Platelets: yin and yang.

نویسنده

  • Peter N Walsh
چکیده

In this issue of Blood, Boulaftali and colleagues have made the important and novel observation that deficiency of the serine protease inhibitor (serpin), PN-1, in platelets results in a prothrombotic state, supporting the role of platelet PN-1 in thrombosis.1 Specifically, Boulaftali et al have initially confirmed previously published studies by Gronke et al indicating that protease nexin-1 (PN-1) is expressed by platelets.2 In studies on human platelets from healthy donors and from patients with the gray platelet syndrome ( -granular deficiency), the authors demonstrate that PN-1 is stored in platelet -granules, from which it is secreted into plasma and bound to the platelet membrane. There, it inhibits thrombin and urokinasetype plasminogen activator (uPA) and reduces thrombin generation by tissue factor (TF). Platelets from PN-1– deficient mice demonstrate increased sensitivity to thrombin in Pselectin expression and platelet aggregation. Thrombus formation, induced ex vivo by collagen under blood flow conditions and in vivo by ferric chloride–induced injury, was significantly increased in PN-1– deficient mice, demonstrating the antithrombotic properties of platelet PN-1. These studies demonstrate that platelet PN-1 has important antithrombotic properties that have heretofore gone unrecognized. It has been amply demonstrated that, in addition to playing a part in primary hemostasis by adhering to sites of vascular injury and aggregating to form the initial platelet plug, activated platelets have an essential role in blood coagulation by exposing receptors and assembling active enzymatic complexes for virtually all the coagulation proteins of the contact and consolidation pathways of the clotting cascade3 (see figure). What is less well appreciated is the regulatory role played by activated platelets in the secretion of coagulation inhibitors that limit the generation and activity of thrombin, localize active coagulation complexes to the platelet surface, and prevent uncontrolled intravascular thrombotic processes (see figure). Thus, for example, in addition to the serpin PN-1, another potent inhibitor stored in and secreted from platelet -granules is the Kunitz-type inhibitor (kunin), protease nexin-2 (PN-2). PN-2 is otherwise known as the Alzheimer -amyloid Schematic diagram representing the procoagulant and anticoagulant properties of activated platelets. The crescentic forms represent the activated platelet membrane, except in the case of the form labeled “TF●PL,” which represents tissue factor expressed on a phospholipid membrane surface. The roman numerals represent coagulation proteins including zymogens or substrates (in circles), enzymes (in circles with segmental excisions), and cofactors (in ellipses). The curved arrows represent conversions from zymogens (eg, prothrombin, shown as II) to active enzymes (eg, thrombin, shown as IIa), whereas the left-pointing arrows represent the inhibition of these active enzymes (eg, factor Xa, shown as Xa) to their inactivated forms (eg, inactivated factor Xa, shown as Xi). Shown in boxes are the Kunitz-type inhibitors, protease nexin-2 (PN-2) and tissue factor pathway inhibitor (TFPI), and the serpin, protease nexin-1 (PN-1). The initiation of the coagulation mechanism occurs as the consequence of the assembly of the FVIIa/FX/TF/PL complex and is regulated by TFPI, whereas the consolidation phase of coagulation, regulated by PN-2 and PN-1, is activated by the resulting generation of low concentrations of thrombin sufficient to activate platelets, FXI, FVIII, and FV to produce thrombin in sufficient quantities to form a fibrin clot.

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عنوان ژورنال:
  • Blood

دوره 115 1  شماره 

صفحات  -

تاریخ انتشار 2010