Hemodilution-Induced Hypercoagulability

To the Editor: McCannon et al’s comment: “a decrease in heparin-dependent serpin activity coupled with unchanged VIII:C results in hypercoagulability” is not quite correct (1). It is not this that causes the hypercoagulability, but rather the alteration of the ratio of spontaneously activated thrombin to the diluted anticoagulants. Hemodilution per se(2) enhances coagulation, both in vitro and in vivo(3–10). Thrombin generation is the central biochemical reaction in both normal hemostasis and thrombosis (11). While it is involved in many pathways, its self-reinforcement through positive feedback into the intrinsic pathway is the most important (12,13). Normal plasma contains idling levels of activated thrombin (14,15). As a result, inhibition of positive feedback, through the effect of anticoagulants, modulates the exponential enhancement of the coagulation cascades. This confers threshold properties on the system-activated thrombin levels below threshold, no response occurs; when above threshold, the response is at, or near, maximum, resulting in an exponential increase of further thrombin formation (16,17). As the spontaneously activated thrombin makes up only a minute fraction of total prothrombin concentrations, and there is a one-to-one, enzyme-to-inhibitor reaction of thrombin with the anticoagulants (18), hemodilution changes the ratio between the two. As a result it decreases the threshold, allowing positive feedback into the intrinsic pathway and coagulation occurs (12). The impairment of VIII:C and platelet aggregation is well described in the starches. This effect secondarily offsets the enhanced coagulation due to hemodilution (4).