EFFECT OF SELECTIVE FACTOR XA INHIBITION ON ARTERIAL THROMBUS FORMATION TRIGGERED BY TISSUE FACTOR FACTOR VIIA OR COLLAGEN IN AN EX-VIVO MODEL OF SHEAR-DEPENDENT HUMAN THROMBOGENESIS/

Tick anticoagulant peptide (TAP) is a potent and selective inhibitor o f factor Xa. TAP has shown good antithrombotic efficacy in experimenta l animal models of disseminated intravascular coagulation and venous a nd arterial thrombogenesis. In the present study we evaluated the effe ct of recombinant TAP (rTAP) on acute thrombus formation in human nona nticoagulated blood triggered either by tissue factor (TF) or by colla gen at arterial shear conditions. The main goal was to establish the r ole of factor Xa in thrombus formation by use of an optimal inhibitory concentration of rTAP. Blood was drawn directly from an antecubital v ein by a pump over the respective thrombogenic surfaces, which were po sitioned in a parallel-plate perfusion chamber, rTAP was mixed homogen eously into the flowing blood by a heparin-coated device positioned pr oximal to the perfusion chamber. The passage of blood through this dev ice caused minor activation of coagulation but little activation of pl atelets. Fibrinopeptide A and beta-thromboglobulin levels after 5 minu tes of blood perfusion were, on average, 14 ng/mL and 45 IU/mL, respec tively. rTAP at a plasma concentration of 0.90 mu mol/L. completely in hibited TF/factor VIIa-dependent thrombus formation at wall shear rate s of 650 and 2600 s(-1). These shear conditions are comparable to thos e in medium-sized arteries and in moderately stenosed small arteries, respectively. In contrast to the TF-coated surface, rTAP was less effi cient in reducing collagen-induced thrombus formation. While a signifi cant reduction of 53% was observed at 650 s(-1), thrombus formation at 2600 s(-1) was not affected by rTAP. Thus, rTAP is an efficient inhib itor of thrombin-driven human thrombus formation on the TF-rich surfac e but less efficient when thrombus formation is elicited by type III c ollagen. The lack of antithrombotic effect on collagen type III at 260 0 s(-1) corroborates earlier findings, showing that collagen-induced t hrombus formation in blood from patients with severe factor VIII defic iency is not affected at this blood flow condition and thus is not dep endent on the prothrombotic effects of thrombin.