A technique for assessing platelet reactivity to shear stress from nonanticoagulated blood samples was employed to compare the relative effects of an unfractionated heparin, a low-molecular-weight heparin, and hirudin. The in vitro platelet effect of unfractionated heparin (5 U/mL) was measured in 290, the effect of a low-molecular-weight heparin (1 anti-Xa unit/mL) in 74, and the effect of hirudin (8 micrograms/mL) in 50 cardiac surgical patients. The relative proportions of patients exhibiting an enhanced platelet reactivity, a mild to moderate inhibition, and a severe inhibition were, respectively: 8.6%, 58.6%, and 32.8% for unfractionated heparin; 22%, 66%, and 12% for the low-molecular-weight heparin; and 6%, 66%, and 28% for hirudin. At the concentrations examined, a significantly greater proportion (p < 0.01) of the patients exhibited enhanced platelet reactivity and a significantly smaller proportion (p < 0.01) showed severely inhibited platelet reactivity associated with the low-molecular-weight heparin versus the unfractionated heparin, whereas there was no significant difference between the patients treated with hirudin and unfractionated heparin. Although the relevance of this study is limited because the clinically appropriate concentration of the alternative anticoagulants and comparative doses are unknown, it can be inferred that low-molecular-weight heparin may reduce the blood loss associated with cardiopulmonary bypass.