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A Retroperitoneal Bleed Induced By Enoxaparin Therapy

June 9, 2005

Retroperitoneal bleeding is one of the most serious, potentially lethal complications of anticoagulation therapy. Although well documented in fully heparinized and coumadinized patients, there are only few reports of life-threatening hemorrhages in low-molecular- weight heparin (LMWH)-treated patients. We present a case of almost fatal spontaneous retroperitoneal bleeding in a 71-year-old woman with pneumonia and acute coronary syndrome. After receiving combination therapy with Lovenox (enoxaparin), aspirin, and Plavix for 5 days, she developed acute hemorrhagic shock and possible intra- abdominal compartment syndrome. Urgent computed tomography scan of the abdomen and pelvis was performed and showed a left retroperitoneal hematoma. The patient’s condition continued to deteriorate, which prompted emergent exploration. After evacuating 3 L of free blood from the peritoneal cavity, we managed to stabilize the patient. Our case of spontaneous retroperitoneal bleeding adds to the growing number of cases in which enoxaparin has been associated with severe bleeding. A high index of suspicion is necessary if the patient displays any of the signs and symptoms that suggest major hemorrhage. It appears that those at highest risk receive doses approaching 1 mg/kg subcutaneously every 12 hours, have renal impairment, are of advanced age, and receive concomitant medications that can affect hemostasis. On average, a retroperitoneal hematoma occurs within 5 days of therapy with enoxaparin. In high-risk patients, enoxaparin activity (anti-factor Xa) should be carefully monitored.

LOW-MOLECULAR-WEIGHT HEPARINS (LMWHS) have proven to be as safe and effective as unfractionated heparin for the prophylaxis and treatment of acute coronary syndrome (ACS), non-Q-wave myocardial infarction (NQWMI), venous thrombosis, and pulmonary thromboembolism. As a result of their safety and efficacy, along with the advantages of decreased laboratory monitoring and outpatient administration, the prescription of LMWH has altered clinical practice in the United States.1 However, a high incidence of local bleeding complications has been reported with enoxaparin (Lovenox), mostly at the injection or instrumentation sites. There have also been reports of more severe bleeding complications, such as abdominal wall hematomas, including rectus muscle sheath hetnatomas, and only a few reports of retroperitoneal hematomas, with a high morbidity and mortality.2 We would like to add another case of an enoxaparinassociated, almost fatal, retroperitoneal hematoma, which led to an abdominal compartment syndrome.

Case Presentation

A 71-year-old female was initially hospitalized for community acquired pneumonia. She had a past medical history of hypertension, chronic obstructive pulmonary disease from heavy smoking, and steroiddependent arthritis. The patient did not have a history of any bleeding disorders or coagulopathies. She was not taking antiplatelet or anticoagulant agents. Admission laboratory values included a creatinine of 1.1 mg/ dL, hemoglobin of 11.9 g/dL, and hematocrit of 35 per cent. The patient was started on levofloxacin and bronchodilators. Enoxaparin, 40 mg daily administered subcutaneously, was added for venous thrombosis prophylaxis. Her shortness of breath gradually improved; however, on the fifth hospital day, she experienced acute discomfort in the chest. Her workup revealed abnormal cardiac enzymes and electrocardiogram, which led to a diagnosis of acute coronary syndrome (ACS). The patient was transferred to the CCU and was started on a Tridil drip, aspirin 325 mg per day, Plavix 75 mg per day, and the enoxaparin was increased to 1 mg per kilogram subcutaneously every 12 hours. Laboratory values at this time were a creatinine of 1.3 mg/dL, hemoglobin of 12.0 g/dL, platelets of 346,000 per mm, activated partial thromboplastin time (aPTT) of 24 seconds, prothrombin time (PT) of 14.2, international normalized ratio (INR) of 1.25, troponin I was normal, and a moderately elevated lactate dehydrogenase (LDH). The patient was scheduled for cardiac catheterization, but the symptoms started to subside and she was reluctant to undergo the procedure. Seventy-two hours later, the patient developed acute, tearing pain in the left flank and back that was increasing in severity, a rapid increase in heart rate, and, shortly thereafter, a drop in her blood pressure. The CCU team worked to rule out a new cardiac event. A dopamine drip was started because of hemodynamic instability and fluid challenges were given.

Surgery was then consulted. Our team evaluated the patient and found a pulsatile tender mass in the left hypogastrium. The patient appeared somnolent but arousable, and she was in significant abdominal distress. Dark blue ecchymoses were found in the left side of the abdominal wall. The foley catheter stopped draining urine. Systolic blood pressure barely measured 65-75 mm/Hg and the heart rate was 130/min. Parallel to the aggressive fluid management, a stat CAT scan of the abdomen and pelvis with intravenous contrast was ordered (Fig. 1 A-IC). Findings showed a huge left-sided retroperitoneal hematoma, measuring 15 18 cm, compressing the bladder and displacing the bowels to the cephalad direction. No evidence of a ruptured aortic aneurysm was found. The patient was intubated and mechanically ventilated. Despite all attempts to stabilize the patient, including transfusing 5 units of packed red blood cells, 2 units of fresh frozen plasma, and 4 units of platelets, her blood pressure remained at 70/30 mm Hg, she was anuric, and the hemoglobin and hematocrit declined from 11.9 g/dL to 7.0 g/dL and 34 per cent to 19.4 per cent, respectively. Her abdomen was extremely distended, firm to the touch, and had absent bowel sounds. Both lower extremities were cool to the touch, with significantly diminished femoral pulses. Ventilatory management was complicated by increasing peak inspiratory pressures, an elevated WBC of 38,000/mm with a left shift, and worsening lactic acidosis. An intraabdominal compartment pressure could not be measured because of a totally compressed and displaced bladder by the hematoma. With the fear of bowel ischemia and abdominal compartment syndrome, urgent operation became mandatory. An exploratory laparotomy was performed, which revealed an extensive retroperitoneal hematoma with rupture into the free peritoneum with more than 2500 cc of free blood. There was no evidence of ongoing bleeding or gangrenous bowel. We evacuated a significant amount of blood and retroperitoneal clot. The abdomen was closed primarily after a pelvic drain was placed. Shortly after laparotomy, the patient’s hemodynamics began to stabilize. The need for vasopressors was limited. The patient was transferred back to the ICU, and she started to make minimal urine.

FIG. 1. Arrows indicate relroperitoneal hematoma. A, Retroperitoneal hematoma extending into the pelvis. B, Some compression of the bladder due to retroperitoneal hematoma. C, Extension of the hematoma deep into the pelvis lateral to the bladder.

In the postoperative period the patient needed prolonged ventilatory support and developed a mild nonoliguric renal failure that did not require hemodialysis. Twenty-eight days later, the creatinine was 1.4 and the patient was tolerating a regular diet. There were no neurological deficits present, and her cardiac function was stable. The patient was discharged to a rehabilitation facility in good condition.

Discussion

Enoxaparin (Lovenox) is a commonly used, injectable, low- molecular-weight heparin that was first approved by the Food and Drug Administration in 1993 for prevention and treatment of thromboembolic diseases. The bioavailability and anticoagulant predictability of enoxaparin is clearly better than unfractionated heparins. In all but high-risk patients, the need for anticoagulation monitoring is unnecessary due to its dose- independent clearing mechanism and longer halflife.3

Retroperitoneal hematoma most commonly occurs as a result of trauma. However, anticoagulation therapy, vascular lesions, tumors, or surgical complications have also been seen as causes. Severe retroperitoneal hemorrhage is an infrequent complication of enoxaparin use. There are only a few reported cases in the world literature of a patient with enoxaparininduced spontaneous retroperitoneal bleeding.4 The ESSENCE study3 showed that enoxaparin was more effective than intravenous unfractionated heparin in reducing the incidence of death, myocardial infarction, or recurrent angina in patients with ACS. However, enoxaparin therapy is not without risks. Among 1528 patients receiving enoxaparin and aspirin for ACS, 17 cases (1%) of major bleeding episodes were reported that included intraocular, intracranial, major abdominal wall, injection- site and retroperitoneal hematomas. In these cases, hemoglobin declined by at least 3 g/dL or a transfusion requirement of 2 or more units of blood products was needed.

The clinical presentation of retroperitoneal hematoma in anticoagulated patients may be varied, and the incidence may be on the rise due to the increasing number of patients prescribed enoxaparin. The clinical manifestations range from leg-hip pain or paresis to abdominal/flank/back pa\in with or without bruises or a catastrophic shock. An early CT scan of the abdomen, preferably with intravenous contrast, is of great value in order to rule out other life-threatening conditions, such as ruptured or leaking abdominal aortic aneurysms, tumors, etc.3

With patients receiving anticoagulation, we should be very vigilant for suspicious signs and symptoms that suggest major bleeding (i.e., hemodynamic instability; back, flank, hip pain; bruising, nausea, vomiting, neurological deficiencies, hematuria, etc.) in order to reverse anticoagulation rapidly and initiate other therapeutic measures.

Knowing that enoxaparin clearance is affected by renal insufficiency as noted in the elderly, extra precaution should be taken in the treatment of these patients, especially if the creatinine clearance is

Use of other medications, in particular antiplatelet agents, which are especially common and recommended in ACS, NQWMI, and postcoronary angioplasties and stents, certainly increases the possible risk of bleeding complications.6

Because enoxaparin is mostly active against factor Xa, anti- factor Xa values should be monitored in the high-risk population. Anti-factor Xa values that are elevated above the determined therapeutic range should raise the suspicion for potential for complications.

In this case, the anti-factor Xa was not measured. Concomitant use of enoxaparin and antiplatelet drugs certainly put the patient at an increased risk for complications. Despite the proven benefits of enoxaparin in the management of ACS, its use has significant risks. Aggressive surgical intervention provided a successful outcome in our case.

Conclusion

Treatment of enoxaparin-induced hemorrhagic complications is multifactorial and should be carried out in a well monitored ICU setting. This includes:

1. Discontinuation of the anticoagulant.

2. Protamine sulfate, as an intravenous bolus of 0.5 to 1.0 mg per 1 mg of enoxaparin administered, given in order to try to reverse the effects of enoxaparin, provided the last dose was given no more than 8 hours ago.

3. Blood products given judiciously and aggressively.

4. Close hemodynamic monitoring and frequent serial hemoglobin and coagulation monitoring.

5. Avoiding instrumentation if possible.

6. The consideration of surgical intervention if all other measures fail to stabilize the patient.

Morbidity and mortality are very high in retroperitoneal bleeds, with significant perioperative and postoperative complications.

Our case of spontaneous retroperitoneal bleeding adds to the growing number of cases in which enoxaparin has been associated with severe bleeding. A high index of suspicion is necessary if the patient displays any of the signs and symptoms that suggest major hemorrhage. It appears that those at highest risk receive doses approaching 1 mg/kg subcutaneously every 12 hours, have renal impairment, are of advanced age, and receive concomitant medications that can affect hemostasis. On average, a retroperitoneal hematoma occurs within 5 days of therapy with enoxaparin. In high-risk patients, enoxaparin activity (anti-factor Xa) should be carefully monitored.

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;447-52.

2. Montoya JP, Pokala N, Melde SL. Retroperitoneal hematoma and Enoxaparin. Ann Intern Med 1999;131;796-7.

3. Lovenox (package insert) Bridgewater, NJ: Aventis Pharmaceuticals, Inc., 2003.

4. Chan-Tack KM. Fatal spontaneous retroperitoneal hematoma secondary to Enoxaparin. South Med J 2003;96;58-60.

5. Dabney A, Bastani B. Enoxaparin-associated severe retroperitoneal bleeding and abdominal compartment syndrome: a report of two cases. Intensive Care Med 2001;27:1954-7.

6. Gonzalez C, Penado S. The clinical spectrum of retroperitoneal hematoma in anticoagulated patients. Medicine 2003;82: 257-62.

MARTIN ERNITS, M.D., PRADEEP S. MOHAN, M.D., LOUIS G. FARES, II, M.D., F.A.C.S., HOWARD HARDY, III, M.D., F.A.C.S.

From the Department of Surgery, Seton Hall University Surgical Residency Program at St. Francis Medical Center, Trenton, NJ

Address correspondence and reprint requests to Pradeep S. Mohan, M.D., 125 Glenwood Ave., Burlington, NJ 08016.

Copyright The Southeastern Surgical Congress May 2005




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