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Stanford University
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 activatedthrombin 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 activatedthrombin (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 activatedthrombin 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).
References
Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, AL
In Response:
We appreciate Dr. Ruttmann’s interest in our recent article (1). He asserts that the source of hypercoagulability associated with hemodilution is an imbalance between the ratio of spontaneously activated thrombin and endogenous anticoagulant activity in the circulation (2), and not the imbalance in VIII:C and anticoagulant activity observed in our rabbit model (1). It would appear that his tacit hypothesis, as first espoused in his recent editorial (2), is that the hemodilution-mediated loss of endogenous anticoagulant is not accompanied by a concordant loss of procoagulant (e.g., tissue factor, factor VII). He supports this contention with an in vitro kinetic study of thrombin-antithrombin interactions (3) and five in vivo studies that could not discern a mechanism responsible for the hypercoagulability observed (4–8). Examination of some of these studies (4,6) revealed that patient populations afflicted with neoplasia were investigated. This is important, as macrophages located at the vessel/tumor interface can express tissue factor activity (9), potentially serving as a source of "spontaneously activated" thrombin formation via the extrinsic pathway that would be resistant to the effects of hemodilution. Regrettably, these studies (4–8) did not report measurements of the procoagulant components of the extrinsic or intrinsic coagulation pathways. Thus, while Dr. Ruttmann’s hypothesis may indeed hold true in some of the patient populations studied (4,6), it remains an untested hypothesis. In contrast, our study (1) reports the effects of hemodilution on several procoagulant/anticoagulant activities, providing data that support our hypothesis that alteration in the ratio of VIII:C and heparin-dependent serpins is the substrate of hypercoagulability.
With regard to Dr. Ruttmann’s unreferenced claim that "the impairment of VIII:C and platelet aggregation is "well described in the starches," we must point out that our data in Table 3 (1) concerning the platelet-mediated contribution to clot strength (GP) demonstrated no significant change in response to either hemodilution or the fluid used to hemodilute. Furthermore, an in vitro study could not demonstrate any direct effect on VIII:C by hetastarch (10). Also of interest, the degree of hemodilution of VIII:C in the group administered hetastarch was 43%—not very different from the 40% calculated hemodilution performed based on rabbit weight (1). In summary, further experimentation is required to determine the role played by the extrinsic coagulation system in hemodilution-mediated hypercoagulability.
References
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