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LETTERS TO THE EDITOR

Can You Reheparinize After Heparinase-I?

Department of Anesthesiology, Albert Einstein Medical Center, Thomas Jefferson School of Medicine, Philadelphia, PA

To the Editor:

I read with interest the Heres et al. article (1) demonstrating that heparinase-I can effectively reverse heparin anticoagulation in lieu of protamine. Although there may be advantages to avoiding protamine, the question arises, can you reheparinize after heparinase-I administration? On occasion, there may be a need to emergently return to cardiopulmonary bypass after protamine administration. Thus I have several questions:

1. How long does it take until the heparinase-I is no longer active so that heparin can be effectively readministered?
   
2. Can you administer a sufficiently large dose of heparin that would overwhelm the capacity of heparinase-I thus permitting sufficient reanticoagulation?
   
3. Is there a way to rapidly inactivate heparinase-I?
   
4. Is there another effective means of anticoagulation that can be used in the presence of heparinase-I?
   
5. Is there another way to deal with this potential problem?
   

Concerning a different potential application, are there any reasons not to use heparinase-I in liver transplant patients after reperfusion if there is a heparin effect contributing to a coagulopathy?

References

1. Heres ER, Horrow JC, Gravlee OP, et al. A Dose Determining Trial of Heparinase-I (Neutralase^TM) for Heparin Neuralization in Coronary Artery Surgery. Anesth Analg 2001; 93 (6): 1446–52.[Abstract/Free Full Text]

Response

Clinical Professor, Anesthesiology, MCP Hahnemann University, Philadelphia, PA

In Response:

Doctor Roth wonders how one might manage the re-establishment of anti-coagulation in a patient who has received Heparinase-I (Neutralase^TM) because of a potential need to return quickly to bypass following neutralization of heparin’s effect. One should first note that use of Heparinase-I should eliminate the most common cause for emergent return to bypass following heparin neutralization, viz., adverse response to protamine, because the latter agent is totally avoided by using Heparinase-I. Most other causes for a rapid return to bypass occur prior to neutralization of heparin’s activity, such as twisted, occluded, stretched, or otherwise nonfunctioning grafts, other causes of myocardial dysfunction, or a need to repair major vessels or cardiac structures.

Even so, rapid return to bypass can occur after reversal of heparin. Heparinase-I (Neutralase^TM, BioMarin Pharmaceutical, Novato, CA) displays a half-life of 12 minutes in patients with coronary artery disease. Its activity will decay accordingly, so that after approximately 36 minutes, little activity remains. Even though Heparinase-I does decay rapidly, larger amounts of heparin can restore anticoagulation in the presence of circulating Heparinase-I. As one might expect, the bolus and infusion amounts required to maintain a given ACT depends on the initial dose of Heparinase-I and on the time elapsed since its administration. A pharmacokinetic model yields suggested doses of heparin for bolus and constant infusion. Investigators using Heparinase-I in clinical trials receive this information in case it is needed and have used it.

In addition, because Heparinase-I totally eliminates the antithrombin activity of heparin but only partially eliminates the anti-Xa activity, anti-Xa activity increases as additional heparin is metabolized by Heparinase-I. This antithrombotic effect itself carries implications on the ACT needed for bypass. This, together with the short half-life of Heparinase-I, predicts a fairly rapid decrease in the heparin requirement with time.

Dr. Roth also asks about the use of Heparinase-I in the reperfusion phase of liver transplantation. This author can think of no reasons that preclude application of Heparinase-I (Neutralase^TM) in this situation. However, because no data exist on administration of Heparinase-I (Neutralase^TM) to patients with liver failure or during liver transplantation, this application cannot be recommended at this time.

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