From the Hemostasis Research Center, Department of Internal Medicine,
Catholic University, Rome, Italy.
Correspondence to Dr Raimondo De Cristofaro, Centro Ricerche Fisiopatologia dell'Emostasi, Istituto di Semeiotica Medica, Università Cattolica S. Cuore, Largo F. Vito 1, 00168 Roma, Italy.
Background—Thrombin-thrombomodulin
(TM) interaction, which is critical for accelerating the protein C
anticoagulant pathway, involves the heparin-like domain of TM. This
study was aimed at investigating the possible effect of heparin on
thrombin-TM binding and protein C activation.
Methods and Results—The affinity of thrombin-TM interaction was
studied by a functional method, based on the ability of thrombin-TM
adduct to activate protein C, and by evaluation of the binding
of thrombin to immobilized TM. Both experimental approaches
showed that the affinity of thrombin-TM interaction was decreased by
micromolar heparin concentrations. Heparin had no significant effect
when a recombinant TM form, lacking the chondroitin sulfate moiety, was
used. Furthermore, it was also shown that the inhibitory
effect of heparin was directly proportional to the heparin molecular
mass (molecular weight range, 3 to 16 kDa), which suggests that the
effect was mediated by formation of electrostatic bonds between heparin
and thrombin.
Conclusions—These results indicate that heparin at therapeutic
concentrations reduces the affinity of thrombin for TM and the rate of
protein C activation. The magnitude of this effect is proportionally
linked to the molecular mass of heparin.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Effect of High- and Low-Molecular-Weight Heparins on Thrombin-Thrombomodulin Interaction and Protein C Activation
Key Words: heparin • glycoproteins • enzymes • proteins
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