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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2308-2313
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Prothrombin protects factor Xa in the prothrombinase complex from
inhibition by the heparin-antithrombin complex
Alireza R. Rezaie
From the Edward A. Doisy Department of Biochemistry and
Molecular Biology, St Louis University School of Medicine, MO.
Heparin is a commonly used anticoagulant drug. It functions
primarily by accelerating the antithrombin inhibition of coagulation proteinases, among which factor Xa and thrombin are believed to be the
most important targets. There are conflicting results as to whether
anticoagulant heparins can catalyze the antithrombin inhibition of
factor Xa in the prothrombinase complex (factor Va, negatively charged
membrane surfaces, and calcium ion), which is the physiologically
relevant form of the proteinase responsible for the activation of
prothrombin to thrombin during the blood coagulation process. In this
study, a novel assay system was developed to compare the catalytic
effect of different molecular-weight heparins in the antithrombin
inhibition of factor Xa, either in free form or assembled into the
prothrombinase complex during the process of prothrombin activation.
This assay takes advantage of the unique property of a recombinant
mutant antithrombin, which, similar to the wild-type antithrombin,
rapidly inhibits factor Xa, but not thrombin, in the presence of
heparin. A direct prothrombinase inhibition assay, monitoring thrombin
generation under near physiological concentrations of prothrombin and
antithrombin in the presence of therapeutic doses of low- and
high-molecular-weight heparins, indicates that factor Xa in the
prothrombinase complex is protected from inhibition by antithrombin
more than 1000 times, independent of the molecular size of heparin.
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