Control of contact activation on end-point immobilized heparin: the role of antithrombin and the specific antithrombin-binding sequence.
The uptake and activation of FXII from blood plasma was studied in small-diameter polyethylene tubing, surface-modified by end-point immobilization of heparin. Two preparations of heparin were used to modify the contact-activating properties of the plastic tubing: unfractionated, functionally active heparin and low-affinity heparin, lacking the specific antithrombin-binding sequence and virtually devoid of anticoagulant activity. The uptakes of FXII on the two heparin surfaces were similar. No activated FXII could be demonstrated on the unfractionated heparin surface, whereas on the low-affinity heparin surface nearly all FXII underwent spontaneous activation. The suppression of FXII activation on the unfractionated heparin surface was investigated by using plasma depleted of antithrombin, complement C1 esterase inhibitor, or both. The removal of antithrombin resulted in extensive activation of FXII, whereas the depletion of C1 esterase inhibitor had only a minor effect. Experiments with recalcified plasma showed rapid clot formation during exposure to the low-affinity heparin surface. After depletion of antithrombin, but not complement C1 esterase inhibitor, the recalcified plasma clotted in contact with the unfractionated heparin surface as well. We conclude that antithrombin and the antithrombin-binding sequence in the surface-immobilized heparin are essential for the prevention of surface activation of FXII and triggering of the intrinsic coagulation system.
Sanchez
J
J
Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
Elgue
G
G
Riesenfeld
J
J
Olsson
P
P
D000818:Animals; D000991:Antithrombins / Q000737:chemistry*; D002118:Calcium / Q000097:blood; D002417:Cattle; D003174:Complement C1 Inactivator Proteins / Q000494:pharmacology; D005174:Factor XII / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding; D013499:Surface Properties; D013917:Thrombin / Q000737:chemistry; D014914:Whole Blood Coagulation Time
D000991:Antithrombins; D003174:Complement C1 Inactivator Proteins; D005174:Factor XII; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa; D002118:Calcium