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Abstract
This article addresses the role of platelet membrane phosphatidylserine (PS) in regulating
the production of thrombin, the central regulatory molecule of blood coagulation.
PS is normally located on the cytoplasmic face of the resting platelet membrane but
appears on the plasma-oriented surface of discrete membrane vesicles that derive from
activated platelets. Thrombin, the central molecule of coagulation, is produced from
prothrombin by a complex ("prothrombinase") between factor Xa and its protein cofactor
(factor V(a)) that forms on platelet-derived membranes. This complex enhances the
rate of activation of prothrombin to thrombin by roughly 150,000 fold relative to
factor X(a) in solution. It is widely accepted that the negatively charged surface
of PS-containing platelet-derived membranes is at least partly responsible for this
rate enhancement, although there is not universal agreement on mechanism by which
this occurs. Our efforts have led to an alternative view, namely that PS molecules
bind to discrete regulatory sites on both factors X(a) and V(a) and allosterically
alter their proteolytic and cofactor activities. In this view, exposure of PS on the
surface of activated platelet vesicles is a key regulatory event in blood coagulation,
and PS serves as a second messenger in this regulatory process. This article reviews
our knowledge of the prothrombinase reaction and summarizes recent evidence leading
to this alternative viewpoint. This viewpoint suggests a key role for PS both in normal
hemostasis and in thrombotic disease.