Animal models of
thrombocytopenia are indispensable for evaluating the in vivo efficacy of
hemostatic agents, cryopreserved platelets, and artificial platelets, but no large animal models are available. In this study, we generated a swine model of acute
thrombocytopenia with prolonged bleeding times by administering the chemotherapeutic drug
busulfan. First, we tested multiple doses of
busulfan (4, 6, and 8 mg/kg) in pigs, and found that 6 mg/kg of
busulfan is an optimal dose for producing a safe and moderate
thrombocytopenia, with a platelet count of less than 30,000/µl. The pigs administered 6 mg/kg of
busulfan (n=8) reached half their initial counts at day 7, counts below 30,000/µl at day 12, and their nadirs at day 15 (on average). The minimal platelet count was 14,000/µl. With this dose of
busulfan (6 mg/kg), bleeding times were significantly prolonged in addition to the decrease in platelet counts (r=-0.63, P<0.01), while there were no cases of apparent
hemorrhage. White blood cell counts were maintained at over 5,000/µl, and there were no
infections or other adverse events including
anemia or appetite or
body weight loss. All pigs were sacrificed on day 16, with subsequent examination showing a significant reduction in cellularity and colony-forming units in the bone marrow, indicating that
thrombocytopenia was the result of myelosuppression. In summary, administration with 6 mg/kg of
busulfan induces safe and moderate
thrombocytopenia with a prolonged bleeding time in swine.