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Anticoagulants Transaminases
Anticoagulants Transaminases
CLINICIAN UPDATE
C
ase 1: Mr F., a 65-year-old randomized controlled trials that are and SPORTIF V; a 6 times higher rate
man with hypertension and required for drug approval.2 of serum transaminase abnormalities
atrial fibrillation, began long- Anticoagulant-induced liver injury was found in patients receiving ximel-
term anticoagulation with warfarin 1 has been infrequently reported. Case re- agatran compared with those receiving
year ago. He presented with a 1-week ports have described the association of warfarin.27–30 Among the 3700 patients
history of nausea, anorexia, jaundice, anticoagulants with asymptomatic eleva- randomized to ximelagatran, there was
and altered mental status. His labora- tion of serum transaminases, clinically 1 case of biopsy-documented drug-
tory workup showed elevated serum significant hepatitis, and fatal liver fail- induced liver failure leading to death
transaminases and direct bilirubin. ure.3–22 As an increasing number of pa- (Figure) and a second probable case of
Could warfarin be potentially tients receive long-term anticoagulation drug-induced liver failure leading to
responsible? for prevention of stroke and venous coagulopathy, massive hemorrhage,
Case 2: Mr S., a 75-year-old man thromboembolism, the rare adverse and death.31
with diabetes and coronary artery dis- event of anticoagulant-induced liver in-
ease, presented with an acute anterior jury is gaining attention. Clinical Significance of
myocardial infarction. Echocardiogra- Ximelagatran is an oral direct Transaminase Elevation
phy showed a left ventricular aneu- thrombin inhibitor that prevents the Levels of transaminases ALT and as-
rysm with apical akinesis and throm- conversion of fibrinogen to fibrin by partate aminotransferase (AST) are
bus. He was started on enoxaparin, and thrombin. This agent is a prodrug and sensitive indicators of drug-induced
3 days later, he developed a rise in is converted to its active form, mel- hepatocellular injury. Elevations in
alanine aminotransferase (ALT) ⬎5 agatran, via hepatic metabolism.23 It ALT and AST can occur from condi-
times the upper limit of normal (ULN). has a short half-life, requires twice tions other than liver injury, but ALT
Could this laboratory abnormality be daily administration, and produces a is relatively more specific because it is
related to enoxaparin? predictable response after oral admin- synthesized primarily by the liver. The
istration. It does not require normal range for any laboratory test is
Epidemiology anticoagulant-level or drug-level mon- mean⫾2 SD. By definition, 5% of
Drug-induced hepatotoxicity is the itoring, and it has virtually no drug- results fall outside the normal range,
most common cause of acute liver drug or drug-food interactions.24 –26 and 2.5% may be above the ULN.32
failure in the United States and is the The Federal Drug Administration Levels of ALT ⬎3 times the ULN are
most frequently cited reason for with- (FDA) did not approve ximelagatran often used as a possible signal for
drawal of an approved drug from the after review of 2 pivotal premarketing drug-induced hepatotoxicity.33,34
market.1 It occurs at rates of 1 in 1000 efficacy trials, Stroke Prevention Us- An elevation in transaminase levels
to 1 in 100 000 patients, making it ing an Oral Direct Thrombin Inhibitor in conjunction with a rise in bilirubin
difficult to detect in the premarketing in Atrial Fibrillation (SPORTIF) III level ⬎2 ULN is a more ominous
From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Samuel Z. Goldhaber, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
sgoldhaber@partners.org
(Circulation. 2006;113:e698-e702.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.603100
e698
Downloaded from circ.ahajournals.org at UNIV OF WISCONSIN MADISON on January 2, 2008
Arora and Goldhaber Anticoagulants and Transaminase Elevation e699
preexisting liver disorder. Although prevent patients from developing fatal Zeneca and is a consultant for Sanofi-
the traditional wisdom among the liver failure. Aventis. Dr Arora reports no conflicts.
hepatologists is that patients with pre-
existing liver disease do not have a Review of Cases References
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toxicity, inasmuch as most reactions The patient presented with prodro- 2. Lee WM. Assessing causality in drug-
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Fulminant hepatic failure can de- was discharged, the patient was restarted and low molecular weight heparin induced
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Disclosures 17. Mix H, Wagner S, Boker K, Gloger S,
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