Studies were performed to determine the cross-reaction rate of the heparin-dependent antibody with Org 10172, a new low molecular weight heparinoid, and to investigate the effect of Org 10172 on platelet activation induced by the antibody. The plasmas of 17 patients with thrombocytopenia induced by standard heparin were shown, by platelet aggregation studies, to contain the heparin-dependent antibody. Of these 17 patient plasmas, only three cross-reacted with the heparinoid, producing a cross-reaction rate of 18%. When Org 10172 was added to a reaction mixture containing normal platelet-rich plasma, patient plasma, and standard heparin with non-cross-reacting plasmas, it inhibited platelet aggregation and thromboxane B2 production induced by the antibody, provided that the ratio of Org 10172 concentration (anti- Xa U/mL) to standard heparin concentration (IU/mL) exceeded 2.5 to 5.0. This inhibitory effect was observed only with platelet activation mediated by the antibody, but not by collagen (2 micrograms/mL) or ADP (5.0 mumol/L). Additionally, three of 17 patients with serious thrombosis, whose plasma showed no cross-reaction with the heparinoid, received Org 10172 treatment with a good response in each case. These findings suggest that Org 10172 may be a useful drug for the treatment of heparin-induced thrombocytopenia.