Surgical management of enoxaparin- and/or warfarin-induced massive retroperitoneal bleeding: report of a case and review of the literature.

Abstract: A 70-year-old man on enoxaparin and warfarin sodium therapy due to pulmonary embolism was admitted for evaluation of a sudden, sharp pain in the left inguinal region. Physical examination revealed a 5 X 10 cm tender mass. Abdominal ultrasound showed a 9 X 9 X 10 cm left retroperitoneal hematoma. INR was 2.1, and anticoagulation therapy was discontinued. A regimen of supportive therapy (vitamin K, fresh frozen plasma and blood transfusion) was started, but the hemorrhage continued to enlarge, up to 9 X 10 X 20 cm, and the patient experienced a significant deterioration in his overall status. He underwent an urgent laparotomy and the hematoma was evacuated. A retroperitoneal abscess developed during the postoperative period which was drained percutaneously. He was discharged on postoperative day 33 with no further complaints. This case demonstrates the importance of surgical therapy in the treatment of spontaneous retroperitoneal hemorrhage caused by anticoagulant therapy.

Key Words: enoxaparin, retroperitoneal hematoma, surgical treatment

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Spontaneous retroperitoneal hemorrhage is a very rare condition specifically related to enoxaparin or warfarin therapy. In recent years, both enoxaparin and warfarin have been used for thromboembolic events such as deep venous thrombosis and pulmonary embolism. Predictable pharmacokinetic profile, high bioavailability, long plasma half-life and effective levels of anticoagulant activity after subcutaneous administration without laboratory monitoring are some of the advantages of enoxaparin. (1) Retroperitoneal hemorrhage is a serious and well-described complication in patients who develop increased anticoagulation, and may result in a femoral neuropathy. (2) Irreversible damage of the lumbar plexus or femoral nerve may result from entrapment of nerves in the hematoma. Both conservative and surgical treatments have been advocated for this complication. (3,4)

Case Report

A 70-year-old male was admitted with sudden onset of right-sided pleuritic chest pain and dyspnea for one month following an arthroscopy. He had no history of coagulopathy, renal tumors, liver disease or abdominal aortic aneurysm. He had no family history of coagulopathy and reported no alcohol use. A diagnosis of pulmonary embolism was made (Fig. 1). On the 15th day of therapy, pulmonary symptoms disappeared but a sudden and severe pain began in the left inguinal region. A 5 X 10 cm painful mass was found on physical examination. His vital signs and laboratory data were completely normal (including a platelet count of 205,000) and INR value was 2.1. Abdominal ultrasonography revealed a 9 X 9 X 10 cm hematoma in the left retroperitoneal space. Enoxaparin and warfarin sodium therapy were stopped as well as oral feeding. Instead, the patient received parenteral fluid therapy, vitamin K injection and fresh frozen plasma infusion. In the meantime, the patient developed iatrogenic pneumothorax during the insertion of a central venous catheter and a chest tube was also placed. The patient's condition deteriorated after this period with marked tachycardia and tachypnea. Despite the transfusion of six units of red blood cells, hemoglobin level decreased to 8 g/dL. Abdominal distention gradually increased and a marked tenderness developed especially in the left lower quadrant. Computed tomography revealed enlargement of the retroperitoneal hematoma up to 9 X 10 X 20 cm with the left kidney and spleen displaced anteriorly and free fluid in the intraperitoneal area (Fig. 2).

At the end of the first 24 hours, due to laboratory findings and deterioration in the patient's general status, the decision was made to operate. A very large retroperitoneal hematoma was seen, originating from a spontaneous left iliopsoas muscle bleed. All clots were removed. The iliopsoas muscle was fragile and oozing. Ligation, electrocauterization and hot towels were used for hemostasis. The retroperitoneal area was also washed with warm saline. Nunit and Spongostan (Johnson & Johnson, Edinburgh, UK) were placed into the bleeding area. Following the insertion of two silastic drains into the abdomen, the operation was terminated. In the early postoperative period the patient's condition improved. On postoperative day 8, the patient was reevaluated for the etiology of a rising fever and a 23 X 9 X 6 cm abscess in the retroperitoneal space, which was drained percutaneously. Anti-platelet therapy was again started on postoperative day 12, and the patient was discharged on postoperative day 33.

Discussion

Low molecular weight heparins (LMWH) have been shown to be effective and safe for the treatment of deep venous thrombosis and pulmonary embolism. (5,6) The LMWH differ in their mechanism of action from unfractionated heparin by their inhibitory effect against factor Xa and thrombin. In addition, the LMWH produce a very predictable anticoagulation response which is due to their better bioavailability, longer half-life and dose-dependent clearance. These advantages, along with the elimination of laboratory monitoring, make LMWH the drug of choice for treatment of acute venous thromboembolism. (7) However, LMWH therapy for other indications is not without risk. Abdominal wall hematoma, (8) thigh hematoma (9) and spinal and epidural hematoma (10) have been reported during treatment with LMWH enoxaparin. Retroperitoneal hematoma is another important and sometimes fatal complication of enoxaparin. To our knowledge, nine previous cases have been reported in English literature. (11-18) The patients, indications of enoxaparin usage, results and complications are summarized in the Table.

[FIGURE 1 OMITTED]

It is a well-known fact that advanced age and renal insufficiency are risk factors for bleeding during treatment with LMWH. (17) The impairment of renal function with decreased drug clearance is the proposed mechanism for predisposition to bleeding in advanced age, although many other factors may contribute to the changes in drug levels and sensitivity in this age group. (19) This hypothesis is supported by the fact that our patient was over the age of 65, as were the seven other reported cases. Although renal function was preserved in our patient, five of the reported cases had renal impairment. The use of acetyl salicylic acid (ASA) and warfarin may be another contributory factor that may interact with enoxaparin in these patients. Our patient was on warfarin treatment with enoxaparin for four days with an INR of 2.1. Six of the reported cases were using ASA, oral anticoagulant, or both of these drugs with enoxaparin.

Retroperitoneal hematoma may be a fatal complication of enoxaparin therapy. Four of the patients died despite supportive measures. Supportive care for enoxaparin-induced hemorrhage consists of discontinuation of the drug, administration of protamine to neutralize the anticoagulant effect of enoxaparin, fresh frozen plasma and packed red blood cells to restore coagulation process. As the two patients who underwent surgical intervention recovered, physicians should consider surgical intervention for patients who do not respond to supportive measures. Surgical intervention should not be delayed if other measures fail to stabilize the patient.

[FIGURE 2 OMITTED]

Conclusion

Enoxaparin has advantages over unfractionated heparins, but clinicians must be aware of potential complications, especially in patients of advanced age and in patients receiving ASA or warfarin therapy with enoxaparin. Physicians should be aware of the signs and symptoms of retroperitoneal hematoma like hypotension, decreasing hemoglobin, abdominal distension, peritoneal signs and flank and/or hip pain. When a retroperitoneal hematoma is discovered, enoxaparin, ASA or warfarin must be discontinued and surgical intervention should be performed if the patient does not respond to supportive therapy.

Table. Patients with bleeding complications: indications of enoxaparin
usage and results (a)

                                        Age   Enoxaparin twice   Renal
Author                 Indication       (yr)    per day (mg)    failure

Klein, 1997            DVT prophylaxis   67       30              ...
Montoya, 1999          DVT               69       80              Yes
Dabney-Bastani, 2001   DVT               68       80              Yes
                       DVT               46       60              Yes
Chan-Tack, 2003        Non-Q-wave AMI    83        1 (mg/kg)      ...
Vaya, 2003             DVT               77      100              ...
Melde, 2003                              70       80              Yes
                                         71       80              Yes
Mrug, 2002             Suspected PT      58       70              ...

                                Oral
Author                   ASA    anticoagulant    Therapy/result

Klein, 1997              Yes    ...              Supportive/recovered
Montoya, 1999            Yes    ...              Supportive/died
Dabney-Bastani, 2001     ...    ...              Surgery/recovered
                         ...    ...              Surgery/recovered
Chan-Tack, 2003          Yes    ...              Supportive/died
Vaya, 2003               ...    Yes              Supportive/died
Melde, 2003              Yes    Yes              Supportive/recovered
                         Yes    ...              Supportive/recovered
Mrug, 2002               ...    ...              Supportive/recovered

(a) ASA, acetyl salicylic acid; DVT, deep venous thrombosis; AMI, acute
myocardial infarction; PT, pulmonary thromboembolism.

Accepted August 13, 2004.

References

1. Bratt G, Tornebohm E, Locker D et al. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment. Thromb Haemost 1985;53:208-211.

2. Chiu WS. The syndrome of retroperitoneal hemorrhage and lumbar plexus neuropathy during anticoagulant therapy. South Med J 1976;69:595-599.

3. Houde JP, Steinberg G. Intrahepatic hemorrhage after use of low-molecular-weight heparin for total hip arthroplasty. J Arthroplasty 1999;14:372-374.

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

5. Lensing AWA, Prints MH, Davidson BL et al. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995;155:601-607.

6. Findik S, Erkan ML, Selcuk MB, et al. Low-molecular-weight heparin versus unfractionated heparin in the treatment of patients with acute pulmonary thromboembolism. Respiration 2002;69(5):440-444.

7. Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest 119(Suppl 1):176-193, 2001.

8. Antonelli D, Fares L, Anene CH. Enoxaparin associated with huge abdominal wall hematomas: A report of two cases. Am Surg 200;66:797-800.

9. Kumar PD. Thigh hematoma after femoral venipuncture in a patient treated with low molecular-weight heparin. Arch Intern Med 2001;161:1113-1114.

10. Wysowski DK, Talarico L, Bacsanyi J et al. Spinal and epidural hematoma and low-molecular-weight heparin. New Engl J Med 1998;338:1174-1175.

11. Klein SM, D'Ercole F, Greengras RA et al. Enoxaparin-associated with psoas hematoma and lumbar plexopathy after lumbar plexus block. Anesthesiology 1997;87:1576-1579.

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

13. Dabney A, Bastani B. Enoxaparin-associated severe retroperitoneal bleeding and abdominal compartment syndrome: A report of two cases. Intensive Care Med 2001;27:1954-1957.

14. Chan-Tack KM. Fatal spontaneous retroperitoneal hematoma secondary to enoxaparin. South Med J 2003;96:58-60.

15. Vaya A, Mira Y, Aznar J et al. Enoxaparin-related fatal spontaneous retroperitoneal hematoma in the elderly. Thromb Res 2003;110:69-71.

16. Melde SL. Enoxaparin induced retroperitoneal hematoma. Ann Pharmacother 2003;37:822-824.

17. Mrug M, Mishra PV, Lusane HC et al. Hemothorax and retroperitoneal hematoma after anticoagulation with enoxaparin. South Med J 2002;95:936-938.

18. Weitz J. Low-molecular-weight heparins. N Engl J Med 1997;337:688-698.

19. Camphell NR, Hull RD, Brant R et al. Aging and heparin-related bleeding. Arch Intern Med 1996;156:857-860.

RELATED ARTICLE: Key Points

* Enoxaparin treatment is widely used for different types of patients in both surgical and nonsurgical practice.

* Spontaneous bleeding is one of the complications of this treatment. Although most cases are treated by conservative means, some need surgical intervention.

* We discuss potential side effects of enoxaparin as well as the need for surgical intervention with emphasis on appropriate timing for surgical intervention.

Koray Topgul, MD, Oguz Uzun, MD, A. Ziya Anadol, MD, and Ali Gok, MD

From the Department of General Surgery, Ondokuz Mayis University, School of Medicine, Samsum, Turkey, and the Department of Chest Diseases, Ondokuz Mayis University, School of Medicine, Samsun, Turkey.

Reprint requests to Dr. Koray Topgul, OMU Tip Fakultesi, Genel Cerrahi Anabilim Dali 55139, Samsun, Turkey. E-mail: [e-mail]