A swine model of acute thrombocytopenia with prolonged bleeding time produced by busulfan

Abstract

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.

Cyberlindnera jadinii Yeast as a Protein Source for Weaned Piglets—Impact on Immune Response and Gut Microbiota

“…The present study indicates that yeast did not have a significant impact on the hematological or biochemical parameters in blood, except for the platelets count. The diet containing a high level of yeast induced significantly lower blood platelet counts at 28 days post-weaning compared with the control group; however, this value was within the value range for a healthy pig (32). Furthermore, the high inclusion level of yeast in the diet did not affect the serum concentration of AST or AP.…”

Platelets Do Not Alter Flow-Mediated Dilation or Arterial Conduction in vivo

“…This method would have been ideal for our acute study but would require access to and development of a suitable pig IgG2a antibody which we do not possess. Other researchers have depleted Plts in pigs using the chemotherapeutic agent busulfan [16]; this approach was also not possible in our study due to ethical considerations, in addition it would necessitate a control cohort which would run the risk of being affected by the non-responder rate of approximately 9% in the iliac flow-induced experiments conducted in our laboratory over the years which would complicate data interpretation. Large animal models are by far the most appropriate ones to employ to study human cardiovascular physiology or pathology [17].…”

Hemostasis vs. homeostasis: Platelets are essential for preserving vascular barrier function in the absence of injury or inflammation

“…To reduce the likelihood that the effects we observed in thrombocytopenic and GPVI-deficient mice were due to the methods used to produce thrombocytopenia and GPVI deficiency, we compared two different methods for accomplishing each. Although busulfan treatment has been reported to increase the bleeding time, it is not clear that this is necessarily due to more than the associated thrombocytopenia (38).…”