Search

Acquired hemophilia A (AHA) is an acquired bleeding disorder caused by neutralizing antibodies (inhibitors) against Coagulation Factor VIII (FVIII:C), causing sudden hemorrhagic symptoms (i.e., subcutaneous bleeding, intramuscular bleeding, and hematuria). Herein, this study is aimed at presenting a case of AHA diagnosed based on hematuria and reviewing patients who were diagnosed with AHA due to hematuria. A 67‐year‐old woman was referred to Atsugi City Hospital with painless gross hematuria that began 4 weeks before presentation. Contrast‐enhanced computed tomography (eCT) revealed an approximately 2 cm mass in the right renal pelvis, and the patient's activated partial thromboplastin time (APTT) was elevated (61.4 s). The day after the endoscopic biopsy, the patient was in shock due to a large retroperitoneal hematoma. Although her condition stabilized after intravenous radioembolization, she underwent emergency surgeries several times because of rebleeding within the next 3 weeks. At that time, APTT was more prolonged at 106.4 s, and the FVIII:C level was 2%. Mixing tests showed an upwardly convex curve after 2‐h incubation, indicating the presence of an inhibitor. Factor VIII inhibitor titer was ≥5.1 Bethesda unit (BU)/mL. A combined product of Plasma‐Derived Factors VIIa and X (pd‐FVIIa/FX), as second‐line hemostatic therapy, as well as cyclophosphamide (CYP), were administered after Recombinant Activated Factor VIIa (rFVIIa) had been ineffective. Following this, the Factor VIII inhibitor titer was undetectable, FVIII:C levels were restored, and APTT decreased to within the normal range. Gross hematuria was significantly alleviated. However, the patient died of cytomegalovirus and fungal infections due to prolonged immunosuppressive therapy. Although AHA diagnosed based on hematuria may have a better prognosis than others, there have been occasional cases with severe outcomes. APTT, detected upon initial hematological testing in patients with hematuria, may be a potential indicator of an existing AHA. [ABSTRACT FROM AUTHOR]

Acquired hemophilia is a rare but potentially life-threatening disorder characterized by the development of acquired hemophilia A, leading to bleeding complications. Spontaneous, mild-to-life-threatening bleeding in typically elderly individuals without a personal or family history of bleeding is the hallmark of acquired hemophilia A (AHA), a rare autoimmune bleeding illness caused by the formation of auto-antibodies against endogenous factor VIII (FVIII). This hallmark represents our present case, with no obvious history related to the bleeding issue. Prompt detection and treatment of bleeding are essential for the best outcomes. We present a case of a 66-year-old male who had acute-onset severe abdominal pain and with constipation for five days, associated with nausea and loss of appetite. On physical examination, the patient appeared pale, and abdominal examination revealed diffuse tenderness with guarding. Initial evaluation revealed tachycardia and hypotension. Initial abdomen X-rays revealed features suggestive of small bowel obstruction. The patient was stabilized with intravenous fluids, referred to a surgical team, and admitted to the acute bed in the general ward for further management. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of FVIII. Several factors have been associated with the activation of the auto-immunity towards FVIII. Emerging evidence implicates CD4+ T cell activation in mediating this autoimmune response, with their involvement like that observed in congenital hemophilia A. Several genes such as HLA II DRB*16, DQB1*0502, and CTLA-4 + 49 are responsible for the pathogenesis of AHA. Epigenetic modifications and mainly long-coding RNAS (lncRNAs) are potentially contributing to the pathogenesis of AHA. The treatment approach of AHA includes the management of acute bleeding events and the administration of immunosuppressive medications. This review aimed to summarize the published data on the genetics and epigenetics of AHA. The severity and the mortality of this disease are creating an emerging need for further research in the field of the genetics and epigenetics of acquired hemorrhagic disorder.

Introduction Acquired hemophilia is a rare disease characterized by the presence of neutralizing autoantibodies against hemostasis factors, most often factor VII. However, a few cases of anti-factor VII (FVII) autoantibodies have been reported in the literature. We report a case in this regard. Case report A 28-year-old woman with no family or personal history presented with a severe hemorrhagic syndrome made of very abundant metrorrhagia with multiple compressive cervical hematomas, associated with pulmonary embolism and thrombosis. of the right external iliac vein. On the biological assessment, the patient presented with an undetectable PT with a factor VII titer less than 6%. The hemorrhagic syndrome was aggravated by infusions of activated factor VII (FVIIa) with the appearance of hemoptysis and hematomas in all four limbs. Etiological assessment concluded the presence of anti-factor VII autoantibodies as well as circulating lupus anticoagulant. Other antiphospholipid syndrome (APS) antibodies as well as antibodies against other hemostasis factors were absent. A treatment combining corticosteroid therapy (1mg per kg per day of prednisone) and Mycophenolate mofetil (MMF) (3g) was initiated. Faced with the persistence of the hemorrhagic syndrome, rituximab was administered according to the rheumatological protocol (1g on D1 and 1g on D15). Metrorrhagia improved initially but recurred with the resumption of menstruation with a drop in hemoglobin from 9 to 7 g/dl. Plasmapheresis sessions were attempted but thromboses on the catheters occurred each time. Immunoglobulin (IVIg) courses were administered. No anticoagulant was administered. TP increased to 23%. Levels of neutralizing antibodies fell from 512 to 2 IBU at the last follow-up at five months from the bleeding event. The circulating lupus anticoagulant was present on the follow-up test after 12 weeks, thus confirming the diagnosis of APS. Conclusion Our patient presents an extremely rare case of acquired haemophilia. The combination of corticosteroid therapy, conventional and biological immunosupressives, IVIG and plasmapheresis saved the patient. In the absence of consensus on the treatment, it remains adapted according to the severity of the haemorrhagic syndrome and the associated comorbidities.

Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5–2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL−1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. French Ministry of Health. ClinicalTrials.gov number: NCT01808911. • Cyclophosphamide and rituximab have similar efficacy and safety in AHA. • Cyclophosphamide seems preferable in patients with low FVIII and high inhibitor titer. • If immunosuppressant is added to steroids, cyclophosphamide should be preferred. • It is crucial to reduce total steroid intake in AHA as much as possible. • Cumulative dose and duration of steroid are correlated with the risk of serious sepsis. [ABSTRACT FROM AUTHOR]

Key clinical message: Acquired hemophilia A is a rare bleeding disorder. Rapid diagnosis with prolonged aPTT and low FVIII, and immediate use of bypassing agents and steroids are crucial for better outcomes, highlighting the importance of early recognition and management. [ABSTRACT FROM AUTHOR]

Key clinical message Acquired hemophilia A is a rare bleeding disorder. Rapid diagnosis with prolonged aPTT and low FVIII, and immediate use of bypassing agents and steroids are crucial for better outcomes, highlighting the importance of early recognition and management.

There is no established method for differentiating acquired hemophilia A (AHA) from lupus anticoagulant (LA) positivity because both present with prolonged activated partial thromboplastin time. We compared various parameters of rotational thromboelastometry (ROTEM), thrombin generation assay (TGA), and clot waveform analysis (CWA) in patients with AHA (n = 10) and LA (n = 44). Compared with AHA, possible (n = 12) and definite (n = 32) LA showed significantly shorter clotting time (CT) in NATEM mode of ROTEM (> 3600 vs. 501/533). In TGA, peak height was significantly lower in AHA (16 vs. 242/174 nM). In CWA, CT was significantly longer (81 vs. 36/41 s) and Ad|min1| was lower (2.1 vs. 8.7/6.7) in AHA. Notably, CT by NATEM and peak height in TGA completely discriminated between AHA and LA, whereas Ad|min1| did not discriminate between them in 4 cases of AHA and 1 of LA. Comparison of 3 patients with both AHA and LA against a patient with only LA and markedly low FVIII activity (3.5%) showed that both CT by NATEM and peak height of TGA precisely classified the former 3 cases as AHA and the latter 1 case as LA, whereas Ad|min1| classified all 4 cases as AHA. ROTEM and TGA can comparably distinguish between AHA and LA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Acquired factor VIII inhibitors can be a rare cause of extensive intramuscular bleeding requiring fasciotomy. The subsequent postoperative period requires close monitoring due to high risk of fatal blood loss. Acquired factor VIII inhibitors are a rare cause of often extensive bleeding and subsequently large hematomas. This disorder's overall mortality can reach 38%, largely due to immunosuppression and subsequent infections or an underlying cause such as malignancy. The patient in this case study presented with a hematoma and extensive ecchymosis of the hand and forearm, which continued to progress, precipitating compartment syndrome of the hand and forearm and ultimately requiring fasciotomy. The combination of factors led to significant blood loss in the postoperative period requiring major fluid resuscitation and intensive care unit (ICU) level care. Due to this disorder's rarity and overall mortality, we present this case report with a literature review for management of acquired hemophilia in the setting of urgent fasciotomy. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is a coagulation disorder related to the factor VIII inhibitors, which might cause intractable bleeding of gastrointestinal tracts. However, its scarcity makes it difficult to recognize AHA as a pitfall of endoscopic hemostasis failure. An 81-year-old female with a history of endoscopic treatment for colon polyps visited a local hospital with chief compliments of bloody stool and severe anemia. During several examinations for the bleeding origin, esophagogastroduodenoscopy depicted a 5 mm-sized hemorrhagic angioectasia of the duodenum, followed by treatment with argon plasma coagulation. However, hemostasis was not achieved by multiple sessions of endoscopic hemostasis and transcatheter arterial embolization, so blood transfusion was repeatedly done and she was transferred to our hospital. Laboratory data showed severe anemia with coagulation disorder. Based on the results of von Willebrand factor activity, factor VIII activity and factor VIII inhibitor, we diagnosed AHA as a comorbidity. Endoscopic hemostasis was confirmed only after improvement of APTT level and negative for the factor VIII inhibitor by hemostatic bypass treatment with recombinant active factor VII and immunosuppressive therapy with prednisolone and cyclophosphamide. In case of refractory bleeding of gastrointestinal tract, we should suspect of a comorbidity of coagulation disorder like AHA. [ABSTRACT FROM AUTHOR]

Key Clinical Message Acquired factor VIII inhibitors can be a rare cause of extensive intramuscular bleeding requiring fasciotomy. The subsequent postoperative period requires close monitoring due to high risk of fatal blood loss. Abstract Acquired factor VIII inhibitors are a rare cause of often extensive bleeding and subsequently large hematomas. This disorder's overall mortality can reach 38%, largely due to immunosuppression and subsequent infections or an underlying cause such as malignancy. The patient in this case study presented with a hematoma and extensive ecchymosis of the hand and forearm, which continued to progress, precipitating compartment syndrome of the hand and forearm and ultimately requiring fasciotomy. The combination of factors led to significant blood loss in the postoperative period requiring major fluid resuscitation and intensive care unit (ICU) level care. Due to this disorder's rarity and overall mortality, we present this case report with a literature review for management of acquired hemophilia in the setting of urgent fasciotomy.

Qi Tang, Jiafen Liao, Xi Xie Department of Rheumatology and Immunology, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Xi Xie, Department of Rheumatology and Immunology, the Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China, Tel/Fax +86 0731 8529 5255, Email Hsixie1997@csu.edu.cnAbstract: To strengthen the understanding of rheumatic diseases (RDs) as the most common underlying conditions associated with acquired hemophilia (AH), a potentially fatal bleeding condition due to the development of autoantibodies or inhibitors to coagulation factor VIII, and rarely to factor IX, here we presented two cases of RDs associated AH to elucidate the disease progression, treatment, and prognosis. The presented 2 cases showed good responses to glucocorticoid (GC) and immunosuppressive agents. And then, a case-based systematic review was conducted to better understand the clinically practiced diagnosis and treatment of RDs associated AH. A total of 14 articles were included in the final literature review. All the identified 14 patients with underlying RDs and AH presented with bleeding symptoms, increased APTT, decreased FVIII activity, and positive FVIII inhibitors. Twelve of the 14 patients (85.7%) started an eradication of autoantibodies treatment with GC and immunosuppressive agents. Among which six patients achieved partial or complete remission, and four patients (28.6%) switched to Rituximab and responded well. Nine of the 14 patients received hemostasis therapy, including recombinant human FVIIa (rFVIIa). Two patients (14.3%) died due to mass bleeding and key organ failure. AH should be highly suspected in patients with RDs presenting spontaneous mucocutaneous or internal bleeding and an isolated prolonged APTT. Given the high morbidity of AH, it is important to facilitate efficient and proper management.Keywords: acquired hemophilia, systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, connective tissue disease

To evaluate the financial impact of utilizing rpFVIII or rFVIIa during a hospital admission for the diagnosis of acquired hemophilia A (AHA) by reviewing the margin between the cost to the hospital for providing care and the amount the hospital is reimbursed by the Centers for Medicare & Medicaid Services (CMS) in the US. Data source was the Medicare Limited Data Set, which contains claims for hospitalizations, charges, and amounts reimbursed by CMS. Study patients were hospitalized with AHA and treated with rpFVIII and/or rFVIIa between 1/1/2015 and 12/31/2019. CMS Fiscal Year 2020 Impact Files, with hospital-level cost-to-charge ratios (CCRs), were used to estimate hospital costs. Sensitivity analyses were conducted to estimate margins at different CCRs. Hospital margins were, on average, positive with use of either rpFVIII or rFVIIa (rpFVIII: $51,548.89; rFVIIa: $35,943.80). Sensitivity analysis results suggest that the use of rpFVIII is similiar, compared with rFVIIa for a large majority of hospitals. While there may be higher reimbursement for rpFVIII hospitalizations, this analysis suggests that the use of rpFVIII, compared to rFVIIa, may have no impact on hospital finances for the majority of hospitals, despite rpFVIII's higher per unit cost. [ABSTRACT FROM AUTHOR]

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorrhagic disease occurring in several underlying conditions. Drug‐associated AHA (D‐AHA) is poorly addressed nowadays. Aim: This work aims to identify and characterize which drugs are associated with AHA using the WHO global database of reported potential effects of medicinal products (VigiBase). Methods: First, we realized a disproportionality analysis using the information component (IC) to identify D‐AHA in VigiBase. IC compares observed‐ and expected‐values in order to find associations between drugs and adverse drug reactions (ADRs) using disproportionate Bayesian reporting. IC025 is the lower end of a 95% credibility interval for the IC. Then, we collected cases of drugs significantly associated with AHA from July 2004 to November 2021. Results: 14 drugs with IC025 > 0 were identified representing a total of 185 cases. D‐AHA occurred more frequently in men (59%) than women (41%). The median (min–max) age at onset was 75 years (8–98). The median [Q1–Q3] time to onset of D‐AHA from the start of the suspected drug was 30 days [9.5–73.75] and 10% of cases resulted in a fatality. The drugs associated with the highest IC025 (IC025 > 2) were Clopidogrel, Alemtuzumab, Omalizumab. This study retrieved for the first time three usually used drugs (3/14) that exhibit a significant pharmacovigilance signal for D‐AHA. Conclusion: This worldwide pharmaco‐epidemiologic study updates the list of the drugs associated with AHA. The clinician should be aware of these possible severe ADR, which might require larger epidemiological and pathophysiologic studies. [ABSTRACT FROM AUTHOR]

Introduction: Immunosuppressive therapy (IST) for acquired hemophilia A (AHA) results in remission within days to months in 60% to 80% of patients. However, little is known regarding the predictors of response. Aim: This study aimed to identify the factors that influence response to treatment. Methods: The data of 42 patients with AHA from three hospitals were retrospectively analyzed. Results: All 42 AHA patients received IST; complete treatment data were available for 34 patients. The response rate was 60% among the 5/34 (14.7%) patients who received steroids alone, 70.8% among the 24/34 (70.6%) patients who received steroids plus cyclophosphamide, and 80% among the 5/34 (14.7%) patients who received steroids plus cyclophosphamide and rituximab. Overall, 29/34 (85.3%) patients achieved CR; 4/34 (13.8%) of them relapsed after a median time of 410 (21-1279) days. Adverse events occurred in 14/34 (41.2%) patients: 13/34 (38.2%) had infections and 1/34 (2.9%) developed pancytopenia. In univariate and multivariate Cox regression analyses, FVIII inhibitor titer ≥20 BU/mL was the only significant prognostic factor affecting time to CR. No variable had significant effect on OS. Conclusion: FVIII inhibitory antibody titer ≥20 BU/mL appears to be an important predictor of time to complete response in patients with acquired hemophilia A treated with immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Objective: Activated prothrombin complex concentrate (aPCC) is a bypassing agent indicated to treat bleeds in patients with acquired hemophilia A (AHA). Nevertheless, its efficacy and safety in the real‐world setting have not often been addressed. Methods: We report the experience of Spanish reference centers for coagulation disorders and from acquired hemophilia Spanish Registry (AHASR) from August 2012 to February 2021. Follow‐up period of 30 days after aPCC withdrawal. Results: Thirty patients with a median age of 70 years old, suffering from 51 bleeds treated with aPCC were finally evaluated. As first‐line treatment, aPCC stopped bleeding in 13 of 14 (92.9%) cases. aPCC as the second line after recombinant factor VIIa failure, stopped bleeding in all cases. In 17 patients, aPCC was used far from initial bleed control as prophylaxis of rebleeding with 94% effectiveness. No thromboembolic episodes were communicated. One patient developed hypofibrinogenemia, which did not prevent aPCC from halting bleeding. No other serious adverse events possibly or probably associated with aPCC were reported. Conclusions: This data support aPCC as hemostatic treatment in AHA with high effectiveness and excellent safety profile in acute bleeds and as extended use to prevent rebleedings, even in aging people with high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Hemostasis reflects a homeostatic mechanism that aims to balance out pro-coagulant and anti-coagulant forces to maintain blood flow within the circulation. Simplistically, a relative excess of procoagulant forces can lead to thrombosis, and a relative excess of anticoagulant forces can lead to bleeding. There are a wide variety of congenital disorders associated with bleeding or thrombosis. In addition, there exist a vast array of autoimmune diseases that can also lead to either bleeding or thrombosis. For example, autoantibodies generated against clotting factors can lead to bleeding, of which acquired hemophilia A is the most common. As another example, autoimmune-mediated antibodies against phospholipids can generate a prothrombotic milieu in a condition known as antiphospholipid (antibody) syndrome (APS). Moreover, there exist various autoimmunity promoting environments that can lead to a variety of antibodies that affect hemostasis. Coronavirus disease 2019 (COVID-19) represents perhaps the contemporary example of such a state, with potential development of a kaleidoscope of such antibodies that primarily drive thrombosis, but may also lead to bleeding on rarer occasions. We provide here a narrative review to discuss the interaction between various autoimmune diseases and hemostasis. [ABSTRACT FROM AUTHOR]

Patients with acquired or congenital hemophilia are at risk for Acute Compartment Syndrome (ACS) and pose a diagnostic challenge and a treatment risk with post-fasciotomy hemostasis of critical importance. We present the case of a woman with ACS of the forearm in the setting of newly diagnosed acquired hemophilia A. [ABSTRACT FROM AUTHOR]

Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies to factor VIII (FVIII). The goals of treatment are two-fold, namely immunosuppressive therapy (IST) to eradicate the inhibitor and hemostatic management to control bleeding. Emicizumab, a bispecific antibody that acts as a factor VIIIa (FVIIIa) mimetic, has seen growing use in AHA following its approval for congenital hemophilia A (cHA). This review provides an overview of the epidemiology, pathophysiology, diagnosis, and treatment of AHA. Registry, trial, and case series data are assimilated and summarized with an emphasis on a standardized approach that integrates the use of emicizumab. With recent registry data suggesting the need to focus on immunosuppression-related mortality in AHA, we provide treatment recommendations in an algorithmic format that have become the standard of care at our institution. These recommendations are intended to minimize hemostatic product usage and potential toxicity related to IST, while reducing morbidity and re-hospitalization rates for bleeding. The proposed treatment algorithm, which includes key interventions by phase of therapy, can be readily implemented at centers that have rapid access to plasma FVIII activity using a one-stage assay. A case is presented to illustrate the proposed diagnostic and management considerations., (Copyright © 2024. Published by Elsevier Inc.)

Background: Factor (F)VIII inhibitors are measured using labor- and resource-expensive Nijmegen or Bethesda assays, which lack sensitivity for low-titer inhibitors and show high variations in quality surveys, mainly because of manual assay procedures., Objectives: The goal of this study was the development of a fast and fully automated FVIII inhibitor assay by using recombinant (r)FVIII as substrate and dedicated equipment for execution of the test., Methods: A new rapid, fully automated, FVIII inhibitor assay is presented, the core of which is use of full-length recombinant FVIII (rFVIII; Kovaltry, Bayer) as inhibitor substrate instead of plasma FVIII, resulting in rapid binding of inhibitors to rFVIII due to absence of von Willebrand factor. Dramatic shortening of incubation time facilitated full automation on an analyzer capable of 3 subsequent sample dilution steps and 3 reagent additions. Equal volume mixtures of sample and rFVIII (1.0 U/mL) were incubated for 10 minutes at 37 °C, whereafter remaining FVIII activity was analyzed with a kinetic chromogenic assay, allowing inhibitor activity calculation without preceding FVIII activity calibration, using a Ceveron s100 analyzer (Technoclone)., Results: Mean titer in 60 nonhemophiliacs was 0.0 BU/mL (SD, 0.1), yielding a limit of blank of 0.1 BU/mL and lower limit of quantification of 0.2 BU/mL. Analyses were performed with the new method and a Nijmegen assay in 28 inhibitor-positive clinical samples, 14 containing emicizumab and 14 without. Correlation coefficient in emicizumab-free type I inhibitor samples was 1.0. Emicizumab dependency of the method was excluded in spiking experiments with inhibitor-positive samples. Reproducibility was tested by analyzing 7 samples in 3 laboratories for 5 days, twice daily; coefficients of variation of all samples were <15%., Conclusion: We present development data of a sensitive and specific rapid, automated FVIII inhibitor assay generating results within 20 minutes that is less resource-intensive than standard assays with potential to improve assay variability., Competing Interests: Declaration of competing interests N.B.B. is an employee of Technoclone. P.J.C.v.V. reports consultancy fees from Technoclone. G.W.M. reports consultancy fees from Technoclone. All other authors report no conflicts of interest relevant to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: Lupus anticoagulant (LAC) belongs to a heterogeneous group of antibodies directed against negatively charged phospholipid-binding proteins, inhibiting phospholipid-dependent reactions. We assessed the frequency, etiological background, clinical and biological expression as well as the appropriate management and outcome of LAC in a pediatric population.

Introduction: Factor XI deficiency or hemophilia C is a very rare coagulation factor deficiency, with a global incidence of 1 in 1 million. Although it is an under-recognized entity, it can cause significant bleeding, resulting in life-threatening complications. Materials and Methods: Coagulation parameters were analyzed using a Sysmex CS-2400 coagulation analyzer. Factor XI levels were detected using Factor XI deficient plasma from Siemens. Activated Partial Thromboplastin Time (APTT) testing was performed using Actin FSL from Siemens. Results: Here, we report the two cases of Factor XI deficiency, one genetic and the other a very rare acquired deficiency due to sepsis, detected during the workup of an isolated APTT prolongation. Conclusion: Factor XI deficiency is a rare bleeding disorder that presents as prolonged isolated APTT. Careful clinical evaluation and complete coagulation workup are necessary for the efficient management of patients, which can prevent life-threatening events.

Background: The mixing test of activated partial thromboplastin time (APTT) is used for differentiating factor deficiency (FD), lupus anticoagulant (LAC), and acquired hemophilia A (AHA). However, the interpretation of the mixing test is not fully standardized. Objectives: The aim of this study was to determine whether the weighted harmonic mean predicts the APTT in mixture of a mixing test samples and is useful for the differentiation of FD, LAC, and AHA. Patients/methods: We examined 27 FD, 26 LAC, and 18 AHA samples. Harmonic means of APTT were calculated from the clotting times with and without 2 h incubation. We defined the index of harmonic mean (IHM) as the ratio of the actual APTT to the predicted APTT calculated by the harmonic mean. We defined IHM of the measured immediate after mixing samples and of delayed (after 2 h of incubation) measured samples as IHMi and IHMd respectively. Results: Actual APTT and predicted APTT were correlated in the FD group. Both IHMi and IHMd in the FD group were equal or lower than 1.02, whereas those in the LAC group were higher than 1.02. In the AHA group, the IHMd was higher than 1.02, whereas half of the IHMi were equal or lower than 1.02. Time dependent inhibition evaluated by IHMd/IHMi was not observed in the LAC group, whereas it was observed in 77% of participants in the AHA group. Conclusions: The harmonic mean was potentially useful in predicting APTT in the mixing test, and the IHM calculated from the predicted APTT had differentiation potency for FD and LAC, and for FD and AHA. IHM was also available for partial differentiation of LAC to AHA.

Acquired hemophilia (AH) is a potentially life-threatening hemorrhagic disorder. We report the second confirmed case of COVID-19-associated AH in a 45-year-old female which, unfortunately, expired as her treatment failed. She presented to the emergency department with abnormal bleeding and spontaneous hemoptysis about ten days after a removal surgery of her epiglottis tumor. Aggregation tests, such as partial thromboplastin time (PTT), are recommended in patients with COVID-19 infection that have bleeding episodes.

Nabil Belfeki, Sarra Hamrouni, Alessio Strazzulla, Sylvain Diamantis Department of Internal Medicine, Groupe Hospitalier Sud-Ile de France, Melun, 77000, FranceCorrespondence: Nabil BelfekiDepartment of Internal Medicine, Groupe Hospitalier Sud Ile de France, 77000, Melun Tel +33 1 81 74 17 04Fax +33 1 81 74 18 12Email belfeki.nabil@gmail.comAbstract: Acquired hemophilia is a rare coagulopathy with hemorrhage into the skin, muscle, or soft tissues and mucous membranes and caused by inhibitor antibodies, mainly against FVIII. We report a case of acquired hemophilia presenting with diffuse cutaneous hemorrhage and hemothorax. The patient was found to have acquired an FVIII inhibitor and a high titer of anti β 2 glycoprotein 1 IgG and IgM, and anticardiolipin IgM in the context of IgA kappa-type monoclonal gammopathy. He received 3 injections of recombinant factor VII (rFVIIa) and blood transfusion. He was started on steroids and oral cyclophosphamide for 6 weeks. Thromboprophylaxis with aspirin at 100 mg/day was started 3 months after discharge. Antiphospholipid antibodies remained positive after 3 months as well as prolonged aPTT, factor VIII raised at 100%, and the inhibitor was not detected. The association between acquired hemophilia and antiphospholipid antibodies is rare and its distinction is mandatory because clinical presentation ranges from massive hemorrhage to thrombosis.Keywords: acquired hemophilia, factor VIII deficiency, antiphospholipid antibodies, hemorrhage, treatment

Acquired Hemophilia A (AHA) is a rare entity, resulting from the production of autoantibodies against Factor VIII of the coagulation cascade. These autoantibodies may develop in response to autoimmune conditions, drugs, neoplastic diseases, and pregnancy. Diagnosis involves clinical presentation, mucocutaneous or intramuscular bleeding, and laboratory findings, such as prolonged activated partial thromboplastin time, decreased levels of Factor VIII, and the presence of Factor VIII autoantibodies. The etiology is diverse, with a variety of underlying culprits. Malignancy-associated AHA has been associated with approximately 15% of cases. Urothelial malignancy-mediated AHA is exceedingly rare, with only two previously published reports. The management of AHA includes stabilization and control of bleeding via the use of hemostatic agents, and elimination of the inhibitor with immunosuppressive therapy. Here, we report a case of AHA secondary to urothelial malignancy and review the pathobiology and pathogenesis of Hemophilia A and AHA.

Abstract This case report highlights the challenges in controlling bleeding and correcting coagulation tests through the use of bypassing agents in patients with FV inhibitors.

Copyright of Wiener Medizinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Acquired hemophilia is a rare coagulation disorder that is not diagnosed by routine clinical laboratory tests. Thus, many perioperative or acute emergent bleeding complications remain unclear until the underlying cause is specified. We report two cases of postoperative bleeding in the context of dental surgery in which subsequent acquired hemophilia could be confirmed and present a short review from the literature. [ABSTRACT FROM AUTHOR]

Acquired coagulation factor deficiencies are caused by inhibitory autoantibodies which are usually directed against clotting factor VIII (FVIII), causing acquired hemophilia A (AHA). Clotting factor inhibitors usually cause abnormalities in screening coagulation tests (activated partial thromboplastin time [aPTT] and/or prothrombin time [PT]). Other coagulation factor inhibitors are much rarer, particularly inhibitors to factor XI (FXI). We present the case of an 82-year-old woman referred to a hematological center for isolated aPTT prolongation in pre-surgery screening tests. No bleeding symptoms were reported either at admission or in the patient's medical history. One stage coagulation factor assays revealed lower factor VIII, IX, XI, XII levels. The Nijmegen modification of the Bethesda assay showed the presence of an inhibitor to factor XI (22.1 BU/mL). No autoantibodies to coagulation factors VIII, IX and XII were found: inhibitor titers were all below 0.6 BU/mL. Acquired hemophilia C was diagnosed (the presence of autoantibodies to clotting factor XI). [ABSTRACT FROM AUTHOR]

Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.

Abstract Background Bleeding is the most common complication of oral anticoagulants, due to inadequate dosing. Case presentation This report describes the clinical course of a patient who developed severe bleeding under therapy with phenprocoumon, despite an INR in the lower therapeutic range. Strikingly, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors. Finally, sequencing part of the factor IX gene including nucleotide position c.110 revealed a hemizygous factor IX mutation c.110C > T p (Ala37Val). Conclusions In rare cases, missense mutations in factor IX propeptide are associated with severe bleeding complications. The substitution of alanin at position 37 to either valin or threonin (Ala37Val or Ala37Thr) leads to hypersensitivity to vitamin k antagonists.

Introduction: Factor XI deficiency or hemophilia C is a very rare coagulation factor deficiency, with a global incidence of 1 in 1 million. Although it is an under-recognized entity, it can cause significant bleeding, resulting in life-threatening complications. Materials and Methods: Coagulation parameters were analyzed using a Sysmex CS-2400 coagulation analyzer. Factor XI levels were detected using Factor XI deficient plasma from Siemens. Activated Partial Thromboplastin Time (APTT) testing was performed using Actin FSL from Siemens. Results: Here, we report the two cases of Factor XI deficiency, one genetic and the other a very rare acquired deficiency due to sepsis, detected during the workup of an isolated APTT prolongation. Conclusion: Factor XI deficiency is a rare bleeding disorder that presents as prolonged isolated APTT. Careful clinical evaluation and complete coagulation workup are necessary for the efficient management of patients, which can prevent life-threatening events. [ABSTRACT FROM AUTHOR]

Madhvi Rajpurkar,1 Stacy E Croteau,2 Lisa Boggio,3 David L Cooper4 1Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan/Wayne State University, Detroit, MI, USA; 2Department of Pediatrics, Boston Children’s Hospital/Harvard Medical School, Boston, MA, USA; 3Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA; 4Clinical Development and Medical Affairs – Biopharm, Novo Nordisk Inc., Plainsboro, NJ, USACorrespondence: Madhvi RajpurkarCarman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd, Detroit, MI 48201, USATel +1 313 745 5515Fax +1 313 745 5237Email mrajpurk@med.wayne.eduPurpose: Recombinant activated factor VII (rFVIIa; NovoSeven® RT; Novo Nordisk A/S, Bagsvaerd, Denmark) is approved in the United States for the treatment of bleeding and perioperative management in congenital hemophilia with inhibitors (CHwI), acquired hemophilia (AH), congenital factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia (GT) with refractoriness to platelets. The aim of the current analysis was to review clinical trials and registries pre- and post-licensure for each indication to establish the estimated rate of thrombosis and then to establish the association of all reported thrombotic events (TEs) with certain risk factors listed for many years in the prescribing information (PI).Patients and methods: A retrospective safety assessment of both clinical trials and registries used to support licensure and postmarketing surveillance was performed. The rate of thrombosis was calculated in the 4 indicated disorders and an assessment of TE risk factors was conducted through a review of all narratives within those indications in the safety database.Results: In clinical trials and registries used to support licensure and in postmarketing surveillance, the overall rate of thrombosis was 0.17% of 12,288 bleeding and surgical episodes. The specific risk by indication was 0.11% for CHwI, 0.82% for FVII deficiency, 0.19% for GT, and 1.77% for AH. The most common associated risk factor—“elderly” (29%), defined in the PI as age ≥65 years—was particularly prevalent in patients with AH. TE was also frequently reported with concomitant cardiac or vascular disease (18%) and use of activated prothrombin complex concentrates (18%).Conclusion: Data show that the rate of TEs within the 4 licensed indications is low, as was originally described in the US PI from 1999 to 2009. It has remained stable over time during postapproval surveillance in multiple US and global registries with active surveillance for safety information across the 4 approved indications.Keywords: postmarketing surveillance, acquired hemophilia, congenital hemophilia with inhibitors, congenital factor VII deficiency, Glanzmann’s thrombasthenia

Objective: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. Method: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. Results: The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long‐term follow‐up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. Conclusion: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non‐specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management. [ABSTRACT FROM AUTHOR]

Acquired Hemophilia A (AHA) is a rare entity, resulting from the production of autoantibodies against Factor VIII of the coagulation cascade. These autoantibodies may develop in response to autoimmune conditions, drugs, neoplastic diseases, and pregnancy. Diagnosis involves clinical presentation, mucocutaneous or intramuscular bleeding, and laboratory findings, such as prolonged activated partial thromboplastin time, decreased levels of Factor VIII, and the presence of Factor VIII autoantibodies. The etiology is diverse, with a variety of underlying culprits. Malignancy-associated AHA has been associated with approximately 15% of cases. Urothelial malignancy-mediated AHA is exceedingly rare, with only two previously published reports. The management of AHA includes stabilization and control of bleeding via the use of hemostatic agents, and elimination of the inhibitor with immunosuppressive therapy. Here, we report a case of AHA secondary to urothelial malignancy and review the pathobiology and pathogenesis of Hemophilia A and AHA. [ABSTRACT FROM AUTHOR]

This case report highlights the challenges in controlling bleeding and correcting coagulation tests through the use of bypassing agents in patients with FV inhibitors. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder that results from autoantibodies against clotting factor VIII (FVIII). Distinguishing acquired hemophilia from other more common causes of bleeding, such as chronic liver disease, disseminated intravascular coagulation, or sepsis-induced coagulopathies, is crucial in guiding the management of life-threatening hemorrhage. This study describes a patient with primary biliary cholangitis who was found to have acquired hemophilia A, a unique cause of life-threatening bleeding that was especially challenging to diagnose and manage with her underlying liver disease. Identifying acquired hemophilia A allowed an avenue of treatment options that would not have otherwise been available., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Soni et al.)

Unlike hereditary hemophilia, acquired hemophilia is a rare life-threatening bleeding disorder that occurs in a person who has no personal or family history of bleeding episodes. It usually presents with new-onset subcutaneous/joint/muscle bleeding causing ecchymoses and hematomas, hematuria, GI bleeding, retroperitoneal bleeding, or rarely acute intracranial hemorrhage in elderly individuals. The diagnosis involves assessing prolonged activated partial thromboplastin time (aPTT) and conducting mixing studies after ruling out lupus anticoagulants and interfering substances such as heparins. Management consists of controlling hemostasis using recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC), along with eradicating autoantibodies against factor VIII from the body system using immunosuppressive therapies. Due to the risk of uncontrolled bleeding in individuals who were previously normal, delayed diagnoses and recurrences are not uncommon, potentially resulting in unfavorable outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Winn et al.)

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of FVIII. Several factors have been associated with the activation of the auto-immunity towards FVIII. Emerging evidence implicates CD4+ T cell activation in mediating this autoimmune response, with their involvement like that observed in congenital hemophilia A. Several genes such as HLA II DRB*16, DQB1*0502, and CTLA-4 + 49 are responsible for the pathogenesis of AHA. Epigenetic modifications and mainly long-coding RNAS (lncRNAs) are potentially contributing to the pathogenesis of AHA. The treatment approach of AHA includes the management of acute bleeding events and the administration of immunosuppressive medications. This review aimed to summarize the published data on the genetics and epigenetics of AHA. The severity and the mortality of this disease are creating an emerging need for further research in the field of the genetics and epigenetics of acquired hemorrhagic disorder.

Acquired hemophilia A (AHA) is a rare condition that may be drug-induced. In this case report, we describe a patient who presented with extensive subcutaneous bleeding three years after beginning treatment with adalimumab for necrotizing scleritis. His workup was compatible with drug-induced AHA. He was treated with high-dose corticosteroids, cyclophosphamide, and rituximab. Adalimumab was discontinued. We present this case as an example of a rare, but potentially life-threatening, complication of adalimumab. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of acquired hemophilia secondary to levofloxacin and provide a guide for the use of anticoagulation in acute coronary syndrome. Case Summary: A 75-year-old female treated with levofloxacin presented with spontaneous bruising of the upper extremities. Levofloxacin was discontinued and the symptoms resolved. Thereafter, the spontaneous bruising recurred and progressed over a few weeks. The patient was treated with recombinant factor VIIA with a time to recuperation of 3 months. The patient was subsequently found to have ST-segment elevation for which they received unfractionated heparin, ticagrelor, and aspirin prior to bare metal stent placement. Conclusion: Hemophilia A is a rare disease associated with high morbidity and mortality. Case studies previously evaluating the association of levofloxacin with acquired hemophilia have shown causality. Initiating anticoagulation in patients with acquired hemophilia has long been a challenge to clinicians as evidence-based guidelines are lacking and bleeding risk may outweigh the benefit of anticoagulation. Furthermore, factor VIII deficiency does not provide additive protection against atherosclerotic plaque formation. This case report supports existing literature associating levofloxacin with acquired hemophilia. Due to the complication of life-threatening bleeds, familiarity with the treatment course following coronary events will allow patients with acquired hemophilia to be adequately and safely anticoagulated. [ABSTRACT FROM AUTHOR]

Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care. [ABSTRACT FROM AUTHOR]