Platelet RNA chips dip into thrombocytosis.

PN-1 is a potent and specific inhibitor of thrombin, PN-2 operates by an entirely different mechanism, characteristic of the kunins, to serve as a potent (K i ϳ 500pM) and highly specific inhibitor of the unique, homodimeric coagulation proteinase, factor XIa (FXIa). Both PN-2 and PN-1 are present in plasma at concentrations far too low to inhibit their cog-nate proteinases, but are secreted from platelet ␣-granules to achieve high concentrations (ϳ 30nM in the case of PN-2) in the surrounding plasma. This is sufficient to inhibit enzymes at the initiation (FXIa) and termination (thrombin) of the consolidation pathway of coagulation, thereby preventing the propagation of intravascular coagulation beyond the nidus of the platelet hemostatic thrombus. Another important inhibitory mechanism relevant to the observations of Boulaftali et al 1 involves another Kunitz-type inhibitor, tissue factor pathway inhibitor (TFPI), which regulates the initiation of blood coagulation at sites of vascular injury. 6 In contrast to PN-1 and PN-2, however, TFPI is present in human plasma at high enough concentrations to inhibit FVIIa and FXa and the generation of thrombin. Once sufficient quantities of FXa have been formed to produce thrombin at the low concentrations required to activate plate-lets, FXI, FVIII, and FV, the consolidation pathway of blood clotting produces thrombin in sufficient quantities to convert fibrinogen to fibrin and form a hemostatic thrombus. 6 Moreover, platelets contain approximately 10% of the TFPI in blood and can release sufficient TFPI to increase the concentration roughly 3-fold to further inhibit the TF pathway. 6 These new findings, 1 interpreted in the context of our current knowledge of procoagu-lant and anticoagulant mechanisms mediated by activated platelets, emphasize the importance of the yin and yang of platelets in blood coagulation. Defects in the procoagulant contributions of platelets to the assembly of co-agulation complexes (yang) results in hemor-rhagic complications, whereas defects in the anticoagulant mechanisms (yin) produce serious thrombotic consequences that account for the vast majority of premature deaths in Western societies. Conflict-of-interest disclosure: The author declares no competing financial interests. ■ REFERENCES 1. Boulaftali Y, Adam F, Venisse L, et al. Anticoagulant and antithrombotic properties of platelet protease nexin-1.tion with platelets: influence of a platelet protease nexin. Progress curve analysis of the kinetics with which blood coagulation factor XIa is inhibited by protease nexin-2. Biochemistry. 1997;36(2):412-420. 5. Badellino KO, Walsh PN. Protease nexin II interactions with coagulation factor XIa are contained within the Kunitz protease inhibitor …