Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial.

BACKGROUND: Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease. METHODS: VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045. FINDINGS: Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%]). INTERPRETATION: These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience. FUNDING: National Heart Lung Blood Institute (National Institutes of Health).

Hemophilia A (Factor VIII Deficiency).

Remarkable changes are occurring in the diagnosis and management of individuals with hemophilia A. Genetic testing, including next-generation sequencing, enables family planning, carrier testing, and prenatal diagnosis. Musculoskeletal ultrasound examination facilitates the early detection of acute bleeds and joint disease in clinic, enabling more rapid bleed resolution and treatment planning. Novel therapies offer simpler weekly or monthly administration, some by subcutaneous injection, with better compliance and quality of life, as well as fewer bleeds. Gene therapy provides a 1-time phenotypic "cure" that is cost effective, but may be complicated by waning levels, vector immune responses, and hepatotoxicity.

Peri-procedural Anticoagulation in Patients with Head and Neck Versus Extremity Venous Malformations.

OBJECTIVE: (1) Review a multidisciplinary vascular anomalies center's practice regarding periprocedural anticoagulation for venous malformations (VM) and the associated risk of thromboembolic and disseminated intravascular coagulation (DIC) events. (2) Compare the risk of thromboembolic events and DIC post-procedure between head and neck (H&N) and extremity VM patients. METHODS: An Institutional Review Board (IRB)-approved, retrospective chart review was performed on 120 VM patients. A thromboembolic event was defined as a thrombus formation post-sclerotherapy or post-surgery within 2 months in a distant or local venous structure not directly addressed by the procedure. RESULTS: There were 39 cases involving the H&N and 81 cases based at the extremities. There were eight cases of post-procedure thrombus formation within the extremity VM group (8/71; 11.3%) as opposed to 0 cases in the H&N group (OR: 0, 95% CI .00-.09), p = .049. There was no difference in incidence of post-procedure thromboembolic events between those with elevated D-dimer (H&N: 0%, extremity: 22.7%, 5/22) and normal D-dimer values (H&N: 0%, extremity: 6.3% [1/16], P = .370). There was no difference in incidence of post-procedure thromboembolic events between those who received periprocedural anticoagulation (H&N: 0%, extremity: 21%, 4/19) and those who did not (H&N: 0%, extremity: 8.2%, 4/49), (Extremity: OR: 3.00, .67-13.50, P = .206). CONCLUSION: Post-procedure thromboembolism is rare in the treatment of venous malformations, especially in the head and neck subsite. Regardless of anticoagulation use, there were no thromboembolic events for H&N VM patients. Such events are rare, and the odds may approach zero, especially with small sample size. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1163-1167, 2021.

Observational study of recombinant factor VIII-Fc, rFVIIIFc, in hemophilia A.

INTRODUCTION: rFVIIIFc (Eloctate) is an extended-half-life recombinant factor VIII-Fc fusion protein that may promote factor VIII (FVIII) tolerance through Fc immunoregulatory properties. Yet, little is known regarding its immunogenicity in patients with hemophilia A (HA) or in HA with inhibitors (HA-I), including tolerized, immune tolerance induction (ITI)-refractory, or ITI-naïve. METHODS: We reviewed medical records of 60 patients, including 2 previously-untreated patients (PUPs) and 58 previously-treated patients (PTPs), cared for between 01/01/06 and 06/01/17, on whom anti-FVIII antibody data were available before and after initiating rFVIIIFc. Continuous data were analyzed by student's t-test, and discrete data by chi square or Fisher's exact test. RESULTS: After initiating rFVIIIFc, one of two HA PUPs developed a low-responding (LR) inhibitor after 10 exposures, which resolved (anti-VIII<0.6 B.U.) within 8 additional exposures, while none of 41 HA PTPS developed an inhibitor. Among 19 HA-I PTPs with detectable inhibitors prior to rFVIIIFc, 5 developed an anamnestic response to rFVIIIFc, including 1 of 8 (12.5%) low-responding (LR), and 4 of 9 (44.9%) high-responding (HR), of whom 3 were ITI-naïve and 1 ITI-refractory. Inhibitors resolved in 4 HR within 2 months of continuing rFVIIIFc (median) but persisted in 1 LR at low titer. The remaining 11 HA-I PTPs, including 4 HR and seven LR, had no detectable inhibitor at the time of or after initiating rFVIIIFc. DISCUSSION: rFVIIIFc was immunogenic in HA PUPs and in HA-I PTPs persistently ITI-naïve or ITI-refractory, with inhibitor resolution in the majority. rFVIIIFc immunogenicity appears to be similar to other FVIII products.

Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors.

INTRODUCTION: Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA-I). As emicizumab differs biochemically from FVIII, there is interest in its real-world haemostatic efficacy. AIM: To describe real-world patient experience with emicizumab by retrospective chart review. METHODS: We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi-square or Fisher's exact test for discrete data. RESULTS: A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA-I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4-week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P = .251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved. DISCUSSION: Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA-I experienced improved health.

Pipeline Embolization of an Infectious Basilar Artery Aneurysm in a 2-Year-Old Child: Case Report, Discussion of the Literature and Perioperative Considerations.

BACKGROUND AND IMPORTANCE: Flow diversion of intracranial aneurysms has been rarely described in the pediatric population. Here we discuss the technical and perioperative complexities inherent in the flow diversion of an infectious basilar apex aneurysm in a 2-yr-old child with significant medical comorbidities. CLINICAL PRESENTATION: Following judicious oral administration of dual anti-platelet agents and intra-arterial administration of calcium channel blockers to treat vasospasm, standard endovascular procedures were used to place a flow diverting stent across the neck of a rapidly enlarging infectious aneurysm of the basilar apex.Following the uncomplicated procedure, the patient demonstrated progressive thrombosis of the previously noted basilar apex aneurysm over a 3-mo period. The patient was therefore felt to be safe to proceed with, and eventually underwent, uncomplicated orthotopic heart transplant. CONCLUSION: Flow diversion of complex intracranial aneurysms in pediatric patients with significant medical comorbidities is feasible and safe; however, considerations have to be made in the pre- and perioperative care of these patients given the propensity for low-weight and complicated systemic disease processes.

Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon in an infant: Successful treatment with prednisolone, vincristine, and addition of sirolimus.

A full-term newborn with kaposiform hemangioendothelioma (KHE) affecting the right thigh with thrombocytopenia due to Kasabach-Merritt phenomenon (KMP) was referred to our center. After biopsy, he rapidly evolved to severe thrombocytopenia and severe coagulopathy. Standard therapy was initiated with prednisolone and vincristine. His coagulopathy worsened to life-threatening hemorrhage necessitating aggressive blood products replacement. Sirolimus was added; he became transfusion independent with no further bleeding and reduction in tumor size. Addition of sirolimus to treatment of vascular anomalies with hemostatic complications should be considered as part of early treatment for patients with KMP/KHE.

Anticoagulant therapy in head injury-associated cerebral sinovenous thrombosis in children.

BACKGROUND: Head injury is a risk factor for cerebral sinovenous thrombosis (CSVT) in children. Literature concerning head injury-associated CSVT (HIA-CSVT) is scarce. Data supporting safety and efficacy of anticoagulant therapy (ACT) in childhood CSVT is emerging. However, intracranial hemorrhage (ICH) occurs frequently in children with HIA-CSVT at diagnosis making initiation of ACT controversial due to the fear of worsening of ICH. PROCEDURE: We conducted a retrospective descriptive review of a consecutive cohort of children with HIA-CSVT from 1998 to 2012. RESULTS: Twenty patients (14 males, mean age 7 years) with HIA-CSVT were identified. Most (19/20 [95%]) had significant ICH at diagnosis. None received ACT at diagnosis. Fourteen (70%) were later (median 7 days post-trauma, range 2-48 days) treated with ACT due to CSVT persistence (nine) and propagation (five), despite ICH in 13. None of the treated patients, including the 13 with pre-existing ICH, had significant worsening of hemorrhage. Three (21%) treated patients had minor asymptomatic extension of their hemorrhage and further ACT was withheld. No patient died while on ACT. No patient experienced CSVT propagation on ACT. Clinical outcomes were normal (no neurologic deficits) in 5/20(25%), mild neurological deficits in 10/20(50%), and moderate-severe neurological deficits in 5/20(25%). Small sample size did not permit assessment of the effect of ACT on outcome. CONCLUSIONS: Anticoagulant therapy is safe in selected children with HIA-CSVT. ICH is not an absolute contraindication to ACT in children with HIA-CSVT.

Complicações e características sociais dos pacientes submetidos a vasectomia no Hospital do Servidor Público Municipal

A vasectomia é um método contraceptivo com eficácia elevada (99,5%) e baixa morbidade. Apesar destes fatos, é menos freqüente executada do que a esterilização feminina. Sua complicação mais comum é a dor testicular crônica, que varia de 1 a 18% dos pacientes, perturbando suas atividades do dia-a-dia. O nível de satisfação com vasectomia é aproximadamente 71%, oferecendo a melhoria na vida sexual dos casais. No serviço da assistência familiar do Hospital do Servidor Público Municipal de São Paulo nós verificamos que a vasectomia é a opção selecionada quase pela metade dos casais submetidos para avaliação cirúrgica da contracepção. A maioria dos casais que escolheram a alternativa da ligadura tubária (80%) eram compostos por mulheres grávidas submetidas a uma cesariana no mesmo procedimento