Modulation of contact system proteases by glycosaminoglycans. Selective enhancement of the inhibition of factor XIa.
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, alpha1-antitrypsin, alpha2-antiplasmin, and antithrombin III. The second-order rate constants for the inhibition of FXIa by C1 inhibitor, alpha1-antitrypsin, alpha2-antiplasmin, and antithrombin III, in the absence of glycosaminoglycans, were 1.8, 0.1, 0.43, and 0.32 x 10(3) M-1 s-1, 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 alpha-FXIIa, beta-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.
Wuillemin
W A
WA
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, University of Amsterdam, Amsterdam, The Netherlands.
Eldering
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E
Citarella
F
F
de Ruig
C P
CP
ten Cate
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H
Hack
C E
CE
D000577:Amides / Q000378:metabolism; D000990:Antithrombin III / Q000494:pharmacology; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D015945:Factor XIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors; D007700:Kinetics; D015843:Serpins / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D000577:Amides; D003169:Complement Inactivator Proteins; D006025:Glycosaminoglycans; D015843:Serpins; D000515:alpha 1-Antitrypsin; D000979:alpha-2-Antiplasmin; D000990:Antithrombin III; D010450:Endopeptidases; D007610:Kallikreins; D015945:Factor XIa