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Echo Corner
An Echo clip and explanation for the April edition
Literature Reviews
Hematocrit on Cardiopulmonary Bypass and Outcome after Coronary Surgery in Nontransfused Patients.
Mitral Repair versus Replacement for Ischemic Mitral Regurgitation
Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin.
Foundation Update
New FOCUS sites sought; SCA Foundation Reception
SCA Bulletin - Printable Version
The Society of Cardiovascular Anesthesiologists (SCA) publishes the SCA Bulletin bimonthly. The information presented in the SCA Bulletin has been obtained by the editors. Validity of opinions presented, drug dosages, accuracy and completeness of content are not guaranteed by SCA.
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Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin
Dutton RJ, Wayman A, Wei JR, Rubin EJ, Beckwith J, Boyd D.
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):297-301.
Reviewers: David S. Palilla, MD and Theodore A. Alston, MD, PhD
Massachusetts General Hospital, Harvard Medical School
Abstract
This lab report does not directly pertain to anesthesia, but it should be of general interest to clinicians dealing with the science of blood coagulation in cardiovascular patients. Researchers at Harvard are attacking tuberculosis (TB) mycobacteria with warfarin. It turns out that TB microbes and humans both have a need for normal vitamin K function.
The target enzyme for warfarin is vitamin K epoxide reductase (VKOR). Genetic deletion of this enzyme caused stunted growth of mycobacteria on rich medium in vitro and completely blocked growth on simple medium. In genetically normal organisms, mycobacterial growth was similarly effected by warfarin inhibition of the enzyme.
Four strains of warfarin-resistant microbes were isolated with the aid of mutagenic chemicals. Interestingly, the four mutations corresponded to genetic variations of VKOR found in warfarin-resistant humans. Further study of the enzyme from TB bacilli will be facilitated by its functional cloning into nonpathogenic E. coli. The authors have accomplished the transfer, which is expected to facilitate the screening for warfarin analogs for improved activity as anticoagulants and/or antibiotics. In allied work toward that goal, the three-dimensional structure of the bacterial VKOR has been elucidated this year (Li W et al, Nature 2010 Jan 28;463:507-12).
Comments
A bacterial role for vitamin K makes sense since GI flora have long been suspected to be a source of the vitamin for human hosts. An antibiotic based on warfarin (and its effects on Vitamin K) would not necessarily result in anticoagulation in humans, but this potential side effect would need to be studied. There are other examples of pharmaceutical agents whose primary mechanism of action does not necessarily cause an expected side effect. Trimethaprim, for instance, was based on methotrexate but inhibits only microbial dihydrofolate reductase.
Though humans and bacteria both seem to require enzymatic reduction of vitamin K, bacteria are not known to carboxylate any of their proteins. Instead, vitamin K is involved in disulfide bond formation in bacterial proteins. It would be interesting to learn if this function of vitamin K was also exhibited in humans as further studies examining this effect of warfarin are undertaken. Regardless, potential uses of warfarin in the future will include more than anticoagulation and rat extermination.