Diagnosis Of Acquired Hemophilia A Research Articles

A Tale of Two Cases: Acquired Hemophilia A and/or Lupus Anticoagulant?

Abstract Distinguishing between acquired hemophilia A (AHA) and lupus anticoagulant (LA) is essential for effective clinical management. This can be challenging due to similarities in laboratory tests and potential interference between their diagnostic tests. Here we present two complex cases. Case 1 is a 69-year-old female with PNH presenting with a subdural hematoma. Prolonged aPTT with no correction on mixing raised clinical suspicion of AHA. Factor VIII activity was low (2%) across three dilutions in the factor assay. A Bethesda assay revealed a low factor VIII inhibitor (1%). LA was negative by DRVVT. Antiphospholipid antibodies (Cardiolipin and Beta-2-Glycoprotein 1) were also negative. Treatment with prednisone and intravenous immunoglobulin was initiated with presumptive diagnosis of AHA. Subsequent samples to check other factor levels uncovered low Factor IX as well. Higher dilutions in factor assays exhibited non-parallelism in Factor IX and VIII, suggesting a non-specific inhibitor. Chromogenic Factor VIII was within the normal range. Another LA test, Staclot-LA was positive. Overall, this case was consistent with LA rather than AHA. The initial ‘positive’ Bethesda assay was attributed to interference by LA. Case 2 is a 20-year-old female with no significant medical history who was admitted elsewhere for a complicated C-section with intraabdominal hemorrhage. She had prolonged aPTT and positive LA by platelet neutralization test there. Upon transfer, the initial assessment confirmed prolonged aPTT and a time-dependent inhibitor pattern in mixing studies. Factor studies revealed significantly diminished factor VIII activity (<1%) using both one-stage clotting and chromogenic assays. A strong factor VIII inhibitor was identified through chromogenic Bethesda assay (126 BU). Non-parallelism was observed in other factors (Factor IX, XI, XII). LA was negative by DRVVT but positive by Staclot-LA. Cardiolipin and beta2-glycoprotein-1 antibodies were negative. The diagnosis of AHA was evident. But is there concurrent LA present? Both Staclot-LA and platelet neutralization tests are PTT-based and susceptible to interference from factor VIII inhibitor. The patient underwent treatment, and factor VIII inhibitor disappeared in 3 months. Staclot-LA also turned negative, suggesting that the initially ‘positive’ LA test was likely a result of interference. In both cases, adopting a holistic approach to differentiate between AHA and LA is beneficial. Relying solely on individual tests may lead to false interpretations, as LA can inhibit FVIII activity assays and produce false positives in the Bethesda assay. It is advisable to include higher dilutions in factor assays and/or chromogenic assays to mitigate interference. The presence of factor VIII inhibitor can also result in false-positive LA results such as Staclot-LA assay. For more reliable results, DRVVT and antibody tests are preferable. If the aPTT-based assay is the sole positive LA test, the presence of LA is suggested when it occurs before and/or after the presence of a factor inhibitor.

Acquired hemophilia successfully treated with recombinant factor VIIa: A case report

Acquired Hemophilia A (AHA) is a disorder characterized by the impaired clotting ability of the blood, primarily resulting from a deficiency in factor VIII, a crucial clotting protein. It is an infrequent disorder that affects a minority of individuals. This condition can pose a life-threatening risk, with reported mortality rates reaching as high as 22%. The diagnosis of AHA is challenging owing to its non-specific presentation and low prevalence rate. The primary objectives of treatment for AHA encompass the cessation and prevention of bleeding episodes, eradication of the inhibitor, and management of the underlying disease in secondary cases. This case report summarizes the successful treatment of a patient with AHA and major bleeding with the repeated use of prednisolone, recombinant factor VIIa, and rituximab.

ПРИОБРЕТЕННАЯ ГЕМОФИЛИЯ А В РЕАЛИЯХ СОВРЕМЕННОЙ МЕДИЦИНЫ: ОПЫТ КЛИНИЧЕСКОЙ ПРАКТИКИ

Abstract. Introduction. Acquired hemophilia A is a rare form of severe coagulopathy with an autoimmune mechanism of development. It occurs due to the formation of circulating inhibitory factor VIII (FVIII) antibodies, which leads to impaired activation of factor X and the occurrence of spontaneous bleeding in patients without previous hemostasis system pathology. In about a half of the cases, FVIII autoantibodies appear in patients without any comorbidities. It should be noted that the average age of patients was 74 years at the time of diagnosis. However, the occurrence of the disease in young women is rare and may be associated with pregnancy and childbirth. Given the rarity of this disease, the management of these patients is a challenging clinical problem. Aim. To describe a clinical case of diagnosis and treatment of a patient with the inhibitor form of acquired hemophilia A (AHA). Materials and Methods. A 38–year–old female patient had acute hemorrhagic syndrome of the hematoma type, manifested by large hematomas in different areas of the body. During the patient’s stay in the hospital, standard lab tests were made, the test results were evaluated over time, and instrumental diagnostics was performed. Results and Discussion. The typical hematoma type of bleeding detected during diagnosing, prolongation of coagulation parameters, presence of factor VIII inhibitor (605 BU), and a decrease in factor VIII level down to 0.5%) verified the AHA diagnosis. Methods of substitution, immunosuppressive therapy, and monoclonal antibodies were successfully used to treat AHA in this patient. The patient is followed up by a hematologist at the place of residence. Hematomas did not recur. Conclusions. This clinical observation demonstrates the peculiarities of the course, diagnostic algorithm, and management of patients with AHA without any concomitant pathology, with a history of only prolonged postpartum uterine bleeding, and with no autoimmune or malignant diseases.

Case Report: Acquired hemophilia A following COVID-19 vaccine

Background: In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and has subsequently been responsible for immense morbidity and mortality. This resulted in the development of vaccines in record time, potentially posing safety issues. Several cases of acquired hemophilia A (AHA) following coronavirus disease 2019 (COVID-19) vaccines have been described in the literature. AHA is a rare autoimmune disease due to the production of IgG autoantibodies to coagulation FVIII that burdens high morbidity and mortality. It is presumed mainly on identifying an increased activated partial thromboplastin time (aPTT), even without bleeding and is confirmed by determining a FVIII inhibitor. To the best of our knowledge, this is the first report of AHA after inactivated virus COVID-19 treated with low dose rituximab (RTX). Lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. Case presentation: We report a case of AHA occurring in a 69-year-old man 60 days after an inactivated Sinovac-coronavac COVID-19 vaccine. Diagnosis of AHA was based on clinical presentation and confirmed with prolonged activated partial thromboplastin time, Factor VIII deficiency and the presence of an FVIII inhibitor. Follow-up showed a significant clinical and biological improvement, aPTT was normalized as of 18 days of treatment with corticosteroids along with low dose rituximab. Conclusions: In the literature, the reported cases of AHA following COVID-19 vaccination occurred after Adenoviral Vector DNA- and SARS-CoV-2 mRNA-based COVID-19 vaccines. Here, AHA was presented following inactivated virus COVID-19 vaccine. AHA treated with low dose rituximab can limit occurrence of side effects and the cost of treatment.

Prevalence and Risk Factors of Diagnostic Delays in Acquired Hemophilia A

Introduction: Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies against factor VIII (FVIII). Delayed diagnosis is frequent, resulting in morbidity and health resource utilization. Predictors of diagnostic delays and their impact on outcomes are unclear. Aims: 1) Evaluate the time from presentation to AHA diagnosis, in a large Canadian province, 2) examine predictors of diagnostic delays, and 3) assess the impact of delays on outcomes and resource utilization. Methods: This multicentre retrospective cohort study included adults (≥18 years) diagnosed with AHA (January 2000-December 2021) in Alberta, Canada. Alberta's 661,848 km 2 geographic area encompasses two adult hemophilia treatment centres (HTCs). We assessed the prevalence of delayed diagnosis (from bleeding or first prolonged aPTT) and examined the impact of sociodemographic variables (age, sex, rural residence, living arrangement, initial presentation to HTC) and disease variables (AHA etiology, major bleed at presentation, comorbidities, FVIII activity and inhibitor titre) on the diagnostic delays. Case-based analysis and logistic regression were used to identify contributory factors and predictors of diagnostic delays, respectively. Kaplan-Meier curves were used to estimate overall survival (OS), and Cox proportional hazards regression analysis was used to assess the impact of diagnostic delays on OS. Ethics board approval was obtained. Results: Of the 38 patients diagnosed with AHA, 25 (66%) were female, 8 (21%) resided in rural areas, and 10 (26%) resided >100 km from HTC. Median age was 74 years (IQR 61-81), with marked comorbidities (median Charlson comorbidity index [CCI] 5, IQR 3-7). Most patients (27; 71%) initially presented to non-HTCs while 32 (84%) were eventually admitted to HTCs. At presentation, 27 (71%) had ISTH major bleeding and 13 (34%) were on anticoagulants or antiplatelets/NSAIDs. The median time from bleeding symptom and prolonged aPTT to diagnosis was 3.5 days (IQR 0-11.0) and 3.5 days (IQR 1.3-9.5), respectively. From first bleeding symptom, diagnosis was delayed ≥7 days in 15 (39%) patients and >30 days in 2 (5%). Case-based analysis identified the top reasons for delays ≥7 days: delayed ordering of aPTT from 7-62 days after bleeding (6/15; 40%), delayed ordering of mixing study following first abnormal aPTT from 7 days to >1 year (9/15; 60%) and attribution of bleeding to antiplatelets/anticoagulants (5/15; 33%). Neither demographic nor disease characteristics were identified as significant predictors of delayed diagnosis by logistic regression (Table 1). Initial presentation to HTCs had no impact on time to diagnosis. While non-statistically significant, there appears to be a clinically significant temporal gradient suggesting higher odds of diagnostic delays in 2010-2015 (OR 1.4) and 2016-2021 (OR 2.1) compared to pre-2010. Delayed diagnosis was not significantly associated with hospitalization rates, LOS, bypassing agent consumption, or units of packed red cells or plasma transfused. At a median follow-up of 3 years, 18 patients (47%) died at a median of 7 months (IQR 3-30). The most common causes of death included: infection (4), malignancy (3), bleeding (2), and thrombosis (2). Delayed diagnosis ≥7 days was associated with a non-significant trend towards worse 3-month OS (80% vs 91%) and 1-year OS (67% vs 87%, log-rank P=0.40; Figure 1). On Cox proportional hazards analysis, male sex (HR 4.0, 95% CI 1.5-10.5) and CCI 4-5 vs 0-3 (HR 7.0, 95% CI 1.5-32.3), but not delayed diagnosis (HR 1.5, 95% CI 0.6-3.9) were associated with increased hazard of death. Conclusion: In our large geographic catchment area, in the absence of an AHA reference centre, the median time to diagnosis (3.5 days) was markedly shorter than that reported in other single-centre studies (14-19 days), although delayed diagnosis ≥7 days was common. We did not identify statistically significant predictors of diagnostic delays, likely limited by small numbers. However, case-based analysis highlighted knowledge gaps as contributory factors, such as delayed ordering of aPTT in bleeding patients and delayed mixing study if aPTT is prolonged. Interestingly, time to diagnosis did not improve in recent years or with initial presentation to HTCs. Given the potential impact of delays on morbidity/mortality, further education is needed to expedite diagnosis in both HTCs and community settings.

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.

Acquired Hemophilia A after SARS-CoV-2 Infection: A Case Report and an Updated Systematic Review.

The role of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been implicated in the pathogenesis of acquired hemophilia A (AHA). The aim of this study is to report our case and to summarize clinical studies on de novo AHA after SARS-CoV-2 infection. We performed a systematic search on the association of SARS-CoV-2 with AHA in four medical databases up to 28 May 2023. Eligible studies should include de novo AHA patients who had SARS-CoV-2 infection before or concomitant with the diagnosis of AHA. Findings were synthesized narratively. In addition, we report the case of a 62-year-old female patient, who presented to our clinic with left flank pain 2 weeks after SARS-CoV-2 infection. Clinical investigations confirmed AHA and imaging studies revealed retroperitoneal bleeding. Her hemostasis was successfully secured with bypassing agents; however, despite immunosuppressive therapy, high inhibitor titer persisted. In the systematic review, we identified only 12 relevant cases with a questionable cause-effect relationship between SARS-CoV-2 infection and AHA. Based on the qualitative analysis of the relevant publications, current clinical evidence is insufficient to support a cause-effect relationship. The analysis of data from ongoing AHA registries can serve further evidence.

A case of acquired hemophilia A after pancreaticoduodenectomy for distal cholangiocarcinoma.

Acquired hemophilia A (AHA) is a rare disease that results from factor VIII inhibitors causing abnormal coagulation, and certain cases may develop after highly invasive surgery. The present case study reports on a 68-year-old male patient who developed AHA after undergoing a subtotal stomach-preserving pancreatoduodenectomy for distal cholangiocarcinoma. The patient experienced complications after surgery, requiring reoperation on postoperative day (PD) 5 due to rupture of the Braun's enterostomy. On PD 6, angiography was performed after bleeding was detected in the jejunal limb, but hemostasis occurred spontaneously during the examination. Bleeding was observed again on PD 8 and direct surgical ligation was performed. On PD 14, bleeding recurred in the jejunal limb and angiography was performed to embolize the periphery of the second jejunal artery. During the procedure, the prothrombin time was normal, but only the activated partial thromboplastin time was prolonged. A close examination of the coagulation system revealed a decrease in factor VIII levels and the presence of factor VIII inhibitors, resulting in the diagnosis of AHA. Administration of steroids was initiated on PD 15 and, in addition to daily blood transfusions, activated prothrombin complex concentrate was administered to achieve hemostasis. The patient was discharged from the intensive care unit on PD 36 but later developed an intractable labial fistula due to suture failure at the gastrojejunostomy site. As the use of factor VIII inhibitors continued despite the administration of steroids, cyclophosphamide (CPA) pulse therapy was added at PD 58. However, CPA was ineffective and the administration of rituximab was initiated on PD 98. After 12 courses of rituximab, the patient tested negative for factor VIII inhibitors on PD 219. On PD 289, labial fistula closure was performed with continuous replacement of factor VIII and the patient was discharged on PD 342.

Acquired hemophilia A following COVID-19 vaccine: a case report

BackgroundIn the literature, reported cases of Acquired hemophilia A (AHA) induced by COVID-19 vaccination occurred after Adenoviral Vector Deoxyribonucleic Acid (DNA)- and SARS-CoV-2 Messenger Ribonucleic acid (mRNA)-Based vaccines. Here, and to the best of our knowledge, we report the first case of AHA occurring after an inactivated Sinovac-coronavac COVID-19 vaccine.Case presentationA 69-year-old Tunisian male patient consulted for severe left leg pain limiting physical mobility due to a 5*6 cm large ecchymosis located at the left inner thigh, having spontaneously appeared 5 days prior consultation and without notion of trauma. The patient had no known personal medical history. He had received the second dose of CoronaVac-SinoVac vaccine 30 days prior to consultation. Further physical examination revealed the presence of two other ecchymoses: one at the inner face of the right forearm, starting at the wrist reaching the elbow and the other at the left flank of the abdomen. Diagnosis of AHA was based on clinical presentation and confirmed with prolonged a PTT, Factor VIII deficiency and the presence of an FVIII inhibitor. The patient was successfully treated with corticosteroids and low dose Rituximab.ConclusionClinicians should consider AHA in front of prolonged aPTT with or without spontaneous bleedings even after inactivated virus COVID-19.

EPH208 Acquired Hemophilia A (AHA) – Trends in Frequency and Treatment Patterns in Germany

The ultra-orphan acquired hemophilia A (AHA) is a bleeding disorder induced by autoantibodies against coagulation factor VIII. AHA causes potentially very severe trauma-induced or spontaneous bleeding. Awareness measurements by professional societies, but also pharmaceutical industry increased awareness of the disease in Germany. Here we examine trends in frequency of AHA diagnosis and treatment based on German hospital billing data.

ORIHIME II Study: Background, Treatment Status, and Outcomes of Patients with Acquired Hemophilia A with Low Activities of Daily Living Scores or Undergoing Rehabilitation - a Japanese Health Claims Database Analysis

Background: Acquired hemophilia A (AHA) is a rare disease in which autoantibodies (inhibitors) develop against blood coagulation factor (F)VIII, resulting in significantly reduced FVIII activity, with onset of bleeding symptoms such as sudden subcutaneous hemorrhage and muscular hemorrhage. The database-based study, 'Obtain Real-World Insights of Acquired Hemophilia A Patients in Japan' (the ORIHIME study) first reported data on rehabilitation and activities of daily living (ADL) scores for patients with AHA in Japan, which had previously been scarce (Ogawa et al. Blood 2021). The need to clarify the clinical experience of patients undergoing rehabilitation and patients with low ADL scores, who are considered to have relatively poor treatment and prognosis among AHA patients, has become apparent. This study evaluated the association between patient background, medication use, and outcomes among patients with AHA who underwent rehabilitation or had low ADL scores between April 1, 2008, and October 31, 2021. Methods: The study was conducted using the Medical Data Vision Co., Ltd. database. Patients with a diagnosis of AHA who were hospitalized and were administered immunosuppressants following admission were included. The primary endpoint examined the association of actual rehabilitation practices and total ADL score (measured using the Barthel Index) at discharge with patient background, medication use, and clinical outcomes. Total ADL score was calculated by adding together the scores for each of the following activities: eating, transferring (e.g. from bed to chair and back), ambulating, toilet use, bathing, mobility, stairs, dressing, and control of bladder and bowel movement. A score of 85 or higher corresponds with 'independence with minimal assistance' in the Barthel Index, therefore, in this analysis, participants are categorized by scores of <85 and ≥85 (Sulter et al. Stroke 1999). The risk of infection due to immunosuppressive therapy was a secondary endpoint. Results: Overall, 427 patients were included in this study. The mean (standard deviation [SD]) age of the patients was 76.3 (11.3) years, and 264 (61.8%) were male. A total of 249 patients underwent rehabilitation following admission to hospital. The median (range) time to the start of rehabilitation from the date of admission to hospital was 10.0 (1.0-133.0) days, and a high proportion of patients had a period of <2 weeks between admission to hospital and the start of rehabilitation (n=142/249 [57.0%]). Hemostatic agents used during rehabilitation were bypassing agents in 44 cases, FVIII in two cases, and tranexamic acid in 50 cases. Of the patients who received hemostatic agents, 36/44 (81.8%) patients who received bypassing agents, 2/2 (100.0%) patients who received FVIII, and 38/50 (76.0%) patients who received tranexamic acid started rehabilitation <2 weeks after the date of admission (Table 1). The ADL score at discharge was ≥85 points in 192 patients (45.0%) and <85 points in 186 patients (43.6%). Most patients with an ADL score at discharge of ≥85 (n=144/192 [75.0%]) were discharged from the hospital to home (attending outpatient visits at the same hospital), and for patients with ADL scores of <85 at discharge, the highest proportion of patients were transferred to other hospitals (n=92/186 [49.5%]; Table 2). Conclusions: Hemostatic agents may be necessary to start rehabilitation earlier. Post-discharge outcomes may be related to ADL scores at discharge. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluating the Impact of Recombinant Porcine Factor VIII Compared with Activated Recombinant Factor VII on Acquired Hemophilia A Outcomes

Objective: To compare mortality and readmission rates for patients with acquired hemophilia A (AHA) who were observed to use activated recombinant factor VII (rFVIIa) and/or recombinant porcine factor VIII (rpFVIII) during a hospital admission. Methods: The Medicare Limited Data Set was used for this analysis. Patients were selected into the study if they had a diagnosis of AHA and were treated with rpFVIII and/or rFVIIa between 1 January 2015 and 31 December 2019, among other criteria. Results: The probability of death or readmission with treatment within 12 months of a previous treatment was 40% lower in rpFVIII cases than rFVIIa cases (p = 0.047). Conclusion: Patients with AHA who received treatment with rpFVIII experienced significant declines in mortality and readmissions compared with patients treated with rFVIIa.

Laboratory coagulation tests and recombinant porcine factor VIII: A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by development of auto-antibodies to endogenous coagulation factor VIII (FVIII). Recombinant porcine factor VIII (rpFVIII) is currently licensed only for the management of bleeding in patients with AHA. Regular monitoring of rpFVIII is recommended to assess treatment effectiveness. This guideline from the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) examines the current publications in the area and aims to offer advice for the laboratory monitoring of rpFVIII in patients with AHA. A review of the current literature was undertaken followed by critical review by the authors. A validated one-stage clotting FVIII assay is recommended for the measurement and regular monitoring of rpFVIII. Assessment of cross-reacting rpFVIII inhibitors by one-stage porcine Bethesda assay should be performed as part of the initial diagnosis of AHA or prior to treatment with rpFVIII. Available data show that chromogenic FVIII assays underestimate rpFVIII and this should be considered if measurement of rpFVIII is required in patients receiving Emicizumab.

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.

Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature.

Since the approval of emicizumab,a bispecific, factor VIII-mimetic antibody, for use in persons with congenital haemophilia A in 2018, there have been increasing case reports and case series of off-label use of emicizumab in other bleeding disorders, including acquired haemophilia A (AHA) and von Willebrand disease (VWD). We conducted a scoping review on the use of emicizumab in AHA and VWD, focusing on the clinical presentation and outcomes. We conducted a comprehensive search in PubMed, EMBASE and Scopus up to July 15, 2021. The following criteria were applied to the studies identified in the initial search: patients had a diagnosis of AHA or VWD; and the study reported on the clinical outcome of emicizumab use. Seventeen studies were included in the final review for a total of 41 patients (33 AHA, eight type 3 VWD). The majority of AHA patients and all type 3 VWD patients were started on emicizumab for active/recurrent bleeds. The dosing regimen of emicizumab used varied significantly in AHA patients. All patients had a clinical response to emicizumab use. One AHA patient developed a stroke on emicizumab use in association with concomitant recombinant FVIIa use for surgery. Data on adverse events from emicizumab use were not specifically reported in 24.4% of patients (four AHA, six type 3 VWD). Based on published case reports and case series, emicizumab appears to be an effective haemostatic therapy for AHA and VWD. Larger confirmatory clinical trials are needed to confirm these findings.

Acquired Hemophilia a Relapse Is Related to Th2 Response, and Increased Expression of B-Cell Activating Factor (BAFF)

Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by the development of autoantibodies against the factor (F)VIII of coagulation with higher incidence in elderly individuals. The treatment includes immunosuppressive alternatives, and the majority of patients reach complete remission of symptoms. Although the role of immune T and B cells in the physiopathology of several autoimmune diseases is widely established, few studies have explored the T and B cells immune response pathway in AHA. This study aimed to determine the role of T cells through their cytokines expression and B cells through their expression of proteins that activate the B cell receptor (BCR), such as B-cell activating factor (BAFF) and A-proliferation inducing ligand (APRIL), in a longitudinal evaluation of patients with AHA.We included in this study 11 patients, 4 (36%) male, with the diagnosis of AHA, based on the occurrence of low FVIII levels (median FVIII level at the diagnosis was 0.10 IU/dL; range 0-18.8) and anti-FVIII inhibitor titer positive (≥0.6 Bethesda units (BU)/mL) (median inhibitor titer at the diagnosis was 60BU/mL; range 7.6-1000.2). The median age at the diagnosis was 59 years (range 9-75). Idiopathic AHA was evident in 72.7% of cases, while autoimmune diseases (18.2%), and pregnancy (9.1%) were the other underlying etiologies. All patients received immunosuppressive therapy (IST). Eight (72.7%) patients used corticosteroid (CS) plus cyclophosphamide (CP), one (9.1%) received only CP, one (9.1%) used CS plus rituximab and one (9.1%) received CS, CP and three cycles of rituximab. The response to IST was defined as complete remission (CR) with anti-FVIII < 0.6BU/mL and FVIII >50IU/dL, without further IST. Relapse was defined when anti-FVIII titer became >0.6BU/mL after previous remission. In this cohort, we observed 64% of sustained CR and 4(36%) AHA patients had at least one relapse, including two AHA patients considered idiopathic and two with other autoimmune diseases associated.Peripheral blood mononuclear cells (PBMC) were collected from all AHA patients at the diagnosis previously IST (baseline), when patient achieved CR, and at the occurrence of relapse. PBMCs were maintaining frozen in liquid nitrogen. Cells were taw and cultivated with RMPI-1640 medium in 7.5x10 5 cells/well in a 48-well plate. After 24h, cells were stimulated with a 1IU/well of a full-length recombinant FVIII concentrate (rFVIII) or phorbol myristate acetate (PMA) (1µM) with ionomycin (1µM). After 24h incubation, cells were analyzed by flow cytometry at BD FACSCalibur™.To determine T CD4 + cells' cytokine production profile, we stained T cells with anti-CD4, anti-interleukins (IL)-17a, IL-4, and IL-21, anti-TGF-b, and anti-TNF-a. We observed a significant increase of IL-17a production in the rFVIII-stimulated cells isolated at baseline from all patients compared to cells isolated from healthy individuals (P=0.01). However, IL-17a expression at baseline was not different between cells from patients who sustained CR to those who relapsed. Interestingly, when we compared cells isolated at baseline from patients that relapsed after different immunosuppressive attempts, we observed a significant difference for IL-4 (P=0.009), IL-21 (P=0.02), and TGF-b (P=0.01) expression in comparison to cells from healthy individuals. However, this difference was not observed in cells from sustained CR vs. cells from healthy individuals (figure 1). Thus, suggesting that all patients present Th17 response, while only patients that relapsed also showed Th2 response at the diagnosis.We also evaluated B cells' expression of BAFF and APRIL. The cells were stained with anti-CD19, BAFF, and APRIL. Only cells isolated at baseline from AHA relapsed patients after rFVIII stimulation or without any stimuli presented increased expression of BAFF (P=0.01 with rFVIII-stimulated and P=0.007 for unstimulated cells) when compared to PBMCs isolated from healthy individuals (figure 1). BAFF is responsible for controlling B-cell maturation and is associated with autoantibody production of different autoimmune conditions.Our finds reveal an increase in the Th17 response in patients with AHA at the diagnosis. However, the presence of Th2 response and increase of BAFF expression was observed only at the diagnosis of patients with recurrence of autoimmune response to FVIII, which suggests a potential biomarker for AHA evaluation. [Display omitted] DisclosuresOzelo: BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Other: Grant review.

Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

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.

Factor VIII Activity and Risk of Bleeding in Acquired Hemophilia a: Results from the Gth-AH 01/2010 Study

Background: Acquired hemophilia A (AHA) is a serious bleeding disorder characterized by the formation of autoantibodies against coagulation factor VIII (FVIII). The condition differs from congenital hemophilia A by its strikingly different bleeding phenotype. Also in contrast to congenital hemophilia, the patient's baseline FVIII activity does not seem to correlate with the risk of bleeding as demonstrated in previous registries. The objective of the current study was to reassess the effect of FVIII activity on the risk of bleeding in AHA.Methods: GTH-AH 01/2010 was a prospective non-interventional study of 102 patients with AHA performed in 29 centers in Germany and Austria. FVIII activity was measured at study baseline and weekly thereafter by local laboratories. FVIII activity was categorized into 5 clinically meaningful intervals: <1%, 1-<5%, 5-<20%, 20-<50%, and ≥50%. Bleeding events were assessed by treating physicians.Results: A total of 289 bleeds were recorded. 141 bleeds occurred after first diagnosis of AHA; 130 (92%) of those occurred in the first 12 weeks after diagnosis, during an observation period of 1069 patient-weeks. The estimated mean bleeding rate was 0.12 bleeds per patient-week, from weeks 1 to 12 after diagnosis of AHA. Bleeding rate strongly declined with increasing time after diagnosis. A multivariate regression model demonstrated significant effects of the current (weekly) FVIII activity on the weekly bleeding rate (figure), with a clear reduction in bleeding seen when FVIII activity recovered to 20% or higher. Achieving partial remission of AHA (FVIII ≥50%) virtually eliminated the risk of bleeding. A good WHO performance status was also associated with a significantly lower risk of bleeding. Other baseline characteristics, including underlying disorder, concomitant coronary artery disease, heart or renal failure or diabetes mellitus did not influence bleeding rate in the multivariate model. Patients with an average FVIII activity of <1% during weeks 1 to 4 received significantly higher cumulative dose of recombinant factor VIIa (rFVIIa) during this time, potentially explaining that the bleeding rate in those patients was not higher than in patients with a FVIII activity of 1-<5% or 5-<20%.Conclusion: This study is the first to systematically assess the risk of bleeding during the course of AHA. About 50% of the bleeds in AHA occur after first diagnosis, with a rate of about 0.12 bleeds per patient-week in the first 12 weeks. The bleeding rate is influenced by the current FVIII activity as assessed weekly during this study. Patients with FVIII <1% received more rFVIIa, potentially reducing their bleeding rate as compared to other patients. These results will help to define future strategies for prophylaxis of bleeding in AHA. [Display omitted] DisclosuresHolstein:Novo Nordisk: Consultancy, Research Funding; Shire: Research Funding. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Dobbelstein:Novo Nordisk: Research Funding; Shire: Research Funding. Spannagl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Heinz:Novo Nordisk: Research Funding; Shire: Research Funding. Scholz:Novo Nordisk: Research Funding; Shire: Research Funding. Eichler:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding. Huth-Kühne:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Klamroth:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Tiede:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding.

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.