Heparin and Thrombus Formation: Early Suppression and Late Enhancement*

It has been demonstrated in animal studies that heparin in suitable doses suppresses fibrin formation and in larger doses prevents the clumping of platelets (Best, Cowan and MacLean, 1938; Zucker, 1947). In view of this, it is surprising that in controlled studies it has not proved a more effective therapeutic agent in the management of arterial thrombosis (Carleton, Sanders and Burack, 1960). This may reflect inadequacy of dosage or too long an interval between doses, or it may indicate that treatment would only be effective if given in an earlier stage of the disease, or that the mechanism of the clinically recognized catastrophe is something other than arterial thrombosis. While the predominant effects of heparin are antithrombotic, there are some indications that they are not unambiguous. Ashwin (1961) found that low doses of heparin produced a higher percentage of animals with thrombosis than that in the control group, and while the difference was not impressive, it is somewhat disturbing that it lay in an unexpected direction. If this effect proved not to be an artefact arising from sampling error it could be attributed to one of a variety of mechanisms of which the two most plausible seem to be that low doses of heparin are directly thrombogenic or that counteracting thrombogenic mechanisms are excited by doses of heparin too small to prevent thrombus formation. In ordinary experiments, it is difficult to determine the time sequence of events. In vitro studies may be done, but their relationship to endogenous thrombus formation has been repeatedly called into question (Poole and French, 1962). Study of endogenous thrombus formation is handicapped by the lack of adequate methods of quantitation and by difficulty of studying tendency to thrombus formation over short periods of time. We have recently described a standardized extracorporeal circulation for use with experimental animals which allows precise quantitation of thrombus formation in a system which allows rapid pulsatile flow to be maintained and in which the blood is repeatedly re-circulated through the animals (Downie, Murphy, Rowsell and Mustard, 1963). This seemed to be a suitable means of exploring the relationship of heparin in thrombosis.