Effect of Aspirin, Hemodilution and Desmopressin on Platelet Dysfunction

Effect of Aspirin, in Vitro Hemodilution and Desmopressin on Platelet Dysfunction Associated With Mild Hypothermia in Healthy Volunteers

Study hypothesis: Desmopressin (DDAVP) can improve platelet function under influence of aspirin, hemodilution and mild hypothermia Mild hypothermia (34-35oC) is known to cause platelet dysfunction. This could lead to increased surgical bleeding and increased transfusion requirement during surgery. Although this hypothermia-induced platelet dysfunction seems to be reversible with warming, this is not always possible or desirable. Desmopressin (DDAVP) is a drug which has proven efficacy in improving platelet function in uraemic and cirrhosis patients, and in reducing blood loss in selected surgeries. In a recent study, we have found that subcutaneous injection of 1.5 mcg (1/10th the usual dose) is already sufficient to fully reverse the platelet dysfunction seen at 32oC. We have demonstrated in another study that prolongation of the bleeding time in a 20% hemodiluted sample predicts increased postoperative bleeding after total knee replacement. We have therefore designed this study as a follow up to our last two studies on DDAVP and hypothermia, to investigate whether hemodilution affects hypothermia induced platelet dysfunction and the response to DDAVP. In addition, another common cause of perioperative platelet dysfunction is the intake of COX inhibitors, particularly aspirin by patients. Therefor the effect of aspirin on hypothermia induced platelet dysfunction and the response to DDAVP, will also be investigated.

Mild hypothermia (34-35oC) is known to cause platelet dysfunction. Increased surgical bleeding and increased transfusion requirement at this temperature range has been reported in both cardiac and noncardiac surgeries. This degree of hypothermia is common during any general anaesthesia, particularly during surgeries which invlove major fluid shift and large area exposure of patients, e.g. trauma and burn patients. Although this hypothermia-induced platelet dysfunction seems to be reversible with warming, warming is not always possible or desirable. During major trauma or burn surgery, surface warming of patient is practically difficult. During surgeries with major blood loss and fluid shift, heat loss usually occurs at a rate that is more rapid than any warming device can catch up with. During neurosurgery, cooling may be beneficial to neurological outcome. Desmopressin (DDAVP) is a drug which has proven efficacy in improving platelet function in uraemic and cirrhosis patients, and in reducing blood loss in selected surgeries. In a previous in vitro study, we have found that desmopressin significantly improves platelet function at 32oC. The improvement is seen with a very low concentration of desmopressin in vitro, which suggests that probably doses much smaller than the "standard dose" (15 mcg slow iv or subcutaneous) may be useful. In keeping with this in vitro study, in a more recent study, we have found that subcutaneous injection of 1.5 mcg (1/10th the usual dose) is already sufficient to fully reverse the platelet dysfunction seen at 32oC. One of the limitations of our previous two studies is that the degree of platelet dysfuction observed at 32oC is relatively mild, with only around 20% prolongation of the closure times on the PFA-100® platelet function analyser. The clinical significance of such prolongation remains uncertain. However, we have demonstrated previously in another study that prolongation of the closure time to >188 sec in a 20% hemodiluted sample predicts increased postoperative bleeding after total knee replacement. We have therefore designed this study as a follow up to our last two studies on DDAVP and hypothermia, to investigate whether hemodilution affects hypothermia induced platelet dysfunction and the response to DDAVP. In addition, another common cause of perioperative platelet dysfunction is the intake of COX inhibitors, particularly aspirin by patients. Therefor the effect of aspirin on hypothermia induced platelet dysfunction and the response to DDAVP, will also be investigated.

Subjects will be given placebo daily for 3 days. On day 4 an early morning urine sample will be collected for detection of aspirin metabolite (11-dehydro thromboxane B2). On day 6 venous blood sample will be collected, 17mls before and 17 mls after injection of DDAVP 15 microgram subcutaneously. The blood samples will then be subjected for platelet function analysis.

Subjects will be given aspirin 100mg daily for 3 days. On day 4 an early morning urine sample will be collected for detection of aspirin metabolite (11-dehydro thromboxane B2). On day 6 venous blood sample will be collected, 17mls before and 17 mls after injection of DDAVP 15microgram subcutaneously. The blood samples will then be subjected for platelet function analysis.

Venous blood sample will be taken from subjects before and after injection of DDAVP. Blood sample will be subjected to: (i) complete blood count, (ii) PFA-100 platelet function analyzer, (iii) fibrinogen, and (iv) vWF:Ag concentration for analysis.

Inclusion Criteria: 60 adult Chinese subjects aged 18-60 without known platelet disorder, thrombocytopenia, history of taking drugs that may affect platelet function including herbal preparations. Exclusion Criteria: Any known platelet or coagulation disorder Expected surgical operation or dental treatment within one week of scheduled drug intake. Known peptic ulcer disease Obesity (BMI >=30) Pregnant or lactating women. Known chronic liver or renal disease. Coronary artery, carotid artery or peripheral artery disease Recent history of taking antiplatelet drugs, anticoagulants or herbal preparations. Smoker or alcohol user Mentally incapable of providing informed consent Students or junior staff members who had direct working relationship with the PI

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