Fatal spontaneous retroperitoneal hematoma secondary to enoxaparin. (Case Report).

Abstract: An 83-year-old woman was transferred to our cardiac intensive care unit with an acute non-Q-wave myocardial infarction and pulmonary edema. Enoxaparin was one component of the treatment regimen used. Her hospital course was complicated by episodes of hypotension, as well as by recurrent left hip and left thigh pain. The defining event occurred when the patient became acutely hypotensive and developed abdominal distention, peritoneal signs, intense left flank pain, and a 3.3 g/dl hemoglobin decrease. Abdominal computed tomography showed a 9 X 6 X 20 cm left retroperitoneal hematoma. The hematoma was spontaneous, secondary to enoxaparin use. The patient died despite vigorous supportive care. Enoxaparin is being increasingly used in patients with acute coronary syndromes. Review of the medical literature revealed that this is the first reported case of a patient with an acute coronary syndrome who died as a result of an enoxaparin-induced, spontaneous retroperitoneal hematoma. This article reviews impo rtant clinical signs and symptoms, identifies high-risk patient populations, and discusses management strategies.

Key Words: acute coronary syndromes, enoxaparin, hematoma

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Enoxaparin use in patients with acute coronary syndromes has increased since the results of the several landmark trials. (1-6) Enoxaparin has several advantages over unfractionated heparin (UFH). (7-9) Its more predictable anticoagulant response than UFH is due to a higher ratio of anti-factor Xa--anti-factor IIa activity. Enoxaparin also has better bioavailability at lower doses than UFH because it binds less to the endothelium. Its dose-independent clearance mechanism and longer half-life make anticoagulation monitoring unnecessary in all but high-risk patients. In addition, enoxaparin has a lower incidence of substantial bleeding since it binds less to platelets and therefore inhibits platelet function less. Enoxaparin also has a lower incidence of heparin-induced thrombocytopenia than UFH. These factors, combined with its easier route of administration (SC) and its potential for reduced hospitalization costs, provide compelling reasons for the expanding role of enoxaparin in the management of patients wit h acute coronary syndromes. (1-6) Despite its benefits, however, enoxaparin use is not without risk. This report describes a patient with a fatal outcome that resulted from enoxaparin administration.

Case Report

An 83-year-old woman was transferred to our cardiac intensive care unit with an acute non-Q-wave myocardial infarction (NQWMI) and pulmonary edema. She had been hospitalized 2 days previously for community-acquired pneumonia. Her medical history included hypertension, chronic renal insufficiency, anemia, and osteoarthritis. Transfer medications were ampicillin-sulbactam, captopril, aspirin, and furosemide. She had no medication allergies. Family history was notable only for hypertension; no history of coagulopathy. Social history was negative for tobacco or alcohol. Her blood pressure was 190/110; pulse, 75; temperature, 37.8[degrees]C; respiration, 28; and oxygen saturation, 93% (40% face mask). Physical examination revealed jugular venous distention, bilateral rales, an S3 gallop, and 2+ pitting lower-extremity edema. Laboratory data were 20,700 white blood cell count (95% neutrophils); hemoglobin, 10.5 g/dl; platelets, 213,000; blood urea nitrogen, 36 mg/dl; and creatinine, 1.7 mg/dl.

Her NQWMI was treated with aspirin and enoxaparin (1 mg/kg SC every 12 h). [beta]-blocker therapy was withheld because the patient was in florid heart failure. Heart failure was managed with Lasix and captopril. Blood pressure was controlled with IV nitroglycerin, and ampicillin-sulbactam continued for pneumonia. On day four, the patient suddenly became hypotensive. Her orthostasis was attributed to aggressive diuresis. Furosemide, captopril, and nitroglycerin were held, and her hypotension resolved with fluid boluses. On day five, she experienced left hip pain. Examination revealed full range of motion, x-ray was unremarkable. The pain was thought secondary to osteoarthritis and treated with acetaminophen. On day six, the patient complained of left lateral thigh pain that appeared musculoskeletal. A small periumbilical bruise was also noted. Four hours later, she became acutely hypotensive with abdominal distention, peritoneal signs, and left flank pain. Repeat hemoglobin was 7.2 g/dl. Enoxaparin and aspirin were discontinued. Abdominal computed tomography showed a 9 X 6 X 20 cm left retroperitoneal hematoma (Fig. 1). No aortic aneurysm was noted. The hematoma was spontaneous, secondary to enoxaparin use. No protamine was given since more than 12 hours had elapsed since the last enoxaparin dose. Surgery was emergently considered, but evacuation of the hematoma was too high risk. The patient died despite vigorous supportive care.

Discussion

Fatal hemorrhage is an infrequent complication of enoxaparin use. This is only the second reported case of a patient with enoxaparin-induced fatal spontaneous retroperitoneal hematoma, (10) and the first when enoxaparin was used in the management of an acute coronary syndrome.

The ESSENCE study showed that enoxaparin was more effective than IV unfractionated heparin in reducing the incidence of death, myocardial infarction or recurrent angina in patients with unstable angina or NQWMI. (1) Benefit was maintained after one year of follow-up; only minor hemorrhage (injection-site ecchymosis) was more common with enoxaparin. (1-6) However, enoxaparin is not without risk. Among 1,578 patients receiving enoxaparin and aspirin for management of acute coronary syndromes, 17 (1%) cases of major bleeding episodes were reported (package insert; Aventis Pharmaceuticals, Inc., Bridgewater, NJ). These included intraocular, retroperitoneal, and IC hemorrhage, hemoglobin decrease by at least 3 g/dl or transfusion requirement of 2 U or more of blood products.

Physicians should be vigilant for symptoms and signs that suggest retroperitoneal hemorrhage (hypotension, decreasing hemoglobin, abdominal distention, peritoneal signs, flank and/or hip pain, increasing bruising), IC hemorrhage (neurologic deficits, nausea, vomiting, headache, mental status changes), or intraocular hemorrhage (visual changes, nausea, vomiting, photophobia, pain, headache). Enoxaparin should be used very cautiously in elderly patients and in patients with renal insufficiency (creatinine clearance <30 ml/min) because of the risk of delayed clearance. Other patients needing close monitoring include those with bleeding diatheses, uncontrolled hypertension, or recent gastrointestinal bleeding (Table 1). (6) In these high-risk patients, the activity of enoxaparin should be monitored by anti-factor Xa assay. Since enoxaparin is highly active against factor Xa, anti-factor Xa values that are within the determined therapeutic range are consistent with adequate drug efficacy and safety. Anti-factor Xa values that are elevated above the determined therapeutic range should alert clinicians to the potential for bleeding complications.

Supportive care for enoxaparin-induced hemorrhage is multifactorial and best provided in an intensive care setting. (6) First, enoxaparin must be discontinued. Second, protamine should be given to neutralize the anticoagulant effects of enoxaparin (Table 2). The protamine dose depends upon the time elapsed since the last enoxaparin dose. Third, fresh frozen plasma and packed red blood cells should be administered, and hemoglobin and coagulation studies monitored serially. Fourth, surgical intervention may be necessary if all other measures fail to stabilize the patient.

Conclusion

This case demonstrates that, despite its proven benefits in the management of patients with acute coronary syndromes, enoxaparin use is not without risk. A high index of suspicion is necessary if patients display any of the symptoms and signs that suggest substantial hemorrhage. In high-risk patient groups, enoxaparin activity should be monitored with the anti-Factor-Xa assay. Treatment of enoxaparin-induced hemorrhage is multi-factorial and best implemented in an intensive care setting.

Table 1

Contraindications, warnings, and precautions regarding the use of
enoxaparin (a)

Contraindications                                Warnings
(do not use)                            (use with extreme caution)

Active major bleeding               History of heparin-induced
Thrombocytopenia associated with a   thrombocytopenia
 positive in vitro test for         Hemorrhage or other conditions with
 antiplatelet in the presence of     increased risk of hemorrhage
 enoxaparin                         Renal insufficiency (calculated
Known hypersensitivity to            creatinine clearance, <30 ml/min)
 enoxaparin, heparin, or pork
 products

Contraindications                              Precautions
(do not use)                                 (use with care)

Active major bleeding               Bleeding diatheses
Thrombocytopenia associated with a  History of recent gastrointestinal
 positive in vitro test for          ulceration, history of recent
 antiplatelet in the presence of     hemorrhage, diabetic retinopathy
 enoxaparin                         Borderline renal function or
Known hypersensitivity to            advanced age (which may cause
 enoxaparin, heparin, or pork        delayed elimination of enoxaprin)
 products                           Uncontrolled arterial hypertension

(a) Adapted from Noble S, Spencer CM

Enoxaprin: A review of its clinical potential in the management of
coronary artery disease.

Drugs 1998;56:259-272 (6); and package insert, Aventis Pharmaceuticals,
Inc., Bridgewater, NJ.

Table 2

Suggested protamine doses to neutralize the anticoagulant effects of
enoxaparin (a)

Time since last
enoxaparin dose
(h)                               Protamine dose

[less than or equal to]8          1 mg protamine per 1 mg enoxaparin

>8 and [less than or equal to]12  0.5 mg protamine per 1 mg
                                  enoxaparin

>12                               No evidence to show any benefit
                                  from protamine

(a) Adapted from package insert, Aventis Pharmaceuticals, Inc.,
Bridgewater, NJ.

Accepted November 13, 2001.

References

(1.) Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease: Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447-452.

(2.) Gurfinkel EP, Manos EJ, Mejail RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26:313-318.

(3.) Thrombolysis in Myocardial Infarction (TIMI) IIA Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI IIA: The Thrombolysis in Myocardial Infarction (TIMI) IIA Trial Investigators. J Am Coll Cardiol 1997;29: 1474-1482.

(4.) Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) IIB trial. Circulation 1999;100:1593-1601.

(5.) Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI IIB-ESSENCE meta-analysis. Circulation 1999; 100:1602-1608.

(6.) Noble S, Spencer CM. Enoxaparin: A review of its clinical potential in the management of coronary artery disease. Drugs 1998;56:259-272.

(7.) Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79: 1-17.

(8.) Frydman A. Low-molecular-weight heparins: An overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996;26(Suppl 2):24-38.

(9.) Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-698.

(10.) Montoya JP, Pokala N, Melde SL. Retroperitoneal hematoma and enoxaparin. Ann Intern Med 1999;131:796-797 (letter).

RELATED ARTICLE: Key Points

* Based on the results from landmark clinical trials, enoxaparin has become an important component in the care of patients with acute coronary syndromes.

* Enoxaparin should be used with extreme caution in patients with 1) creatinine clearance less than 30 ml/min, 2) a history of heparin-induced thrombocytopenia, and 3) hemorrhage or conditions with increased risk of hemorrhage.

* If enoxaparin is used in patients at risk for the above conditions, monitoring its activity with an anti-factor-Xa assay is recommended.

From the Department of Medicine, University of Missouri-Columbia, Columbia, MO.

Reprint requests to Kirk M. Chan-Tack, MD, Department of Medicine, Evanston Hospital, 2650 Ridge Avenue, Evanston, IL 60201. Email: [e-mail]

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