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.