Do cardiac glycosides affect platelet function? A flow cytometric study in healthy volunteers

Objective: Cardiac glycosides exert their inotropic effect by increasing intracellular calcium. Increased intracellular calcium is a key event in platelet aggregation. In aggregometer studies, digitalis has been found to augment platelet agonist responses. A prothrombotic effect of digitalis might be concealed since heart failure and atrial fibrillation per se predispose to thromboembolism. The present study investigates the effects of digitoxin on platelet function in healthy volunteers. Methods: Twenty healthy, non-smoking volunteers were randomised to receive digitoxin (n = 10, 0.6 mg day 1, 0.4 mg day 2, then 0.1 mg daily) or placebo (n = 10) for 10 days. Platelet function was then analysed ex vivo using three-colour whole-blood-flow cytometry, both in non-stimulated mode and after agonist stimulation with 0.1 mumol/l adenosine diphosphate (ADP), 10 mumol/l ADP and 5.0 mumol/l epinephrine (final concentrations). Expression of activated fibrinogen receptor, von Willebrand's factor receptor and P-selectin, formation of platelet-platelet and platelet-leukocyte aggregates and particle size were examined. Results: No significant difference between the placebo and the digitoxin group (digitoxin levels 17-42 nmol/l) was found, neither on a global level nor for any isolated parameter. Conclusions: Theory and in vitro data suggest that digitoxin treatment could activate platelets. No evidence for this was found in healthy volunteers. This observation is strengthened by the unequivocal results for all parameters measured. However, thrombosis-prone patients with heart failure and/or atrial fibrillation may respond differently to digitalis therapy.