Factor VIII Inhibitors - Acquired or Induced

4/06/2003

Question:  What is 'induced' or 'acquired' Factor VII inhibition and how is it managed?

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Unique Identifier:12199681

Authors: Kleinman MB.

Institution: Rush North Shore Medical Center, Department of Internal Medicine, North Shore Cancer Research Association, Skokie, IL, USA.

Title: Anti-inhibitor coagulant complex for the rescue therapy of acquired inhibitors to factor VIII: case report and review of the literature. [Review] [12 refs]

Source: Haemophilia. 8(5):694-7, 2002 Sep.

Abstract: A 62-year-old African-American man with a history of hypertension, asthma, and prostate cancer, but no prior history of haemophilia presented with gross haematuria following a motor vehicle accident. Coagulation studies revealed a prolonged partial thromboplastin time. Subsequent mixing study and factor analysis confirmed factor VIII (FVIII) deficiency. The patient subsequently developed a knee haemarthrosis associated with persistent haematuria and a profoundly elevated FVIII inhibitor titre. Fresh frozen plasma was initiated upon presentation. Once FVIII inhibitor was discovered, immunosuppressive agents were started. Concurrent treatment with acute bypass agents including porcine FVIII, and recombinant human factor VIIa (rFVIIa;NovoSeven), was also given. Ultimately, anti-inhibitor coagulant complex (Autoplex T) was administered, stabilizing the haematuria and haemarthrosis. There was no additional bleeding 6 months after the last dose of anti-inhibitor coagulant complex. This case is consistent with others in which anti-inhibitor coagulant complex therapy was used successfully to manage patients with serious acute bleeding problems who are found to have acquired inhibitors to factor VIII. [References: 12] CAS Registry/EC Number 0 (Autoantibodies). 0 (Blood Coagulation Factor Inhibitors). 0 (Blood Coagulation Factors). 0 (Immunosuppressive Agents). 0 (Recombinant Proteins). 0 (rFVIII). 37224-63-8 (prothrombin complex concentrates). 53-03-2 (Prednisone). 9001-27-8 (Factor VIII).

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Unique Identifier:11686352

Authors: Santagostino E. Morfini M. Rocino A. Baudo F. Scaraggi FA. Gringeri A.

Institution: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan, Italy. hemophilia_ctr@polic.cilea.it

Title: Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors.[comment].

Source: Thrombosis & Haemostasis. 86(4):954-8, 2001 Oct.

Abstract: A multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out. Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 microg/kg (median: 100) were followed by CI given at median rates of 20 microg/kg/h for major surgery and of 17 and 16 microg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 microg/kg/h, respectively; median FVII:C:14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed. CAS Registry/EC Number 0 (Antigens). 0 (Hemostatics). 0 (Isoantibodies). 0 (Recombinant Proteins). 0 (factor VII clotting antigen). 1197-18-8 (Tranexamic Acid). 9001-25-6 (Factor VII). 9001-27-8 (Factor VIII). EC 3-4-21-21 (Factor VIIa).

 Link Directly to Fulltext article in Ovid

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Unique Identifier:10555100

Authors: Alumkal J. Rice L. Vempathy H. McCarthy JJ. Riggs SA.

Institution: Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Texas, USA.

Title: Surgery-associated factor VIII inhibitors in patients without hemophilia.

Source: American Journal of the Medical Sciences. 318(5):350-2, 1999 Nov.

Abstract: The acquisition of antibodies to factor VIII (ie, factor VIII protein) by patients without hemophilia is associated with conditions such as pregnancy, lymphoma, and autoimmune disorders. We present three patients who acquired factor VIII antibodies in the postoperative setting. Preoperatively, none gave a history of bleeding even with past surgeries and all had normal coagulation tests. Within days of surgery (bowel resection, cholecystectomy, coronary bypass), a bleeding diathesis emerged with prolonged partial thromboplastin time, decreased factor VIII levels, and demonstrable factor VIII antibodies. All patients required multiple blood transfusions and urgent reexploration for hemostatic control. All were treated with high dose human factor VIII infusions, corticosteroids, and various forms of immunosuppression. We wish to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, dramatic bleeding, subsequent persistence, but potential reversal by immunosuppression. CAS Registry/EC Number 0 (Antibodies). 0 (Anticoagulants). 9001-27-8 (Factor VIII).

 Link Directly to Fulltext Article at Science Direct

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Unique Identifier:9831424

Authors: Bossi P. Cabane J. Ninet J. Dhote R. Hanslik T. Chosidow O. Jouan-Flahault C. Horellou MH. Leynadier F. Liozon E. Pouchot J. Robin JP. Sanderson F. Schaeffer A. Sicard D. Staikowsky F. Wechsler B. Zittoun R.

Institution: Hospital Saint Antoine, Paris, France.

Title: Acquired hemophilia due to factor VIII inhibitors in 34 patients. [Review] [87 refs]

Source: American Journal of Medicine. 105(5):400-8, 1998 Nov.

Abstract: BACKGROUND: Acquired hemophilia is a rare disease caused by the development of auto-antibodies against factor VIII. SUBJECTS AND METHODS: We studied the characteristics and outcomes of 34 patients (19 women and 15 men) with acquired hemophilia from 1980 to 1997. RESULTS: The mean age of the patients was 61 years (range, 22-93 years). An underlying disease was observed in 18 (53%) patients: 5 patients had cancer, 4 an autoimmune disorder, 2 a dermatologic disorder, 3 asthma, 3 were postpartum, and 1 had an adverse reaction to ampicillin. Factor VIII level was <5% in 30 (90%) patients; factor VIII antibodies were elevated (>10 Bethesda units) in 23 (69%) patients. Bleeding requiring transfusions was reported in 25 (75%) patients. Human factor VIII was given to 14 patients and porcine factor VIII to 5. Six patients received prothrombin complex concentrates and one desmopressin. Several immunosuppressive treatments were used, mainly corticosteroids, cyclophosphamide, and intravenous immunoglobulin. Bleeding stopped in all but one patient within 2 weeks. Most patients achieved complete remission, although two relapses were observed subsequently. CONCLUSION: This large study helps to clarify the presentation and clinical course of acquired hemophilia. Prospective studies are needed to determine the efficacy of treatment. [References: 87]

 Link Directly to Fulltext Article at Publisher

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Unique Identifier:9063379

Authors: Sohngen D. Specker C. Bach D. Kuntz BM. Burk M. Aul C. Kobbe G. Heyll A. Hollmig KA. Schneider W.

Institution: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Dusseldorf, Germany.

Title: Acquired factor VIII inhibitors in nonhemophilic patients.

Source: Annals of Hematology. 74(2):89-93, 1997 Feb.

Abstract: Antibodies against factor VIII occur in about 15-35% of hemophilia A patients and induce refractoriness to factor VIII substitution. In most cases, these antibodies are of the IgG class. Strategies to avoid or to treat such inhibitors are controversial. In very rare cases, factor VIII inhibitors also develop in nonhemophilic patients. Although there are anecdotal reports that these antibodies may disappear spontaneously without occurrence of bleeding tendencies, in the majority of patients the clinical course is characterized by severe hemorrhages. From 1980 to 1995, we observed ten nonhemophilic patients with acquired factor VIII inhibitors at our hospital. In most cases, a sudden bleeding tendency was observed shortly after an injury or surgery. Coagulation tests showed a prolonged aPTT and a decreased F VIII level. Other deficiencies of blood-clotting factors and acquired or hereditary von Willebrand's disease were excluded. Therapy with F VIII concentrates did not produce the expected increase. Measurement of F VIII inhibitor levels in Bethesda units/ml (BU/ml) revealed maximal values in the range of 2-128 BU/ml. Immunosuppressive therapy with azathioprine or cyclophosphamide in combination with methylprednisolone led to complete disappearance of the inhibitor, normalization of the coagulation tests, and complete remission of the bleeding tendency in seven treated patients within 6 weeks. Although the clinical course is not predictable and inhibitors may disappear spontaneously, combined therapy with methylprednisolone and azathioprine or cyclophosphamide is recommended for patients with bleeding tendency. In pregnancy, therapy should be started only with methylprednisolone; post-partum, azathioprine should be used additionally if methylprednisolone as a single drug does not lead to complete remission. In emergency situations, therapy with high doses of human factor VIII concentrate may be used. When bleeding does not cease, the additional use of activated prothrombin-complex concentrates or porcine factor VIII is indicated. Possible side effects may include hepatitis and short-lived intravascular thrombin production. CAS Registry/EC Number 0 (Antibodies). 0 (Immunoglobulin M). 0 (Immunosuppressive Agents). 446-86-6 (Azathioprine). 83-43-2 (Methylprednisolone). 9001-27-8 (Factor VIII).