INHIBITION OF RED BLOOD CELL-INDUCED PLATELET-AGGREGATION IN WHOLE-BLOOD BY A NONIONIC SURFACTANT, POLOXAMER 188 (RHEOTHRX(R) INJECTION)

RheothRx Injection, an aqueous solution of a nonionic block copolymer (poloxamer 188) formulated for intravenous administration, was investi gated as an inhibitor of red blood cell (RBC)-induced platelet aggrega tion at plasma concentrations of 0.05-5mgmL(-1). Platelet aggregation was determined by measuring the fall in single platelet counts after m echanical agitation of 2mL aliquots of citrated whole blood in a 37 de grees C shaking waterbath. Inhibition of RBC-induced platelet aggregat ion of >95% was observed for poloxamer 188 at a concentration of 1mgmL (-1), and 41% inhibition was observed at 0.05mgmL(-1). Poloxamer 188 w as observed to be a more effective inhibitor of RBC-induced platelet a ggregation than 2-chloradenosine (2-ClAd) or phosphoenolpyruvate/pyruv ate kinase (PEP/PK). Studies using platelet rich plasma (PRP) showed t hat platelet aggregation could not be induced by shaking in the absenc e of RBC, though aggregation was induced by the addition of exogenous adenosine diphosphate(ADP). Poloxamer 188 did not inhibit ADP-induced platelet aggregation. We propose that poloxamer 188 protects RBC from mechanical trauma by non-specific adsorption of copolymer to the RBC s urface (via the hydrophobic polyoxypropylene moiety), and that this ef fect prevents mechanical damage and hence leakage of ADP from RBC. Rhe othRx Injection has been shown to have value in the treatment of acute ischemic disorders such as myocardial infarction. The observation of significant inhibition of RBC-induced platelet aggregation at clinical ly relevant concentrations suggests that RheothRx Injection may have a ntithrombotic properties in vivo, and may therefore have potential not only in acute ischemia but also to prevent thrombosis within vascular prostheses or to prevent rethrombosis after angioplasty or endarterec tomy. Poloxamers are nonionic ABA block copolymers of polyoxyethylene (A) and polyoxypropylene (B) (Fig. 1) and are commercially available o ver a wide range of molecular weights (1000 to 14000 gmol(-1)) and pol yoxyethylene/polyoxypropylene ratios. These copolymers are produced co mmercially under several tradenames [e.g. Pluronics (BASF, Wyandotte, MI.), Synperonic PE nonionic surfactants (ICI, Middlesbrough, U.K.)] a nd have numerous industrial uses (1-3) for example as emulsion stabili zers, foaming, defoaming, antistatic and wetting agents. The desired h ydrophobic/hydrophilic balance is achieved by varying the total molecu lar weight and polyoxypropylene/polyoxyethylene ratio.