Treatment Of Acquired Hemophilia A Research Articles

Differentiation of Acquired Hemophilia a from Lupus Anticoagulant Using Global Coagulation Assays and Magnesium-Dependent Activated Partial Thromboplastin Time Assay

CONCLUSION Rapid and reliable differentiation between bleeding and thrombotic tendency in cases with prolonged activated partial thromboplastin time (APTT) remains challenging in clinical practice, in particular, distinguishing cases positive for coagulation factor inhibitor or lupus anticoagulant (LA). To differentiate acquired hemophilia A (AHA) from LA using three global coagulation assays: rotational thromboelastometry (ROTEM), thrombin generation assay (TGA), and clot waveform analysis (CWA); also to validate the effectiveness of magnesium-dependent APTT (APTT-Mg) assay. This method uses APTT-Mg and normal APTT using Ca to screen for LA, and APTT-Mg/APTT ratio is smaller in LA. We included patients with prolonged APTT without congenital coagulation factor deficiency who were referred to our department between November 2019 and September 2021. APTT prolongation was defined as >35 s (normal range: 25-35 s) measured routinely with Coagpia APTT-N (Sekisui Medical). The AHA group had a confirmed diagnosis and underwent treatment of AHA. The LA group was divided into LA1 (possible LA) and LA2 (definite LA). LA1 was defined by any of the following conditions: (1) index of circulation anticoagulant ≥15 in the cross-mixing test performed with Coagpia APTT-N; (2) positive dilute Russell's viper venom time (DRVVT) phospholipid neutralization method using Gladipore LA (Medical & Biological Laboratories); (3) positive APTT phospholipid neutralization test using Hemosil SCT (Instrumentation Laboratory); (4) positive for anti-CL antibody; (5) positive for anti-CLβ2GPI antibody; or (6) positive for phosphatidylserine-dependent anti-PT antibody. LA2 was defined by index of circulation anticoagulant >12.4 in the cross-mixing test performed by Thrombocheck APTT-SLA (Sysmex Corporation), or item (2) or (3) above, in accordance with criteria of LA in the International Society of Thrombosis and Haemostasis. LA1 and LA2 did not overlap, because cases that did not meet the conditions of LA2 were treated as LA1, and global coagulation assays were performed in all LA cases. In the global coagulation assays, 12 healthy volunteer samples were tested and regarded as the normal goroup. For the APTT-Mg assay, equal volumes of 25 mmol MgCl 2 and 25 mmol CaCl 2 were used instead of the normally used CaCl 2, and Thrombocheck APTT-SLA was used to measure APTT-Mg, which was then divided by the normal APTT concentration measured with the same APTT reagent. Ten patients in the AHA, 12 in the LA1, and 32 in the LA2 groups were eligible. ROTEM showed that clotting time in the non-activated rotational thromboelastometry assay (NATEM) mode was >3600 s (minimum 1363 s) for AHA, 501 s (IQR: 430-632 s) for LA1, 533 s (IQR: 443-641 s) for LA2, and 500 s (IQR: 429-645 s) for the normal group. TGA showed that peak thrombin concentration was 16 nM (IQR: 13-29 nM) in the AHA group, 242 nM (IQR: 175-273 nM) in the LA1 group, 174 nM (IQR: 129-259 nM) in the LA2 group, and 190 nM (IQR: 125-288 nM) in the normal group. In the CWA, Ad|min1| was 2.1 (IQR: 1.7-3.2) in the AHA group, 8.7 (IQR: 8.0-9.5) in the LA1 group, 6.7 (IQR: 5.8-8.4) in the LA2 group, and 10.3 (IQR: 9.8-10.6) in the normal group. APTT-Mg/APTT was 1.23 (IQR: 1.18-1.29), 1.26 (IQR: 1.23-1.38), and 1.05 (IQR: 0.95-1.20) in the AHA, LA1, and LA2 groups, respectively. ROTEM, TGA, and CWA effectively differentiated between the LA1/2 and AHA groups. Clotting time in non-activated rotational thromboelastometry assay mode (ROTEM) and peak height (TGA) were better at distinguishing high-titer LA cases from LA-positive AHA cases. APTT-Mg/APTT could be suitable for distinguishing AHA from high-titer LA; however, it may not be useful for differentiating AHA from low-titer or suspected LA.

A Single Center Experience of 13 Episodes of Acquired Hemophilia A (2019 - 2023)

Background: Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by neutralizing autoantibodies to factor VIII (FVIII). Treatment of AHA involves immunosuppression to eliminate the autoantibody and hemostatic management involving bypassing agents (BPAs). While the use of BPAs, including activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa), is primarily derived from studies of congenital hemophilia with inhibitors, registry studies of AHA have also demonstrated the efficacy of rVIIa ( Baudo et al., Blood, 2012) and aPCC ( Borg et al., Haemophilia, 2015) ( Zanon et al., Br J Haem 2019) in this population. Given the changing treatment landscape, low incidence of AHA, and high morbidity and mortality associated with the disease, our study aims to describe a single institution's experience with treating AHA. Methods: We retrospectively reviewed the records of adult patients diagnosed with AHA at a single academic medical center between January 1, 2019, and June 30, 2023. Results: Eleven patients were treated for 13 distinct episodes of AHA, with one patient admitted for three discrete episodes of AHA with responses to therapy followed by relapses once lost to follow-up. The patients were predominantly white (63.7%, n=7) and female (63.7%, n=7), with a median age of 74 years and weight of 87 kg on admission (Table 1). One patient (9.1%) had concomitant autoimmune disease. No patients presented peripartum or with active malignancy, liver disease, or a family history of bleeding disorders. The median FVIII level on admission was 1% (IQR=1%, 3.5%), with a median anti-FVIII antibody titer of 27 BU (IQR=4.5 BU, 47 BU). Given mild bleeding presentation, Patient 2 was treated as an outpatient with immunosuppression only. All patients received aPCC as the first-line BPA. Patient 5 developed uncontrolled bleeding from an arterial line despite receiving aPCC and was transitioned to rFVIIa for two days before resuming aPCC once hemostasis was achieved. The median duration of aPCC therapy was eight days. The use of aPCC (FEIBA) instead of rFVIIa (NovoSeven) as the first-line BPA led to total estimated cost avoidance of $13.5 million (calculated using average wholesale price). No patients had thrombotic events after the diagnosis of AHA. Six episodes (46.1%) were treated with prednisone and rituximab. Six episodes (46.1%) were treated with prednisone and oral cyclophosphamide. One episode (7.7%) was treated initially with prednisone and cyclophosphamide but was eventually transitioned to rituximab following a lack of response and bleeding complications after two weeks. This patient was also subsequently treated with emicizumab for five months until FVIII activity was recovered. P neumocystis jirovic i i pneumonia prophylaxis was prescribed in eight episodes (61.5%), and antiviral prophylaxis was prescribed in one episode (7.7%). No infections were noted during the follow-up period, other than two documented cases of COVID-19, one of which required admission. The median time to achieve FVIII >50% was 5.1 weeks, with a median of 8.6 months of follow-up (Figure 1). Patient 11 relapsed twice, as described in Table 1. No other patient relapsed during the follow-up period. No patient deaths occurred during the follow-up period. Conclusions: We describe 13 episodes of AHA successfully treated at a single academic medical center between 2019 and 2023. aPCC was the first-line BPA administered in all patients, with significant cost savings relative to rFVIIa. Immunosuppression, including prednisone and either cyclophosphamide or rituximab, was used to successfully eliminate autoantibodies in all patients. One patient received emicizumab for ongoing hemostatic control until achieving improvement in FVIII activity. No significant infections, thrombotic events, or deaths were noted in this cohort.

Combining Low-Dose Rituximab and Bortezomib as Immunosuppressive Therapy for Acquired Hemophilia A: 6 Case Series.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII. Persistently positive inhibitor titers increase the risk of bleeding. Upfront combined regimen with multiple mechanisms has the potential to shorten remission time to lower bleeding risk and reduce immunosuppressor exposure time. We administered lowered dose of rituximab and bortezomib in combination with corticosteroids and cyclophosphamide (rituximab: 100mg weekly × 4 or 500mg once in week 1, bortezomib: 0.65mg/m2 once in week 1, prednisone: 1mg/kg daily, cyclophosphamide: 11.5-2mg/kg daily). We retrospectively analyzed 6 cases (male = 3, female = 3, median age = 51years) treated on this therapeutic regimen. All patients achieved complete remission (range from19 to 66days); adverse event: infection (1/6). This is the first time that this regimen has been reported for treating AHA. It has shown good therapeutic efficacy and the potential to shorten the time to CR. The incidence of adverse events is within a reasonable range. This regimen is feasible and offers a new alternative treatment for AHA.

Acquired Hemophilia A: An Update on the Etiopathogenesis, Diagnosis, and Treatment.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII). AHA is a disease that most commonly affects the elderly but has also been observed in children and in the postpartum period. AHA is idiopathic in 50% of cases and is associated with autoimmune diseases, malignancies, and infections in the remaining 50%. Recently, cases of association between AHA, COVID-19 vaccination, and infection have been reported in the literature. For diagnoses, determining FVIII levels is crucial to distinguish the different causes of aPTT prolongation. Treatment of AHA is based on bypassing agents (recombinant factor VIIa, activated prothrombin complex concentrate) and porcine FVIII to control the bleeding and immunosuppressive therapy (corticosteroids, rituximab, cyclophosphamide) to suppress autoantibody production. It is important to start a prophylactic regimen to prevent further bleeding episodes until the inhibitor is negative. Recently, the series of cases reported in the literature suggest that emicizumab may provide effective and safe haemorrhage prophylaxis in the outpatient setting.

Advances in Acquired Hemophilia A.

Acquired Hemophilia A (AHA) is a rare, life-threatening bleeding disorder from autoantibodies against clotting factor VIII. These autoantibodies occur with increasing incidence with advanced age and are often associated with other medical conditions such as autoimmune diseases and malignancy. Not uncommonly, AHA presents as a new bleeding disorder in a person with prior thrombosis or thrombotic risk. Treatment of AHA focuses on managing and preventing bleeding, as well as immunosuppression with the goal to eradicate the autoantibody. Despite current treatment approaches, morbidity, and mortality are high due to complications from bleeding, immunosuppression, and underlying comorbidities. The most pressing needs to improved outcome for this disease are better bleeding prophylaxis in the outpatient setting and reduction of the need for intense immunosuppression. Because of the rare nature of this disease, there is limited prospective data and most treatment standards have been based on case series. The field has recently focused on improved diagnostics and advanced risk stratification, with a potential of tailoring the need and intensity of immunosuppression. Case reports of off label use of emicizumab, a factor FVIII mimetic approved for congenital hemophilia A, suggest emicizumab may provide effective and safe bleeding prophylaxis in the outpatient setting; this could permit reducing immunosuppression and decreasing the risk of treatment related infections. Two ongoing prospective clinical trials of emicizumab will help clarify the safety and efficacy in AHA.

Time is Blood: The Impact of Diagnostic Delays on Acquired Hemophilia A.

Background and objectiveAcquired hemophilia A (AHA) is an uncommon autoimmune bleeding disorder caused by the formation of neutralizing antibodies against endogenous factor VIII (FVIII). Delays between the onset of symptoms and the correct diagnosis of the condition lead to poor outcomes and a higher mortality rate. In this study, we aimed to analyze the impact of delays in diagnosis on AHA patients.MethodsWe conducted a retrospective study at a single hospital system between March 1, 2010, and January 17, 2017, which included six patients meeting the criteria for AHA diagnosis.ResultsInitial analysis revealed a median age of 79.5 years and a median time to diagnosis from the onset of bleeding of 14 days. Among the six patients, three had cancer (bladder, renal, and prostate) and three had unknown etiologies. One of the patients died prior to the initiation of a bypassing agent. The remaining five patients received recombinant FVIIa (NovoSeven®, Novo Nordisk, Bagsværd, Denmark), and two of those five required a second-line bypassing agent, recombinant porcine sequence FVIII (Obizur®, Takeda Pharmaceutical, Tokyo, Japan) for refractory bleeding. All five patients achieved hemostasis; however, three died within a year, and none of the patients survived for five years. Four of these five patients died directly from bleeding complications.ConclusionsBased on our study findings and review of the literature, we propose an algorithm to potentially aid in the early diagnosis and treatment of AHA in emergency and non-specialized settings.

Feasibility of therapeutic plasma exchange-based combination therapy in the treatment of acquired hemophilia A: A retrospective 6 case series.

Poor availability and a lack of affordability of bypassing agents (recombinant activated factor VII and activated prothrombin complex concentrate) in west China prompted us to investigate an alternative cost-effective combination therapy. We aimed to explore the feasibility of therapeutic plasma exchange (TPE)-based combination therapy in the treatment of acquired hemophilia A (AHA).We retrospectively investigated the clinical features of AHA in 6 patients who were treated with a combination of TPE, corticosteroids, and rituximab in our department for 9 years between January, 2011 and December, 2019.We examined 1 male and 5 female patients. The median age at diagnosis of AHA was 51 years (18–66 years). In all patients, FVIII activity levels were low (median: 1.5%; 1–3%), FVIII inhibitor titers were high (median: 24.5 BU/mL; 13.2–48.6 BU/mL), and activated partial thromboplastin time was markedly prolonged (median: 99.4 s; 60.9–110.1 s). They underwent 2 to 8 cycles of plasma exchange and were given varying combinations of dexamethasone, methylprednisolone, prednisone, and rituximab. After TPE bleeding gradually stopped, and activated partial thromboplastin time decreased. After 3 months of treatment, FVIII inhibitors completely disappeared.TPE when combined with corticosteroids and rituximab, as adjunctive immunosuppressive agents, may be an effective and reliable treatment for AHA. When there is no alternative, intensive first-line treatment including TPE may be lifesaving.

Successful Treatment of Bleeding in Acquired Hemophilia A with Activated Prothrombin Complex Concentrate in Spain

INTRODUCTION. Acquired hemophilia A (AHA) is a rare autoimmune disorder characterized by development of autoantibodies against coagulation factor VIII (FVIII). Bypassing agents are recommended as first-line for the treatment of bleeding episodes in patients with AHA. Due to the low incidence of AHA, available clinical data on efficacy and safety of the activated prothrombin complex concentrate (aPCC) in patients with AHA are limited. The objective of this retrospective multicenter study was to detail AHA management in patients treated with aPCC in real life in Spain.METHODS. Data from patients with AHA, treated in any moment with aPCC, in five reference centers for coagulopathies disorders, between June 2012 and June 2017, have been collected.Bleedings were classified as initial (first episode after AHA diagnosis or relapse), concurrent (new bleeding at the same time but at a different anatomical location), subsequent (a new bleed recurring 72 hours after the resolution of the previous bleed) or re-bleed (same anatomical location within 72 hours of the resolution of the previous bleeding). Severity of the bleed was evaluated according the Word Health Organization scale. Hemostatic efficacy was assessed as bleeding cessation and pain control. Safety was evaluated during bypassing agent treatment and until 30 days after discontinuation.RESULTS . Ten patients (6 males), 40% idiopathic AHA, median aged 70 years (64-84, IQR) at diagnosis. Seven patients out of 10 had at least 1 thrombotic risk factor, but no history of thrombotic events previous AHA. The median baseline residual FVIII level was 1% (0-1%, IQR), the median inhibitor titer was 24 BU (9-40, IQR).In all cases the suspected diagnosis of AHA was precipitated by a bleeding event (combined with a prolonged aPTT in 7 patients). Suspected diagnosis came from hematology (80%), emergency room (10%) and internal medicine (10%). The diagnosis was made promptly by hematology after the suspicion at a median of 1 day (0-7, IQR). 10 patients presented 19 bleedings (13 initial, 4 subsequent, 1 concurrent, 1 re-bleed) (WHO severity: grade 1, n=1; grade 2, n=5; grade 3, n=12; grade 4, n=1) that were recorded. 84% of these bleedings arose spontaneously, 44% of them manifested primarily as muscle hematomas. There was emergency surgery because of acute abdominal surgey complication. Seventeen bleedings were treated with aPCC as first line (n=11) or second line after rFVIIa (n=6), achieved bleeding cessation and pain control in the 100% of the evaluated bleeding episodes. The mean initial dose per infusion was 54.4 (± 12.9 SD) U/kg, the median total dose was 48000 U (32000-68000 U, IQR), the initial dosing interval was 8 hours (8-12, IQR), the median duration of treatment was 5.5 days (3.5-10.5 days, IQR), and the median number of injections was 15 (7.5-21, IQR). No adverse events, including thromboembolic events, were described during aPCC treatment. A 75-years-old female patient died due to a severe respiratory insufficiency after 19 days of aPCC discontinuation. The reasons to change from rFVIIa to aPCC were non bleeding control in 2 patients and necessity to reduce the number of infusions per day for ambulatory management in the rest. All patients received first line immunosuppressive therapy: prednisone 1 patient, corticosteroids plus cyclophosphamide 7 patients, rituximab plus other immunosuppressive drug 2 patients. Patient with prednisone alone and one with rituximab plus esteroides needed a second line treatment for no response after more than 4 weeks. Median time to response in the group of corticosteroids plus cyclophosphamide was 56.5 days (40-108, IQR), rituximab plus other immunosuppressive drug 56.5 days (50-56.5 days, IQR).CONCLUSIONS . This is the first study providing information on the daily use of aPCC in the treatment of AHA in Spain. With a hemostatic efficacy rate of 100% and a good safety profile, in line with other published real-life data. This multicenter Spanish experience supports the role of aPCC as first-line treatment for bleedings in AHA. DisclosuresNo relevant conflicts of interest to declare.

United States Post-Marketing Safety (PMS) Study of rpFVIII in Patients with Acquired Hemophilia A: Preliminary Data

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune disorder characterized by development of neutralizing autoantibodies to circulating factor VIII (FVIII). Obizur® is a recombinant, B-domain deleted, porcine-sequence FVIII (rpFVIII) with low cross-reactivity to anti-human-FVIII antibodies for the treatment of AHA. The objective of this study is to collect data assessing the safety, safety-related factors, utilization, and effectiveness of rpFVIII in real-world clinical practice.Methods: This is a multi-center, non-controlled, open-label, non-interventional Post-Marketing Safety (PMS) surveillance study conducted in the United States for AHA patients treated with rpFVIII. This is a prospective and retrospective data will a target enrollment of 40 patients. Statistical analyses will be conducted and include, specifically but not exclusively, descriptive statistics.Results: A second, preliminary, unplanned data read-out was conducted on March 31, 2017, on 19 patients (11 males and 8 females) from 11 centers in the US. Complete demographic data was available for 15 patients and they had a median age of 73 years (range: 54-81) and the median weight was 85.1 kg (range: 43.7-159.3). The mean lag time of AHA diagnosis was 13.2 days (range: 16 [pt with no bleed at the diagnosis] -127) and the median was 6 days. The mean days from bleeding onset to first Obizur infusion was 98.1 (range: 3-581) with a median of 19 days. The first bleeding episode was spontaneous in 10/19 (52.6%) and described as located in other, 42.1%, while 7/19 (36.8%) of patients experienced bleeds described as deep (musculoskeletal, retroperitoneal). The bleed characteristics of 14 patients with sufficient data are described in Table 1. The loading dose of rpFVIII administered ranged from 50 to 300 U/kg (mean 125.5 U/kg) to treat the bleeds, which significantly differs from the initial dose of 200 U/kg recommended in the Summary of Product Characteristics. Among the evaluable subjects for whom enough data has been collected, 14 bleeding episodes were resolved in 11 patients (11 initial bleeds, 2 subsequent bleeds and one (1) concurrent bleed), and five (5) bleeding episodes were not resolved in three (3) patients (3 initial bleeds and 2 subsequent bleeds). A mean of three (3) infusions (range: 1-46; median of 8.5) were required to resolved the bleeds for patients evaluable for efficacy at the time of this analysis, with an overall population mean of 6 infusions (range: 1-85; median of 13.3). Among the evaluable patients evaluable for treatment modality, six (6) were treated with rpFVIII as first line therapy for their initial bleeding event, and four (4) as first line for the subsequent bleeds. The remaining six (6) patients were treated with rpFVIII after other treatments as 2nd, 3rd or even 5th line therapy. To date, no thromboembolic events have been reported and one patient experienced a hypersensitivity reaction (rush). One therapy related serious adverse event was reported, a moderate vascular disorder (hemorrhage) considered “possibly related” to rpFVIII, which occurred more than 24 hours after the last treatment of rpFVIII.Conclusions: From this preliminary data read out of the patients currently enrolled in the Post Marketing Surveillance study ongoing in the US, rpFVIII appears to be safe and effective in patients with AHA, a disease that is confirmed to occur in a very heterogeneous way. This study, along with a similar one in Europe, will provide a relevant amount of real world clinical data and may help with further assessment of the dosing regimen as well as guidance regarding appropriate dosing in order to personalize the treatment for each individual. [Display omitted] DisclosuresCrea:Shire: Employment, Equity Ownership. Huang:Shire: Employment, Equity Ownership. Bajwa:Shire: Employment. Gringeri:Shire: Employment.

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Acquired hemophilia A (AHA) is a severe auto‐immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi‐center cohort study (1992‐2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow‐up of 16.8 months (IQR 3.6‐41.5 months). First‐line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti‐FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease‐related and treatment‐related morbidity and mortality. A high anti‐FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.

Susoctocog-alfa (Obizur®) in the treatment of nine elderly patients with acquired haemophilia A: an Italian multicentre real world experience.

In 2016, a new recombinant B-domain deleted porcine FVIII (rpFVIII) was licensed in Italy for the treatment of acquired haemophilia A (AHA). But only a few cases of patients receiving this have been reported in the literature. Here we report the largest registry of the use of rpFVIII for the treatment of AHA. The objective of this retrospective study was to describe the efficacy and the safety of susoctocog-alfa for AHA. We studied a population of nine patients, recruited in five Italian haemophilia centres presenting AHA, and treated with Obizur® as first- or second-line therapy. fir RESULTS: rpFVIII was used as a first-line therapy in one-third of the patients. The median delay between clinical onset and diagnosis was 16 days. Initial bolus of infused susoctocog-alfa was 100 IU/kg, lower than the recommended dose. The treatment was maintained for a median of four days. Only one patient with serious co-morbidities and recurrent infections was treated for 32 days. All patients reached a complete resolution of AHA, and no recurrences were reported. Two patients developed a low-titre inhibitor against rpFVIII, neither experienced any complications. In our real world experience, susoctocog-alfa was proven to be an effective and safe therapeutic option for patients with AHA, also at a lower than recommended dosage. In our report, the appearance of low-titre inhibitors.

Efficacy of therapeutic plasma exchange in a patient with coagulation inhibitors (acquired haemophilia A) – A case report

Acquired haemophilia A (AHA) is a rare disorder with mostly idiopathic aetiology that leads to factor VIII (FVIII) deficiency due to coagulation inhibitors formation. Treatment protocol includes immunosuppression and Factor VIII bypassing agents including activated Prothrombin Complex Concentrates (PCC). Nevertheless, the role of plasma exchange is not clear in the treatment of AHA. We report a case of 73 year old male who presented with haematuria, prolonged activated partial thromboplastin time (APTT) and a very high titres of Factor VIII inhibitors of 98 Bethesda units (BU) and was diagnosed with acquired haemophilia A. He failed to respond to multiple immunosuppressive therapies including rituximab. Therefore, therapeutic plasma exchange (TPE) therapy was planned due to persistence of haematuria despite immunosuppressive therapies. After five cycles of plasma exchange, APTT became normal, haematuria subsided and Factor VIII inhibitors became negative. Patient was discharged without any bleeding and in a stable condition. In this index case, plasma exchange played a very crucial role, resulting in recovery of the patient. These results advocate that therapeutic plasma exchange is an effective therapy for acquired haemophilia A.

Acquired hemophilia A

Acquired hemophilia A (AHA) is a bleeding disorder due to the autoantibody (inhibitor) production targeting blood coagulation factor VIII. It is characterized by a sudden onset, and it often causes extensive and severe bleeding in soft tissue. The incidence of AHA is 1.48 cases per 1 million individuals per year and is common among postpartum women and elderly with underlying diseases. The risk factors include autoimmune diseases, malignancy, and aging. The diagnosis requires exclusion of other diseases with activated partial thromboplastin time (APTT) prolongation and an APTT cross-mixing test during early differential diagnosis. The treatment of AHA is immunosuppressive therapy to reduce the inhibitors. In case of bleeding that requires hemostasis, hemostatic therapy with bypass agents should be administered. The first-line immunosuppressive therapy is prednisolone (1 mg/kg/day) alone or in combination with cyclophosphamide (1-2 mg/kg/day). Recently, the effect of a rituximab-based-regimen has also been utilized.

The Frequency and Effect of Baseline Cross-Reacting and De Novo Inhibitors to Recombinant Porcine FVIII in Patients with Congenital and Acquired Hemophilia a

Background Patients with severe congenital hemophilia A (CHA) have a 25-40% lifetime risk of alloantibody (inhibitor) development to FVIII. Patients with acquired hemophilia A (AHA) spontaneously develop neutralizing autoantibodies to factor VIII. In both cases, patients require pro-hemostatic therapy with bypassing agents: recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC) and more recently recombinant porcine factor VIII (rpFVIII). Anti-human FVIII (hFVIII) inhibitors typically bind to the A2 and C2 domains of the FVIII molecule. RpFVIII is an effective pro-hemostatic treatment for AHA and CHA given the immunologic difference in the A2 and C2 domains of the rpFVIII while maintaining sufficient hFVIII homology to act as an effective cofactor to human FIX in the intrinsic tenase. However, some anti-hFVIII antibodies cross-react with rpFVIII and may interfere with its hemostatic function. Cross-reacting antibodies were reported in 35% of subjects in a phase II/III trial prior to initiation of rpFVIII. Moreover, de novo rpFVIII inhibitors may develop during or after the treatment with rpFVIII and may affect its hemostatic function. Here we describe the largest case series to date on baseline cross-reactivity of rpFVIII inhibitors and post-treatment de novo inhibitor development in patients with CHA and AHA to address the paucity of published literature in this area. Aim First, we describe the frequency of baseline cross-reacting rpFVIII inhibitors in patients with AHA and CHA (with inhibitors) at our institution. Second, we describe the effect of baseline rpFVIII antibodies on FVIII recovery after treatment with rpFVIII. We also describe the frequency and timing of de novo rpFVIII inhibitor development after exposure to rpFVIII. Methods Institutional research ethics board approval was obtained. Electronic charts of patients admitted to our institution with AHA or CHA who underwent testing for rpFVIII inhibitors were reviewed retrospectively. RpFVIII inhibitor assay is performed in the special coagulation laboratory using the Nijmegen modified Bethesda assay. The patient sample is initially heat-treated at 57 Results Twenty-seven patients (7 CHA, 20 AHA) underwent testing for porcine inhibitors since assay availability in 2016. 61% (5/7 CHA, 11/20 AHA) of patients had a detectable rpFVIII inhibitor prior to exposure to rpFVIII; median titer 1.6 BU/ml (range 0.6-192). Eight patients with AHA with baseline cross-reacting inhibitors received rpFVIII. Of those, three achieved an initial FVIII recovery beyond 100% (132%, 148% and 177%) after approximately 100U/kg of rpFVIII and all three had very low anti-rpFVIII Bethesda titers (0.70, 0.85 and 0.9 BU/ml). Five patients did not achieve a FVIII recovery above 50% (46%, 46%, 40%, 36% and 0%) despite approximately 100U/kg of rpFVIII. Most patients who received rpFVIII were tested weekly for the duration of their treatment or hospital stay. Upon discharge, patients who were seen in clinic for follow up were tested for anti-hFVIII and anti-rpFVIII. Two AHA patients without a baseline inhibitor who received rpFVIII treatment developed a de novo inhibitor after 20 days (1 BU/ml) and 133 days (12 BU/ml), respectively. One AHA patient had a rise in baseline anti-rpFVIII titer after exposure to rpFVIII. Conclusion In conclusion, we found that 61% of patients with AHA and CHA tested for rpFVIII inhibitors had a detectable baseline cross-reacting inhibitor which is higher than previously described. Of those patients with a baseline inhibitor treated with rpFVIII, only 37.5% of patients had an appropriate rise in FVIII. Finally, 13% of patients without baseline inhibitors developed a de novo inhibitor after exposure to rpFVIII, an incidence comparable to previously published findings. Disclosures Pavenski: Bioverativ: Research Funding; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria; Ablynx: Honoraria, Research Funding. Teitel:BioMarin: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Sholzberg:Takeda: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. OffLabel Disclosure: Recombinant porcine factor VIII is used to treated patients with congenital hemophilia A with allo inhibitors

PS1108 CLINICAL FEATURES AND TREATMENT OUTCOMES OF ACQUIRED HEMOPHILIA A IN KOREA: RETROSPECTIVE ANALYSIS

Background:Acquired hemophilia A (AHA) is a rare disease caused by depletion or suppression of coagulation factor FVIII by autoimmune antibodies. Factor VIII inhibitory antibodies neutralize the activity of Factor VIII and, if not properly treated, can lead to life‐threatening hemorrhage or death, with mortality rates as high as 9–22%. There is no report on the incidence and treatment of AHA in Korea. Only a small number of cases have been reported.Aims:The purpose of this study was to evaluate the clinical characteristics and treatment outcome of patients with AHA in Korea.Methods:Patients diagnosed with AHA from January 2006 to May 2016 were enrolled from the 15 institutions in Korea. The diagnostic criteria for AHA were defined as FVIII: C 50% or less and FVIII inhibitory antibody was 0.6 BU/mL or more. A total of 55 patients were enrolled and their medical records were analyzed retrospectivelyResults:Median age was 66 (18–86) years old. In epidemiology, idiopathic was 38% and associated disease was 62%. In epidemiology, 21 patients (38%) were idiopathic and 34 (62%) patients had associated diseases. Associated disease was followed by autoimmune disease (19%), surgery of other disease (13%), infection (13%), pregnancy/postpartum (12%) and hematologic malignancy (12%). The mean FVIII:C activity at diagnosis was 2.69 ± 2.97%, and 14 (26%) patients were less than 1%. The mean titer of FVIII inhibitor was 24.38 ± 34.87 U, and 55 (45%) patients had less than 10 BU. The time from the onset of symptoms to diagnosis was 15.5 (0–100) day, and the time from the first contact with the hematologist to the diagnosis was 3.0 (0–74) day. Overall, the time from symptom onset to diagnosis was relatively long. The sites of bleeding were subcutaneous/skin (83%), muscular (43%), gastrointestinal (21%), mucosal (19%), retroperitoneal (17%), genitourinary (4%), respectively. The severity of bleeding was major in 39 of 55 (71%), and a mean of 14.32 ± 3.332 U red blood cells were transfused per patient who experienced major bleeding.Of the 30 patients who treated for hemostasis, 14 received bypassing agents and 16 received factor VIII concentrates as 1st line hemostatic therapy. The efficacy of the bypassing agent was 86%, which was statistically higher than that of FVIII concentrates (31%) (p &lt;0.05). As immune‐suppressive therapy to eradicate the FVIII antibody, 18 patients (33%) were treated with glucocorticoid alone, and 12 patients (22%) with glucocorticoid and cyclophosphamide combination therapy. The response rate (CR + PR) of glucocorticoid therapy alone was 61%, and the combination of glucocorticoid and cyclophosphamide was 91% (p &lt;0.05). Adverse events were not different between the two groups. The overall survival rate at 1 year was 81.6% and 6 patients died. The causes of death were infection (4 cases) and intracranial hemorrhage (2 cases).Summary/Conclusion:The clinical features of AHA in Korea were not significantly different from the previously published registry data. However, it is considered that the time from symptom onset to diagnosis was relatively long because lack of awareness of AHA. In addition, due to financial problems including national health insurance, only ∼30% of patients were treated with bypassing agent as primary hemostatic therapy. It is necessary to establish more effective treatment strategies in Korea based on the large‐scale prospective analysis of Korean AHA patients.

Prevention and Management of Bleeding Episodes in Patients with Acquired Hemophilia A.

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies inhibiting the function of coagulation factor VIII. It is characterized by spontaneous bleeding in patients with no previous family or personal history of bleeding. Although several large registries have collected clinical data on AHA, limited information is available on the optimal management of AHA because controlled clinical trials are lacking. AHA can easily be diagnosed if the problem (prolonged activated partial thromboplastin time in a bleeding patient) is recognized. After the effects of anticoagulants are excluded, low factor VIII activity and the detection of circulating inhibitors confirms the diagnosis. However, lack of familiarity with this rare condition may delay diagnosis and adequate therapy. Treatment of AHA is based on measures for prompt hemostatic control to stop (and prevent) bleeding, immunosuppression to eradicate the autoantibodies, and supportive care for the adverse effects of that treatment and patients’ often complex comorbidities. This article gives a comprehensive overview of the current knowledge about the pathophysiology, diagnosis, and treatment of AHA.

Can the plasmaderived factor VIII still play a role in the treatment of acquired hemophilia A at the time of new drugs?

: Bypassing agents are the first-line therapy in the treatment of acquired hemophilia A (AHA), but not the only one. Other options as recombinant porcine factor VIII or plasmaderived concentrates (pdFVIII) are available to clinicians. Aim of this study was to evaluate whether the pdFVIII can still play a role in the treatment of AHA, and which patients could benefit from this therapy. All patients with AHA, presenting severe cardiovascular comorbidities, and treated with pdFVIII with or without von Willebrand factor (vWF), referred to two different hospitals, were initially considered. Eight patients were studied and divided into two groups: first, patients treated with daily infusion of pdFVIII; second, patients treated with pdFVIII continuous infusion. After 6 months of follow-up, all patients reached complete response. Mean consumption of clotting factor (219 000 vs. 142 000 IU), mean duration of therapy (61.5 vs. 10.5 days), and mean time necessary to disappearance of the inhibitors (INHs) (64 vs. 9 days) were higher in group 1, and the differences between the two groups were statistically significant (P < 0.05). Patients in group 1 also had a mean INH titer of 20.4 BU, higher than that of group 2 patients (8.4 BU), with a lower detectable FVIII level. Our study showed that pdFVIII can be an effective option for patients at high thromboembolic risk, even for those with high-titer INHs, especially if combined with vWF. The immunomodulatory role of vWF should, however, be better investigated in wider trials. The days of treatment with pdFVIII continuous infusion was proven to be similar to those reported with other drugs.

Acquired factor VIII deficiency: two case reports and a review of literature

BackgroundAcquired factor VIII (FVIII) deficiency, or acquired hemophilia A (AHA), is a rare autoimmune disorder involving antibody-mediated depletion of coagulation FVIII, leading to severe, life-threatening bleeding. The condition is often associated with other autoimmune disorders, and its treatment involves replacement of FVIII and various modes of immunosuppression. Recently, a few noteworthy therapeutic advances have been made. We present two cases of severe AHA in Chinese women. One of these women developed this disorder in the setting of possible parvovirus B19 infection, which has not yet been reported in association with AHA. Other notable features of her case included paradoxical venous thrombosis and possible association with Sjogren’s syndrome and myositis. The other woman failed to respond to usual first-line therapies despite exhibiting a less severe clinical course, illustrating the varied but potentially stubborn behavior of this disorder.Case 1An 87-year-old woman presented with diffuse ecchymoses, melena, vaginal bleeding. Labs showed hemoglobin (Hgb) nadir of 5.7 mg/dL, elevated partial thromboplastin time (PTT), FVIII level <1%, mixing study consistent with an inhibitor, elevated anti-Sjogren’s-Syndrome-related antigen A antibody, elevated creatinine kinase, and elevated parvovirus IgM and IgG. Imaging of her arm showed diffuse myositis and deep venous thrombosis. After intravenous and oral steroids, her FVIII levels normalized, and her symptoms subsided.Case 2A 59-year-old woman presented with recurrent ecchymoses and hematomas in her extremities. Labs showed Hgb of 11.7 mg/dL, elevated PTT, FVIII level of 3%, and mixing study consistent with an inhibitor. Despite receiving a long course of steroids, several courses of IVIG, and a few courses of Rituximab, her FVIII level remained critically low.ConclusionThe rarity of AHA limits our understanding of this disease and the ability to perform trials to discover optimal therapies. We hope that these case reports and discussion will shed further light on the varied clinical manifestations and natural histories of this disorder to guide better recognition and treatment of AHA.

Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n=15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range<1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5days (range 19-714days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.

An extra X does not prevent acquired hemophilia – Pregnancy-associated acquired hemophilia A

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care.