Snake venom-derived disintegrin is a family of low molecular weight, cysteine-rich, RGD-containing peptides that inhibit the binding of ligands to the glycoprotein IIb/IIIa receptor on the platelets, and this is known to mediate the final common pathway in platelet aggregation. A Disintegrin And Metalloproteinase (ADAM) was recently discovered in humans, and it contains a disintegrin domain that shows high homology with the snake venom disintegrin. However, the effect of ADAM on platelet aggregatioin is not yet clear. The aim of this study was to evaluate the antiplatelet effect of ADAM-derived recombinant human disintegrin and the synthetic peptides that were produced on the basis of the RGD sequence of this disintegrin. A cDNA encoding the disintegrin domain of ADAM 15 was cloned, expressed and then highly purified in Pichia pastoris. The cyclic peptides were synthesized on the basis of the sequence including the RGD pepetides on ADAM 15. The antiplatelet effects of saxatilin, snake venom disintegrin, ADAM 15-derived human disintegrin, and the ADAM 15-derived cyclic peptides was analyzed using a platelet aggregometer. The antithromotic effect of these peptides was evaluated by measuring the occlusion time after the induction of thrombosis in a mouse carotid artery occlusion model. The IC50 for the human platelets was 137 nM, 50 uM, 100 uM, and 270 uM for saxatilin, ADAM 15-derived disintegrin, cyclic peptide A1, and the peptide GRGDSP, respectively. Although ADAM 15-derived disintegrin showed no detectable effect to prolong the time to occlusion, cyclic peptide A1 (80 mg/kg) exhibited a significant prolongation time similar to saxatilin (2.1 mg/kg). In contrast, ADAM 15-derived disintegrin exhibited stronger inhibitory effect on adhesion of HUVEC to vitronectin, with an IC50 of 21 uM. In conclusion, ADAM 15-derived human disintegrin exhibited a much weaker antiplatelet effect than did the snake venom-derived disintegrin, suggesting that the 3-dimensional structure may be crucial for their biological activiey. This work is the first report on the mass production of human disintegrins in recombinant Yeast P. pastoris as well as on the in vivo antithrombotic effects of human disintegrins.