ABSTRACT
Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb‐IX‐V complex, a platelet receptor for von Willebrand factor (VWF). Most of ...the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.
We present a comprehensive spectrum of mutations of GP1BA (GPIbα), GP1BB (GPIbβ) and GP9 (GPIX) causing Bernard‐Soulier syndrome (BSS), a rare bleeding autosomal recessive disorder. Of the 211 families enrolled, 28% have mutations in GP1BA, another 28% in GP1BB and the remaining 44% in GP9. Excluding a few founder effects, most of the 112 different mutations identified are private. Missense variants, whose pathogenetic role should be determined through functional studies, accounts for more than half BSS alleles.
Abstract Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers–Danlos syndrome, clinically characterized by hyperextensible skin, easy ...bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30 kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.
Background
Turoctocog alfa is a recombinant Factor VIII used in patients with hemophilia A. The aim is to assess the real‐life evidence of turoctocog alfa in surgery.
Study Design and Methods
Data ...were extracted from a national database.
Results
Turoctocog alfa was used for 86 surgeries (49 major and 37 minor) in 56 patients. The results are expressed as medians (interquartile range).
Six (10.7%) patients had severe hemophilia A, four (7.1%) moderate, and 46 (82.2%) mild. For patients who underwent major surgeries, basal plasma FVIII coagulant activity (FVIII:C) levels were 15 IU.dL−1 (8–22). Eight (5–14) infusions were given, at a preoperative loading dose of 40.0 (35.0–45.5) IU.kg−1 and a total dose of 253.3 (125.0–507.0) IU.kg−1. In patients who underwent minor surgeries, basal FVIII:C levels were 18 IU.dL−1 (9–31). Two (1–3) infusions were required, at a preoperative loading dose of 34.0 (28.8–38.5) IU.kg−1 and a total dose of 73.7 (37.6–122.1) IU.kg−1. The overall clinical efficacy was judged excellent/good in 77 procedures (89.5%) and fair/poor in nine (10.5%). The fair/poor efficacy concerned seven patients (six mild hemophilia and one severe), for four urological surgeries, two dermatological procedures, one heart surgery, one ear‐nose‐throat procedure, and one dental avulsion in the patient with severe hemophilia. Three out of those seven patients received antiplatelet therapy. No thromboembolic events, anti‐FVIII antibodies, or adverse events were reported.
Discussion
The efficacy and safety of turoctocog alfa were confirmed for the management of surgery in patients with hemophilia A. No adverse events were observed and overall efficacy was good.
Abstract Introduction Dominant‐negative effects have been described for 10 F11 variants in the literature. Aim The current study aimed at identifying putative dominant‐negative F11 variants. Material ...and methods This research consisted in a retrospective analysis of routine laboratory data. Results In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant‐negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant‐negative effect. Our findings also do not support a dominant‐negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant‐negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. Conclusion Our data show that for some F11 variants recognized has having dominant‐negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild‐type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.
Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines ...recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.
Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. ...Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations.
We conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity <10 IU dL−1 were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.
Among 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0–35), and at inclusion it was 30 years (range: 15–63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.
Altogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines.
•Owing to its role in pregnancy achievement, factor XIII deficiency increases the risk of miscarriages.•Without prophylaxis, the rate of miscarriages is high in women with FXIII deficiency•Full term-pregnancies were observed in women with prophylactic regimen•Early infusion at least once a month leads to successful pregnancy outcome
Background
Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half‐life (rFVIII‐Fc), has been hypothesized to lower FVIII consumption in patients with severe ...Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life?
Method
MOTHIF‐II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII‐Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number.
Results
A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis.
Conclusion
The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII‐Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.
Introduction
Dominant‐negative effects have been described for 10 F11 variants in the literature.
Aim
The current study aimed at identifying putative dominant‐negative F11 variants.
Material and ...methods
This research consisted in a retrospective analysis of routine laboratory data.
Results
In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant‐negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant‐negative effect. Our findings also do not support a dominant‐negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant‐negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect.
Conclusion
Our data show that for some F11 variants recognized has having dominant‐negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild‐type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.
Introduction
Von Willebrand Disease is a common inherited haemorrhagic disorder due to a deficiency of Von Willebrand Factor (VWF). In case of surgical procedures in patients who are not responsive ...or have contraindications to desmopressin, replacement therapy with VWF concentrates is indicated. Until recently, only plasma‐derived VWF concentrates were available. A new recombinant VWF (rVWF) concentrate that contains no Factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France since 2018.
Aim
Describe real‐world experience of using rVWF in surgical procedures.
Methods
Sixty‐three surgeries for 55 patients were retrospectively analysed in 7 French haemostasis centres.
Results
During minor surgeries, the median (range) number of infusions was 1 (1–8) with a preoperative loading dose of 35 (19–56) rVWF IU/kg and a total median dose of 37.5 IU (12–288). During major surgeries, the median (range) number of infusions was only 3 (1–14) with a median preoperative loading dose of 36 IU (12–51) rVWF IU/kg, and a total median dose of 108 IU (22–340) rVWF IU/kg. The overall clinical efficacy was qualified as excellent/good in 61 of the procedures (97%), moderate in 1 (1.5%) and poor in 1 (1.5%). There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events, anti‐VWF antibodies or adverse events were reported.
Conclusion
This French ‘real‐world’ experience shows that a few infusions and low doses of rVWF provided effective prevention of bleeding in major and minor surgeries in inherited VWD, with no clinically significant safety concerns.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. However, studies of hospitalisation patterns with replacement treatment are scarce.
The aim of this study was to ...investigate the current therapeutic management of VWD and determine the key drivers of coagulation factor uses in patients during hospitalisation.
Hopscotch-WILL was a multi-centric retrospective study conducted over a 48-month period in any patients with VWD. The data were collected from the BERHLINGO Research Database and the French Hospital database.
A total of 988 patients were included; 153 patients (15%) were hospitalised during 293 stays requiring treatment with von Willebrand factor (VWF) concentrates-pure or in association with Factor VIII (FVIII). Their median basal concentrations of VWF and FVIII were significantly lower than in untreated patients: VWF antigen < 30 IU/dL, VWF activity < 20 IU/dL and FVIII:C < 40 IU/dL. The median (interquartile range) concentrate consumption was similar between highly purified VWF or VWF combined with FVIII (72 110 vs 57 89 IU/kg/stay, p = 0.154). The use of VWF was highly heterogeneous by VWD type; type 3 had a particularly high impact on VWF consumption in non-surgical situations. The main admissions were for ear/nose/throat, hepato-gastroenterology, and trauma/orthopaedic conditions, besides gynaecological-obstetric causes in women.
The use of VWF concentrates is mostly influenced by low basal levels of VWF and FVIII, but also by VWD type or the cause for hospitalisation. These results could inform future studies of newly released recombinant VWF.
PDF
