Activation of blood coagulation at heparin-coated surfaces.
It is hypothesized that immobilized heparin exerts a dual role in blood coagulation. On the one hand, the heparinized surface is because of its dense negative charge, thought to initiate the intrinsic pathway of blood coagulation. On the other hand, heparin is known as a potent anticoagulant drug. However, it remains to be seen how much contact-phase activation of factor XI contributes to thrombin formation and how this process is counterbalanced by which of the anti-protease activities of immobilized heparin. In the present study we examined the generation of factors XIa, IXa, and Xa, and thrombin in recalcified normal and antithrombin-depleted plasma exposed to polyacrylamide-graft polyurethane (PU) sheets modified by multipoint attachment of two different heparin species. One of them, HAH, contained the specific antithrombin binding sequence and the other one, NAH, had a low affinity for antithrombin and had no anticoagulant activity. Our data demonstrate that in contrast to PU, PU-NAH and PU-HAH are strong mediators of factor XIa and factor IXa formation in normal and antithrombin-deficient plasma. Interestingly, compared to PU-HAH and PU-NAH, thrombin formation was only slightly diminished in antithrombin-deficient plasma exposed to PU. In contrast, thrombin formation was dramatically delayed and diminished in normal plasma exposed to PU-HAH. These findings indicate that very low amounts of factor XIa apparently suffice to induce significant amounts of thrombin. In this sense, heparinized surfaces are highly thrombogenic, but our data also indicate that this activity is effectively counterbalanced by the anti-thrombin activity of the immobilized anti-coagulant species of heparin.
Blezer
R
R
Department of Biochemistry, University of Limburg, Maastricht, The Netherlands.
Fouache
B
B
Willems
G M
GM
Lindhout
T
T
D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000378:metabolism; D001672:Biocompatible Materials / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D015949:Factor IXa / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008422:Materials Testing; D013499:Surface Properties; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D001672:Biocompatible Materials; D000990:Antithrombin III; D006493:Heparin; D015949:Factor IXa; D015945:Factor XIa; D013917:Thrombin; D015951:Factor Xa