Post-viral idiopathic purpura fulminans is associated with inherited thrombophilia and anti-cardiolipin antibodies.

Introduction: Idiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication. Method: This is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aß2GP1). Results: Among the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aß2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.

Characterizing hospital pathways for the care of acquired hemophilia in France using comprehensive national health data.

PURPOSE: Acquired hemophilia (AH) is a rare, serious bleeding disorder most often associated with older age and life-threatening complications. The patient care pathway for AH is complex because of the different types of bleeding, the presence of comorbidities, and the heterogeneity of medical specialists who care for these patients. METHODS: This observational study used the French national PMSI (Programme de médicalisation des systèmes d'information) database to characterize patients with AH in real-life practice and analyze their hospital pathway. In total, 180 patients with AH were identified over a 5-year study period (January 2010 to December 2014), based on three criteria: bypassing agent use, International Classification of Diseases, 10th revision code allocation, and aged over 65 years. Comparison of the incidence rate of AH versus registry data validated the PMSI as an epidemiological database. RESULTS: Rituximab was prescribed more often (60/180; 33.3%) than expected following guidelines and was associated in half of cases to early infections (32/60; 53.3%), surgery procedures were frequently performed during the year before AH onset (29/159; 18.2%), which may suggest a triggering effect, extended hospital stays (median: 20 days) and mortality remaining high (66/180; 36.7%) that occurred mainly during the first month after AH diagnosis. Median costs and number of injections were comparable between recombinant activated factor VII and plasma-derived activated prothrombin complex concentrate. CONCLUSION: These findings could inform future medico-economic approaches in this AH population (duration of stays, bypassing agents, rituximab use, comorbidities, hospitalizations with infections).

[Time in therapeutic range (TTR) and follow-up of patients on vitamin K antagonist: A cohort analysis]. / Utilité du TTR (temps passé dans la cible thérapeutique) dans le suivi des patients sous antivitamine K : analyse d'une cohorte de patients.

INTRODUCTION: Despite the increasing utilization of direct oral anticoagulant (DOAC) prescriptions, vitamin K antagonists (VKAs) remain the treatment of choice for treating and preventing thromboembolic events. The morbidity and mortality of VKAs are partly due to the difficulty of keeping the patient within the therapeutic range. For patients treated by VKA, time in therapeutic range (TTR) is a quality parameter of treatment, widely used in clinical trials but rarely by prescribers. It is well established that its use correlates with the risk of hemorrhage, thrombosis or mortality. We studied this parameter in a cohort of patients to evaluate the quality of their therapeutic follow-up and tried to identify risk factors for low TTR. METHODS: The study was made in collaboration with LaboSud Oc Biologie for a duration of 4 months. It included 3387 patients representing 2,4029 INR. We calculated the patients' TTR. The laboratory transmitted to us the sex and age of each patient and the VKA molecule used, the therapeutic range and the specialty of the prescriber. We then analyzed the odds ratio associated with these different factors. RESULTS: The mean TTR was 68%, close to the TTR recommended by scientific societies. Patient's sex was the only statistically correlated factor, with a worse equilibrium in females taking VKAs (OR=1.22, 95% CI: 1.06-1.39, P=0.00552). Many factors usually correlated with poor equilibrium under VKA have not been studied due to lack of information. CONCLUSION: Given the context of economic restriction and the TTR of our cohort close to the recommended 70%, there would be no benefit in terms of safety to prefer DOAC for the patients involved in this study. Regular monitoring of the individual patient's as well as the cohort's TTR should optimize the management of patients receiving VKAs.

[Direct oral anticoagulants (DOACS): A necessary focus]. / Anticoagulants oraux directs (AOD) : une mise au point nécessaire.

In 2008, we decided to enter the era of direct oral anticoagulants (DOACS). Was that the right decision to make? The answer will depend on how well we meet the conditions of proper use. This means avoiding underdosing and overdosing as well as understanding how DOACS were validated so that our prescriptions fulfill their role in the management of thrombotic disease.

PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding.

INTRODUCTION: Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS: A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 µg/kg or 225 µg/kg initial doses with 75 µg/kg subsequent doses by schedule were administered until clinical response. RESULTS: The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 µg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 µg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION: The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

[Vitamin K antagonist, direct oral anticoagulants: Where is the truth?] / Antivitaminiques K, anticoagulants oraux directs : où est la vérité ?

Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) are now in competition. The companies are trying to replace VKA by DOACs, totally or at least greatly VKA should VKA disappear in favor of DOACs? There are still many questions about DOACs. The purpose of this article is to make a well-considered decision in this area. The aim is not to denigrate one or the other but to share things between these two families of anticoagulants. Physicians using these drugs must have a full knowledge about compared efficacy and safety. We feel necessary to increase distance between effective results of the clinical trials and industrial communication around DOACs.

Rare coagulation disorders: fibrinogen, factor VII and factor XIII.

Rare coagulation disorders (RCDs) include the inherited deficiencies of fibrinogen, factor (F) II, FV, combined FV and VIII, FVII, FX, combined FVII and X, FXI, FXIII and combined congenital deficiency of vitamin K-dependent factors (VKCFDs). Despite their rarity, a deep comprehension of all these disorders is essential to really understand haemostasis. Indeed, even if they share some common features each RCD has some particularity which makes it unique. In this review, we focus on three disorders: fibrinogen, FVII and FXIII.

Circulating FVIII-specific IgG, IgA and IgM memory B cells from haemophilia A patients.

INTRODUCTION: Approximately, 25% of haemophilia A (HA) patients treated by factor VIII (FVIII), develop antibodies, known as inhibitors, neutralizing the activity of infused FVIII. This immune response involves B cells (BC), including FVIII-specific memory B cells (MBC). Production of anti-FVIII antibodies after stimulation of FVIII-specific MBC suggests a role of these cells in the immune response to FVIII. Animal models allowed the study of circulating FVIII-specific cells, however few data are available on HA patients. AIM AND METHODS: In the present study, we simultaneously detected, via ELISpot assay, different isotypes of MBC in the blood of HA patients, after polyclonal activation. Patients included: three with active inhibitors; three with a history of inhibitors; six without any past or active inhibitor. RESULTS: FVIII-specific MBC were detected in peripheral blood of HA patients: (i) patients with active inhibitors (IgG: 4-5.2/10(6) BC; IgA: 2.9-4/10(6) BC) (ii) patients with a past of inhibitors (no IgG BC; IgA: 5-7.5/10(6) BC) (iii) patients without inhibitors (no IgG BC or IgA BC except one patient had two FVIII-specific IgA BC/10(6) BC). CONCLUSION: FVIII-specific IgA MBC were detected in HA patients with past and current immune responses against FVIII and FVIII-specific IgG MBC were found only in those with positive inhibitors. This study shows the possibility to detect and characterize easily and simultaneously the MBC from patient blood and that MBC seem different according to anti-FVIII immune history. It could be a useful tool to study anti-FVIII response and Immune Tolerance Induction cellular mechanisms.

Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

INTRODUCTION: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. AIM: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. METHODS: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. RESULTS: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 µg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 µg kg(-1) (divided as three doses). CONCLUSION: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.

Influence of surgical bleeding on the relationship between admission coagulopathy and risk of massive transfusion: lesson from 704 severe trauma patients.

BACKGROUND: This study hypothesized that the relationship between early coagulopathy and massive transfusion (MT) in trauma was highly dependent on the presence of surgical bleeding. METHODS: Consecutive severe trauma patients admitted to our institution over a 4-year period were included in this retrospective study. Surgical bleeding was defined as an injury requiring an invasive endovascular or surgical haemostatic procedure. The ability of prothrombin time ratio (PTr) and activated partial thromboplastin time ratio (aPTTr) to predict MT (≥10 units of packed red blood cells during the first 24 h) was determined by ROC curves. The strength of association and interaction between PTr, surgical bleeding and MT was assessed using a logistic regression analysis. RESULTS: Among the 704 patients included (ISS 21·0 ± 16·2), MT rate was higher in patients with surgical bleeding than in those with no surgical bleeding (47% vs. 5%; P < 0·001). The global performance of PTr and aPTTr to predict MT was only fair in our study population (AUCs 0·83 and 0·81). MT rate was widely higher in the surgical bleeding group whatever the severity of coagulopathy (P < 0·001). PTr was found to be significantly associated with TM [PTr ≥ 1·5, OR 23·6 (95% CI 13·4-41·7); PTr 1·2-1·5, OR 3·0 (95% CI 1·7-5·3)]. Corresponding ORs were reduced after adjusting for the surgical bleeding: 12·1 (95% CI 6·5-22·5) and 2·1 (95% CI 1·2-4·0), respectively. However, no significant interaction was found regression models. CONCLUSION: The strength of association between MT and coagulation status on admission was found strongly influenced by surgical bleeding. The admission coagulopathy monitoring in trauma patients without considering the surgical bleeding does not allow a reliable determination of MT probability.

[Hemorrhagic congenital diseases: What can be the future of plasma-derived products against recombinants?]. / Maladies hémorragiques congénitales: quel avenir pour les dérivés plasmatiques par rapport aux recombinants et aux produits sanguins labiles ?

Until 1990, congenital hemorrhagic disorders were treated by plasma-derived concentrates. The first recombinant drug, recombinant factor VIII was available after this date and few years later recombinant factor IX could also be proposed to patients. The evolution of market share in France was different between these two drugs: while recombinant factor VIII took a large place in hemophilia A treatment (85%), plasma-derived factor IX represent 50% of the French market. In the next years, the arrival of long-acting antihemophilic factors may lead to the dramatically reduce the amount of plasma-derived antihemophilic factors used to treat hemophilia. For rare bleeding coagulation disorders, plasma-derived concentrates are still widely used, while they are the only concentrates available in most diseases. This situation is unlikely to evolve significantly in the next years.

Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A.

BACKGROUND: Hemophilia A (HA) is a congenital bleeding disorder resulting from factor VIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision. OBJECTIVES: To identify predictive markers of ITI efficacy. METHODS: The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n = 7] and ITI failure [n = 8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis). RESULTS: Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P < 0.018). ROC analysis showed that anti-A1 and anti-A2 Abs were the best at discriminating between outcome groups (area under the ROC curve of > 0.875). CONCLUSION: Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA.

[Carriers of haemophilia: Experience of a French university hospital]. / Conductrices d'hémophilie: expérience d'un CHRU en France.

OBJECTIVES: To report the management of carriers of haemophilia in a French university hospital and assess different issues of these patients. PATIENTS AND METHODS: Retrospective study of the carriers of haemophilia who consulted at the university hospital of Montpellier, France, between 1995 and 2011. Information were obtained from medical records and from a questionnaire sent to carriers. We recorded data about biological characteristics, bleeding tendency and management of pregnancies. RESULTS: Sixty-four carriers of haemophilia A or B were included. Their median FVIII or FIX level was 52 % (range, 15-137 %). Menstrual bleeding lasted more than 7 days in 31 % of carriers. A total of 142 pregnancies started in 54 carriers, and 101 resulted in live births with 26 boys with haemophilia. Sixty-two prenatal diagnoses carried out, 15 have terminated their pregnancy because of a hemophiliac male fetus. Seventy-six percent of deliveries were vaginal delivery and 49 % took place in a level-3 maternity. There were 10.8 % and 8.5 % primary and secondary post-partum hemorrhage, respectively. CONCLUSION: The risk of bleeding among carriers of haemophilia is associated with their antihemophilic factor level. To improve the management of carriers, a multidisciplinary and standardized medical record, with a specific questionnaire to evaluate bleedings, could be considered. A regional register that lists all carriers, regardless of their antihemophilic factor level, would also be useful.

Computer-predicted peptides that mimic discontinuous epitopes on the A2 domain of factor VIII.

Development of antibodies (Abs) against factor VIII (FVIII) is a severe complication of haemophilia A treatment. Recent publications suggest that domain specificity of anti-FVIII antibodies, particularly during immune tolerance induction (ITI), might be related to the outcome of the treatment. Obtaining suitable tools for a fine mapping of discontinuous epitopes could thus be helpful. The aim of this study was to map discontinuous epitopes on FVIII A2 domain using a new epitope prediction functionality of the PEPOP bioinformatics tool and a peptide inhibition assay based on the Luminex technology. We predicted, selected and synthesized 40 peptides mimicking discontinuous epitopes on the A2 domain of FVIII. A new inhibition assays using Luminex technology was performed to identify peptides able to inhibit the binding of anti-A2 Abs to A2 domain. We identified two peptides (IFKKLYHVWTKEVG and LYSRRLPKGVKHFD) able to block the binding of anti-A2 allo-antibodies to this domain. The three-dimensional representation of these two peptides on the A2 domain revealed that they are localized on a limited region of A2. We also confirmed that residues 484-508 of the A2 domain define an antigenic site. We suggest that dissection of the antibody response during ITI using synthetic peptide epitopes could provide important information for the management of patients with inhibitors.

Short-term and mid-term outcome of total ankle replacement in haemophilic patients.

BACKGROUND: Ankle arthropathy is very frequent in haemophilic patients. Prostheses are valuable alternatives to arthrodesis in non-haemophilic patients. We report the experience of a single centre in France on the use of prostheses in haemophilic patients. METHODS: Retrospective study of 21 patients with haemarthropathy who underwent ankle arthroplasty (32 ankles), with additional surgery, if needed, from July 2002 to September 2009 (mean follow-up 4.4±1.7 years). The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale was used to evaluate pain, function, ankle mobility and alignment. RESULTS: The overall AOFAS score improved from 40.2±19.4 (pre-surgery) to 85.3±11.4 (post-surgery). The function score increased from 23.6±7.7 to 35.9±6.7 and dorsiflexion from 0.3°±5.0° to 10.3°±4.4°. Two patients underwent further ankle arthrodesis. On X-ray, both tibial and talar components were stable and correctly placed in all ankles. Alignment was good. CONCLUSION: Ankle arthroplasty is a promising alternative to arthrodesis in haemophilic patients.