Acquired Hemophilia A Patients Research Articles

Acquired Hemophilia a: A Single-Center Study of 165 Patients

Introduction and aim: Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the existence of factor VIII (FVIII) inhibitors with an estimated annual incidence of 1.5 per million people. AHA patients are characterized by exceeding bleeding of varying severity, while approximately 10% of AHA patients have no bleeding symptoms. It's a challenge to diagnose and manage AHA due to its rarity and heterogeneity. We conducted a retrospective study to report the characteristics and outcomes of AHA and enhance its recognition and management. Methods: Patients diagnosed and treated with AHA at the Blood Disease Hospital, Chinese Academy of Medical Sciences between July 1997 to December 2021 were retrospectively enrolled. Demographics, clinical characteristics, treatments, and outcomes were collected. All Patients were followed immediately from admission to our center and ended in March 2022. Bleeding severity was assessed retrospectively in March 2022 by bleeding score (BS), a summary score aggregated by the International Society on Thrombosis and Hemostasis/ Scientific and Standardization Committee (ISTH/SSC) bleeding assessment tool (BAT) (2010 edition). Results: A total of 165 AHA patients admitted to our center were enrolled. The median age at diagnosis was 45 (10-90) years. Overall, a female preponderance (106/165, 64.2%) was observed in this cohort. Notable, the proportion of male patients increased with age. Most patients (126/165, 76.4%) were idiopathic with no underlying diseases discovered. Of the 39 (23.6%) patients with associated diseases, 12 patients had autoimmune diseases, 16 patients had infections, eight patients had malignancies (all solid tumors) and three patients were secondary to pregnancy. All patients presented at least one bleeding episode. Subcutaneous bleeding was most common affecting 84.8% (140/165) of patients, while hemarthrosis was infrequent (n=11, 6.7%). The median time from bleeding to be diagnosed as AHA was delayed (30, 2-5650 days). Anti-FVIII antibody titer and FVIII level showed no correlation. A significant difference in FVIII activity was observed between patients with anti-FVIII antibody titer < 20 BU/ml and ≥ 20 BU/ml. The BS varied among all patients ranging from 2 to 12 with a median of 4. A significant difference in BS was observed among the mild (FVIII: C > 5 IU/dl), moderate (1 IU/dl < FVIII: C ≤ 5 IU/dl), and severe (FVIII: C ≤ 1 IU/dl) AHA patients (p < 0.05). The same conclusion was also drawn between patients with low anti-FVIII antibody titer (< 20 BU/ml) and high antibody titer (≥ 20 BU/ml). BS was not correlated with APTT (r=0.-0.04, 95% CI (-0.19-0.12), p > 0.05). Hemostatic treatment was applied to 129 (78.2%) AHA patients. Of the 163 patients who received immunosuppressive therapy (IST), 22 (13.5%) received steroids alone, with an 82.4% complete remission (CR) rate, 50 (30.7%) received steroids plus cyclophosphamide (CTX), with an 85.0% CR rate, 80 (49.1%) received rituximab-based therapy, which includes rituximab plus steroids, rituximab plus steroids and CTX, and rituximab plus steroids and other immunosuppressants, with a 93.3% CR rate (Figure 1A). There were seven deaths. Causes of death were bleeding (n=3), underlying disease (n=1), pulmonary infection (m=1), and unknown (n=2). FVIII inhibitor titer ≥ 20 BU/ml was the only significant poor prognostic factor for CR (HR 0.56; 95% CI, 0.37-0.85; p < 0.01). In addition, patients with FVIII inhibitor titers ≥ 20 BU/ml needed more time to achieve CR (130 days vs. 35 days; p < 0.01) and showed a lower CR rate (77.6% vs. 94.9%, p < 0.01) than those with FVIII inhibitor titers < 20 BU/ml (Figure 1B). Conclusions: Delayed diagnosis of AHA patients is a severe issue. The rituximab-based regimen is more likely to achieve a CR in AHA patients. The only poor predictor of CR for AHA patients was FVIII inhibitor titer ≥ 20 BU/ml.

Single-Dose Rituximab Plus Glucocorticoid Versus Cyclophosphamide Plus Glucocorticoid in Patients with Newly Diagnosed Acquired Hemophilia a: A Multicenter, Open-Label, Randomized Clinical Trial

Introduction Cyclophosphamide plus glucocorticoid is a first-line immunosuppressive therapy for acquired hemophilia A (AHA), a serious bleeding disorder, but brings risks of myelosuppression, secondary tumor, and reproductive toxicity. Rituximab plus glucocorticoid therapy shows comparable efficacy but lacks results from randomized controlled trials. We aimed to establish whether the single-dose rituximab regimen was non-inferior to the cyclophosphamide regimen. Methods This study was the first noninferiority, multicenter, open-label, randomized controlled clinical trial comparing these two combination therapies in AHA patients (ClinicalTrails.gov number, NCT03384277). Adult patients (18-80 years) with newly diagnosed AHA from five centers in China were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single-dose rituximab (375 mg/m 2) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks). The primary outcome was complete remission (CR, defined as FVIII activity ≥ 50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 hours without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. The secondary outcomes included partial remission (PR) rate, time to PR, time to CR, time for inhibitor titer to decrease by 50% of baseline, relapse rate, time to relapse and so on. Safety was assessed in all patients. Results Between December 29, 2017 and June 9, 2022, 67 patients were screened, of whom 63 (33 female and 30 male) were assigned: 31 to single-dose rituximab group and 32 to cyclophosphamide group. The baseline characteristics of these patients were balanced between the single-dose rituximab group and cyclophosphamide group. Twenty-four (77.4%) patients in the rituximab group and twenty-two (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single-dose rituximab-based regimen (absolute difference=-8.67%, lower limit of the 95% confidence interval=-13.11%; P noninferiority=0.005). PR was observed in 25 (80.6%) of 31 patients in the single-dose rituximab group and 26 (81.3%) of 32 patients in the cyclophosphamide group (P=0.95). The median time to PR was similar between two groups (23.0 days for rituximab group vs. 25.5 days for cyclophosphamide group, P=0.47). The median time to CR was 8 days shorter in the single-dose rituximab group than in the cyclophosphamide group, but with no statistically significant difference (28.0 days vs. 36.0 days, P=0.41). The median time for inhibitor titer to decrease by 50% of baseline also showed a shorter trend in the single-dose rituximab plus glucocorticoid group (8.0 days vs. 11.0 days, P=0.39). Subgroup analysis showed patients with high FVIII inhibitor titer (>20 BU/ml) were less likely and slower to achieve both CR and PR. The percentage of patients who experienced treatment-related adverse events (TRAEs) or grade 3 or 4 TRAEs were comparable between the rituximab and cyclophosphamide groups (58.1% vs. 37.5%, P=0.10 and 12.9% vs. 6.3%, P=0.43 respectively). Conclusion Single-dose rituximab plus glucocorticoid regimen showed similar efficacy and safety in this trial, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first-line therapy for AHA, especially in China where there is a young age trend in AHA patients.

Appropriateness of Immunosuppression and Blood Product Utilization in Acquired Hemophilia A: A Multicentre Provincial Practice Audit

Introduction: Acquired hemophilia A (AHA) is a life-threatening bleeding disorder associated with significant morbidity and mortality. Despite publication of international consensus guidelines, quality of care and guideline adherence have not been examined. While some jurisdictions have reference centres for AHA management, in Canadian provinces outside of Quebec, AHA is managed in both hemophilia treatment centres (HTCs) and community hospitals. We performed a multicentre practice audit in a Canadian province to assess use of immunosuppressive therapy (IST), blood product utilization, and evaluate treatment burden and outcomes. Methods: We included adults diagnosed with AHA (January 2000-December 2021) in Alberta, Canada, and examined the following quality of care indicators: delayed IST initiation from diagnosis, corticosteroid use alone in high-risk AHA (FVIII <0.01 IU/ml or FVIII inhibitor >20 BU/ml), cyclophosphamide use in low-risk patients (FVIII ≥0.01 IU/ml and inhibitor ≤20 BU/ml), prolonged cyclophosphamide use (>6 weeks), and inappropriate use of plasma, intravenous immunoglobulin (IVIG) and hemostatic products. Outcome measures included response, length of stay (LOS) and 30-day readmission. We evaluated treatment burden including frailty syndromes, increased level of care and hospitalization for treatment-related adverse events. Results: Of the 38 patients diagnosed with AHA, 25 (66%) were female, the median age was 74 years (IQR 61-81), and median Charlson comorbidity index was 5 (IQR 3-7). Cardiovascular comorbidities were common, including venous thromboembolism (5; 13%), atrial fibrillation (5; 13%), and myocardial infarction (4; 11%). Fifteen (39%) had ≥1 frailty syndromes, including functional dependence (6; 16%), dementia (6; 16%), falls/fractures (5; 13%), and depression/anxiety (3; 8%). Five (13%) patients required higher levels of care (long term care placement) following discharge. Twenty-one (55%) patients had high-risk disease and 17 (45%) had low-risk. In those with low-risk disease, 11 (29%) had inhibitor titres 5-20 BU/ml and 6 (16%) had inhibitors <5 BU/ml. Despite diagnostic delays ≥7 days from bleeding in 15 (39%), most received prompt initiation of IST (median 0 days [IQR 0-3] from diagnosis). First-line IST included: prednisone (38; 100%), cyclophosphamide (23; 61%), and rituximab (13; 34%). IVIG was prescribed in 5 (13%), out of keeping with guideline recommendations. We observed very high rates of first-line cyclophosphamide use in low risk AHA (11/17; 65%), including 4/6 with inhibitor titres <5 BU/ml (Table 1). First-line cyclophosphamide was also used in 3 reproductive-aged women. Prolonged courses of cyclophosphamide >6 weeks and >6 months were used in 21/23 (91%) and 7/23 (30%) patients, respectively. Two high-risk patients did not receive cyclophosphamide or rituximab-containing therapy. Of the 58 episodes of bleeding events, 41 (71%) were ISTH major bleeds. Fifteen (26%) bleeding events did not receive hemostatic therapy, whereas 27 (47%), 19 (33%), and 3 (5%) were treated with recombinant factor VIIa, activated prothrombin complex concentrates, and porcine FVIII, respectively. Dosing of bypassing agents was in keeping with guidelines. DDAVP and human FVIII were inappropriately used in 3/58 (5%) and 1 (2%) bleeding episodes, respectively. Most patients (24; 63%) received red cell transfusions with a median of 2 (IQR 0-7) units each. Five (13%) patients received a total of 18 units of plasma. Clinical responses included: complete remission (CR) in 30 (79%), partial remission in 3 (8%), and unevaluable due to early deaths in 5 (13%). All 5 patients who relapsed (13%) achieved second CR. The median LOS was 38 days (IQR 19-57) across 95 hospitalizations. The 30-day readmission rate was 24%. Reasons for admission included bleeding (50/95; 53%), infections (14/95; 15%), and other treatment side-effects (13/95; 14%). Conclusion: In this provincial cohort of AHA patients with high comorbidity and frailty, we identified gaps in quality of care including overuse of cyclophosphamide in patients with low-titre inhibitors, prolonged duration of cyclophosphamide, and inappropriate use of IVIG and plasma. Aggressive cytotoxic therapy predisposes patients to unnecessary risks of infections and malignancies. Our findings highlight the need for centralization of care in specialized centres and education initiatives.

The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A

BackgroundAn inhibitor can develop in congenital hemophilia A (HA) patients against exogenous infused factor (F)VIII, whereas in acquired HA (AHA) inhibitors initially develop against endogenous FVIII. Inhibitors can be detected with the Nijmegen Bethesda Assay (NBA), which has an international cut-off level of 0.60 Nijmegen Bethesda Units/mL (NBU/mL). Thereby, very low-titer inhibitors may remain undetected. AimTo describe the design and validation of the Nijmegen ultra-sensitive Bethesda Assay (NusBA) for the detection of very low-titer inhibitors. MethodsThe NusBA is a modification of the NBA in which the ratio of patient plasma to normal pooled plasma is changed from 1:1 to 9:1. Analytical validation was performed according to the CLSI EP10 guideline in order to determine trueness and reproducibility. Clinical validation was performed in two cohorts of congenital HA patients (82 adults) with pharmacokinetic data and four AHA patients. The limit of quantitation (LOQ) was determined by measuring plasma samples spiked with inhibitor levels in the low range (0.05–0.80 NBU/mL). ResultsThe LOQ for the NusBA was 0.10 NusBU/mL, with a coefficient of variation of 24.2 %. Seven (8.5 %) congenital HA patients had a positive NusBA result, of which only one was detected with the NBA. There was no correlation between NusBA and FVIII half-life. In three of the AHA patients the NusBA remained positive, when the NBA became negative. DiscussionThe NusBA is able to detect very low-titer FVIII inhibitors of ≥0.10 NBU/mL. Thereby, it may have added value in early inhibitor detection and therapy adjustments in patients with congenital HA and AHA.

Agreement between one stage and chromogenic assays in samples from patients receiving recombinant porcine FVIII (Obizur, Susoctocog-alfa).

Recombinant porcine FVIII (rpFVIII) (Obizur, Susoctcog-alfa, Takeda, Japan) is licensed for the treatment of bleeding in acquired Haemophilia A (AHA). The summary of product characteristics state that monitoring should be by one stage assay (OSA) rather than chromogenic assay (CSA). CSA have been shown to underestimate activity when rpFVIII is added to plasma in vitro. Samples from three AHA patients (n = 21) (pre- and post rpFVIII) were assessed using FVIII:C assays; OSA methods: Actin, Actin FS, Actin FSL and Pathromtin SL performed on CS5100i (Sysmex, Kobe, Japan); APTT-SP, SynthASil and SynthAFax performed on ACL TOP (Werfen, Barcelona, Spain). CSA methods on CS5100i: Siemens Chromogenic Assay, Biophen FVIII:C, Technochrom FVIII:C; on ACL TOP: Rox Factor VIII, Coamatic Factor VIII and CRYOcheck Factor VIII. OSA and CSA varied according to reagent used median OSA 61 IU/dL (range 41.5-81 IU/dL (ANOVA p < 0.0001)) median CSA 46.5 IU/dL (range of method specific medians 36.5-84 IU/dL (ANOVA p < 0.0001)). Amongst OSA, Actin FS was associated with the highest FVIII:C, APTT-SP was associated with the lowest. Variation in CSA results by different methods was also seen with highest FVIII:C levels obtained using the Technochrom FVIII:C and the lowest levels obtained with Siemens Assay. The relationship between OSA and CSA was not consistent between method or patient. Previously there has been reports of underestimation by CSA in in vitro spiked samples. Investigation into concentration of phospholipids in the APTT reagents may explain some of these variations.

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.

The IgG-degrading enzyme, Imlifidase, restores the therapeutic activity of FVIII in inhibitor-positive hemophilia A mice.

Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in non-hemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human immunoglobulin G (IgG); it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive HA mice. IdeS cleaved anti-FVIII plasma IgG from PwHA and AHA patients, and hydrolyzed recombinant human anti-FVIII IgG independently from their subclass or specificity for the A2, A3, C1 or C2 domains of FVIII. In HA mice passively immunized with recombinant human anti-FVIII IgG, IdeS restored the hemostatic efficacy of FVIII, as evidenced by the correction of the bleeding tendency. Our results provide the proof of concept for the transient removal of FVIII inhibitors by IdeS, thereby opening a therapeutic window for efficient FVIII replacement therapy in inhibitor-positive patients.

The diagnosis and Management of HIV Associated Acquired Hemophilia A: A Case Series From Durban, South Africa.

In acquired hemophilia A (AHA), the body produces auto-antibodies against Factor VIII. Although AHA is rare, with an incidence of 1.5 patients/1 million population/year, there is a strong association with human immunodeficiency virus (HIV) infection. The accurate interpretation of screening coagulation tests is critical to identify patients with AHA, as the mortality rate secondary to bleeding is high. This was a retrospective case series which included all newly diagnosed AHA patients that were referred to Hemophilia care unit at King Edward VIII Hospital, Durban, South Africa from January 2011 to December 2021. The clinical presentation and laboratory results were documented. Five patients were included in this case series. All patients were females aged between 28 and 64 years of age and they were HIV seropositive. They presented with spontaneous cutaneous and intramuscular bleeding. Four patients were virologically suppressed on anti-retroviral therapy, and no patient had a family history of congenital bleeding diathesis. Laboratory investigations confirmed AHA with high Factor VIII inhibitor titers, which ranged from 41 to 900 Bethesda Units (BU). All patients were managed with bypassing agents and oral corticosteroids. The monitoring of patients after the initiation of treatment was difficult as they all defaulted treatment. In view of the prevalence of HIV in sub-Saharan Africa, there is a possibility that AHA is under-diagnosed in our setting. The clinician and the laboratory have a combined critical role in identifying patients with AHA as the investigation of a prolonged APTT is mandatory. There are challenges in managing AHA patients in a resource-constrained setting.

Single-Cell Sequencing of Immune Cells from Hemophilia a Patients with Inhibitors and Acquired Hemophilia a Patients

Background: FⅧ inhibitors are antibodies that neutralize the coagulation activity of FⅧ, resulting in bleeding tendency with poor prognosis, which are the products of the adaptive immune response in patients with hemophilia A (HA) after FⅧ replacement therapy or autoantibodies produced during the autoimmunity to FⅧ of patients with acquired hemophilia A (AHA). Previous studies have proposed potential mechanisms of FⅧ inhibitor production in pediatric HA patients, and the immune response to FⅧ in different types of patients remains to be studied. Methods: PBMCs of three AHA patients, three adult patients with HA and three pediatric HA patients producing FⅧ inhibitors were isolated for single-cell (sc) RNA-seq, scBCR-seq and scTCR-seq on 10× Genomics, and Cell Ranger was used to preprocess the raw data (Fig. 1A). After the quality control of the cells, "Seurat” R package was applied to merge the data and perform transcriptome analyses including cell clustering and differential analysis. Results and Discussion: Totally 47,458 PBMCs of the nine patients passed quality control for transcriptome analyses. PBMCs were clustered into 14 subtypes, including naïve B cell_1, naïve B cell_2, memory B cell, plasma cell, T/B dual-expressing (DE) cell, naïve CD4+ T cell, naïve CD8+ T cell, naïve T cell_2, CD4+ Th cell, CD8+ CTL, KLRB1+ CD8+ T cell, NK cell, myeloid cell and platelet (Fig. 1B), and the cell markers for annotating the clusters were shown in Fig. 1C. As depicted in Fig. 1D, PBMCs of different groups of patients have different distribution characteristics of subtypes, and some subtypes only covered several patients. For instance, naïve B cell_2 consisted of the cells from an AHA patient and an adult HA patient; naïve T cell_2 was from an AHA patient and two adult patients. Besides, T/B DE cell was mainly from pediatric HA patients, though it covered the cells from eight patients. These phenomena indicated that the immune response to FⅧ of adults might differs from that of pediatric HA patients as children's immune systems were still developing. Concerning the amounts of subtypes in different groups of patients, the proportions of CD4+ Th cells and NK cells in total lymphocytes were significantly lower in pediatric HA patients than those in adult HA patients, without any significant between pediatric HA patients and AHA patients or between adult HA patients and AHA patients. The proportions of total B cells, total T cells, CD8+ CTLs, memory B cells, plasma cells and T/B DE cells didn't show significance between any two groups of patients (Fig. 1E). Unexpectedly, Cytotoxicity-associated genes including GZMH, GZMA, GZMK and NKG7 of the CD4+ Th cells in the AHA group were upregulated compared to the other two groups, while transcription factors including JUND and FOSB in the adult HA patients were upregulated, suggesting that the CD4+ Th cells were in a relatively more obvious state of activation and proliferation (Fig. 1F). A leukocyte adhesion and migration related receptor, CX3CR1, was expressed more highly in the NK cells of the adult HA patients, and CD69, a marker of activation, was upregulated in pediatric HA patients’ NK cells (Fig. 1G). The results of the immune repertoire sequencing showed that most patients have dominant T cell clones during the immune response to FⅧ, while the B cell clone dominance was only observed in an adult HA patient. The results above suggest that the immune response to FⅧ differs among adult AHA patients, adult HA patients and pediatric HA patients, and T cells are critical in all three types of patients who produce FⅧ inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Rituximab and Bortezomib for Patients with Newly Diagnosed Acquired Haemophilia: Single Arm, Single Center, Prospective Phase 2 Study

Introduction Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against factor VIII (FVIII). The most common IST treatment used are Steroids-based regimens. However, patients with AHA are often elderly with comorbidities. Steroids-based regimens have significant side effects in patients with AHA. In particular, the risk of dying from infection appears to be higher than the risk of fatal bleeds today. This dilemma highlights the lack of safe and rapid response IST therapy in AHA. Bortezomib targets plasma cells rather than B cells and has reported efficacy in refractory AHA. It is an attractive agent because it depletes plasma cells that can continue to produce autoantibody even after CD20-positive B cells have been depleted by rituximab. The combination of bortezomib and rituximab regimen showed rapid response without severe adverse event in refractory and relapsed warm autoimmune hemolytic anemia. This phase 2, prospective, single-center study was designed to evaluate the efficacy and safety of rituximab and bortezomib (RB) treatment regimen in newly diagnosed AHA patients. Methods All patients 18 years of age or older who met the following criteria were considered as eligible candidates for this study: 1) plasma FVIII activity (FVIII:C) <50 l/dl, detectable inhibitor to FVIII. 2) newly diagnosed without any IST treatment. After obtaining the written informed consent from the patients, the information of demographic and medical history were collected and laboratory tests were performed.The patients were received the following regimens: Rituximab 375mg/m2 intravenous infusion on day 0 and bortezomib 1.3 mg/m2 subcutaneous on day 1,4,8,11. Best supportive care, including administration of hemostatic treatment and blood product transfusions if needed were used. Safety was evaluated according to NCI-CTCAE v4.0. Results From March 2018 to May 2022, 30 patients were eligible for the study. The baseline characteristics of the patients are summarized in Table 1. Overall, 19 patients were male (63.3%). The median age was 53.5 years (range 22 - 90 years). The underlying disorders that could be associated with AHA included rheumatoid arthritis, systemic lupus erythematosus and pemphigus. One patient was diagnosed at her postpartum. One patient was diagnosed soon after surgery. Traditional Chinese medicine was suspected as the inducement in one patient. No patient in our cohort was reported to have coexisting malignancy. 24 patients (80.0%) were regarded as idiopathic AHA. The median time from disease onset to the diagnosis was 36.5 days (range 10-249 days). The median FVIII activity at baseline was 1.5 IU/ml (range 0 to 10.4 IU/ml), and the median inhibitor concentration was 25.6 BU/ ml (range 2.7 to 600 BU/ ml). The bleeding event that precipitated diagnosis was reported as spontaneous in 27 patients (90.0%), by surgery in 3 patients (10.0%). All patients presented with bleeding diathesis as listed in Table 1. Sixteen patients (61.5%) received haemostatic treatment for initial bleeding, all of them received prothrombin complex concentrate (PCC). Nine patients experienced further bleeding after the treatment of BR. All patients completed protocol treatment. Overall, 23 patients (76.7%) achieved CR, 6 patients (20.0%) achieved PR and 1 patients died of cardiac events 3 month after last dose of bortezomib. The ORR was 96.7%. Median time to CR was 74 days (range 12-179 days). After a median follow-up of 39 months (range 3-50 months), one patient had relapse of the disease, 2 months after achieved CR. Major toxicities and adverse events are summarized in Table 2. One patient (3.8%) had grade 3 neutropenia; One patient (3.8%) had grade 4 thrombocytopenia and grade 3 thrombocytopenia each. Eight patients experienced infectious fever, including 2 grade 3 and 2 (7.7%) grade 4. Five patients (19.2%) developed grade 1-2 peripheral neuropathy.No treatment-related deaths occurred. Conclusion Here we report the results of a phase 2 prospective study of newly diagnosed AHA. This study confirmed that rituximab plus bortezomib was an efficient and safe regimen with ORR of 96.7%, and the median time to CR was 74 days.This trial was registered at www.clinicaltrials.gov as #NCT03700229. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Emicizumab for the treatment of acquired hemophilia A: Retrospective review of a single-institution experience.

Acquired haemophilia A (AHA) is a rare and potentially life-threatening bleeding disorder arising from autoantibodies that inhibit coagulation factor VIII (FVIII). Treatment entails achieving haemostasis with bypassing agents or factor replacement, and eradication of the inhibitor with immunosuppressive therapy (IST). Due to the rarity of AHA, there are few prospective data to guide management. We present a retrospective report of 11 AHA patients treated with emicizumab, a FVIII-mimetic bispecific antibody, administered at 3mg/kg weekly for 4 weeks in conjunction with rituximab-based immunosuppressive therapy. The chromogenic FVIII inhibitor assay was used to assess for inhibitor eradication. The median follow-up was 13.9 months. The median number of days of additional haemostatic therapy or red blood cell transfusions after initiating emicizumab was 2 (range 0-15). The median was 0 days (range 0-8) for patients who did not require vascular embolization to achieve haemostasis. Eight patients achieved a complete remission (defined as recovery of FVIII activity to>50% with a negative inhibitor test in the absence of haemostatic and IST); two patients achieved a partial remission (FVIII activity>50% but with detectable inhibitor); one patient experienced refractory disease. One patient experienced rebleeding and two patients experienced inhibitor recurrence. No thrombotic, thrombotic microangiopathic or infectious complications occurred. Our observations suggest emicizumab can facilitate haemostasis for AHA patients and be combined with safer, lower-intensity immunosuppressive therapies to achieve remission.

Usefulness of anti-factor VIII IgG ELISA in acquired hemophilia A follow-up.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder due to the presence of neutralizing autoantibodies directed against the coagulation factor VIII (FVIII). The reference method to detect and quantify anti-FVIII antibodies is the Bethesda assay (BA), but it presents some limitations such as a lack of sensitivity for low titers of inhibitor and the need for experienced laboratory. A commercially available ELISA detecting anti-FVIII antibodies has demonstrated excellent sensitivity and specificity. The aim of our study was to assess the performance of this ELISA for the detection of anti-FVIII IgG in AHA patients during the follow-up. In total, 11 acquired hemophilia A patients were recruited, and anti-FVIII antibody levels were monitored by BA and ELISA. Anti-FVIII IgG ELISA showed 100% sensitivity and 100% specificity, and it correlated with the BA. Discrepancies observed in 13.3% of cases were consistent with patients' biological evolution. All these data suggest the possible use of anti-FVIII IgG ELISA for both diagnosis and follow-up of AHA patients.

Acquired Hemophilia A In Adults: A Multicenter Study from Turkey.

Acquired hemophilia A (AHA) is a rare disease caused by autoantibodies inhibiting factor VIII (FVIII) activity. Although the conditionis usually idiopathic, there may be other underlying diseases. Treatment consists of two steps: treatment of acute bleeding and immunosuppression. In this multicenter study, we aimed to demonstrate the clinical characteristics, management details, and survival of AHA patients in Turkey. Data was collected from eleven centers in Turkey. aPTT, FVIII, FVIII inhibitor, and hemoglobin (HB) levels, mixing test results, and demographics at diagnosis, treatment information, adverse events, bleeding episodes during follow-up, relapses, and outcome were analyzed. Twenty-nine patients were analyzed (58.6% female). No underlying disorder could be detected in 14 patients. The most prevalent etiologies were pregnancy, malignancy and infections. The median FVIII activity and FVIII inhibitor titer at diagnosis were 0.7% (0.0-29.4%) and 32.6 BU (0.6-135.6 BU) respectively. Bleeding was severe in 44.8% of patients. The HB value was significantly lower in patients with severe bleeding. Most of the patients (n = 25, 86.2%) had only one bleeding episode without relapse, three patients (10.3%) had two bleeding episodes, and one patient had more than three bleedings. 21 (75%) patients received hemostatic therapy. The use of recombinant FVIIa was slightly higher than activated prothrombin complex concentrate (15 versus 10 patients). Immunosuppressive treatment was initiated in 26 (93%) patients. Regimens containing steroid, cyclophosphamide, and rituximab in different combinations were the most preferred. The median follow-up period was 13 months (2-156 months). Median overall survival was 154.97 months. Four and six-year survival were 90.9 ± 0.8% and 77.9 ± 14.1% respectively. This is a unique study that investigated the demographic characteristics, treatment approaches, and patient survival of AHA in Turkey.

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

Introduction:Acquired hemophilia A (AHA) is a rare disorder characterized by severe, spontaneous bleeding caused by autoantibodies against factor (F)VIII (inhibitors). It is known that onset of AHA is triggered by malignancy, autoimmune disease, dermatological disease, and pregnancy/delivery. As the standard therapy, immunosuppressive therapy (IST) should be started immediately to eliminate inhibitors and hemostatic therapy is also necessary in case of bleeding. Many patients require prolonged bed rest because of the bleeding risk; therefore, it is difficult to determine the best time to start rehabilitation. Additionally, the early deaths and high thrombotic rates are frequently reported in AHA. Since it is a rare disorder, the actual situation has not been fully clarified. This study was to describe the epidemiology and clinical practice of AHA in the real world using a large health claims database in Japan.Methods:This was a retrospective observational study using a health claims database provided by Medical Data Vision Co., Ltd. The data period was Apr. 2008-Mar. 2020. Patients who met all of the following criteria were included; patients with disease diagnosis of AHA; patients were hospitalized on the day of AHA diagnosis; and patients had immunosuppressants on/after the date of the first hospitalization. The first date of hospitalization was set as an Index date. Patients with disease diagnosis code of antiphospholipid syndrome, lupus anticoagulant, acquired factor XIII deficiency, acquired von Willebrand disease, or acquired factor V deficiency were excluded. Treatment/procedure patterns (IST, hemostatic therapy, and rehabilitation) and clinical outcome (Activities of Daily Living [ADL], death, and thromboembolism in the hospitalization) in AHA patients were investigated.Results:The study population of 338 patients (214 males: 124 females) was with the mean age of 75.7 (21-96) years. A total of 105 patients (pts) (31.1%) had concurrent diseases, including malignancy (61 pts, 18.0%), autoimmune diseases (40 pts, 11.8%), and dermatological diseases (18 pts, 5.3%). In bypassing agent use (153 pts, 45.3%), recombinant activated factor VII (rFVIIa) was the most frequently used (129 pts, 38.2%) followed by activated prothrombin complex concentrate (aPCC) (36 pts, 10.7%), and plasma-derived factor VIIa and factor X (FVIIa/FX) (14 pts, 4.1%). FVIII agent uses (8 pts) were very few. Median duration of treatment for bypassing agents ranged from 2.5 (FVIIa/FX) to 6.0 (aPCC) days. Steroids alone were used predominantly in the first line for immunosuppression (292 pts, 86.4 %) and oral prednisolone was the most frequently used. The category of rehabilitation most commonly implemented in AHA patients was disuse syndrome (104 pts, 30.8%) followed by locomotor (73 pts, 21.6%) and cerebrovascular (49 pts, 14.5%). Median time (days) from Index date to initiating rehabilitation was 16.5 for disuse syndrome, 23.0 for locomotor, 19.0 for cerebrovascular. In the total ADL scores (Barthel Index) in 196 patients with all 10 items, the proportions of patients with less than 70 points were high at both initial admission and final discharge (47.4% and 38.8%, respectively). The median number of times and length of hospitalization were 1.0 time and 62.0 days, respectively. Of evaluable population (328 pts), thromboembolism during hospitalization was recorded in 15 patients, by type of which disseminated intravascular coagulation (10 pts, 3.0%) was the most frequently recorded. Acute coronary syndrome (3 pts, 0.9%), pulmonary embolism and other (1 pt, 0.3%, each) were fewly recorded. The proportion of deaths during hospitalization was 18.6% (63 pts). Table 1 shows study result summary.Conclusions:This was the first study in a large AHA population using a health claims database in Japan. From an epidemiological point of view, the number of male patients was slightly larger and the mean age was slightly higher compared to the demographics in previous reports. The possible reason is regional variance or data source, whereas, the treatment patterns and the proportion of deaths during hospitalization are mostly aligned with the previous studies. Also this was the first report publishing the data on ADL and rehabilitation in AHA patients. The results showed that it took median 2-3 weeks to start rehabilitation. Further development of treatment strategies to enable early start of rehabilitation is awaited. [Display omitted] DisclosuresOgawa: Chugai Pharmaceutical Co., Ltd.: Consultancy. Amano: Chugai Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Bioverativ Inc.: Speakers Bureau; Bayer AG: Speakers Bureau; Shire Plc: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau; Sanofi S.A.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer Inc.: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau. Matsuo-Tezuka: Chugai Pharmaceutical Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Yamaguchi-Suita: Chugai Pharmaceutical Co., Ltd: Current Employment. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure:Data on the uses of cyclophosphamide, cyclosporin A, and rituximab for acquired hemophilia may be included in the poster presentation. However, with regard to these drugs, treatments for other diseases may also be included because this study was conducted with a secondary use of a health claims database. Off-label drug use is explained in the poster.

Clot characterization by multidisciplinary approach: biochemical and imaging parameters in a hypocoagulative setting. A pilot study.

BackgroundClot characterization is, to the present days, a multimodal approach: scanning the clot by electron microscopy (SEM) is helpful for the visualization of fibrin structure along with laboratory parameters such as the clot waveform analysis (CWA) and thrombin generation in different settings of clot abnormalities. This study aimed to assess whether the coagulative parameters were consistent with the clot images texture acquired by SEM, and therefore to propose a more generalist and integrative approach to clots classification.Design and methodsIn this pilot study, the examined population consists of eight healthy subjects, seven patients affected by Acquired Hemophilia A (AHA) and seven patients treated with Vitamin K Antagonists (VKAs), similar for age and gender. We studied the velocity and acceleration (1st and 2nd derivative of the aPTT) of clot formation (CWA), the thrombin generation, and the clots’ scanning by SEM. Images acquired with SEM were then analyzed with the MATLAB software with the “Texture Analysis” methods to perform classification. Among the various texture parameters, we reported Contrast and Energy.ResultsSignificant differences among healthy subjects, patients with AHA and those treated with VKAs were detected for the coagulative parameters. We found no differences between VKAs and AHA patients. Contrast and energy highlighted a significant difference among the three groups in agreement with the laboratory's parameters. We found no significant differences between VKAs and AHA patients.ConclusionsThe use of SEM, CWA and thrombin generation parameters may be a starting point for studies aimed to demonstrate the general characteristics of clot formation in different clinical conditions with a multiparametric approach.

Clinical Outcomes of Acquired Factor VIII Inhibitors in Cancer Population: A Systematic Review

Background: In cancer patients, the development of autoantibodies against coagulation factors is a rare but a life-threatening bleeding disorder. Acquired hemophilia A (AHA) is the most common subset of the disorder and is caused by the inhibitory antibodies against coagulation factor VIII (FVIII) activity which can cause significant bleeding diathesis in those patients. Therefore, a prompt diagnosis is necessary for management of controlling the suppression of the inhibitor and the bleeding diathesis.Aims: We conducted a systematic review to study the occurrence of FVIII inhibitors in cancer patients, particularly their clinical outcomes and treatment responses.Methods: We performed an electronic search through March 31, 2017 with search terms “acquired hemophilia factor VIII inhibitor and cancer”, “acquired hemophilia A” in PUBMED and EMBASE. Manuscripts with unavailable details, other coagulation factor inhibitors, hereditary cases and in other languages were excluded. The primary endpoint was measuring clinical response to treatments as defined by reduction of at least 50% in the baseline FVIII inhibitor level. Secondary endpoints were identifying early (defined a time to response ≤ 1.5 months from the initiation of therapy) vs. late responders to treatments and overall survival (OS) between responders and non-responders.Results:47 cases of AHA associated with malignancies were analyzed. Several cancer and hemophilia characteristics were compared between treatment responders and non-responders. Findings include 68% males, median age 70 (58-74), hematologic vs. solid malignancy of 62% vs. 38%, median FVII inhibitor level 14 BU/mL. The most common therapy used to eradicate the inhibitor was immunosuppressive therapy; differences in treatment modalities did not result in significant differences between responders and non-responders (Table 1). Treatment responders have lower median FVII inhibitor level as compared to non-responders (12 vs. 41 BU/mL; p = 0.027). There was equal number of cases for early and late responders. Median OS for responders was 41 months with 95 % CI [10.7-71.3] vs. 2 months for non-responders with 95% CI [1.3-2.7].Conclusion:The amount of inhibitor overall seems to be the best predictor of clinical outcomes in AHA patients regardless of the type of therapy used and the type of malignancy. Earlier detection of FVIII inhibitors could lead to earlier interventions with suppression therapy, potentially improving outcomes. Larger studies are needed to confirm our findings. [Display omitted] DisclosuresRojas Hernandez:Daichii Sankyo: Research Funding. Oo:Daichii Sankyo: Research Funding.