Acquired hemophilia A as a disease of the elderly: A comprehensive review of epidemiology, pathogenesis, and novel therapy.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). This review provides an in-depth exploration of AHA, covering its epidemiology, pathogenesis, clinical presentation, diagnosis, complications, and treatment strategies, focusing on recent advancements. AHA can manifest in both men and women with no prior bleeding history. The annual incidence is estimated to be approximately 1 case per million individuals in the general population. The incidence increases significantly with age: the incidence among individuals aged 60 years or older is approximately 3 to 4 cases per million individuals per year. Typically, patients present with an acquired bleeding disorder that is characterized by an isolated, prolonged activated partial thromboplastin time stemming from FVIII deficiency. Diagnosis relies on the detection of neutralizing antibodies using the Nijmegen-modified Bethesda assay. Hemostatic control strategies involve bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII for bleeding patients. Emicizumab, a novel bypassing agent, exhibits several potential advantages. In the realm of immunosuppressive treatment for inhibitor eradication, the CyDRi regimen emerged as a remarkable advancement, significantly enhancing the outlook for the management of AHA even in the elderly frail population.

Relationship between mutations in severe hemophilia A and risk of inhibitor development: A large single-center study.

BACKGROUND: One of the major problems for patients with severe hemophilia A (HA) is the development of neutralizing antibodies against factor VIII. This study aimed to analyze the molecular and clinical profiles of patients with severe HA and to determine if certain genetic variants predispose to inhibitor development in these patients. METHODS: A single-center study was conducted among patients with severe HA between March 20, 2000, and June 31, 2023. Demographic data and laboratory results of patients were collected. The inverse-shifting PCR (IS-PCR) technique was initially used to screen patients for intron 22 and 1 inversions (Inv-22 and Inv-1). RESULTS: A total of 480 patients with severe HA (408 without inhibitors and 72 with inhibitors) were enrolled in this study. The median age of the patients at the time of diagnosis was 6 months (IQR: 3 months to 18 months). Inv-22 was observed in 199 (41.5 %) of the cases. Among those patients who developed inhibitors, 53 (73.6 %) were classified as high-titer and 19 (26.4 %) as low-titer. Inv-22, positive family history of inhibitor formation, and history of intense injections revealed a statistically significant association with the risk of inhibitor development. CONCLUSION: The results of this study confirm the important role of different genetic variants, family history of inhibitor formation, and history of intense injections for the formation of inhibitors in patients with severe HA. This would allow us to stratify the patients which can have important clinical implications, especially in terms of their management and outcome.

Emicizumab in Children with Severe Hemophilia A.

OBJECTIVES: To assess the effectiveness and tolerability of emicizumab prophylaxis in hemophilia A (HA). Emicizumab is a novel therapeutic drug which is the first and only non-factor replacement agent licensed for use in people with HA. METHODS: Pediatric patients aged 1 mo to 12 y with severe HA and frequent / life threatening bleeding events, with or without coagulation protein factor VIII inhibitors were enrolled (n = 18) in this observational pre-post study. Patients were switched from therapy involving on-demand or prophylactic factor VIII/bypassing agents/immune tolerance induction to emicizumab prophylaxis and followed up for 52 wk. RESULTS: One year before initiating emicizumab, a total of 229 bleeding events occurred among the enrolled children. After emicizumab prophylaxis, 5 patients had one episode of bleeding event each with a mean bleeding duration of 1.2 d in one year. The mean annualized bleeding rate significantly reduced from 12.7 ± 8.61 events pre-emicizumab prophylaxis to 0.28 ± 0.46 events post-emicizumab prophylaxis (p < 0.001). Out of the total cohort (n = 18), 72.2% of patients (n = 13) had no bleeding events (95% Confidence interval: 46.4-89.3) while on emicizumab. The mean annualized joint bleeding rate reduced from 9.72 ± 7.44 to 0.17 ± 0.38 (p < 0.001). The target joint resolution was 100% and no adverse events were noted. CONCLUSIONS: Emicizumab was found to be effective and safe as a prophylactic agent for the treatment of severe HA with and without factor VIII inhibitors. Emicizumab prophylaxis can optimize treatment outcomes and promote a better quality of life in children with severe HA.

Emicizumab and unmet needs of patients with hemophilia a who are managed with replacement therapies.

INTRODUCTION: Hemophilia A is managed with coagulation clotting factor VIII (FVIII) therapy that poses significant challenges, such as a high treatment burden, immunogenicity, inconsistent hemostatic cover, poor treatment outcomes, and musculoskeletal progression despite adequate prophylactic treatment. Various non-factor therapies, such as several natural anticoagulant inhibitors and factor FVIII mimetics, have been developed to address these unmet needs. However, the role of emicizumab in addressing these unmet needs remains underexplored. AREAS COVERED: This review delves into the evolution of hemophilia A replacement clotting therapy from plasma-derived products to recombinant products and, more recently, nonfactor therapies. It underscores the unmet needs of replacement therapy and explores the nonfactor therapies developed to address them. The review then comprehensively summarizes the clinical trial and real-world experience data, demonstrating how emicizumab tackles these unsatisfied demands. EXPERT OPINION: Replacement clotting factor therapies as the standard of care has exposed several needs that have yet to be addressed. However, data from numerous emicizumab clinical trials and real-world experience offer a promising outlook, suggesting that it may effectively address many unmet needs. As hemophilia treatment goals continue to evolve, the role of currently developed nonfactor therapies in hemophilia management is yet to be fully defined.

Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B.

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.

Pharmacokinetic evaluation of efanesoctocog alfa: breakthrough factor VIII therapy for hemophilia A.

INTRODUCTION: Blood coagulation factor (F)VIII functions as a cofactor in the tenase complex responsible for phospholipid-dependent FIXa-mediated activation of FX in plasma. Congenital defect of FVIII causes severe bleeding disorder hemophilia(H) A. Intravenous FVIII replacement therapy is the gold standard therapy in patients with HA (PwHA), but requirement for frequent dosing of FVIII owing to pharmacokinetics burdens PwHA a lot. Efanesoctocog alfa is a new class of recombinant FVIII and has ability to overcome conceivable unmet needs in treatment for PwHA. AREAS COVERED: Efanesoctocog alfa is a B domain-deleted single-chain fusion FVIII connected to Fc-region of human immunoglobulin G1, D'D3-fragment of von Willebrand factor (VWF) and unstructured hydrophilic recombinant polypeptides (XTEN). Owing to its novel design, it can function independently of endogenous VWF and elicits 2 to 4 times longer half-life compared to other existing FVIII products. The prolonged half-life contributes to maintain high level of FVIII activity for most of the week and has led to excellent hemostatic effect by once-weekly administration in phase 3 clinical trials. EXPERT OPINION: Efanesoctocog alfa with outstanding pharmacological properties, well tolerated in the clinical trials, is a promising FVIII therapy for PwHA. Future studies should include long-term safety especially in previously untreated patients.

Cross-reacting antiporcine factor VIII inhibitors in patients with acquired hemophilia A.

•Recombinant porcine factor VIII (rpFVIII) is a hemostatic treatment for bleeding in acquired hemophilia A.•The efficacy of rpFVIII can be negatively affected by cross-reacting anti-human FVIII antibodies.•In this cohort, 52% of patients with acquired hemophilia A had baseline cross-reacting antibodies.•Cross-reacting antibodies were associated with decreased FVIII activity levels post-rpFVIII infusion.

Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life.

Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup (n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) (p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA (p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA (p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.

Minor surgical procedures during immune tolerance induction in people with hemophilia A and inhibitors: results from the Brazilian Immune Tolerance (BrazIT) study cohort.

INTRODUCTION: Surgeries are implicated in the development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) in hemophilia A individuals with immune tolerance induction (ITI) treatment being the recommended therapy to eradicate these inhibitors. We evaluated the association of surgical procedures performed during ITI and treatment outcome. METHODS: Patients were treated according to the Brazilian ITI Protocol with outcomes being defined as successful (i.e., recovered responsiveness to exogenous FVIII) and failed (i.e., unresponsiveness to exogenous FVIII thus requiring bypassing agents for bleeding control). Surgical procedures during induction therapy were managed following international recommendations. RESULTS: Treatment success rate was 68.7 % in 163 patients; 33 (20.2 %) were submitted to 43 (96 %) minor and two major surgeries. Personal, hemophilia, inhibitor, and treatment characteristics were similar between patients submitted to surgical procedures or not while on ITI; the success rates were 72.7 % and 67.7 % (p-value = 0.577), respectively. CONCLUSION: No association was found between having a minor surgical procedure and ITI treatment outcome.

Lack of FVIII detection in humans and dogs with an intron-22 inversion challenges hypothesis regarding inhibitor risk.

BACKGROUND: Almost half of severe hemophilia A (HA) cases are caused by an intron-22 inversion mutation (Int22Inv), which truncates the 26-exon F8 mRNA after exon 22. Another F8 transcript, F8B, is initiated from within F8-intron-22. F8B mRNA consists of a short exon spliced to exons 23-26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial FVIII proteins expressed from these two transcripts. FVIII is expressed in endothelial cells, primarily in liver and lung. Several studies have reported FVIII expression in other cell types, although this has been controversial. OBJECTIVES: To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8B mRNA and if FVIII is expressed in non-endothelial cells. METHODS: A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues, and for immunoprecipitation followed by western blots and mass spectrometry-proteomics analysis. RESULTS: Immunofluorescent (IF) staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIIIB was detected in human PBMCs, B-cell or T-cell lines, or in cell lines expanded from PBMCs, whereas FVIII antigen and activity were readily detected in primary non-hemophilic liver sinusoidal endothelial cells. CONCLUSIONS: If FVIII is expressed in non-endothelial cells, or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.

Real-world use of recombinant porcine sequence factor VIII in the treatment of acquired hemophilia A: EU PASS.

Background: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is indicated for the treatment of bleeding events (BEs) in adults with acquired hemophilia A (AHA). Objectives: To assess the safety, utilization, and effectiveness of rpFVIII in clinical practice. Design: EU post-authorization safety study (PASS) (NCT03199794) was a multicenter, noninterventional, post-authorization safety study conducted in adults with AHA. Methods: Data were collected retrospectively or prospectively for up to 180 days after the last rpFVIII dose. The primary objective was safety, as assessed by adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) (e.g. immunogenicity, hypersensitivity reactions, thromboembolic events). Secondary endpoints included immunogenicity, rpFVIII hemostatic effectiveness, and rpFVIII utilization. Results: Fifty patients were enrolled; 31 completed the study. The median (range) follow-up for patients who completed or discontinued the study was 178 (26-371) days. The median (range) first dose of rpFVIII was 54.0 (11-200) U/kg. Thirty patients reported 46 SAEs; 5 SAEs were considered probably related to rpFVIII, of which 1 was lack of rpFVIII efficacy, and 4 were AESIs: drug resistance due to FVIII inhibition (one patient), antibody test positive for anti-pFVIII inhibitors (one patient), and de novo anti-pFVIII inhibitors (two patients). No hypersensitivity reactions or thromboembolic events were reported. Of the 50 initial BEs, 37 resolved [in a median (interquartile range) of 8.0 (4.0-16.0) days]. Conclusion: Results from this real-world study support the use of rpFVIII for AHA, aligning with findings from the clinical trial of rpFVIII (NCT01178294) in the treatment of BEs in adults with AHA. Trial registration: EUPAS16055; NCT03199794.

Association of bullous pemphigoid with acquired hemophilia A: a case report.

Acquired hemophilia A, a rare condition resulting in spontaneous bleeding without prior bleeding disorders, arises due to autoantibody-mediated inhibition of coagulation factor VIII and is typically associated with autoimmune, neoplastic, drug, or obstetric factors. We present the case of a 31-year-old woman with bullous pemphigoid, managed with corticosteroids since 2013, who presented spontaneous hemorrhagic manifestations. Upon admission, laboratory tests revealed hypochromic microcytic anemia, prolonged activated partial thromboplastin time, and a factor VIII level < 1%, indicative of acquired hemophilia A. Further assessments showed elevated Ristocetin cofactor activity, von Willebrand factor antigen, and a factor VIII inhibitor level of 665 BU. This underscores the importance of considering acquired hemophilia A in autoimmune dermatological conditions like bullous pemphigoid, highlighting the association between autoimmune disorders and coagulation abnormalities, particularly in cases of spontaneous hemorrhagic events.

[Acquired haemophilia: Update in 2024]. / Hémophilie acquise : quoi de neuf en 2024 ?

Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against factor VIII, with a high mortality risk. It should be suspected in subjects with abnormal bleedings, especially subcutaneous bleed associated with prolonged activated partial thromboplastin time (aPTT). AHA is often idiopathic but is associated with autoimmune diseases, malignancies, pregnancy and postpartum period or drugs. Treatment is based on haemostatic agents as by-passants agents such as factor VIIa and activated prothrombine concentrate complex or recombinant porcine factor VIII for severe bleeding. Eradication of inhibitor should be established as soon as the diagnosis is confirmed with steroid alone often associated with cytotoxic agents or rituximab, depending on FVIII activity and inhibitor titer. The purpose of this review is to summarize the epidemiology, etiopathogenesis, diagnosis, treatment of AHA and discuss current recommendations.

Efficacy and safety of recombinant porcine factor VIII in Japanese patients with acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies inhibiting human factor VIII (hFVIII). This phase II/III open-label study evaluated the safety and efficacy of recombinant porcine factor VIII (rpFVIII, susoctocog alfa) in adults with AHA and severe bleeding episodes in Japan (NCT04580407). The initial rpFVIII dose was 200 U/kg, with subsequent doses based on clinical measures including plasma FVIII activity. The primary efficacy endpoint was the proportion of severe bleeding episodes with a positive response to rpFVIII therapy 24 h after treatment initiation. Five patients were eligible for, and completed, rpFVIII treatment (age group: 60s-80s; median hFVIII inhibitor: 52 BU/mL; porcine FVIII [pFVIII] inhibitor: 3/5 patients). The median (range) total dose/patient was 548.4 (198-1803) U/kg with a median 3.0 infusions/patient. All patients responded positively to rpFVIII therapy at 24 h regardless of baseline pFVIII inhibitor status. rpFVIII treatment was well tolerated with no adverse events of special interest such as thromboembolic events or de novo pFVIII inhibitors. This study supports the use of rpFVIII as a novel therapy in the clinical management of patients with AHA in Japan. rpFVIII was approved for treating bleeding episodes in adults with AHA in Japan in 2024.

[Hemophilia: is a revolution in treatment options taking place?] / Hämophilie ­ Revolution der Therapiemöglichkeiten?

Prophylactic replacement therapy for hemophilia A (hereditary factor VIII deficiency) is a success story of the production of coagulation factor concentrates from donor plasma. Recombinant factor concentrates, which are also produced with modified gene constructs for coagulation factor VIII in order to improve pharmacological properties, have since proven their worth. This successful development over many years of factor concentrates for the successful treatment of hemophilia patients has now been followed by the innovation of a factor VIII mimetic in the form of a monoclonal antibody, which was developed in Japan already some years back. Emicizumab is a humanized, bispecific monoclonal antibody for therapeutic use in hemophilia A. With this therapeutic agent, the treatment of the hereditary coagulation defect is based, for the first time, on a completely new active principle. The specific antibody simulates the properties of coagulation factor VIII as a cofactor for the formation of the tenase complex with the coagulation factors IX and X. As a result under steady state conditions almost normal thrombin and thus fibrin formation can be achieved.

[Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-ß and IL-10 in Hemophilia A Patients with Fâ § Inhibitor].

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Adeno-associated viral vector integration: implications for long-term efficacy and safety.

Adeno-associated virus (AAV) vector gene therapy provides a promising platform for treatment of monogenic inherited disorders. Clinical studies have demonstrated long-term expression with reduction in bleeding using this approach for the treatment of hemophilia. Despite these advances, there are unknowns surrounding the natural history of recombinant AAV (rAAV) vectors and the cellular mechanisms mediating vector persistence. These unknowns underpin questions regarding long-term efficacy and safety. The predominant mechanism via which AAV is proposed to persist is in circular double-stranded extrachromosomal DNA structures (episomes) within the nucleus. Studies of wild-type AAV (WT-AAV) and rAAV have demonstrated that AAV also persists via integration into a host cell's DNA. It is important to determine whether these integration events can mediate expression or could result in any long-term safety concerns. WT-AAV infection affects a large proportion of the general population, which is thought to have no long-term sequelae. Recent studies have highlighted that this WT-AAV has been detected in cases of acute hepatitis in children and in a minority of cases of hepatocellular carcinoma. Integration following treatment using rAAV has also been reported in preclinical and clinical studies. There have been variable reports on the potential implications of integration for rAAV vectors, with data in some murine studies demonstrating recurrent integration with development of hepatocellular carcinoma. These findings have not been seen in other preclinical or clinical studies. In this review, we will summarize current understanding of the natural history of AAV (wild-type and recombinant) with a focus on genomic integration and cellular implications.

Navigating the Challenges of Factor X Deficiency: A Case Study.

The clotting pathway involves intrinsic and extrinsic pathways converging into a common pathway. These pathways require activated factors that sequentially convert prothrombin to thrombin, which then converts fibrinogen to fibrin, forming a stable clot. Clotting factor deficiency impairs this cascade leading to excessive bleeding or bruising due to insufficient clot formation. Here, we present the case of a 47-year-old female who initially complained of epigastric pain. By the third day of admission, she experienced four to five episodes of bleeding gums, resulting in a blood loss of approximately 300 mL. The patient exhibited abnormal prothrombin time (PT) and international normalized ratio (INR) values, leading to a diagnosis of Factor X (FX) deficiency upon further evaluation. This case report emphasizes the need to diagnose coagulopathies such as FX deficiency and how early diagnosis will help not only in patient care and management but also in screening family members who may be affected.

Acquired Hemophilia A Diagnosed Based on Gross Hematuria: A Case Report and Literature Review.

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.

Primary postpartum hemorrhage in women with von Willebrand disease and carriers of hemophilia: a retrospective analysis.

Background: Between 2002 and 2011, the incidence of severe primary postpartum hemorrhage (PPH) in Dutch women with von Willebrand disease (VWD) and hemophilia carriers (HCs) was 8% vs 4.5% in the general population. Objectives: To determine the contemporary incidence of severe primary PPH in women with VWD and HCs. Methods: All women with VWD or HCs who delivered between 2012 and 2017 were selected from all 6 Dutch hemophilia treatment centers. Data on patient and disease characteristics, peripartum hematologic and obstetric management, and outcomes were retrospectively collected. Incidence of severe primary (≥1000 mL of blood loss ≤24 hours after childbirth) and primary (≥500 mL within ≤24 hours after childbirth) PPH was compared with the (1) previous cohort and (2) general Dutch population and between (3) women with VWD and HCs with third-trimester coagulation activity levels <50 international units (IU)/dL vs ≥50 IU/dL and (4) women treated with vs without peripartum hemostatic prophylaxis. Results: Three-hundred forty-eight deliveries (151 VWD, 167 hemophilia A, and 30 hemophilia B carriers) were included. The severe primary PPH incidence was 10% (36/348) and remained stable over time, whereas this incidence has increased in the general population (to 8%), leading to a similar risk (P = .17). Severe primary PPH risk was comparable between women with coagulation activity levels <50 and ≥50 IU/dL (11% [7/66] vs 10% [29/279]; odds ratio, 1.02; 95% CI, 0.43-2.44) and comparable between those with and those without prophylaxis (12% [11/91] vs 10% [25/254]; odds ratio, 1.26; 95% CI, 0.59-2.68). Conclusion: Severe primary PPH in women with VWD and HCs remained stable and is comparable with the increasing prevalence in the general population. More research is needed to find the optimal pregnancy management strategy for safe delivery in VWD and HC.