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Volume 271, Number 22, Issue of May 31, 1996 pp. 12913-12918
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Modulation of Contact System Proteases by Glycosaminoglycans
SELECTIVE ENHANCEMENT OF THE INHIBITION OF FACTOR XIa

(Received for publication, December 14, 1995, and in revised form, February 27, 1996)

Walter A. Wuillemin , Eric Eldering , Franca Citarella ^¶ , Cornelis P. de Ruig , Hugo ten Cate and C. Erik Hack ^''

From the  Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands, ^¶ Dipartimento di Biopatologia Umana, Sezione di Biologia Cellulare, Università di Roma ``La Sapienza,'' 00161 Roma, Italy,  Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Center, and Slotervaart Ziekenhuis, Department of Internal Medicine, 1066 CX Amsterdam, and ^'' Department of Internal Medicine, Free University Hospital, 1081 HV Amsterdam, The Netherlands

We investigated the influence of dextran sulfate, heparin, heparan sulfate, and dermatan sulfate on the inhibition of FXIa (where FXIa is activated factor XI, for example), FXIIa, and kallikrein by C1 inhibitor, ₁-antitrypsin, ₂-antiplasmin, and antithrombin III. The second-order rate constants for the inhibition of FXIa by C1 inhibitor, ₁-antitrypsin, ₂-antiplasmin, and antithrombin III, in the absence of glycosaminoglycans, were 1.8, 0.1, 0.43, and 0.32 × 10³ M¹ s¹, respectively. The rate constants of the inactivation of FXIa by C1 inhibitor and by antithrombin III increased up to 117-fold in the presence of glycosaminoglycans. These data predicted that considering the plasma concentration of the inhibitors, C1 inhibitor would be the main inhibitor of FXIa in plasma in the presence of glycosaminoglycans. Results of experiments in which the formation of complexes between serine protease inhibitors and FXIa was studied in plasma agreed with this prediction. Glycosaminoglycans did not enhance the inhibition of -FXIIa, -FXIIa, or kallikrein by C1 inhibitor. Thus, physiological glycosaminoglycans selectively enhance inhibition of FXIa without affecting the activity of FXIIa and kallikrein, suggesting that glycosaminoglycans may modulate the biological effects of contact activation, by inhibiting intrinsic coagulation without affecting the fibrinolytic potential of FXIIa/kallikrein.

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