a wound.
A report of the research appears in the online edition of the Journal of Biological Chemistry; print publication is slated for August. Senior author is Dr. Barry R. Lentz, professor of biochemistry and biophysics at the UNC School of Medicine.
Dr. Harold Roberts, Sarah Graham Kenan professor of medicine and pathology at the medical school and a renowned hematology expert, hailed the new results as "a major accomplishment in our understanding of blood coagulation which is essential to our understanding of blood clotting disorders that cause heart attacks and strokes, the major causes of mortality in the United States and the rest of the Western world."
Lentz said the new paper is the culmination of a series of reports from his laboratory countering a popular belief in the field about blood cell membranes' role in thrombin production. In that view, thrombin production occurs in a reaction occurring on the surface membranes of platelets, the blood cell responsible for clotting. Although Lentz, and then others, showed that membranes containing PS work best in thrombin formation, the popular view proposed no role for PS except that it is a negatively charged component of platelet membrane structure.
Lentz said the new findings unequivocally support a new view, that PS can activate conversion of prothrombin to thrombin in the absence of the platelet membrane surface. And it does so by triggering assembly of the enzyme complex, prothrombinase, which is crucial to that process, he added.
"Our research findings demonstrate clearly that we formed the complex in solution and that the formation and activity of the complex are regulated by phosphatidylserine," Lentz said.
Roberts agreed. "Dr. Lentz's results settle a long-running controversy in the field of blood coagulation as to the role of fatty acids in blood coagulation. Most investigators have long held the belief that PS was simply a co-factor for other components on platelets necessary to form normal amounts of the clotting enzyme but now Dr. Lentz and his colleagues have clearly shown that PS is the major, if not the only, component necessary for this reaction."
Platelets are the components of blood affected by aspirin, Lentz said. "When doctors prescribe aspirin to 'thin the blood,' what that does is reduce activation of platelets and exposure of PS on their surface membranes to the plasma. That's what aspirin therapy is."
Prothrombinase, which catalyzes prothrombin conversion to thrombin, contains the blood coagulation proteins, factors Xa and Va. Previous work in Lentz's lab with a soluble form of PS showed that both proteins have a small number of specific binding sites for PS and that soluble PS binds to these sites, as does normal PS located in a platelet membrane. In doing so, factors Xa and Va bind to each other in solution as tightly as they are bound together on a membrane surface.
Moreover, the study indicates that PS triggers catalysis and makes sure that prothrombinase biochemically "cuts" prothrombin properly, thereby allowing conversion to an effective thrombin molecule, not a dead-end bi-product.
In addition, Lentz and co-authors Drs. Rinku Majumder, Gabriel Weinreb and Xin Zhai suggest that platelet membrane PS can be thought of as a "second messenger" in regulating blood coagulation. Thus, in the ever-ongoing stream of cell signaling, activation of platelets when a wound occurs triggers exposure of PS on the platelet membrane surface, which Lentz's work shows regulates the key event of the coagulation process, thrombin formation.
In that context and in light of the new findings, Lentz sees a role for PS in drug development. "If you want to control blood coagulation - either to promote it or to diminish it in a setting where you don't want clots to form - the binding sites for phosphatidylserene may be good targets for drug design," he said.
The study was supported by a grant from the National Heart, Lung and Blood Institute of the National Institutes of Health.
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