Successful treatment of severe gastrointestinal bleeding secondary to Crohn disease with recombinant factor VIIa.

Abstract: A 58-year-old man diagnosed with ileocolonic Crohn disease was admitted to the emergency room with massive lower gastrointestinal hemorrhage and hypovolemic shock. Treatment was started with methylprednisolone, metronidazole and omeprazole. Within the next 24 hours, he received a total of 9 U of red blood cell concentrate and 2 U of fresh frozen plasma. Because of persistence of bleeding, hypovolemic shock and life-threatening situation, we started therapy with rFVIIa. One dose of 120 [micro]g/kg and another dose of 120 [micro]g/kg three hours after the first dose were administered as compassionate use, with resolution of bleeding in the next 12 hours. On day 4 the patient was stabilized. We performed a total colonoscopy and intubation of the ileocecal valve that showed patchy deep ulcerations in the rectum with bleeding inflammatory pseudopolyps. Acute gastrointestinal bleeding is an unusual complication in Crohn disease. In this case, the use of recombinant activated factor VIIa controlled the massive gastrointestinal bleeding secondary to Crohn disease and without clinically significant adverse effect. There are few case reports documenting the use of recombinant activated factor VIIa for this type of off-label indication. Clinical trials should be carried out to define the dosage and dose interval schedule of rFVIIa in the treatment of uncontrolled massive gastrointestinal bleeding secondary to Crohn disease.

Key Words: recombinant factor VIIa, Crohn disease, surgery, bleeding, hemorrhage

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Acute lower gastrointestinal bleeding is an unusual complication in Crohn disease. In the literature, its occurrence has been quoted as 0.9 to 6%. (1,2) Preoperative diagnosis of the bleeding site is not easy, and enteroscopy should be mandatory in such patients. (3,4) The new method of carrying out enteroscopy using a double-balloon technique allows not only diagnostic but also therapeutic endoscopic interventions for lesions in the small bowel. There is increasing evidence that capsule endoscopy for suspected Crohn disease may be diagnostic in individual cases after inconclusive conventional tests. (5) Recently, recombinant factor VIIa (rFVIIa) has been used in the treatment of upper gastrointestinal bleeding (6) and portal hypertension. (7,8) We report the successful use of rFVIIa in a patient with life-threatening massive gastrointestinal bleeding secondary to Crohn disease.

Case Report

A 58-year-old man with a prior history of hypertension, hypercholesterolemia and isolated diverticula of the sigmoid colon presented to the emergency room with massive lower gastrointestinal hemorrhage. He had no history of allergic drug reactions, and no personal or family history suggestive of a bleeding disorder. Three months before admission, the patient was found to have distal rectum sparing, but his proximal rectum and colon were affected. His first colonoscopy revealed severe and extensive ulceration and pseudopolyps in the proximal rectum and colon. Biopsies on the first and second colonoscopy confirmed the diagnosis of colonic Crohn disease. The ileum was normal in ileoscopy, but there was microscopic Crohn disease, and he was diagnosed with colonic Crohn disease. He started treatment with metronidazole 250 mg p.o. q.8 hours., mesalazine 1 g p.o. q.8 hours., prednisone 50 mg mg p.o. q.d., calcium 600 mg p.o. q.d., D3 vitamin 400 IU p.o. q.d., omeprazole 20 mg p.o. q.d. and iron sulfate 256 mg p.o. q.d. Three weeks later, the patient presented to the emergency room with massive lower gastrointestinal hemorrhage and hypovolemic shock. He was transferred to the critical care unit. On physical examination, the patient had a temperature of 37.5[degrees]C, blood pressure was 77/55 mm Hg and pulse was 110 beats/min. A thorax x-ray and echocardiogram were normal. No abnormality was found on computed tomography scan of the stomach. The initial laboratory tests revealed a hemoglobin of 10 g/dL, hematocrit 28%, white cell count 26 [10.sup.3]/[mm.sup.3], platelet count 431,000/[mm.sup.3], neutrophils 21 [10.sup.3]/[mm.sup.3], APTT 23.6 seconds (normal range 25-40 seconds), quick index 90%, fibrinogen 494 mg/dL, PT 12.5 seconds, urea, 40 mg/dL, creatinine 0.76 mg/dL, and the other laboratory findings were normal. As our patient was unstable, we first performed urgent resuscitation, followed by treatment with methylprednisolone hemisucci-nate 60 mg intravenously (IV) once daily, metronidazole 1000 mg IV once daily and omeprazole 40 mg IV once daily. The patient continued to have massive gastrointestinal bleeding. Over the next 24 hours, he received a total of 9 U of red blood cell concentrate and 2 U of fresh frozen plasma. Laboratory tests at that time revealed a hemoglobin of 8.9 g/dL, hematocrit 25.1%, and platelets 326,000/[mm.sup.3]. We decided not use therapeutic options such as octreotide, somatostatin, or tran-examic acid because mesenteric angiography with embolization was not available at the hospital. In addition, given the persistence of massive bleeding, hypovolemic shock, high risk of surgical procedure and life-threatening situation, we decided to start therapy with rFVIIa. One dose of 120 [micro]g/kg was given, followed by another dose of 120 [micro]g/kg three hours later as compassionate use, with resolution of bleeding over the next 12 hours. Within 24 hours after rFVIIa administration, the hemoglobin was stabilized. On day 3, we started treatment with azathioprine. On day 4, the patient was stabilized and laboratory tests revealed a hemoglobin of 14 g/dL, hematocrit 41%, white cell count 11.5 [10.sup.3]/[mm.sup.3], and a platelet count of 357,000/[mm.sup.3]. We performed a total colonoscopy and intubation of the ileocecal valve that showed patchy deep ulcerations in the proximal rectum and colon with rubbing, bleeding, inflammatory pseudopolyps. Sigmoid mucosa was intact with the presence of isolated diverticula without signs of bleeding. The patient had severe and extensive ulceration of the proximal rectum and colon. The descending colon revealed multiple aph-thous ulcers with numerous pseudopolyps extending as far as the cecum. The terminal ileum was examined to approximately 10 cm, and no lesions were noted. These alterations were compatible with colonic Crohn disease with severe endoscopic affectation. Biopsy samples of ulcers also revealed histologic changes compatible with active Crohn disease. There was ileitis in the biopsies of the ileum. Upper endoscopy and computed tomography scans of the abdomen and barium-contrast small bowel study were normal. The remainder of the patient's clinical course was uneventful over the next week. The patient did not start bleeding again. Twenty days later the patient had fully recovered and was discharged from the hospital. Six months later the patient was free of symptoms, and to date, the patient has had no further bleeding episodes.

Discussion

Recombinant factor VIIa is indicated for the treatment of hemorrhages in patients with hemophilia A or B with inhibitors of factor VIII or factor IX. rFVIIa is useful in the treatment of factor VII deficiency and in patients with congenital or acquired thrombocytopathy. (9,10) The mechanism of action of rFVIIa is controversial, but it is believed that initiation of hemostasis occurs with the formation of a complex between tissue factor and activated FVIIa. The tissue factor pathway must be intact for FVIIa to have an effect. FVIIa will bind weakly to activated platelets and can directly activate factor X to factor Xa, such that in the presence of factor V, thrombin generation can be improved over and above that generated by the tissue factor/VIIa complex alone. (10) The binding of rFVIIa to activated platelets may explain why rFVIIa is localized only in the site of bleeding. The onset of action, once rFVIIa is infused, appears to be almost immediate, with clinically apparent hemostasis noted within 10 minutes. The reported half-life values for adults varied from 2.4 to 3.2 hours with bolus administration of rFVIIa. (9) rFVIIa is useful in the management of inherited and acquired deficiencies of factor VII and platelet function defects. (11) The standard dosing regimen in this indication has been 90 to 110 [micro]g/kg every 2 to 3 hours for two or three doses. More recently, it has been used effectively in controlling excessive hemorrhage in patients undergoing cardiac surgery, liver transplantation, intestinal hemorrhage and necrotizing pancreatitis. (12,13) Its off-label use as a hemostatic agent has been extended to the treatment of upper gastrointestinal bleeding in patients with esophageal varices unresponsive to standard treatment. (8) In the literature, there is currently lack of experience with the use of rFVIIa in massive gastrointestinal bleeding secondary to Crohn disease. A MEDLINE search was performed (1966 to November 2006) and only one report of treatment with rFVIIa in severe bleeding associated with Crohn disease was found. White et al reported two cases of the successful use of rFVIIa with intractable intra-abdominal bleeding associated with bowel resection for Crohn disease and large bowel lymphoma. (14) Both patients were treated with two doses of rFVIIa 90 [micro]g/kg 2 hours apart, which resulted in immediate resolution of bleeding. One of the patients died, although there was no evidence of disseminated thromboses on postmortem examination. The authors concluded that rFVIIa should be used in intractable intra-abdominal hemorrhage which has failed to respond to conventional therapy.

The first-line treatment option of controlling massive gastrointestinal bleeding is mesenteric angiography with embolization. However, in instances where this is not available, as in our case, the administration of rFVIIa has been shown to control the massive gastrointestinal bleeding secondary to Crohn disease. In our patient, there were no clinically significant adverse effects; however, some adverse reactions associated with rFVIIa have been recently described. O'Connell et al reported thromboembolic events occurring in patients administered rFVIIa for unlabeled indications. Thromboembolic events occurring within the first 24 hours of the last rFVIIa dose accounted for 50% of the patients. The most common use was surgical bleeding, followed by no surgical hemorrhage. The authors concluded that randomized, controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia. (15)

The optimal doses of rFVIIa in the treatment of bleeding have not been well defined. The dose response effect of rFVIIa when used in surgical prophylaxis and in the reversal of coagulopathy was established in dose-finding studies. (16) However, this phenomenon was not observed in the treatment of uncontrolled massive bleeding. Dosages of 50 to 100 [micro]g/kg were also recommended for patients weighing 50 to 100 kg for 1 or 2 doses for treatment of uncontrolled profuse bleeding based on their institutional experiences. (17) On the other hand, results from two trials seemed to support the use of higher doses in patients with extensive injury. (18) It is possible that the interpatient variability in the pharmacokinetic profile of rFVIIa, as well as certain disease conditions, may affect the efficacy of rFVIIa. Generally, rFVIIa clearance in adults is approximately 30 to 35 mL/kg/h. (19) rFVIIa has recently been utilized in refractory bleeding where current evidence, consisting mostly of case reports, suggests remarkable safety and efficacy. (14) The first randomized controlled trials related with hemostasis are only now being published with less remarkable results. In this report, rFVIIa was successful in stabilizing a patient who may have been otherwise unsalvageable for surgery. In this case, we would not expect rFVIIa to be the definitive management of the bleeding lesions, but it was certainly useful. There are few case reports documenting the use of rFVIIa for this type of off-label indication. It is necessary to ensure the safe use of rFVIIa in these situations, since patients with inflammatory bowel disease have a threefold increased risk of thrombosis, a major cause of morbidity and mortality. Although the exact mechanism explaining the initiation of thrombosis remains unclear, it is a multifactorial process including the activation of markers of the coagulation cascade, disturbed fibrinolysis and the activation of platelets. Clinical trials should be carried out to define the dosage, dose interval schedule, and safety in the treatment of uncontrolled massive gastrointestinal bleeding secondary to Crohn disease.

References

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2. Driver CP, Anderson DN, Keenan RA, et al. Massive intestinal bleeding in association with Crohn's disease. J R Coll Surg Edinb 1996;41:152-154.

3. Belaiche J, Louis E, D'Haens G, et al. Acute lower gastrointestinal bleeding in Crohn's disease: characteristics of a unique series of 34 patients. Am J Gastroenterol 1999;94:2177-2181.

4. Veroux M, Angriman I, Ruffolo C, et al. Severe gastrointestinal bleeding in Crohn's disease. Ann Ital Chir 2003;74:213-215.

5. Keuchel M, Hagenmuller F. Small bowel endoscopy. Endoscopy 2005;37:122-132.

6. Vlot AJ, Ton E, Mackaay AJC, et al. Treatment of a severely bleeding patient without preexisting coagulopathy with activated recombinant factor VII. Am J Med 2000;108:421-423.

7. Ejlersen E, Melsen T, Ingerslev J, et al. Recombinant activated factor VII (rFVIIa) acutely normalized prothrombin time in patients with cirrhosis during bleeding from esophageal varices. Scand J Gastroenterol 2001;36:1081-1085.

8. Romero-Castro R, Jimenez-Saenz M, Pellicer-Bautista F, et al. Recombinant-activated factor VII as hemostatic therapy in eight cases of severe hemorrhage from esophageal varices. Clin Gastroenterol Hepatol 2004;2:78-84.

9. Jurlander B, Thim L, Klausen NK, et al. Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development. Semin Thromb Hemost 2001;27:373-384.

10. Lisman T, Adelmeijer J, Heijnen HF, et al. Recombinant factor VIIa restores aggregation of alphallbbeta3-deficient platelets via tissue fac-torindependent fibrin generation. Blood 2004;103:1720-1727.

11. Conesa V, Navarro-Ruiz A, Borras-Blasco J, et al. Recombinant factor VIIa is an effective therapy for abdominal surgery and severe thrombocytopenia: a case report. Int J Hematol 2005;81:75-76.

12. Borras-Blasco J, Conesa-Garcia V, Navarro-Ruiz A, et al. Use of recombinant factor VIIa for life-threatening bleeding in a patient with severe necrotizing pancreatitis. Pancreas 2005;31:292-294.

13. Lam MS, Sims-McCallum RP. Recombinant factor VIIa in the treatment of non-hemophiliac bleeding. Ann Pharmacother 2005;39:885-891.

14. White B, McHale J, Ravi N, et al. Successful use of recombinant FVIIa (Novoseven) in the management of intractable post-surgical intra-abdominal haemorrhage. Br J Haematol 1999:107;677-678.

15. O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-298.

16. Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet 2003;361:201-205.

17. Goodnough LT, Hewitt PE, Silliman CC. Transfusion medicine: joint ASH and AABB educational session. Am Soc Hematol Educ Program 2004;457-472.

18. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomised, placebo-controlled, double-blind clinical trials. J Trauma 2005;59:8-15.

19. Erhardtsen E. Pharmacokinetics of recombinant activated factor VII (rFVIIa). Semin Thromb Hemost 2000;26:385-391.

Eva Girona, MD, PhD, Joaquin Borras-Blasco, PharmD, PhD, Venancio Conesa-Garcia, MD, Andres Navarro-Ruiz, PharmD, Javier Solis, MD, Mariana Fe Garcia-Sepulcre, MD, PhD, and Israel Oliver-Garcia, MD, PhD

From the Gastroenterology Section, Hematology Service, Pharmacy Service, Critical Care Unit, and Surgery Service, Hospital General Universitario de Elche; and Pharmacy Service, Hospital de Sagunto, Valencia, Spain. The authors have no affiliation or financial interest in any company or organization that could present a conflict with the views expressed and presented in this manuscript.

Reprint requests to Dr Joaquin Borras-Blasco, Pharmacy Department, Hospital de Sagunto, Avda Ramon y Cajal s/n, Sagunto 46520 (Valencia), Spain. Email: [e-mail]

Accepted January 25, 2007.

RELATED ARTICLE: Key Points

* Acute gastrointestinal bleeding is an unusual complication in Crohn disease. The use of recombinant activated factor VIIa controls the massive gastrointestinal bleeding secondary to Crohn disease and without clinically significant adverse effect.

* There are few case reports documenting the use of recombinant activated factor VIIa for this type of off-label indication.

* Clinical trials should be carried out to define the dosage and dose interval schedule of rFVIIa in the treatment of uncontrolled massive gastrointestinal bleeding secondary to Crohn disease.