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Acquired hemophilia: a clinical experience.

Introduction

Acquired hemophilia A is a rare bleeding disorder due to autoantibodies produced against Factor VIII. We report two cases of acquired hemophilia A seen in our practice. The first case involves a 20 year female who presented with retroperitoneal bleeding 3 months postpartum, and the second case is of a 61 year old female who presented with forearm bleeding and compartment syndrome. In this article, we review our clinical experience and current clinical expert opinion and treatment guidelines.

Case 1: Postpartum Acquired Hemophilia

A 20 yr old Caucasian female was transferred from an outside healthcare facility with a history of ankle sprain and bilateral bruising and swelling in both calves three days post injury. Her hemoglobin was 6 g/ dL and a PTT was 70 seconds at the outside facility. Lupus anticoagulant was positive. A diagnosis of lupus anticoagulant coagulopathy with intramuscular hemorrhage in both legs without evidence of DVT or compartment syndrome was made. Over several days the patient developed progressive left sided abdominal pain and was transferred to our hospital. CT scan of the abdomen and pelvis showed a large hemorrhagic collection in the left lateral peritoneum and descending colon. Her stool was hemoccult negative with no evidence of external bleeding. She required a total of 10 units of packed red cell transfusion in the first week of her admission. Serial CT scans performed for persistent worsening of abdominal pain showed interval increase in the retroperitoneal hematoma. The patient was 3 month postpartum. Her family history was negative for bleeding diathesis or connective tissue disorders.

Admission laboratory studies revealed: white blood count 10.5 THOU/UL; hemoglobin, 9.2 g/dL, platelets, 524THOU/UL, prothrombin time, 11.3 Sec; activated partial thromboplastin time 66.9 Sec. Lupus anticoagulant screen and hexagonal lipid correction assay were positive. PTT mixing study was consistent with lupus anticoagulant and an inhibitor to a coagulation factor. The lupus anticoagulant is rarely associated with bleeding but can coexist with a specific Factor VIII inhibitor. Further investigation showed the patient to have an inhibitor to Factor VIII with corresponding Bethesda inhibitor titer of 6 units. A diagnosis of acquired hemophilia A with Factor VIII inhibitor secondary to postpartum state was made.

The patient was started on oral prednisone 1mg/kg/day. She received one dose of 150 units/kg of Recombinant Factor VIII with no improvement in her Factor VIII level; Factor VIII level remained 2%. The patient was started on Recombinant Factor VIIa (Novo Seven) 270mcg/kg followed by 180 mcg/kg every six hours. Twenty four hours later a repeat CT scan showed interval increase in retroperitoneal bleed and her hemoglobin dropped to 7 g/dL. The dose of Novo Seven was increased to 270 mcg/kg every 6 hours and IVIG 22g/day was administered for a total of 5 days. Her condition improved; her abdominal pain gradually lessened and then disappeared. Retroperitoneal hematoma was stable on repeat CT. PTT trended down to 35.5 seconds; Bethesda titer also decreased to <1 unit and Factor VIII level increased to 23%. Factor VIIa infusions were subsequently stopped and prednisone was continued. Over the next 48 hours, she remained asymptomatic, with stable hemoglobin and PTT slightly trending up to 39.4 seconds. She was discharged on prednisone after a protracted 20 day hospital stay.

The patient was subsequently seen in the hematology clinic where she remained stable with minimal bruising in her shins. PTT improved to 36.9 seconds with Factor VIII assay 34%, and later the PTT decreased to normal at 29.4 seconds with Factor VIII at 77%. Her repeat lupus anticoagulant study came back negative. The prednisone dose was decreased to 40 mg/d from 60 mg/d.

A repeat PTT later came back elevated to 36.9 seconds with Factor VIII decreased to 50%. Her steroid dose was increased to 60mg and 2 weeks later her PTT improved. After discussions with the patient, she was started on Rituximab 375 mg/m2 per week x 4 doses. Her steroid dose was gradually tapered and the patient remained clinically well with a normal PTT and Factor VIII level 8 weeks post-Rituximab treatment. Repeat Bethesda titer was negative for the presence of a Factor VIII inhibitor. A repeat lupus anticoagulant at 6 weeks remained negative.

Case 2: Acquired Hemophilia with Compartment Syndrome

The patient is a 61 year old woman who presented initially with hematomas of the left and right forearm following intravenous blood draws. She developed compartment syndrome of the right forearm and underwent surgical release at an outside facility with excessive bleeding. She was found to have prolonged activated partial thromboplastin time. On transfer to our center, she was noted to have a Factor VIII of 6% and Bethesda titer of 5-10 units. No underlying cause for her inhibitor was found.

She received treatment with Novo Seven (Recombinant Factor VIIa), intravenous immunoglobulin, and oral prednisone for her Factor VIII inhibitor. She did well on tapering doses of prednisone until the dose was lowered to 2.5 mg a day with the Factor VIII level decreasing to 31%.

The prednisone dosage was increased to 5 mg. bid with normalization of the Factor VIII level to 90%. The prednisone was increased to 10 mg in the morning and 5 mg in the evening prior to right forearm revision surgery seven months after her initial presentation. She safely underwent a right wrist Guyon canal release, right carpal tunnel release and extensive neurolysis to the right forearm for a distance of 10 cm at both the medial and ulnar nerve. Scar revision of the hypertrophic keloid type scar in the volar right forearm 10-11 cm was also performed with considerable benefit to the patient.

Cyclophosphamide 100 mg. daily was added to prednisone. Her PTT and Factor VIII levels remained normal. Subsequently, prednisone was tapered off while cyclophosphamide was continued for a total of 10 months. A mild neutropenia corrected after stopping the cyclophosphamide. Factor VIII and PTT have remained normal with no recurrence of her inhibitor with follow up 3 years after initial presentation.

Discussion

Acquired inhibitors of coagulation are most often due to antibodies that either inhibit the activity or increase the clearance of a clotting factor. The most common auto antibodies affecting clotting factor activity leading to bleeding are directed against the activity of Factor VIII, a condition called acquired hemophilia A. (1-3) Patients with acquired hemophilia A can produce antibodies of different IgG subclasses directed against different epitopes on the Factor VIII molecule. (4-6)

Collins et al (7-8) have reported an incidence of 1.3-1.5 cases per million population per year of acquired hemophilia A. (7-8) In another survey, it was found that most of the patients were over age of 50, except for women who were pregnant or postpartum. The major identifiable causes were pregnancy or the postpartum period, rheumatoid arthritis, malignancy, drug reactions, systemic lupus erythematosus and other autoimmune disorders. However, in almost half of the cases no underlying disorder was present. Our first patient was postpartum with no other obvious underlying cause. In the second patient, no underlying cause was found. On multivariate analyses, factors predicting improved overall survival were attainment of complete remission, age less than 65 and postpartum status. (9) Our first patient meets all three criteria and the second meets two of the three criteria for improved survival. The risk of developing an inhibitor is greatest after first delivery. (10) The median time to acquire an inhibitor after delivery was two months in this study with a range of less than 1 month to 12 months. Our first patient, with no other obvious underlying cause, developed acquired hemophilia A 3 months after her second delivery.

The hallmark of Factor VIII inhibitor is bleeding. Symptomatic patients often present with large hematomas, extensive ecchymoses or severe mucosal bleeding including epistaxis, gastrointestinal bleeding, and gross hematuria. In women who were postpartum, soft tissue bleeding was the most common presenting symptom followed by intramuscular, vaginal, intraarticular bleed and hematuria. (2) Our patients had soft tissue and intramuscular bleeding at the time of presentation.

The treatment of this condition consists of two steps, control of bleeding and elimination of the inhibitor. (11,12) Treatment strategies to control active bleeding include the use of desmopressin (DDAVP), Factor VIII concentrate, activated prothrombin complex or APC (FEIBA - Anti-inhibitor coagulant factor), and Recombinant VIIa (NovoSeven). (3,11-15) Patient with non life threatening bleeding and low inhibitor titers (less than 5 Bethesda units) may respond to DDAVP (0.3 mcg/kg/d x 3-5 days) or intravenous Factor VIII concentrate in high doses. For patients with high titer inhibitor, APC or Recombinant Factor VIIa should be employed. Our first patient had a moderately high titer inhibitor that did not respond to Factor VIII concentrate and required Factor VIIa infusions. Eliminating the inhibitor most often requires immunosuppressive therapy. Prednisone and cyclophosphamide are the first line agents followed by IVIG, (16) Rituximab, Cladarabine and Cyclosporine. (17-18) In a randomized trial of 14 patients, various immunosuppressive regimens with prednisolone, cyclophosphamide, or both reduced the inhibitor titers to undetectable levels in 68% of patients with low-titer inhibitors (less than 5 BU/mL). (19,20) The response to chemotherapy, especially in high-titer patients, may require several months. A meta-analysis by Delgado et al of 245 inhibitor patients focused on the response to various treatments and prognostic factors. (21) Patients in whom the inhibitor could not be eliminated had a mortality rate of 42%, providing a strong argument for rapid and long-term inhibitor elimination as part of treatment. The metaanalysis showed an overall mortality rate of up to 16% for various treatment regimens and a high rate of complications, which were mainly associated with infections related to chemotherapy-induced neutropenia. The leading cause of death in patients with acquired hemophilia is not the bleeding itself but the complications that occur as a result of extended bleeding and its treatment, such as surgery for compartment syndrome, transfusion-related reactions, and infections caused by prolonged chemotherapy, particularly in elderly patients. (22)

Despite the low estimated incidence of the disease, it is a devastating disorder, and the costs of treatment can be immense. Therefore, there is considerable interest in improving and optimizing existing treatment regimens. Long-term immune tolerance induction (ITI) may be effective in acquired hemophilia. The modified BonnMalmo" Protocol (MBMP) for the treatment of acquired hemophilia, published in 2004, involves the combination of 4 therapeutic steps: (1) immunoadsorptive inhibitor removal, (2) high-dose Factor VIII administration, (3) Intravenous immunoglobulin (IVIG), and (4) immunosuppressive medication. MBMP protocol incorporates immunoadsorption in addition to conventional treatment. In all 35 patients in their study, the acute bleeding episodes were rapidly controlled within the first 2 to 3 apheresis procedures, and no subsequent episodes were encountered and the complete remission (CR) was 97%. They attribute the high efficacy of the MBMP to the immunoadsorption.

The primary objectives for treating patients with acquired hemophilia should be control of the bleeding and rapid elimination of the inhibitor. The inhibitor in our patients responded to IVIG and corticosteroids initially but relapsed when steroids were tapered. The first (postpartum) patient then responded to a second course of high dose steroids and simultaneous treatments with Rituximab (a monoclonal antibody directed against the CD20 antigen on B-lymphocytes). The second patient required the addition of oral cyclophosphamide to eliminate the inhibitor.

In conclusion the sudden presence of large hematoma or extensive ecchymoses especially in the elderly or in postpartum women without significant trauma or known bleeding disorder should raise suspicion of an acquired Factor VIII inhibitor. Since the lupus anticoagulant may occasionally be associated with the presence of a Factor VIII inhibitor, it is important to exclude the coexistence of these entities in any given case. Prompt diagnosis and appropriate treatment is important in this potentially life threatening acquired bleeding disorder.

References:

(1.) Green D, Lechner K. A survey of 215 non hemophilic patients with inhibitors to Factor VIII. Thrombo Haemost 1981; 45(3):200-3.

(2.) Hauser I, Schneider b, Lechner K. Postpartum Factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thrombo Haemost 1995; 73(1):1-5.

(3.) Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: A concise review. Am J Hematol 2005; 80(1):55-63.

(4.) Fulcher CA, de Graaf Mahoney S, Zimmerman TS. FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood 1987; 69(5):1475-80.

(5.) Fulcher CA, Lechner K, de Graaf Mahoney S. Immunoblot analysis shows changes in Factor VIII inhibitor chain specificity in Factor VIII inhibitor patients over time. Blood 1988; 72(4):1348-56.

(6.) Moreau A, Lacroix-Desmazes S, Kazatchkine MD. Antibodies to the Factor VIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Blood 2000; 95(11):3435-41.

(7.) Collins P, Macartney N, Davies R, Majer R. A population based, unselected, consecutive cohort of patients with acquired hemophilia A. Br J Haematol 2004; 124(1):86-90.

(8.) Collins PW, Hirsch S, Hay CR. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctor's organization. Blood 2007; 109(5):1870-7.

(9.) Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121(1):21-35.

(10.) Franchini M. Postpartum acquired Factor VIII inhibitors. Am J Hematol 2006; 81(10):768-73.

(11.) Hay CR, Brown S, Collins PW. The diagnosis and management of Factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006; 133(6):591-605.

(12.) Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost 2007; 5(5):893-900.

(13.) Lusher JM. Recombinant Factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with Factor VIII and IX inhibitors. Haemostasis 1996; 26 Suppl 1:124-30.

(14.) Sallah S. Treatment of acquired hemophilia with eight inhibitor bypassing activity. Haemophilia 2004; 10(2):169-73.

(15.) Holme PA, Brosstad F, Tjonnfjord GE. Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies. Haemophilia. 2005; 11(5):510-5.

(16.) Lafferty TE, Smith JB, Schuster SJ, DeHoratius RJ. Treatment of acquired Factor VIII inhibitor using intravenous immunogloblulin in two patients with SLE. Arthritis Rheum 1997; 40(4):775-8.

(17.) Franchini M. Rituximab in the treatment of adult acquired hemophilia A: A systematic review. Crit Rev Oncol Hematol 2007; 63(1):47-52.

(18.) Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br. J Haematol 2008; 141(2):149-69.

(19.) Nemes L, Pitlik E. New protocol for immune tolerance induction in acquired haemophilia. Haematologica. 2000; 85(10 Suppl):64-8.

(20.) Green D, Rademaker AW, Briet E. A prospective randomized trial of prednisone and cyclophosphamide in the treatment of patients with Factor VIII autoantibodies. Thromb Haemost. 1993; 15;70(5):753-7.

(21.) Delgado J, Yuste V, Navarro F, Villar A. Acquired haemophilia: review and metaanalysis focused on therapy and prognostic factors. Br J Haematol. 2003; 121(1):21-35.

(22.) Schwartz R, Gabriel D, Aledort L, Green D, Kessler C. Prospective study of treatment of acquired (autoimmune) Factor VIII inhibitors with high dose intravenous gammaglobulin. Blood. 1995; 15;86(2):797-804.

Muhammad A. Mirza, MD

Fellow, Section of Hematology/Oncology, West Virginia University, Morgantown, WV

Farhad Khimani, MD

Resident, Department of Internal Medicine, West Virginia University, Morgantown, WV

John Rogers, MD

Professor, Department of Medicine, Section of Hematology/Oncology West Virginia University, Morgantown, WV
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Title Annotation:Scientific Article
Author:Mirza, Muhammad A.; Khimani, Farhad; Rogers, John
Publication:West Virginia Medical Journal
Article Type:Case study
Geographic Code:1USA
Date:Nov 1, 2010
Words:2582
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