Investigation of the clinical safety and efficacy of lyophilized platelets in the treatment of bleeding associated with thrombocytopenia in dogs

Abstract

Introduction Platelets (thrombocytes) are an essential part of the mammalian haemostasis system. Platelets localise to sites of injury, adhere, activate and aggregate in a process termed primary haemostasis. Thrombocytopenia (a reduction in circulating platelets), can lead to an increased risk of bleeding and is an important cause of morbidity and mortality in dogs. Treatments for this condition are suboptimal and there is an unmet clinical need for superior therapies. Lyophilized platelet preparation involves freeze drying platelets that can be rehydrated and administered into patients intravenously. Despite the potential of lyophilized platelet products to improve the treatment of canine thrombocytopenia, the clinical efficacy of this product is not yet fully understood. AimsThe aim of this MSc was to undertake a veterinary clinical trial to examine the safety and clinical efficacy of lyophilized platelet products in the treatment of canine thrombocytopenia, using Good Laboratory Practice (GLP) standards utilized in human medical research. MethodsThe study was a prospective, multicentre, randomized, blinded, controlled trial comparing the administration of test (lyophilized platelets within a buffer) solution versus control (lyophilized buffer) solution, alongside medical treatment for underlying disease. Trial patients were evaluated over a 24-hour period after enrolment and followed up for 14 days. Nine UK veterinary centres enrolled dogs from July 2019 to July 2020 (ongoing) with a platelet count of <50 x 109/l and visible signs of bleeding. Aetiology of thrombocytopenia was not restricted, so long as study inclusion and exclusion criteria were met. The study was designed to evaluate for superiority between groups in primary endpoints and to analyse secondary endpoints. A power calculation determined that the study should enrol 40 patients, 20 to treatment and 20 to control, which represents 80% power to obtain a statistical difference between treatment groups at the 5% (p=0.05) significance level and takes into account up to 4 dropouts per group.ResultsWithin the MSc timeline, the study was designed and 20 dogs were enrolled, including 11 in the test group and 9 in the control group. This included 15 females and 5 males, mean age 6 years. A diagnosis of Immune Thrombocytopenia (ITP) was made in 19 of 20 cases. Interim analysis determined there were no significant differences between groups for the clinical endpoints. Three dogs, including two in the control group and one in the treatment group died within the 24-hour study period. Mean hospitalisation times in the test group was 4 (1-7) days and in the control group 5 (2-8) days. There were no adverse events associated with trial solution administration. Discussion and conclusionsThis study demonstrated the feasibility of undertaking an ambitious, multicentre study to assess the efficacy and safety of a novel therapy for a challenging clinical disorder. Whilst results are from an interim analysis, they reveal that lyophilized platelet administration was not related to any incidence of adverse event. No evidence was found that the novel therapy worsens clinical outcome. Additional recruitment will further define clinical safety and efficacy.