Successful treatment of acquired haemophilia with prednisolone therapy

Acquired hemophilia is a rare, life threatening coagulopathy in adults caused by the development of autoantibodies against to factor VIII. No general consensus exists on the best therapeutic approach. We report here a case that presented with extensive cutaneous and mucosal bleedings due to factor VIII inhibitors and treated successfully with steroid therapy alone but complicated with a life threatening thromboembolic attack during her follow up. In conclusion, corticosteroids are "cost effective therapy" associated with high inhibitor elimination rates and although recurrence of inhibitor in a patient with factor VIII inhibitor is an expected clinical situation thrombosis risk should also be considered.     

A case of acquired hemophilia caused by factor VIII inhibitor with rheumatoid arthritis,successfully treated with immunosuppressive treatment and recombinant activated factor VII

We report the case of a patient who presented with acquired hemophilia associated with rheumatoid arthritis. The patient's factor VIII activity was less than 1% and factor VIII inhibitor was detected. Based on the blood analysis, the patient was diagnosed as having the factor VIII inhibitor. She was successfully treated with prednisolone, cyclophosphamide, and gammaglobulin to suppress the factor VIII inhibitor, and the administration of recombinant activated factor VII was effective in controlling severe bleeding episodes.     

A case of acquired hemophilia caused by factor VIII inhibitor with rheumatoid arthritis,successfully treated with immunosuppressive treatment and recombinant activated factor VII

Abstract

We report the case of a patient who presented with acquired hemophilia associated with rheumatoid arthritis. The patient's factor VIII activity was less than 1% and factor VIII inhibitor was detected. Based on the blood analysis, the patient was diagnosed as having the factor VIII inhibitor. She was successfully treated with prednisolone, cyclophosphamide, and gammaglobulin to suppress the factor VIII inhibitor, and the administration of recombinant activated factor VII was effective in controlling severe bleeding episodes.     

When coagulation fails in the oldest: Acquired hemophilia caused by chronic lymphocytic leukemia in a 92-years-old woman

Acquired hemophilia is a severe, potentially life-threatening condition usually involving elderly patients, caused by an auto-antibody against factor VIII of coagulation. We describe the case of a 92-years-old woman who came to our attention for severe acute anemia associated with many spontaneous diffuse skin bleedings secondary to a prolonged aPTT 110 sec, factor VIII < 1% with a titer of factor VIII inhibitor of 5.5 Bethesda Units. A diagnosis of chronic lymphocytic leukemia was determined. We treated the patient with a blood transfusion and intravenous corticosteroids with prompt reduction of aPTT and inhibitor factor VIII titer. The present case report involving a very old patient could represent an example of acquired hemophilia as a first manifestation of a lymphoproliferative syndrome.     

Acquired hemophilia A with sigmoid colon cancer: successful treatment with rituximab followed by sigmoidectomy

Acquired hemophilia A is a rare and potentially fatal condition of coagulopathy caused by autoantibodies against clotting factor VIII (factor VIII inhibitor). We report a case of a 63-year-old woman, who presented with a sudden onset of severe hemorrhagic tendency with exclusively prolonged activated partial thromboplastin time (APTT). She was diagnosed with acquired hemophilia A due to a decrease in factor VIII activity and a high titer of factor VIII inhibitor. Hemorrhage was well controlled by recombinant activated factor VII. Although the level of factor VIII inhibitor did not decline with prednisolone and cyclophosphamide, it became undetectable with rituximab. In parallel with controlling hemorrhage, malignancy, which may cause acquired hemophilia A, was searched for and sigmoid colon cancer was found. After the eradication of factor VIII inhibitor, surgical resection was performed uneventfully. Thereafter, acquired hemophilia A has been in complete remission without any additional therapy. The present case suggests the efficacy of rituximab for refractory acquired hemophilia A and the importance of the identification of underlying diseases that can cause acquired hemophilia A.     

Acquired factor VIII inhibitor associated with prostatic cancer: successful treatment with steroid and immunosuppressive therapy

Factor VIII inhibitors are antibodies of the IgG class that block functional epitopes or antigenic sites of factor VIII. They occur in about 5-20% of hemophilia A patients after infusions of factor VIII concentrate. Antibodies to factor VIII can also arise spontaneously in association with various autoimmune and chronic inflammatory diseases, hematologic malignancies, solid tumors, certain drugs, dermatologic conditions, and in puerperium. In the majority of cases, the clinical course is characterized by severe hemorrhages. Strategies to treat such inhibitors are controversial. We present the case of a patient with prostatic cancer who developed acquired factor VIII inhibitor. His severe bleeding complications were treated successfully with cyclophosphamide in combination with methylprednisolone. Within a few months, moreover, the immunosuppressive therapy brought about complete disappearance of the inhibitor and normalization of coagulation parameters. Our case illustrates that, although the clinical course in patients with acquired factor VIII inhibitor is not predictable, and the inhibitor may disappear spontaneously, combined therapy with cyclophosphamide and methylprednisolone should be considered for patients with severe hemorrhages.     

Unterschiedliche Proportionen von Faktor VIII und Faktor VIII-Inhibitoren in ihren Antigen-Antikörper-Komplexen

Summary We examined the physico-chemical properties of factor VIII inhibitors in two patients. There is no stoichiometric mixture of factor VIII and factor VIII inhibitor since one polyvalent factor VIII particle can be bound by various numbers of factor VIII inhibitor particles. The balance between free factor VIII and inhibitor and their antigen-antibody complexes cannot be explained by the homogeneous natural law of mass action. A patient with classical hemophilia A exhibited an inhibitor which shows conformity with the Poisson distribution as far as the portion of free factor VIII activity is concerned. The spontaneously occuring inhibitor showed a different binding characteristic to factor VIII. We demonstrated here that the Freundlich's adsorption isotherme is effective for a spontaneous factor VIII inhibitor. During follow up qualitative and quantitative changes of both inhibitor types were observed. We assume that the change of property of inhibitor in hemophiliacs is due to a stronger binding to factor VIII and of the spontaneous inhibitor to a poorer fit of antigen and antibody.

     

Immunoblot cross-reactivity of factor VIII inhibitors with porcine factor VIII

Porcine factor VIII has been used successfully to treat factor VIII inhibitor patients whose plasmas have minimal cross-reactivity to porcine factor VIII. However, some inhibitor plasmas do inhibit porcine factor VIII, and the extent of procoagulant inhibition often increases after treatment with porcine factor VIII. Because there is no information about the porcine factor VIII epitopes with which these antibodies react, we have compared the immunoblot and enzyme-linked immunosorbent assay (ELISA) reactivities with porcine and human factor VIII for 20 inhibitor plasmas (11 from hemophilia A patients and 9 autoantibodies). Immunoblots identified binding to porcine factor VIII for only 2 of the 12 plasmas from patients who had not received porcine factor VIII, but this reactivity could not be predicted from the inhibitor titer to porcine factor VIII. Immunoblot reactivity with porcine factor VIII was detected for 7 of 8 inhibitor plasmas from patients who had been previously treated with porcine factor VIII, and the strength of this reactivity was generally related to the inhibitor titer. Of the 5 plasmas that were immunoblot positive with the porcine factor VIII A2 domain, 4 had inhibitor titers greater than 45 Bethesda units when tested with porcine factor VIII, whereas only 1 of 15 of the other plasmas had this level of inhibitor activity with porcine factor VIII. In contrast, immunoblot reactivity to the porcine factor VIII A1 domain did not correlate with the antiporcine VIII inhibitor titer. We also determined the effect of preincubation with human or porcine factor VIII on immunoblot reactivity. In one case, immunoblot reactivity with porcine factor VIII was absorbed with porcine, but not human, factor VIII, which is consistent with antibody formation after treatment with porcine factor VIII. In no cases did human factor VIII reduce the reactivity of inhibitor plasmas with the porcine A1 domain, suggesting that these antibodies are directed at unique porcine factor VIII determinants. The reactivity to porcine A2 in 2 plasmas probably represented cross-reactivity of similar A2 determinants, because it was absorbed by both human and porcine factor VIII. Although the ELISA assays with porcine factor VIII detected antibodies in some plasmas that could not be identified by inhibitor assay or immunoblot, the level of ELISA reactivity was generally consistent with the titers of the other assays.     

Antibody studies of factor VIII inhibitor in a case with Waldenström's macroglobulinemia

We report a case of Waldenstr?m's macroglobulinemia with prominent bleeding tendency; laboratory investigation revealed an elevated activated partial thromboplastin time. Further laboratory evaluation showed circulating factor VIII anticoagulant, deemed polyclonal IgG, with a titer of 700 Bethesda Units/ml. The factor VIII inactivation kinetics of the patient plasma were identical to those of a type II inhibitor, and the inhibitor was found to recognize the A2 domain of the factor VIII heavy chain. Apparently, paraprotein is not always the cause of reduced activity of coagulation factors in neoplastic dysproteinemias.     

Acquired factor VIII inhibitor associated with chronic interferon-alpha therapy in a patient with haemophilia A

SUMMARY. Both the development of factor VIII inhibitors and infection by hepatitis C virus are serious complications of haemophilia A. We describe the first reported case of the subsequent development of a factor VIII inhibitor in a patient with haemophilia A after treatment with interferon-alpha for chronic active hepatitis C.     

Treatment of a high titer anti-factor-VIII antibody by continuous factor VIII administration: report of a case

Daily administration of large doses of factor VIII concentrate in a hemophiliac with a high titer factor VIII inhibitor resulted in marked reduction in the titer and response of the inhibitor to factor VIII administration and made possible elbow and bilateral knee replacements under conventional factor VIII coverage. Studies performed during the course of treatment indicated that the reduction in the inhibitor was the result of specific tolerance to factor VIII.     

Recurrent bleeding tendency due to factor VIII inhibitor during therapy for bullous pemphigoid

A 67-year-old woman with bullous pemphigoid (who had no history of hemorrhagic disease or blood transfusion) experienced extensive ecchymosis of the trunk and extremities and marked submucosal bleeding of the pharynx and larynx with risk of obstruction and suffocation. This bleeding tendency was the manifestation of a coagulation disorder due to factor VIII inhibitor. Immunosuppressive therapy, steroid pulse therapy, prednisolone (PSL), and cyclophosphamide (CPA) alleviated the bleeding and yielded negative assays for factor VIII inhibitor. However, because the patient stopped treatment, the bleeding recurred and was especially severe from a large hematoma with ruptured skin on the right hand. The bleeding was mitigated by transfusion of factor VIII concentrate combined with steroid pulse therapy. This was followed by CPA pulse therapy and oral PSL and CPA, resulting in the disappearance of factor VIII inhibitor again. We reported this case because factor VIII inhibitor complication of bullous pemphigoid is very rare and immunosuppressive therapy consisting of PSL, CPA, and pulse therapy was effective.     

LIFE-THREATENING HAEMORRHAGE IN A PATIENT WITH RHEUMATOID ARTHRITIS AND A LUPUS ANTICOAGULANT COEXISTING WITH ACQUIRED AUTOANTIBODIES AGAINST FACTOR VIII

A case history of a patient with RA and a lupus anticoagulantcoexisting with an acquired inhibitor to factor VIII is described.The factor VIII inhibitor was heralded by life-threatening haemorrhagewhich followed an invasive procedure. KEY WORDS: Lupus anticoagulant, Factor VIII, Inhibitor, Bleeding, Rheumatoid arthritis     

Hémophilie A acquise découverte au cours de la grossesse : à propos d’un cas et revue de la littérature

Introduction

Acquired hemophilia A (AH) is a rare hemorrhagic disorder, secondary to the occurrence of factor VIII inhibitor. In young patients, this disorder is commonly observed during the post-partum period, and has been rarely documented in the prepartum. We report a new case of a prepartum AH and review literature data.

Case report

An isolated prolongation of the activated partial thromboplastin time (APTT) was fortuitously discovered in a 31-year-old pregnant women, with spontaneous ecchymosis of her lower limbs few days prior to delivery. Coagulation tests revealed decreased factor VIII activity (18%) and the presence of factor VIII inhibitor (1,4 Bethesda unit). In order to eradicate the autoantibody, the patient was first treated with prednisone and then with rituximab.

Conclusion

Prepartum factor VIII inhibitors need to be precociously recognized to allow prophylactic management of the delivery bleeding.     

Factor VIII Inhibitor Postpartum

Acquired factor VIII deficiency in women postpartum due to a factor VIII inhibitor is rare and the etiology is unknown. In this study a case report and a review of the literature are given. The haemorrhagic diathesis resembles classic haemophilia, with the exception that ecchymoses and tissue bleeding occur more frequently. The potency of the inhibitor may vary from weak to strong and the inactivation of factor VIII coagulant activity (factor VIII-C) by the inhibitor is of a non-linear type. Severe bleeding has been fatal in a few cases, but factor VIII concentrate substitution has usually been successful without anamnestic response of inhibitor activity. There is no convincing evidence that immunosuppression is effective, also because the natural history of the disease is characterised by a spontaneous disappearance of the factor VIII-C inhibitor. Treatment of bleeding symptoms with factor VIII concentrate should therefore not be reserved for life threatening haemorrhages only.     

Acquired hemophilia as the presenting manifestation of neoplasia: diagnostic workup and monitoring

Acquired haemophilia is a rare disorder caused by the development of autoantibody to factor VIII. It is sometimes associated with malignancies, and usually appears during disease course. In rare instances, acquired haemophilia is the presenting manifestation of a malignant disease. We report a 76-year-old man, who presented with spontaneous haematomas of his four limbs. A factor VIII inhibitor was found and the patient diagnosed with acquired haemophilia. Initial etiologic diagnostic workup including a thoracic and abdominal computed tomographic scan was negative. Factor VIII inhibitor disappeared on corticosteroids and factor VIII level normalized. Seven months later, the patient died from a multimetastatic cancer. About 15% of acquired haemophilia are associated with malignant disease (malignant lymphoma or solid neoplasia). Although rare, the development of a factor VIII inhibitor few months before the diagnosis of the malignant disease raised the issue of the appropriate initial investigations and further monitoring to recommend these patients. We propose a regular clinical monitoring and a thoracic and abdominal computed tomographic scan at six-month follow-up to screen for malignant disease.     

Successful treatment with rituximab in a patient with an acquired factor V inhibitor

Rituximab has already been successfully used to treat immune-mediated bleeding disorders such as acquired factor VIII inhibitor. We report here a case of severe acquired factor V (FV) inhibitor deficiency due to FV inhibitor which has been dramatically improved after rituximab.     

Treatment of acquired factor VIII inhibitor using intravenous immunoglobulin in two patients with systemic lupus erythematosus

Acquired inhibitors of factor VIII have rarely been reported in the presence of systemic lupus erythematosus (SLE). Treatment is usually corticosteroids, with or without immunosuppressive agents such as cyclophosphamide or azathioprine. We report here case histories of 2 patients, one with documented SLE, the other with a forme fruste of SLE. Both patients had inadequate responses to corticosteroids and immunosuppressive agents. Both responded to intravenous immunoglobulin, with a decrease in their titers of factor VIII inhibitor and significantly decreased frequency of bleeding episodes despite persistent low-level inhibitor titers. Better control of their SLE symptoms and findings was also observed. Previously reported treatments of acquired factor VIII inhibitors in SLE are discussed.     

Factor VIII epitopes recognized by inhibitors in hemophiliacs]

A 44-year-old male hemophiliac with high titer anti-factor VIII antibody (66 bethesda units/ml) was admitted on November 11, 1989 because of epigastralgia and melena. A gastric ulcer with a spurting artery was revealed by an upper gastrointestinal endoscopy. Infusion of activated prothrombin complex concentrates and endoscopical ethanol injection to the bleeding vessel were ineffective. After clipping of the vessel, the bleeding was completely ceased. The inhibitor antibody was purified by Sephacryl S 200 and Protein A cellulofine column chromatography. Purified IgG showed factor VIII inhibitor activity. Factor VIII epitopes recognized by the inhibitors was examined by western blotting. Factor VIII concentrate purified by the antigen. This factor VIII preparation was composed of a doublet of light chains (M.W. 80 kD) and 3 heavy chains (M.W. 160-200 kD) when examined by SDS-PAGE followed by immunoblotting using monoclonal antibodies against factor VIII light and heavy chains. The inhibitor in this case reacted to the heavy chains of factor VIII, whereas antifactor VIII antibody in the other case reacted to the light chain of factor VIII.     

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.