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.     

Continuous infusion of monoclonal antibody-purified factor VIII: Rational approach to serious hemorrhage in patients with allo-/autoantibodies to factor VIII

Hemorrhage in a patient with factor VIII inhibitor is associated with increased morbidity and mortality. Treatment with factor IX complex concentrates or recombinant factor VIIA (rVIIa) may not control bleeding and may induce thrombosis. In this study, continuous infusion of a monoclonal antibody-purified factor VII concentrate (Monoclate-P) was used successfully in two hemophilic patients with factor VIII alloantibodies and one nonhemophilic patient with a factor VIII autoantlbody. In two patients, hemorrhage was life-threatening, and, in one, bleeding did not stop with repeated infusions of activated factor IX complex concentrates. The patients' ages ranged from 4 to 15 years, and the inhibitor levels from 6 to 300 Bethesda units/ml. Clinical hemostasis was excellent, and In vivo recovery of infused factor VIII was achieved. When an excess of monoclonal factor VIII was added to the inhibitor plasma in vitro, a stable level of residual factor VIII activity was noted after an initial rapid loss. This second-order reaction occurs in plasmas of patients with type I factor VIII inhibitors. In one patlent, we showed that the saturation dose of the factor VIII inhibitor predicted in vivo recovery of factor VIII:C. These data emphasize the importance of characterizing the kinetic reactions of the factor VIII inhibitor. Furthermore, we confirm previous reports that continuous infusion of monoclonal factor VIII is a safe and effective treatment of patients with factor VIII inhibitors in whom hemorrhage Is either life-threatening or refractory to standard treatment. © 1994 Wiley-Liss, Inc.     

Failure of Combined Factor VIII and Cyclophosphamide to Suppress Antibody to Factor VIII in Hemophilia

Two patients with hemophilia A and antifactor VIII antibodies were treated withinfusions of factor VIII concentrates andintravenous cyclophosphamide in an attempt to suppress the antibody response.Factor VIII levels of 23% and 95% wereachieved immediately postinfusion, andprompt control of bleeding ensued. Sequential antibody titers demonstrated nochange in antibody response in eitherpatient when compared to previous studies following factor VIII infusion alone.These results are in contrast to the previously reported suppression of factor VIIIantibody in a nonhemophilic patient usingan identical regimen.

Submitted on April 17, 1973 Revised on June 8, 1973 Accepted on June 11, 1973     

Porcine factor VIII provides clinical benefit to patients with high levels of inhibitors to human and porcine factor VIII

The development of an inhibitor against Factor VIII is an important complication of haemophilia and occurs in approximately 31% of patients [1]. Despite various approaches to their management, the presence of these inhibitors remains a major cause of morbidity and mortality. Inhibitors may be low level [<5 Bethesda Units (BU)] or high level [>10 BU]. Low-level inhibitors usually remain low and do not respond to administered factor VIII with a rise of the inhibitor titre; high-level inhibitors, in contrast, are characterized by a rapid rise in titre following treatment with factor VIII. Modalities of treatment of acute bleeding episodes in patients with inhibitors include 'overcoming' the inhibitor with very large doses of factor VIII, 'bypassing' the inhibitor blockade with products such as activated prothrombin complex concentrates or recombinant factor VIIa, 'removing' the inhibitor by plasmapheresis or immunoabsorption and 'repressing' it with immunosuppressive drugs and immune tolerance induction. An alternative approach is to use a porcine factor VIII concentrate which does not cross-react with the human factor VIII inhibitor. Following treatment with porcine factor VIII, functional factor VIII can be detected and the therapeutic levels correlate with cessation of bleeding. The use of porcine factor VIII may, however, result in the development of antiporcine factor VIII antibodies, limiting its use. Experience in patients with high-titre inhibitors indicates that porcine factor VIII therapy could be used in the presence of factor VIII inhibitors [2-11], including inhibitors to porcine factor VIII [5,7], and that haemostasis may be obtained in the absence of detectable levels of circulating factor VIII [7,11].     

Acquired haemophilia: experiences with a standardized approach

Acquired haemophilia is a rare, life-threatening, acquired bleeding diathesis. No general consensus exists on the best therapeutic approach. We report on the standardized approach at our institution evaluated in ten patients with acquired haemophilia. Factor VIII inhibitors were found in all patients, activities ranging from 1 to 648 Bethesda units (BU). Eight of the ten patients presented with severe bleeding. Two patients died during the acute phase, one from intracranial bleeding and one due to Mycoplasma pneumonia. One patient with mild bleeding was treated with immunosuppression alone. Two patients with factor VIII inhibitor activities below 5 BU were started on factor VIII concentrate therapy. Therapy was successful in one and was changed to recombinant human activated factor VII infusion (rFVIIa) in the other, owing to insufficient factor VIII recovery. Six patients with factor VIII inhibitor activities above 5 BU were started on activated prothrombin complex concentrate (APCC) therapy. APCC treatment was successful initially in all six patients and was changed to rFVIIa infusion in one for rebleeding. One patient did not receive any specific therapy. Immunosuppression with prednisolone (2 mg kg(-1)) was begun in nine patients and was continued with cyclophosphamide (2 mg kg(-1)) in six. A complete remission of the acquired haemophilia was found in seven of the eight patients surviving the acute phase, one had a partial remission. All patients with acquired haemophilia could be managed effectively following our standardized approach. Routine administration of immunosuppression was associated with high inhibitor elimination rates.     

The use of continuous infusion of factor concentrates in the treatment of hemophilia

Bolus infusion of clotting factor concentrates remains the most common approach to the treatment or prevention of bleeding in patients with hemophilia. Although successful use of continuous infusion of such concentrates has been reported by several groups, this alternative treatment method has not achieved widespread popularity. We report here our experience in one hemophilia center with the use of continuous infusion of factor VIII and factor IX concentrates in 13 patients, 11 with hemophilia A, and 2 with hemophilia B. All patients were treated successfully for bleeding episodes (e.g., hemarthroses, intracranial, or gastrointestinal bleeding) or for surgical procedures (appendectomy, thoracotomy, etc.). Three patients with low titer factor VIII inhibitors were treated successfully with constant infusion therapy, requiring a mean dose of factor VIII concentrate 2.3 fold (8.20 u/kg/h) higher than that of the patients without inhibitors (3.63 u/kg/h) to maintain a circulating plasma level of factor VIII of 1 u/ml. The use of constant infusion of clotting factor concentrates is safe, efficacious, and more convenient than bolus therapy of factor concentrates and should be considered for hospitalized hemophilia patients requiring replacement therapy.     

Development of factor VIII inhibitor in three non-hemophiliac patients

Infrequently, inhibitors against factor VIII can develop in non-hemophiliac patients and cause serious bleeding. In the last year, we have experienced 3 non-hemophiliac patients who developed factor VIII inhibitors. Here, we describe the clinical courses of the three patients and the characteristics of the inhibitors. Case 1: A 69-year-old man underwent a partial gastrectomy because of early gastric cancer, and one month later developed signs of a bleeding tendency such as hematemesis, tarry stools and intramuscular hemorrhage. Blood coagulation tests revealed prolongation of the activated partial thromboplastin time (aPTT), which had been normal on admission. Case 2: A 78-year-old woman with no previous disease history developed generalized subcutaneous purpura. Blood coagulation tests performed on admission revealed a prolonged aPTT. Case 3: A 30-year-old man was admitted to an emergency hospital because of left intrapleural hemorrhage and liver injury caused by a traffic accident. Two months later, a hematoma developed at the site of drainage in the left chest, and blood coagulation tests revealed prolongation of the aPTT, which had been normal on admission. Plasma factor VIII procoagulant activities in cases 1, 2 and 3 were 3%, 1% and 5%, respectively. The respective factor VIII inhibitor titers were 78, 870 and 0.5 Bethesda units/ml. The immunoglobulin class and subclass of the inhibitors examined by an ELISA method were: case 1, IgG1 and 4; case 2, IgG2 and 4 (dominant); case 3, IgG4. In cases 1 and 3, the patients recovered after glucocorticoid therapy, but in case 2 the patient died of intraperitoneal hemorrhage despite receiving two courses of methylprednisolone pulse therapy. The above clinical experience suggests that patients, who develop high titers of inhibitors may be refractory to ordinary immunosuppressive therapy, and therefore more aggressive therapy such as plasma exchange and/or bypass therapy using activated prothrombin complex concentrates or an activated factor VII preparation should be considered.     

Postpartum acquired factor VIII inhibitors: Results of a survey

Postpartum factor VIII inhibitors are rare; thus, collecting clinical and treatment data may provide valuable information in guiding patient management. This paper reports the results of a survey of United States and Canadian hemophilia centers on 14 patients with postpartum acquired factor VIII inhibitors. Patients ranged in age from 23 to 40 years. Parity at diagnosis was most frequently the first gestation. Two patients were diagnosed prepartum, but two patients only up to one year postpartum. Initial inhibitor titers ranged from two to 550 Bethesda units (BU), and rose to five to 885 BU. The median duration of the inhibitor was 27 months, with two of the 14 inhibitors unresolved at the time of the survey. A total of 80 bleeding episodes occurred, five of which were life or limb threatening. Three patients received no blood products and were not hospitalized. Of those treated for hemostasis, activated prothrombin complex concentrates and porcine factor VIII were most often reported to be effective. For immunosuppression, all patients received steroids and most received additional treatment. Steroids were reported ineffective more frequently than cyclophosphamide. No adverse fetal events were noted and there was no maternal mortality. These results underline the clinical heterogeneity of the severity of postpartum factor VIII inhibitors, and provide treatment guidelines in the absence of prospective studies. Am. J. Hematol. 59:1–4, 1998. © 1998 Wiley-Liss, Inc.     

The use of recombinant factor VIIa in the treatment of bleeding disorders

Recombinant factor VIIa was initially developed for the treatment of hemorrhagic episodes in hemophilic patients with inhibitors to factors VIII and IX. After its introduction, it has also been used "off-label" to enhance hemostasis in nonhemophilic patients who experience bleeding episodes not responsive to conventional therapy. Evidence so far indicates that the use of factor VIIa in hemophilic patients with inhibitors is both safe and effective. Anecdotal reports also suggest that the product is safe and effective in controlling bleeding in nonhemophilic patients. However, its use in these conditions has not been approved by the FDA, and conclusive evidence of its effectiveness from controlled clinical trials is not yet available. Several questions pertaining to the use of factor VIIa require further investigation, including the mechanism of action; the optimal dose; definitive indications; ultimate safety; and laboratory tests for monitoring therapy.     

Disappearance of factor VIII:C antibodies in patients with haemophilia A upon frequent administration of factor VIII in intermediate or low dose

In 18 haemophilia A patients with antibodies against factor VIII:C (F VIII:c) the effect of regular treatment with factor VIII (F VIII) in intermediate or low dose was studied. All patients with previous maximal F VIII:c antibody levels between 5 and 60 Bethesda Units per millilitre (BU/ml) showed a decrease of antibody level and normal F VIII recovery within 1-2 months. From nine patients with previous maximal antibody levels above 60 BU/ml four showed a decrease of antibody level within 2-26 months. In four young patients F VIII prophylactic therapy was started or continued as soon as there was evidence of F VIII:c antibody activity. In three of these patients F VIII recovery normalized within a few months.     

Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII

Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.     

Clinical evaluation of three elderly cases with acquired hemophilia A

In this paper we report our clinical investigation of three cases with acquired hemophilia A treated in our department. These patients were all elderly males (79, 77, and 68 years old), and presented with subcutaneous bleeding, a prolonged activated partial thromboplastin time (APTT), and anemia. On the basis of these findings as well as decreased factor VIII activities (0.9~3.1%) and the presence of factor VIII inhibitors (57.1~173 BU/ml), we made a diagnosis of acquired hemophilia A. In cases 1 and 2, a recombinant activated factor VII was used to achieve hemostasis. The factor VIII inhibitor disappeared with prednisolone (PSL) alone in case 1 and a combination of PSL and cyclophosphamide in case 2. In case 3, treatment involving five courses of weekly rituximab (RTX) reduced the activity of factor III inhibitor to 3.5 BU/ml (and subsequently to zero). During this time, the patient achieved hemostasis without using a specific hemostatic agent, and was again referred to the previous hospital for the treatment of hepatocellular carcinoma. Although PSL is often chosen as a first-line therapy to suppress the production of factor VIII inhibitor, which may cause acquired hemophilia A, RTX may be another therapeutic option in some patients.     

Acquired hemophilia: a case report

Acquired hemophilia is a severe bleeding diathesis that affects both males and females. It is caused by suddenly appearing autoantibodies that interfere with coagulation factor VIII activity. This disorder is characterized by spontaneous and post-traumatic subcutaneous bleeds and massive mucosal hemorrhages. We report in the current article a case of acute renal failure and bleeding from the urinary tract caused by idiopathic acquired hemophilia in a 54-year-old woman. Hemostatic tests indicated prolonged activated partial thromboplastin time (APTT) to 107.8 sec (norm 26-36 sec), normal value of the prothrombin index which was 82% (norm 70-130%), increased fibrinogen concentration to 583 mg/dl (normal value 200-400 mg/dl), the bleeding time was 5 min and 20 s (norm < 10 min) and the platelet count was 366 x 10(9)/l (norm 130-400 x10(9)/l). The autoantibody against factor VIII in a titer of 121 Bethesda Units/ml (BU/ml) and decreased factor VIII activity to 2% (norm 50-150%) with normal plasma concentration of factor IX. Activated (FEIBA, Baxter) and nonactivated prothrombin complex concentrates (factor IX concentrate) have been used in the treatment of bleeding episode. Immunosuppressive treatment with the combination of oral prednisone 60 mg/24h and cyclophosphamide 150 mg/24h was administered in order to remove the factor VIII inhibitor. Reduction of the factor VIII inhibitor titer to 38 BU/ml and increase of factor VIII activity to 4% was initially achieved. This treatment has been continued for two years and led to normalization of hemostatic parameters (APTT 26 sec, factor VIII activity 108%) which means a total removal of factor VIII inhibitor.     

Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven.

Recombinant factor VIIa (rFVIIa) (NovoSeveng) is used to treat bleeding episodes in hemophilia A and B patients with inhibitor antibodies against factor VIII (FVIII) and factor IX. rFVIIIa has been studied in home treatment of mild-to-moderate joint, muscle, and mucocutaneous bleeds to assess safety and efficacy. Treatment with other factor concentrates was allowed according to treating physician's judgment. Blood samples were drawn before study start and after 6 and 12 months. It has thus been possible to follow the inhibitor titres during this period. Analyses of 53 patients (49 hemophilia A, four hemophilia B) showed inhibitor levels up to 1,208 BU/ml before study start. Based on the first analysis, hemophilia A patients were divided into high responders (> 5 BU/ml; 28 patients), low responders (> 1 and < 5 BU/ml; 15 patients) and very low responders (< or = 1 BU/ml; six patients). In high responders receiving rFVIIa as only treatment, FVIII inhibitor titre decreased to one-third of the initial level. For high responders receiving other factor treatments such as FVIII or prothrombin complex concentrates, inhibitor titre remained unchanged. Titres for low responders and very low responders remained unchanged independent of treatment. Thus, when rFVIIa is used as the only coagulation factor to treat hemophilia A/B high-responder inhibitor patients, inhibitor level declines significantly.     

Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy

Acquired factor VIII (FVIII) inhibitors are a rare cause of coagulopathy which are associated with a high mortality rate. Treatment of bleeding episodes is often difficult and may vary with the degree of titre elevation. Individuals with very high-titre antibodies [>100 Bethesda units mL(-1) (BU)] may have difficulty achieving a complete sustained remission and, consequently, various treatments including immunosuppression, cytotoxic chemotherapy and plasmapheresis have been reported. Rituximab is an anti-CD20 monoclonal antibody which has demonstrated efficacy in the treatment of individuals with acquired FVIII inhibitors, however there is limited data in the subgroup of patients with inhibitor titres >100 BU. In this study, we present four patients with acquired FVIII inhibitor titres >100 BU who were resistant to initial therapy with cyclophosphamide, vincristine and prednisone. The patients' inhibitor titres ranged from 249 BU mL(-1) to 725 BU mL(-1) and all received 4 weekly infusions of rituximab at 375 mg m(-2). Each patient partially responded to rituximab therapy with an improvement in inhibitor titres and FVIII activity, however, three of the four patients relapsed thereafter. The individual who did not relapse achieved a partial response for 13 months and then died of causes unrelated to her coagulopathy. We conclude that in patients with acquired FVIII inhibitors and titres >100 BU, treatment with rituximab alone is effective but not sufficient to achieve a sustained response. Rituximab in combination with other therapies may provide a better result in this high-risk population.     

Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII

Eight patients with inhibitors to factor VIII (4 hemophilia A and 4 nonhemophilic) were treated with recombinant activated factor VII (rFVIIa) to control severe abdominal bleeding. The recombinant factor was supplied under an open-label, emergency-use program to patients previously unresponsive to one or more alternative therapies. Therapy with rFVIIa was administered for nine separate bleeding events; one patient was treated for two separate bleeding episodes. Patients were treated for an average of 9 days and received a mean total dose of 5.2 mg of rFVIIa for control of bleeding. Treatment was considered successful and hemostasis adequate in 7 of the 9 episodes (78%). Treatment with rFVIIa was partially successful in one other episode. Four patients in this series experienced serious adverse events; all the adverse events were considered unrelated to rFVIIa therapy. The results of this limited series indicate that rFVIIa is an effective means of managing life-threatening abdominal bleeding in individuals with hemophilia or acquired antibodies to factor VIII.     

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.     

Acquired factor VIII inhibitors

Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality. This autoimmune disorder most commonly occurs in the elderly. Although it may be associated with several underlying pathologies, up to 50% of reported cases remain idiopathic. In contrast with congenital hemophilia, which is commonly characterized by hemarthroses, hemorrhages in patients with acquired hemophilia involve most frequently soft tissues. The 2 treatment priorities are to arrest the acute bleeding and to eradicate the factor VIII autoantibody. Acute bleeding episodes in patients with low-titer inhibitors can be treated using human factor VIII concentrates, whereas factor VIII bypassing agents, such as activated prothrombin complex concentrates or recombinant activated factor VII, are effective for the treatment of those with high-titer inhibitors. An analysis of the literature shows that the most effective first-line treatment for the eradication of factor VIII autoantibodies is the combination of steroids and cyclophosphamide. However, there is increasing evidence on the effectiveness of other treatment approaches, such as immune tolerance regimens and rituximab. If confirmed by large controlled studies, these innovative therapies might become a valid option for long-term eradication of factor VIII inhibitors.     

Fatal opportunistic infection following disappearance of antibodies by immunosuppressive therapy in a patient with acquired factor VIII inhibitor

An 83-year-old man without history of the hemorrhagic diathesis was admitted to our hospital with a 4-months history of purpura and subcutaneous hematoma. He had an extraordinarily prolonged activated partial thromboplastin time, and his factor VIII (F VIII) activity level was 0.2%. A study revealed the existence of an IgG type anti-F VIII inhibitor at a titer of 1004 Bethesda units/ml. He received recombinant factor VIIa and immunosuppressive therapy with cyclophosphamide, prednisolone and cyclosporin, but despite this the titer of F VIII inhibitor remained high. Although the inhibitor disappeared after methylprednisolone mini-pulse therapy, the patient died of opportunistic infections with cytomegalovirus and pneumocystis carinii. The majority of patients with acquired F VIII inhibitor belong to the elderly population, and the standard therapeutic strategy to eliminate the acquired F VIII inhibitor has not been established. Those patients with high titers of F VIII inhibitor require particularly long term immunosuppressive therapy. Therefore, it is important to bear in mind treatment-related opportunistic infections in a case with a high titer of acquired F VIII inhibitor.     

Management of factor VIII inhibitors: evolution and current status.

Management of patients with factor VIII (and IX) inhibitors includes management of acute bleeds and methods to induce immune suppression and tolerance and to detect patients at risk of developing inhibitors. The methods used over the years to treat acute bleeding have been more or less successful. The best method is to raise factor VIII levels by human or porcine factor VIII concentrate, but this is not usually possible. Prothrombin complex concentrates, activated or non-activated, have enjoyed some success as factor VIII by passing agents, but the development of recombinant activated factor VII represents a new and promising method of inducing haemoslasis at the site of bleeding whilst minimizing the risk of disseminated intravascular coagulation. Alternatively, the use of tissue factor is under consideration to exploit the extrinsic system. Methods to induce immunological tolerance by use of the 'Bonn' regime or by the introduction of immunomodulation with the 'Malm?' regime of extracorporeal immunodepletion, cyclophosphamide, and intravenous immunoglobulin continue to be attempted with significant but variable success. Gradually the inhibitor problem is being contained, but it is still an important complication of haemophilia therapy.