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High molecular weight kininogen inhibits thrombin-induced platelet
aggregation and cleavage of aggregin by inhibiting binding of thrombin to
platelets
RN Puri, F Zhou, CJ Hu, RF Colman and RW Colman
Thrombosis Research Center, Temple University Health Sciences Center,
Philadelphia, PA 19140.
In this study we show that high molecular weight kininogen (HK) inhibited
alpha-thrombin-induced aggregation of human platelets in a dose-dependent
manner with complete inhibition occurring at plasma concentration (0.67
mumol/L) of HK. HK (0.67 mumol/L) also completely inhibited
thrombin-induced cleavage of aggregin (Mr = 100 Kd), a surface membrane
protein that mediates adenosine diphosphate (ADP)- induced shape change,
aggregation, and fibrinogen binding. The inhibition of HK was specific for
alpha- and gamma-thrombin-induced platelet aggregation, because HK did not
inhibit platelet aggregation induced by ADP, collagen, calcium ionophore
(A23187), phorbol myristate acetate (PMA), PMA + A23187, or 9,11-methano
derivative of prostaglandin H2 (U46619). These effects were explained by
the ability of HK, at physiologic concentration, to completely inhibit
binding of 125I-alpha-thrombin to washed platelets. As a result of this
action of HK, this plasma protein also completely inhibited
thrombin-induced secretion of adenosine triphosphate, blocked intracellular
rise in Ca2+ in platelets exposed to alpha- and gamma-thrombin, inhibited
thrombin- induced platelet shape change, and blocked the ability of
thrombin to antagonize the increase in intracellular cyclic adenosine
monophosphate (cAMP) levels induced by iloprost. Because elevation of cAMP
is known to inhibit binding of thrombin to platelets, we established that
HK did not increase the intracellular concentration of platelet cAMP.
Finally, HK did not inhibit enzymatic activity of thrombin. To study the
role of HK in the plasma environment, we used gamma-thrombin to avoid
fibrin formation by alpha-thrombin. Platelet aggregation induced by gamma-
thrombin was also inhibited by HK in a dose-dependent manner. The EC50
(concentration to produce 50% of the maximum rate of aggregation) of
gamma-thrombin for washed platelets was 7 nmol/L and increased to 102
nmol/L when platelets were suspended in normal human plasma. The EC50 for
platelet aggregation induced by alpha-thrombin in plasma deficient in total
kininogen was 40 nmol/L. When supplemented with HK at plasma concentration
(0.67 mumol/L), the EC50 increased to 90 nmol/L, a value similar to that
for normal human plasma. These results indicate that (1) HK inhibits
thrombin-induced platelet aggregation and cleavage of aggregin by
inhibiting binding of thrombin to platelets; (2) HK is a specific inhibitor
of platelet aggregation induced by alpha- and gamma- thrombin; and (3) HK
plays a role in modulating platelet aggregation stimulated by
alpha-thrombin in plasma.
Volume 77,
Issue 3,
pp. 500-507,
02/01/1991
Copyright © 1991 by The American Society of Hematology
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