Acquired Factor VIII Inhibitors Research Articles

Management of Acquired Hemophilia: A Real-World Experience, 2007-2023

Introduction.Acquired hemophilia A (AH) is a rare, potentially life-threatening, bleeding disorder caused by the development of autoantibodies directed against coagulation factor VIII (FVIII). Incidence is 1-1.5 per million people per year with a morality rate as high as 22% and is especially dangerous in the elderly. Since autoantibodies rarely resolve spontaneously, initial management involves controlling acute bleeding episodes, and immunosuppressive treatment (IST) to eradicate the autoantibodies to restore hemostasis. There are no evidence-based guidelines for the management of AH and treatment decisions rely on the clinical judgement and expertise of the treating provider, which impacts overall health outcomes. There is a dearth of prospective, controlled clinical trials to guide management of AH and much of the reported data come from observational studies and extrapolation from studies on patients with congenital hemophilia complicated by inhibitors. Methods.Retrospective chart review of AH patients treated by a single provider at Jackson Memorial Hospital from 2007 through May 2023 utilizing in-house medical record systems and supplemental external health records from transferring facilities. Partial remission (PR) was defined as FVIII activity >50 IU/dL and no active bleeding after stopping hemostatic drugs >24 hours. Complete remission (CR) was defined as PR plus negative inhibitor, prednisone tapered to <15 mg/day, and cessation of other IST. Results.We identified 17 patients with first episode of AH with laboratory evidence of acquired FVIII inhibitor (aFVIIIi) (see Table 1). The majority were male (76%), Hispanic (53%) and White (88%). The median age at diagnosis was 72 (range 31-88). While 65% of cases were idiopathic, other associated conditions included malignancy and trauma. The median aFVIIIi was 23.2 BU/mL (range 2.2-400) and median FVIII activity was 1% (range 0-12) at presentation. The most common presenting symptom was hematoma (59%) followed by mucocutaneous bleeding (41%). Hematuria was also seen frequently and initially attributed to another cause. To control bleeding, 47% received activated prothrombin complex concentrate (aPCC), 17% received recombinant factor VIIa, and 12% received emicizumab. Emicizumab was initiated at an outside facility lacking bypassing agents for one patient, while the other had bleeding with neutropenic sepsis. All patients received IST with glucocorticoids; cyclophosphamide was used in 82%, rituximab in 41%, and IVIG in 12%. For patients with appropriate follow-up (median follow-up 707 days), 7/9 (78%) achieved a CR to IST and 2/9 (22%) developed PR. The median time to PR was 41 days and median time to CR was 168 days in patients who achieved those respective responses. Five patients (29%) responses were not assessable due to lack of appropriate follow-up. Three patients (17%) had a clinically evident relapse requiring retreatment at 617, 730, and 1427 days after initial response. Ultimately, three patients (17%) died or were discharged to hospice within a median of 8 days, but only one death was directly related to bleeding (which was prior to receiving any appropriate hemostatic agents). Discussion.We report a single-provider experience on patients treated for AH, with focus on acute management and CR due to its impact on health outcomes. Our experience confirms the importance of initiating IST early in diagnosis and tapering as FVIII levels recover, finding the lowest effective dose to eradicate the inhibitor. It should be noted that bypassing agents are not always required if bleeding is not significant. While no one who received hemostatic agents died of hemorrhage, several patients required dozens of doses of these expensive medications. Recent reports using emicizumab off-label for AH suggest effective hemostasis in the acute phase, which was successful in two patients described here. Monitoring the response to emicizumab is more challenging due to lab interference with PTT and single-stage factor assays, and therefore requires bovine assays that are costly, untimely, and not widely available. A large proportion of patients referred from outside lacked appropriate follow-up after initial diagnosis for acute management. For optimal long-term outcomes, patients with AH should have ongoing follow up with periodic lab monitoring as relapses may occur several years after initial response in 17% or more of patients.

P385 A case of immune thrombocytopenia (itp) and acquired factor viii inhibitor refractory to immunosuppression

P385 A case of immune thrombocytopenia (itp) and acquired factor viii inhibitor refractory to immunosuppression

Prolonged Activated Partial Thromboplastin Time: Difficulties in Discriminating Coexistent Factor VIII Inhibitor and Lupus Anticoagulant.

To review the diagnostic difficulties of a prolonged activated partial thromboplastin time (aPTT) when 2 inhibitors with opposite clinical presentations coexist, we searched MEDLINE from January 1970 to November 2013 using acquired, factor VIII (FVIII), factor IX, hemophilia A and B, inhibitor, lupus anticoagulant (LA), antiphospholipid, anticardiolipin, anti-β2-glycoprotein I, antibodies, syndrome, bleeding, and thrombosis. We identified 13 articles for a total of 15 cases of possible coexistence of FVIII inhibitor and LA. The presenting clinical manifestation was thrombosis in 6 cases and bleeding in 9 cases. Activated partial thromboplastin time was the presenting laboratory abnormality in all cases, and first-line investigations suggested the coexistence of LA and acquired FVIII inhibitor. None of the articles addressed the diagnostic accuracy of the screening tests by performing "second line" assays. We reviewed the diagnostic pitfalls of the cases under study and provide some guidance for alternative tests when facing a prolonged aPTT that may have a double meaning.

Unexpected Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor.

Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Rituximab and intravenous immunoglobulin (IVIG) for the management of acquired factor VIII inhibitor in multiple myeloma: case report and review of literature

Acquired factor VIII inhibitor (AFI) is a rare disorder and is even more uncommon in multiple myeloma patients, with only five cases reported in literature. Solid and hematologic malignancies, autoimmune conditions, drugs, and infections are the conditions commonly associated with the development of this condition, with mucocutaneous bleeding being the most common presenting sign. Diagnosis is usually made with the laboratory finding of an elevated partial thromboplastin time aPTT that cannot be corrected by plasma mixing, and further confirmed by low factor VIII activity/antigen levels along with elevated factor VIII inhibitor levels using the Bethesda assay. Treatment is usually based on the clinical picture with factor VIII inhibitor bypass activity (FEIBA) and recombinant factor VIIa (rFVIIa) employed to control acute bleeding; steroids and cyclophosphamide to suppress the inhibitor with Rituximab, in combination with other immunosuppressants in cases not suitable for steroids, and finally wherever possible, to remove the offending drug or control the underlying pathology that might predispose to the development of this condition. This case report highlights the successful management of a myeloma patient who presented with life-threatening hemorrhagic pericardial effusion and hemarthrosis. The patient was treated with FEIBA to control the acute bleeding and then received Rituximab in combination with intravenous immunoglobulin to suppress the AFI.

Treatment of Acquired Hemophilia A (AHA) with Rituximab (R): Clinical Outcomes and Cost of Hemostatic Agents

Abstract 3143 Background:AHA is a rare bleeding disorder caused by autoantibodies (inhibitors) to coagulation factor VIII (FVIII). Acquired FVIII inhibitors are associated with a high rate of complications, with major bleeding reported in up to 90% of affected individuals and mortality rates as high as 22%. There are currently no formal guidelines for the treatment of AHA, due to the paucity of data from randomized clinical trials and limited number of cases. However, there is general agreement that treatment should consist of a two-pronged approach that includes 1) achieving hemostasis in bleeding patients by administering FVIII bypassing agents, and 2) reducing or eradicating the inhibitor with immunosuppressive treatments such as rituximab (R), cyclophosphamide (C), prednisone (P) or a combination. C and P have been used as first-line treatment for AHA until the late 1990s, when R began to be used off-label for inhibitor eradication. Data from case reports and series suggest that R is effective as both first and second-line therapy for AHA. We hypothesized that the use of R rather than C and P may be cost-effective by reducing the overall use of expensive hemostatic agents. The purpose of this study was to compare clinical course, use of hemostatic agents and costs in patients who received R to historical patients who did not receive R for treatment of AHA. Methods:We performed a retrospective study of patients with AHA, defined by prolonged aPTT (>37 sec), FVIII level <50% and detectable FVIII inhibitor (>0.40 Bethesda Unit (BU)) at Dartmouth-Hitchcock Medical Center (DHMC) using the hospital’s electronic medical record system, CIS, to collect pertinent demographic and clinical information. The data collection variables included: age, sex, co-morbidities, FVIII levels, FVIII antibody titers, type of bleeding, amount and total acquisition cost of hemostatic products administered, immunosuppressive regimens administered, time to complete remission (CR) (defined as FVIII level > 30%), and relapses. Results:We identified 16 patients with AHA treated at DHMC from 4/1997 to 3/2010. The median age at diagnosis was 78 (range 66 to 93), and 56% were women. Co-morbidities included current or prior malignancy (62%) and autoimmune disease (12%). Idiopathic cases accounted for 32%. One patient had both a malignancy and autoimmune disease. The median aPTT at diagnosis was 80 sec (range 53 to >160 sec); FVIII level, 3% (range <1 to 19%); FVIII antibody, 26 BU (range 2 to 220 BU). The types of bleeding included mucocutaneous (94%), intracranial (19%), gastrointestinal (6%) and genitourinary (6%). Two types of bleeding were noted in 19%, and 69% of patients received hemostatic products. R was used in 63% of patients as first-line immunosuppressive treatment. The remaining patients received C and P, P alone or no immunosuppressive treatment. A CR was documented in 63% of patients, of whom 60% received R. Three patients had no documentation of remission and three patients died. The median time to CR for all patients was 33 days. The median time to CR for R-treated patients was 28 days (range 23 to 86) and 66 days (range 28 to 154) for non-R-treated patients. Relapses were documented in two patients who achieved CR. The first patient was treated initially with P alone, and died of a major hemorrhage in relapse without receiving salvage treatment. The second patient was treated with R initially and relapsed twice, achieving a CR after retreatment with R for both relapses. The total acquisition cost of hemostatic agents for the entire AHA population was $2, 211, 262. The median cost of hemostatic agents for R-treated patients was $180, 853 (range $9, 666 to $554, 026), while the median cost for non-R-treated patients was $169, 075 (range $35, 076 to $319, 115). Conclusions:Our findings suggest that R is an effective first-line immunosuppressive treatment for AHA and appears to shorten the time to CR substantially compared to traditional immunosuppression. The cost for hemostatic agents in our population was similar for both R-treated and non-R-treated patients, suggesting that despite the decreased time to CR, the use of R may not result in decreased use of hemostatic products. A hemostatic agent-sparing effect attributable to R may have been missed due to our small AHA population size, however, and is worthy of further investigation. Disclosures:Off Label Use: Rituximab for treatment of acquired hemophilia A.

Bleeding in the patient with a malignancy

Many different factors can account for hemorrhagic complications in patients with malignancies. Potential etiologies include disease- or treatment-related impairment of bone marrow function, or trauma to highly friable and vascularized malignant tissues. Immune impairment may also occur in solid or hematologic malignancies, leading to spontaneous formation of inhibitory antibodies against coagulation factor VIII (FVIII). Because hemorrhage due to acquired FVIII inhibitors will not respond to conventional treatment algorithms for bleeding, failure to promptly recognize and diagnose this condition may result in undue morbidity and mortality. The persistence of FVIII autoantibodies in the patient with cancer may further complicate necessary invasive diagnostic or therapeutic procedures in the short term and lead to lethal bleeding in the long term. Oncologists must therefore maintain a high index of suspicion for this diagnosis as 1 of many potential causes of bleeding in patients with a malignancy.

Experience of four UK comprehensive care centres using FEIBA® for surgeries in patients with inhibitors

Increasing evidence indicates that factor VIII (FVIII) inhibitor bypassing agents (FEIBA® and NovoSeven®) can provide effective peri-operative haemostasis in haemophilia patients with high-responding inhibitors. We report the collected experience of all major and minor surgeries, conducted between December 1998 and September 2008, at four UK haemophilia Comprehensive Care Centres with FEIBA® as the first-line bypassing agent in patients with inhibitors. A total of 26 surgical procedures were performed in 18 patients of ages 34-83 years including five patients with acquired FVIII inhibitors. A single pre-operative infusion of FEIBA was followed by 6-12 h interval dosing for major surgeries at the discretion of the physician to approximate a maximum of 200 U kg(-1) day(-1), with tapering when postoperative haemostasis and wound healing permitted. Haemostatic outcomes were retrospectively reviewed against European consensus thresholds for blood loss and duration of treatment compared with expectations for equivalent procedures in non-inhibitor patients. Peri-operative haemostatic outcome with FEIBA was rated excellent or good in 78% of 18 major surgeries in 12 patients, including 11 major orthopaedic procedures. Haemostatic outcome was rated excellent in all seven procedures in five patients with acquired FVIII inhibitors and in all eight minor surgical procedures in six patients. FEIBA was well tolerated with no intra-operative haemostatic complications. A single, transient postoperative thrombotic adverse event occurred in a patient with cerebrovascular disease. This case series adds significantly to existing evidence that FEIBA can provide adequate, well-tolerated, peri-operative haemostatic cover for a wide variety of major and minor surgical procedures.

Inhibitor Eradication In Acquired Factor VIII Inhibitor: A Case Series

AbstractAbstract 1423Acquired factor VIII (FVIII) inhibitor is an uncommon condition, with an incidence of ≂f1.5 cases/million/year, as reported by Collins et al. (Blood 2007. 109: p. 1870–1877) in a two year observational study in the UK. However, this is a serious condition, characterized by auto-antibodies against circulating factor VIII and has high mortality from bleeding. Controlling the acute bleeding event with FVIII inhibitor bypassing agents like recombinant activated factor VII or activated prothrombin complex concentrates is of utmost importance. Equally important is the eradication of inhibitor, in order to restore normal hemostasis. There are several approaches for inhibitor eradication, including, but not limited to, the use of Corticosteroids, Cyclophosphamide, Azathioprine, Vincristine, IVIG, Cyclosporine, Mycophenolate and, recently, Rituximab, either singly, or, in different combinations. However, there is no single standard approach. We report 4 cases of acquired FVIII inhibitor from our center that were initially treated with factor VIII bypassing agents. Inhibitor eradication was achieved by using a combination of Rituximab, Prednisone and Cyclophosphamide.Table 1:Patient Demographics and Co-morbid conditionsPatientAge (in years)Sex/RaceCo-morbid conditions144F/WhiteMultiple Sclerosis267M/WhiteRheumatoid arthritis383F/WhiteHypertension466M/Middle EasternDiabetes Mellitus, Obstructive uropathyTable 2:Treatment DetailsPatientHemoglobin(g/dl) Range:12.0-16.0WBC(x109/l)PT(in seconds) Range:11.5-15.5PTT(in seconds) Range:23.2-36112.69.834712.38329.69.429911.97937.910.555513.497.549.518.727514.395.2Table 3:Treatment DetailsPatientTreatment DurationCyclophosphamidePrednisoneRituximab13 cycles of 28 days each500mg iv day 1 200mg PO days 2-5,q4weeks x 3 cycles100mg PO days 1-5,q 4 weeks x 3 cycles375mg/m2 day 1, then q 4 weeks x 3 doses26 cycles of 21 days each500mg iv day 1 200mg PO days 2-5,q 3 weeks x 6 cycles100mg PO days 1-5,q 3 weeks x6 cycles375mg/m2 day 1, then q 4 weeks x 3 doses34 cycles of 28 days each500mg iv day 1 200mg PO days 2-5,q 4 weeks x 4 cycles100mg PO days 1-5,q 4 weeks x 4 cycles375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses43 cycles of 28 days each500mg day 1 200mg PO days 2-5,q 4 weeks x 3 cycles100mg PO days 1-5,q 4 weeks x 4 cycles375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses [Display omitted] [Display omitted] Table 5:Factor VIII inhibitor titer (in Bethesda Units): Baseline and Post-Treatment (Normal: Undetectable)PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6#117.21.71.2Undetectable#2117NANANANANANA#3416307177Undetectable#420.910.8UndetectableTable 4:Factor VIII Activity (in%): Baseline and Post-Treatment (Range: 50-180%)PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6116139521NANA141228123315123612446221137NA: not availableTable 4:Factor VIII Activity (in%): Baseline and Post-Treatment (Range: 50-180%)PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6116139521NANA141228123315123612446221137NA: not availableTable 6: Follow upPatientTime from last treatment (in months)Most recent factor VIII activity (Range: 50-180%)Inhibitor titer#19100%NA#26126%NA#316105%Undetectable#4355%UndetectableTable 4:Factor VIII Activity (in%): Baseline and Post-Treatment (Range: 50-180%)PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6116139521NANA141228123315123612446221137NA: not availableTable 4:Factor VIII Activity (in%): Baseline and Post-Treatment (Range: 50-180%)PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6116139521NANA141228123315123612446221137NA: not availableComplete and sustained remission was achieved in all 4 patients (100%).All 4 patients tolerated the therapy well. None of the patients had significant adverse effects like neutropenia, hemorrhagic cystitis or other complications, either immediately or during follow up. Thus, the combined use of Cyclophosphamide, Rituximab and Prednisone seems to be an effective and safe regimen for inhibitor eradication in patients with acquired FVIII inhibitor. Disclosures:Off Label Use: Rituximab.For th purpose of auto-antibody supression.

Acquired hemophilia A may be associated with itraconazole

Acquired hemophilia A is a rare disorder, with an annual occurrence rate of 1.48 cases per million [1], caused by autoantibodies against coagulation factor VIII (FVIII) [2].These autoantibodies mainly affect elderly patients and are often present without any underlying disease, but may occur in various conditions such as pregnancy, autoimmune disorders, solid tumors, and lymphoproliferative syndromes. Several drugs, such as penicillin and its derivatives, phenytoin, and sulfa drugs, have also been reported to be associated with antibodies to FVIII [3]. Collins et al. [1] reported the results of a 2-year national study of acquired hemophilia A performed by the UK Haemophilia Centre Doctors’ Organisation; the results of this study indicated that diagnosis of underlying disorders associated with acquired hemophilia A was very difficult, especially in old age (patients between 60 and 79 years, 42%; those aged 80 or over, 23%). Here, we report a 74year-old case of acquired hemophilia A associated with itraconazole. A 74-year-old woman was admitted to our hospital with a 3-week history of peripheral edema, palpable purpura, and arthritis. There was no previous personal or family history of bleeding. She also had no past history of illness until 4 weeks before admission, but she took 200 mg/day of itraconazole because of tinea pedis for 4 weeks before admission. On examination, the results of laboratory work-up were as follows: hemoglobin level, 5.7 g/dl; platelet count, 324 9 10 ml; white blood cell count, 9.3 9 10 ml; prothrombin time, 91% (normal 80–120%); activated partial thromboplastin time (APTT), 80.3 s (normal 25–39 s). Tests for lupus anticoagulant, anticardiolipin antibody, antinuclear factor, double stranded DNA, and rheumatoid factor were negative. Fiberscopy examination revealed esophageal ulcer as the reason for the anemia. Remarkably prolonged APTT (166.5 s) and huge iliopsoas hematoma appeared 15 days after admission. The levels of FVIII activity (FVIII:C) and FVIII-inhibitory activity on admission were \1% and 23 Bethesda units, respectively, thus confirming the presence of acquired FVIII inhibitor. The levels of von Willebrand factor (VWF) antigen (VWF:Ag) and VWF-inhibitory activity were prepared to be examined when the levels of FVIII:C were low and FVIII-inhibitory activity was negative. A diagnosis of acquired hemophilia A was made and the patient was treated with activated prothrombin complex concentrate (APCC); 1500 units every 12 h in addition to 50 mg/day of cyclophosphamide and 1 mg/kg of prednisolone. Her iliopsoas hematoma was effectively controlled with no subsequent recurrence. APCC was discontinued after 3 days. Cyclophosphamide and prednisolone were continued with slow tapering, and FVIII inhibitor became undetectable after 10 weeks, and FVIII:C level got normalized after 18 weeks. In spite of additional examination of another underlying disease, none of autoimmune disorders, solid tumors, and lymphoproliferative syndromes were detected. A possible link between autoimmune acquired hemophilia and itraconazole has not been previously reported. Itraconazole has been associated with neutropenia [4], suggesting other possible immune mediated adverse events. This patient could be cured because of the rapid diagnosis. Investigation of FVIII:C and FVIII-inhibitory H. Tamai S. Tanosaki Department of Hematology, The Fraternity Memorial Hospital, Tokyo, Japan

Rituximab for the Treatment of High Titer Acquired Factor VIII Inhibitor with Long Term Follow up

Acquired factor VIII inhibitors are auto antibodies directed against factor VIII (FVIII) and have a reported incidence of 0.2–1.0 per million individuals per year. It is a rare cause of serious bleeding associated with high mortality. Individuals with high titer antibodies (> 100 Bethesda units (BU)), often have difficulty achieving a complete sustained remission although different strategies have been advocated for these patients. Rituximab has been demonstrated to show efficacy in patients with acquired hemophilia. In this study we retrospectively studied three patients with high titer acquired FVIII inhibitors with long term follow up. Two of the patients were resistant to steroids and Intravenous Immunoglobulin, one patient had received steroids and Cyclophosphamide prior to rituximab therapy. Patients ages were 36, 45 and 48 years, two were women and one male. One of the women has a h/o pregnancy about 8 months ago and other two were thought to have idiopathic inhibitors. The patient's inhibitor titers ranged from 124–800 BU at the time of treatment with Rituximab. All received 4 weekly infusion of rituximab at 375mg/m2. No significant treatment related complication was noted. One patient did not respond to treatment. Two patients had a decline in inhibitor titers. One patient had a gradual drop in titer from 124 BU to 0.00 BU over 18 months. The other responder had a drop in titer from 800 BU to 41 BU in 16 months and then relapsed with significant bleeding and anti factor 8 titers of 700 BU and was retreated with rituximab and had a gradual drop in inhibitor titers to 50 BU over 8 months. The two patients have been followed for 28 and 30 months respectively. The non responder continues to have high tires of antibodies and has been followed for 25 months.We conclude that in patients with high titer of acquired inhibitors rituximab alone may produce a drop in inhibitor titer but is not sufficient to achieve a complete response. Rituximab in combination with other therapies or novel agents may provide better results,

A Case Report of Plasma Exchange, Steroids, Mycophenolate Mofetil and Cyclophosphamide in Acquired Factor VIII Inhibitors

Induction of factor VIII (FVIII) inhibitors sometimes occurs in patients with hemophilia due to frequent supplementation of FVIII. The inhibitor is rarely detected in non-hemophilic patients; however, an association has been described in patients with chronic inflammatory diseases, such as autoimmune diseases (e.g. SLE and rheumatoid arthritis), malignant tumors and drug allergies, and also to pregnant or aged individuals without underlying disease. We report on an 82-year-old patient who was transferred to our hospital after the diagnosis of acquired FVIII inhibitor. On admission the laboratory results showed no detectable FVIII activity (0%, normal range 70-100%), prolongation of coagulation time (APTT 102.4 s), and severe anemia 7.8 g/dL (normal range 12-16 g/dL). On physical examination multiple subcutaneous hematomas were detected and further bleeding in his left pectoralis muscle was observed. Despite extensive investigation no underlying disease was detected. Thirty-six courses of plasma exchange with 360 units of fresh frozen plasma replacement daily were conducted. High dose steroids and mycophenolate mofetil (MMF) were given throughout the course, and cyclophosphamide was administered once. Thirty-four units of erythrocytes were applied during this time. After 36 courses of plasma exchange in combination with high dose steroids, FVIII activity and coagulation time normalized and bleeding could be stopped. The patient was discharged in good health 48 days after admission. Hence, we present a case of severe idiopathic FVIII inhibitor-positive hemophilia successfully treated with the combination of plasma exchange, corticosteroids, cyclophosphamide and MMF.

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.

Two Cases of Acquired Hemophilia A Successfully Treated with Oral Steroid or Danazol

Acquired Hemophilia A is a rare and considerably life-threatening coagulopathy, which is caused by the development of autoantibodies against factor VIII (FVIII) in non-hemophilic adults. Acquired FVIII inhibitors can be associated with diverse conditions, such as malignant disorders, medications, autoimmune diseases, postpartum states and others. These autoantibodies inhibit normal coagulation, had results in bleeding complications, which can contribute to mortality in a high percentages of cases. Effective control of the disorder can be achieved by prompt diagnosis and appropriate managements. Generally, the managements of acquired hemophilia A are aimed at treating the acute bleeding and eliminating inhibitors by immunosuppression. Although a range of treatment options exists for patients with acquired hemophilia A, there is no consensus with regard to the optimal therapies for this disorder. Herein, two cases, an 82-year-old man and a 78-year-old man who were successfully treated by steroid or danazol, which is a relatively mild immunosuppressive agent, are reported. (Korean J Hematol 2005;40:58-63.)

Acquired factor VIII inhibitors in pregnancy: data from the Italian Haemophilia Register relevant to clinical practice

Objective To review the clinical problems related to the inhibitor of factor VIII (FVIII) in pregnancy. Design Retrospective analysis. Setting Haemophilia and haemotology centres. Population Patients registered and followed up at the centres. Methods Data were collected from the Italian Haemophilia Register of acquired FVIII inhibitor. Results Twenty of 96 cases with FVIII inhibitor were identified postpartum. The time of appearance was 3–150 days postpartum. All but one of the cases were idiopathic; 11/20 patients required blood transfusions. In six patients, the inhibitor was identified because of surgical bleeding, four after hysterectomies carried out because of postpartum haemorrhage. A prolonged activated partial thromboplastin time was present in all women in whom the test was carried out. Nine women did not require treatment because the bleeding was mild; in 11 patients bleeding was promptly controlled by different therapeutic modalities. Immunosuppressive therapy was used to suppress the inhibitor. The majority of the patients who achieved complete remission received steroids; in 6/6 patients who relapsed, a second remission was obtained with combined therapy. Conclusions In a review of 20 pregnancies with FVIII inhibitor, over a 15 year period, bleeding was controlled in all cases with no fatalities. Correct evaluation of coagulation screening tests, in particular, activated partial thromboplastin time, is essential.

Combined prednisolone and intravenous immunoglobulin treatment for acquired factor VIII inhibitors: a 2-year review.

Acquired inhibitors to factor VIII (FVIII) are rare, but life-threatening in up to 22% of cases. The optimal therapy for suppression of these inhibitors remains unclear. Prednisolone is the mainstay of therapy, producing responses in approximately 30% of cases. Intravenous immunoglobulin (IVIg) has a similar response rate, but a more rapid effect. We report the results of prednisolone 1 mg kg(-1) combined with IVIg 2 g kg(-1) in divided doses as first-line therapy in seven consecutive patients with acquired FVIII inhibitors. All patients were bleeding at the time of diagnosis with prolonged activated partial thromboplastin time. There were four complete responses, one partial response, one nonresponse and one with an inadequate follow-up for assessment of response, giving an overall response rate of 71%. In all complete responders the inhibitor declined rapidly and was undetectable by day 21 from start of treatment. Therapy was well tolerated and responses have been maintained off treatment for 2-8 months. This is a safe, well-tolerated rapidly acting regimen with good response rates.

Future approaches to factor VIII inhibitor therapy

Future progress in our ability to treat acquired factor VIII (FVIII) inhibitors must be based on advances in knowledge of both the FVIII molecule and the nature of the human immune response. New therapeutic approaches to patients with acquired FVIII inhibition likely will emphasize modifications of the immune response. This concept holds considerable promise, because studies have characterized the critical steps leading to tolerance of self-antigens. Development of FVIII inhibitors represents a loss of self-tolerance, which any successful therapy must restore. Conceivably, restoration of self-tolerance can be accomplished in many ways: prevention of antigen binding to helper T lymphocytes, deletion of self-antigen-reactive T cells, inhibition of major histocompatibility complex (MHC) recognition, or enhancement of the antigen-specific suppressor T lymphocyte population. Recent data have demonstrated that highly specific methods can suppress ongoing immune responses against defined autoantigens. Antibodies that inhibit T-cell activation, peptides that block self-antigen binding, and antibodies that inhibit MHC recognition all have been successful in modifying experimentally induced autoimmune diseases. Whether any of these immunotherapeutic approaches will be effective in the treatment of acquired FVIII inhibition remains to be determined. Until data from animal model systems establish the feasibility of immune intervention, scrutiny of other new therapeutic approaches to patients with spontaneous inhibitors will continue to be important. Administration of FVIII-bypassing procoagulant proteins shows promise, as does removal of inhibitors by affinity reagents, such as FVIII peptides containing relevant epitopes (antigenic sites). Farther on the horizon is development of recombinant FVIII molecules so modified as to remove antigenic determinants while preserving procoagulant function. Articles in this supplement summarize several avenues for treatment of patients with acquired FVIII inhibitors. Alternatives include treatment with sufficient human or porcine FVIII to offset inhibitors, use of materials that reestablish hemostasis even though FVIII levels are not increased (the so-called FVIII-bypassing agents), manipulation of immune responses through physical depletion of inhibitor by plasmapheresis or affinity chromatography, and administration of intravenous immunoglobulin or immunosuppressive cytotoxic drugs. Thus, the heterogeneous clinical presentation is paralleled by the wide range of available therapeutic approaches.

Failure of high‐dose I.V. Gammaglobulin in the treatment of spontaneously acquired factor VIII inhibitors

Two patients with spontaneously acquired factor-VIII-C inhibitors were treated with high-dose i.v. gammaglobulin. Minimal inhibition of anti-VIII-C activity was demonstrated in vitro in one patient when i.v. gammaglobulin was mixed directly with his plasma. In neither patient, however, was there any significant reduction in titer of antifactor VIII-C after i.v. gammaglobulin administration, nor was there any shortening of the aPTT or reduction in bleeding. The possible mechanisms of the previously reported salutary benefits of high-dose i.v. gammaglobulin in patients with spontaneously acquired factor-VIII inhibitors as well as the potential reasons for failure in our patients are discussed. Our cases demonstrated that high-dose i.v. gammaglobulin is not uniformly successful in the treatment of patients with acquired factor-VIII-C inhibitors. The true frequency of clinically significant responses will require further clinical trials.