Oral surgery in people with inherited bleeding disorder: A retrospective study.

INTRODUCTION: The objectives were to describe the peri-operative management of people with inherited bleeding disorders in oral surgery and to investigate the association between type of surgery and risk of developing bleeding complications. MATERIALS AND METHODS: This retrospective observational study included patients with haemophilia A or B, von Willebrand disease, Glanzmann thrombasthenia or isolated coagulation factor deficiency such as afibrinogenemia who underwent osseous (third molar extraction, ortho-surgical traction, dental implant placement) or nonosseous oral surgery between 2014 and 2021 at Bordeaux University Hospital (France). Patients and oral surgery characteristics were retrieved from medical records. Odds ratio (OR) and 95% confidence interval (CI) were estimated using logistic regression. RESULTS: Of the 83 patients included, general anaesthesia was performed in 16%. Twelve had a bleeding complication (14.5%) including six after osseous surgery. The most serious complication was the appearance of anti-FVIII inhibitor in a patient with moderate haemophilia A. All bleeding complications were managed by a local treatment and factor injections where indicated. No association was observed between type of surgery (osseous vs. nonosseous) and risk of bleeding complications after controlling for sex, age, disease type and severity, multiple extractions, type of anaesthesia and use of fibrin glue (OR: 3.21, 95% CI: .69-14.88). CONCLUSION: In this study, we have observed that bleeding complications after oral surgery in people with inherited bleeding disorders were moderately frequent and easily managed. However, in this study, we observed a serious complication highlighting the necessity of a thorough benefit-risk balance evaluation during the preoperative planning of the surgical and medical protocol.

Surgery in rare bleeding disorders: the prospective MARACHI study.

Background: Despite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. Objectives: This multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. Methods: One hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto's bleeding score, and perioperative hemostatic protocols were collected. Results: Among the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). Conclusions: The current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

Five new F10 variants in hereditary factor x deficiency detected by high-throughput sequencing.

INTRODUCTION: Factor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10-gene variant database. AIM: This study aimed to describe new F10 variants. METHOD: The F10 gene was analysed in 16 consecutive families with FX deficiency by a targeted high-throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated to haematological malignancies. RESULTS: We identified 19 variants (17 missense, one nonsense and one frameshift) and two copy number variations. Two patients presenting a combined FVII-FX deficiency showed a loss of one F10 gene copy (del13q34) associated with a missense variant on the remaining allele, leading to a FX:C significantly lower than the FVII:C level and explaining their unusual bleeding history. We reported five novel variants. Three missense variants (p.Glu22Val affecting the signal peptide cleavage site, p.Cys342Tyr removing the disulphide bond between the FX heavy and light chains, and p.Val385Met located in FX peptidase S1 domain) were detected at compound heterozygosis status in three patients with severe bleeding symptoms and FX:C level below 10 IU/dL. Two truncating variants p.Tyr279* and p.Thr434Aspfs*13 leading to an altered FX protein were found at heterozygous state in two patients with mild bleeding history. CONCLUSION: This study showed the feasibility and the interest of high-throughput sequencing approach for rare bleeding disorders, enabling the report of F10 gene screening in a 3-weeks delay, suitable for clinical use. The description of five new variants may contribute to a better understanding of the phenotype-genotype correlation in FX deficiency.

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.

Prostate biopsy and prostate cancer management in patients with haemophilia: The experience of French Haemophilia Treatment Centres.

BACKGROUND: Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH). AIM: To describe PC screening and diagnosis, treatment modalities and bleeding complications in a group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs) PATIENTS AND METHODS: PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018. RESULTS: Among> 1549 > 50-year-old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe-moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post-prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC-based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found. CONCLUSION: Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long-term post-procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).

Guided Implant Surgery to Reduce Morbidity in Von Willebrand Disease Patients: A Case Report.

INTRODUCTION: Von Willebrand Disease is the most common inherited bleeding disorder. In the general population, 1/8000 patients are affected. Primary hemostasis (platelet adhesion) and coagulation (protection of Factor VIII) are altered. Among several bleeding symptoms, these patients suffer from excessive bleeding of oral mucosa and dental management requires a close collaboration between haematologists and oral surgeons. MATERIALS & METHODS: Guided implant surgery can be used to increase the accuracy of implant placement and to reduce the overall morbidity of this surgical procedure by using a flapless surgery technique. CASE REPORT: We report the case of a 49 years old woman having a Type 2A von Willebrand disease and who presented to replace tooth #.46 because of interradicular fracture and peri-apical infection. After planning the implant surgery using Codiagnostix® software, a surgical guide was prepared. The patient received 4 injections of von Willebrand factor (Willfactin®) for this particular surgical procedure. The implant was placed immediately after tooth removal and local haemostasis was performed. DISCUSSION: The follow-up was uneventful and the implant was restored by a crown 4 months later. Two cases of implant placement in haemophiliac patients have been reported before in the literature. CONCLUSION: As far as we know, this is the first case report of implant placement in a patient having a von Willebrand disease. The use of guided surgery allowed to perform a mini-invasive procedure and thus contributed to prevent bleeding complications in this patient.

Candida prosthetic infections: case series and literature review.

Candida prosthetic joint infections are considered to be rare. We retrospectively studied patients treated for Candida prosthetic infections between 1 January 1995 and 31 December 2007 in our infectious diseases department, a tertiary referral centre. We identified 7 patients, 4 with knee and 3 with hip prosthetic infections. The most frequent fungal agent was Candida albicans (4 cases), followed by Candida parapsilosis (2 cases) and Candida guillermondii (1 case). All the patients received antifungal treatment for a prolonged period. Five patients had their prosthesis removed and 3 had reimplantation, 1 patient was treated with debridement and prosthetic retention, and the last patient refused surgery. The mean follow-up time was 2.5 y. At the last evaluation, 3 patients were considered as cured, 3 patients presented a secondary bacterial infection leading to amputation for 2 of them, and 1 patient died from heart failure. During Candida prosthetic joint infections, the epidemiological characteristics and the location of the prosthesis are very similar to bacterial prosthetic infections. The benchmark antifungal therapies remain amphotericin B and/or fluconazole.