Regulation of factor XIa activity by platelets and alpha 1-protease inhibitor.

Abstract

We have studied the complex interrelationships between platelets, Factor XIa, a1-protease inhibitor and Factor IX activation. Platelets were shown to secrete an inhibitor of Factor XMa, and to protect Factor XIa from inactivation in the presence of a1-protease inhibitor and the secreted platelet inhibitor. This protection of Factor Ma did not arise from the binding of Factor XIa to platelets, the presence of high molecular weight kininogen, or the inactivation of a1-protease inhibitor by platelets. The formation of a complex between a1-protease inhibitor and the active-site-containing light chain of Factor XMa was inhibited by activated platelets and by platelet releasates, but not by high molecular weight kininogen. These results support the hypothesis that platelets can regulate Factor XIa-catalyzed Factor IX activation by secreting an inhibitor of Factor XIa that may act primarily outside the platelet microenvironment and by protecting Factor XIa from inhibition, thereby localizing Factor IX activation to the platelet plug.

Characterization of a Heparin Binding Site on the Heavy Chain of Factor XI

“…Heparin and similar polyanions have been demonstrated to enhance several biochemical reactions involving FXI and FXIa. These include the activation of FXI by factor XIIa, thrombin, and autoactivation (16,17,35); and the inhibition of FXIa by the serpins ATIII (7,8,13), protease nexin II (11,38), and C1-INH (12). In the cases of autoactivation and protease nexin II-mediated inhibi- tion, there is clear evidence for a template mechanism in which FXI/FXIa must bind to heparin.…”

“…There is conflicting data concerning the major protease inhibitor of FXIa in plasma. Initial studies using kinetics and plasma-based assays suggested that ␣ 1 -antitrypsin (4 -6) is the predominant plasma inhibitor of FXIa with some contribution from antithrombin III (ATIII) (7,8,13). C1-inhibitor (C1-INH) (40,41), ␣ 2 -anti-plasmin (42), and protein C inhibitor (43) were also shown to inhibit FXIa.…”

“…The regulation of activated FXI (FXIa) appears to involve several plasma serine protease inhibitors (serpins). Initial work suggested that ␣ 1 -antitrypsin (4 -6) is the predominant plasma inhibitor of FXIa with some contribution from antithrombin III (ATIII) (5,7,8). Recent reports using monoclonal antibody-based enzyme-serpin complex capture techniques disagree with the earlier findings, and indicate a predominant role for C1-inhibitor (C1-INH) and a significant contribution from ␣ 2 -anti-plasmin (9).…”

The Role of Factor XI in Coagulation: A Matter of Revision

“…[41][42][43] In ad dition, a low molecular weight inhibitor was identi fied, called PIXI, but this platelet inhibitor is not wellcharacterized. 44 Although reversible inhibitors released from plate lets seem to protect factor XIa from irreversible inhibi tion by the plasma protease inhibitor α 1 -antitrypsin 45 and possibly other serine protease inhibitors, the precise role of the platelet inhibitors in the inactivation of factor XIa in vivo is not known.…”

The Mechanism by Which Heparin Promotes the Inhibition of Coagulation Factor XIa by Protease Nexin-2

“…In our present study, we found that exogenous heparin does not promote FXIa inhibition by PN-2 secreted from activated platelets (data not shown), probably as a consequence of the neutralization of heparin by platelet factor 4, which is also secreted, along with PN-2, from the ␣-granules of activated platelets (28 -30). Thus, the major regulator of FXIa within the vicinity of activated platelet thrombi is PN-2, a potent, slow, tight binding, reversible inhibitor of FXIa which is much less effective in inhibiting FXIa bound to the platelet surface in the presence of HK (8,10,31). Nonetheless, PN-2 may be much more effective in inhibiting FXIa bound to heparin-like molecules such as heparan sulfate on the surface of nonthrombogenic cells such as endothelial cells.…”