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Anesth Analg 2003;96:1539-1540
© 2003 International Anesthesia Research Society

LETTERS TO THE EDITOR

Hemodilution-Induced Hypercoagulability

Tom Ruttmann, MD

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

  1. McCannon AT, Wright JP, Figueroa M, Nielsen VG. Hemodilution with albumin, but not Hextend, results in hypercoagulability as assessed by thrombelastography in rabbits: role of heparin-dependent serpins and Factor VIII complex. Anesth Analg 2002; 95: 844–50.[Abstract/Free Full Text]
  2. Ng KF, Lam CC, Chan LC. In vivo effect of haemodilution with saline on coagulation: a randomised controlled trial. Br J Anaesth. 2002; 88: 475–80.[Abstract/Free Full Text]
  3. Ruttmann TG, James MF, Viljoen JF. Haemodilution induces a hypercoagulable state. Br J Anaesth 1996; 76: 412–4.[Abstract/Free Full Text]
  4. Ruttmann TG, James MF, Aronson I: in vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth 1998; 80: 612–6.[Abstract/Free Full Text]
  5. Ruttmann TG, James MF, Wells KF. Effect of 20% in vitro haemodilution with warmed buffered salt solution and cerebrospinal fluid on coagulation. Br J Anaesth 1999; 82: 110–1.[Abstract/Free Full Text]
  6. Jamnicki M, Zollinger A, Seifert B, et al. The effect of potato starch derived and corn starch derived hydroxyethyl starch on in vitro blood coagulation. Anesthesiology 1998; 53: 638–44.
  7. Ng KF, Lo JW. The development of hypercoagulability state, as measured by thrombelastography, associated with intraoperative surgical blood loss. Anaesth Intensive Care 1996; 24: 20–5.[Web of Science][Medline]
  8. Gibbs NM, Crawford GP, Michalopoulos N. Thrombelastographic patterns following abdominal aortic surgery. Anaesth Intensive Care 1994; 22: 534–8.[Web of Science][Medline]
  9. Tuman KJ, Spiess BD, McCarthy RJ, Ivankovich AD. Effects of progressive blood loss on coagulation as measured by thrombelastography. Anesth Analg 1987; 66: 856–63.[Abstract/Free Full Text]
  10. Ruttmann TG, James MFM. Pro-coagulant effect of in vitro haemodilution is not inhibited by aspirin. Br J Anaesth 1999; 83: 330–2.[Abstract/Free Full Text]
  11. Ruttmann TG, James MF, Lombard EM. Haemodilution-induced enhancement of coagulation is attenuated in vitro by restoring antithrombin III to pre-dilution concentrations. Anaesth Intensive Care 2001; 29: 489–93.[Web of Science][Medline]
  12. Jesty J, Beltrami E, Willems G. Mathematical analysis of a proteolytic positive-feedback loop: dependence of lag time and enzyme yields on the initial conditions and kinetic parameters. Biochemistry 1993; 32: 6266–74.[Medline]
  13. Griffith MJ. Kinetic analysis of the heparin-enhanced antithrombin III/thrombin reaction: reaction rate enhancement by heparin-thrombin association. J Biol Chem 1979; 254: 12044–9.[Free Full Text]
  14. Nossel HL, Yudelman I, Canfield RE, et al. Measurement of fibrinopeptide A in human blood. J Clin Invest 1974; 54: 43–53.
  15. Nossel HL. Radioimmunoassay of fibrinopeptides in relation to intravascular coagulation and thrombosis. N Engl J Med 1976; 295: 428–32.[Web of Science][Medline]
  16. Ruttmann TG. Haemodilution enhances coagulation. Br J Anaesth. 2002; 88: 470–2.[Free Full Text]
  17. Jesty J. The kinetics of inhibition of alpha-thrombin in human plasma. J Biol Chem 1986; 261: 10313–8.[Abstract/Free Full Text]
  18. Rosenberg RD, Davies PS. Purification and mechanism of action of human anti-thrombin-heparin cofactor. J Biol Chem 1973; 248: 6490.[Abstract/Free Full Text]
 

Response

Vance G. Nielsen, MD

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

  1. McCannon AT, Wright JP, Figueroa M, Nielsen VG. Hemodilution with albumin, but not Hextend, results in hypercoagulability as assessed by thrombelastography in rabbits: Role of heparin-dependent serpins and Factor VIII complex. Anesth Analg 2002; 95: 844–50
  2. Ruttmann TG. Haemodilution enhances coagulation. Br J Anaesth 2002; 88: 470–2.
  3. Jesty J. The kinetics of inhibition of alpha-thrombin in human plasma. J Biol Chem 1986; 261: 10313–8.
  4. Ng KF, Lam CC, Chan LC. In vivo effect of haemodilution with saline on coagulation: a randomised controlled trial. Br J Anaesth 2002; 88: 475–80.
  5. Ruttmann TG, James MF, Aronson I. In vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth 1998; 80: 612–6.
  6. Ng KF, Lo JW. The development of hypercoagulability state, as measured by thrombelastography, associated with intraoperative surgical blood loss. Anaesth Intensive Care 1996; 24: 20-5.
  7. Gibbs NM, Crawford GP, Michalopoulos N. Thrombelastographic patterns following abdominal aortic surgery. Anaesth Intensive Care 1994; 22: 534–8.
  8. Tuman KJ, Spiess BD, McCarthy RJ, Ivankovich AD. Effects of progressive blood loss on coagulation as measured by thrombelastography. Anesth Analg 1987; 66: 856–63.
  9. Helin H. Macrophage procoagulant factors: mediators of inflammatory and neoplastic tissue lesions. Med Biol 1986; 64: 167-76.[Web of Science][Medline]
  10. Bick RL. Evaluation of a new hydroxyethyl starch preparation (Hextend) on selected coagulation parameters. Clin Appl Thromb Hemost 1995; 1: 215–29.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press