Despite major advances in platelet transfusion therapy, bleeding remains a problem in patients with thrombocytopenia due to chemotherapy induced marrow aplasia and hematopoietic stem cell disorders. Bleeding incidence does not appear to be affected by increasing the platelet transfusion threshold and does not appear to be dependent on the platelet count when it is above 5,000/l. In the PLADO (Platelet Dose) Trial of 1272 patients, WHO grade 2 bleeding occurred in approximately 70% of subjects regardless of platelet dose transfused. Withholding transfusion can lead to serious and fatal bleeding. In a 600 patient trial of therapeutic vs. prophylactic platelet transfusion (TOPPS), bleeding was a common event. Maintenance of a safe platelet count may be difficult due to shortened platelet survival in severely thrombocytopenic and critically ill patients. Patients refractory to platelet transfusion may require expensive and difficult to obtain matched platelets to prevent serious bleeding. Maintenance of the platelet count above a prescribed trigger in outpatients can require daily laboratory work and frequent transfusions. Other means used to decrease bleeding include treatment with antifibrinolytic agents, used for years intra- and postoperatively and in patients with platelet function and coagulation defects such as hemophilia. Reports of antifibrinolytic drugs to prevent or treat thrombocytopenic bleeding are encouraging, suggesting that in many patients bleeding can be prevented or stopped. Such anecdotal, retrospective single center reports lead many physicians to prescribe antifibrinolytic agents to prevent or treat bleeding in thrombocytopenic patients refractory to platelet transfusions, however lack of evidence of efficacy and safety prevent its use from becoming standard of care. A pivotal study of Epsilon Aminocaproic Acid (EACA), an inhibitor of fibrinolysis, will improve patient care by leading physicians to either adopt or abandon its use as treatment to prevent thrombocytopenic bleeding. If effective in decreasing bleeding and transfusion it would have major impact on health care costs. We plan to conduct a prospective, randomized, placebo controlled trial evaluating the usefulness of EACA therapy to prevent bleeding in patients thrombocytopenic due to primary bone marrow disorders or chemotherapy, immunotherapy and/or radiation therapy with or without hematopoietic stem cell transplant. This study will change practice by providing evidence as to whether EACA is effective and safe and can decrease transfusion needs when used as an adjunct to platelet transfusion therapy. The objectives are to compare the 30 day incidences of bleeding, transfusion requirements, and thrombosis in patients with hypoproliferative thrombocytopenia who receive EACA or placebo. The study design is a double blind, randomized, placebo controlled trial. Subjects likely to have platelet counts of =10,000/l for =5 days will be screened for eligibility. Bleeding and thrombotic assessments will be performed on inpatients daily using chart review, subject interview and physical examination. Outpatient subjects will maintain a diary daily and be seen at least weekly in clinic.

Public Health Relevance

Patients with low platelet counts due to chemotherapy, radiation or bone marrow transplantation have a high risk of bleeding despite platelet transfusions. Anecdotal evidence suggests that bleeding and transfusion rates decrease with treatment by drugs called 'antifibrinolytic agents' that slow the dissolving of blood clots that fom normally to protect against bleeding. We will conduct a clinical trial to test whether one such drug, epsilon aminocaproic acid, can decrease the rates of bleeding and transfusion needs in patients with low platelets due to treatment with chemotherapy and/or bone marrow transplantation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Clinical Trials Review Committee (CLTR)
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El Kassar, Nahed
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing et al. (2017) Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins. Sci Transl Med 9: