Post-procedural bleeding rate and haemostatic treatment use for dental procedures before and after the implementation of a standardized protocol for people with inherited bleeding disorders.

INTRODUCTION: Persons with inherited bleeding disorders are at a substantial risk of bleeding following dental procedures. AIM: To compare the outcomes and use of haemostatic treatment pre- and post-implementation of a standardized protocol for dental procedures at a Hemophilia Treatment Centre. METHODS: We conducted a retrospective cohort study of outpatient and inpatient dental procedures and maxillofacial surgeries sustained by people with bleeding disorders treated at a comprehensive Hemophilia Treatment Centre (2013-2020), comparing patients' outcomes before and after the introduction of the protocol in 2018. The protocol, built using a multidisciplinary approach, suggested haemostatic treatment based on the invasiveness of the dental procedure and the proposed anaesthesia. Our primary outcome was the rate of procedural bleeding leading to medical or dental reintervention within 10 days. Secondary outcomes included the use of systemic haemostatic treatment and treatment-related adverse effects. RESULTS: Overall, 137 dental procedures in 95 patients (median age: 29 years; 78% males; 74% haemophilia, 14% von Willebrand disease, 12% other disorders) were included. Seventeen procedural bleedings were reported (12.4%). Procedural bleeding occurred in 14.8% and 8.9% of patients in the control and intervention groups (p = .304). No major bleeding occurred. Tranexamic acid was used more consistently after protocol implementation (72.8% vs. 89.3%, p = .019), while factor concentrates use decreased (65.4% vs. 44.6%, p = .016), and desmopressin use remained constant (46.4% vs. 32.1%, p = .100). No treatment-related adverse effects were reported. CONCLUSION: The use of a standardized protocol increased the use of tranexamic acid, with a nonstatistically significant reduction in procedural bleeding rate.

Patterns of joint damage in severe haemophilia A treated with prophylaxis.

OBJECTIVE: The primary objective of this study was to assess whether there are different patterns (classes) of joint health in young boys with severe haemophilia A (SHA) prescribed primary tailored prophylaxis. We also assessed whether age at first index joint bleed, blood group, FVIII gene abnormality variant, factor VIII trough level, first-year bleeding rate and adherence to the prescribed prophylaxis regimen significantly predicted joint damage trajectory, and thus class membership. METHODS: Using data collected prospectively as part of the Canadian Hemophilia Primary Prophylaxis Study (CHPS), we implemented a latent class growth mixture model technique to determine how many joint damage classes existed within the cohort. We used a multinomial logistic regression to predict the odds of class membership based on the above predictors. We fitted a survival model to assess whether there were differences in the rate of dose escalation across the groups. RESULTS: We identified three distinct classes of trajectory: persistently low, moderately increasing and rapidly increasing joint scores. By multinomial regression, we found that only age at first index joint bleed predicted rapidly increasing joint scores. The rapidly increasing joint score class group moved through dose escalation significantly faster than the other two groups. CONCLUSIONS: Using tailored prophylaxis, boys with SHA follow one of three joint health trajectories. By using knowledge of disease trajectories, clinicians may be able to adjust treatment according to a subject's predicted long-term joint health and institute cost-effective programmes of prophylaxis targeted at the individual subject level.

Relapse pattern and long-term outcomes in subjects with acquired haemophilia A.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by neutralizing antibodies against factor VIII (FVIII). Despite significant initial morbidity and mortality, most patients achieve remission with immunosuppressive therapy. AIM: Long-term follow-up data from the Quebec Reference Centre for Inhibitors (QRCI) were analysed to identify factors predictive of AHA relapse and the influence of relapse on survival. METHODS: Criteria used to define AHA were levels of FVIII <0.3 IU/mL and FVIII inhibitor titres ≥0.6 Bethesda Units (BU). Complete remission was defined as FVIII >0.5 IU/mL and/or FVIII inhibitor titres <0.6 BU while not on immunosuppression. RESULTS: Between 2000 and 2012, 111 subjects met the inclusion criteria and were followed for a median of 25.6 months. Ninety per cent of them reached remission on immunosuppression in a median time of 45 days. Fourteen patients presented one or more relapses in a median time of 13.4 months. Most relapse episodes were successfully treated. Associated lymphoproliferative syndromes (LPS) were predictive of relapse, whereas FVIII activity and inhibitor titres at initial diagnosis or immunosuppressive regimens were not. The overall survival (OS) was the same, with or without relapse. CONCLUSION: Among the recognized potential risk factors for relapse, only LPS was statistically significant. The long-term follow-up of our patients also showed that late or multiple relapses may occur, but that relapse is not associated with a worse OS. Thus, long-term follow-up is important for optimal management of AHA.

Harvey and Gurvir's Law: Ontario Bill for Quality Prenatal Information about Down Syndrome: Terminology, Feasibility, and Ethical Issues.

Harvey and Gurvir's Law is a bill proposed to the Legislative Assembly of Ontario (Canada) to reduce stigma and bias associated with Down syndrome, by developing and disseminating quality information about Down syndrome in the context of prenatal testing.

Transcatheter Patent Foramen Ovale Closure in Stroke Patients with Thrombophilia: Current Status and Future Perspectives.

Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke as demonstrated in multiple large randomized clinical trials. However, these trials excluded a significant proportion of patients who could have benefited from percutaneous PFO closure due to coexisting potential confounders such as additional thromboembolic risk factors, namely thrombophilia. Since scarce and conflicting data existed on such patients, current clinical management guidelines on patients with PFO mainly recommended against PFO closure in patients with thrombophilia and failed to provide any recommendation on the type and duration of antithrombotic treatment after transcatheter PFO closure. In the past 2 years, there has been new evidence supporting transcatheter PFO closure as a clinically meaningful alternative (vs. medical treatment) in this high-risk group of patients, along with additional data supporting the important role of systematic screening for thrombophilia in PFO-associated cerebrovascular events. This review article provides an updated overview of the incidence, clinical characteristics and outcomes of PFO closure in patients with thrombophilia, also commenting on the most appropriate medical treatment after PFO closure and future perspectives in the field.

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation.

Montreal platelet syndrome (MPS), hitherto described in only one kindred, is a hereditary thrombocytopenia associated with mucocutaneous bleeding, giant platelets, and spontaneous platelet aggregation in vitro. These are features shared with some forms of type 2B von Willebrand disease (VWD); however, the MPS kindred had not been investigated for VWD. We found that all affected MPS family members had borderline to normal von Willebrand factor antigen (VWF:Ag; 0.43-0.75 U/mL), discrepantly low ristocetin cofactor activity (VWF:RCo; 0.16-0.29 U/mL), and normal factor VIII coagulant activity (FVIII:C; 0.57-1.04 U/mL). Unaffected family members all had normal VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, persons with MPS, but not unaffected family members, had loss of plasma (but not platelet) high molecular weight VWF multimers, and were heterozygous for the previously reported V1316M type 2B VWD mutation. Thus, in reevaluating this kindred, we determined that patients with MPS have type 2B VWD with the V1316M VWF mutation.

Magnetic resonance imaging in boys with severe hemophilia A: Serial and end-of-study findings from the Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: This study examined the structural outcomes for joints of boys with severe hemophilia A receiving frequency/dose-escalated primary prophylaxis using magnetic resonance imaging (MRI), and the importance of interval MRI changes. METHODS: Forty-six subjects (27 with interval studies) were evaluated by radiographs (X-rays) and mid- and end-of-study MRIs (using the International Prophylaxis Study Group scale), as part of the Canadian Hemophilia Prophylaxis Study. The primary outcome was the presence of MRI osteochondral findings. RESULTS: The median (range) time on study at the end-of-study MRI examination was 9.6 (4.8-16.0) years, during which 18 of 46 subjects (39%) had osteochondral changes in at least one joint. An interval change in MRI score of at least 1 point was observed in 44% of joints (43 ankles, 21 elbows, 4 knees); at least one joint showed this change in all 27 subjects. Self-reported interval hemarthrosis was associated with a higher likelihood of interval osteochondral change (odds ratio [OR], 1.49; 95% confidence interval [CI] = 1.08-2.06). Presence of synovial hypertrophy or hemosiderin on interval MRIs was associated with an OR of 4.71 (95% CI, 1.92-11.57) and 5.25 (95% CI, 2.05-13.40) of later osteochondral changes on MRI. DISCUSSION: MRI changes were seen in 39% of subjects. Interval index joint bleeding was associated with an increased risk of later MRI changes, and earlier soft-tissue changes were associated with subsequent osteochondral changes.

Hemophilia prophylaxis adherence and bleeding using a tailored, frequency-escalated approach: The Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: Standard of care for persons with severe hemophilia A includes regular replacement of factor VIII (FVIII). Prophylaxis regimens using standard half-life (SHL) FVIII concentrates, while effective, are costly and require frequent intravenous infusions. AIM: This study evaluated the adherence of 56 boys with severe hemophilia A to tailored, frequency-escalated prophylaxis with an SHL recombinant FVIII concentrate. METHODS: We reviewed the factor infusion and bleeding logs of study subjects. Adherence to the prescribed regimen was calculated on a weekly basis, and bleeding rates were determined from self/proxy-reported bleeding logs. The primary outcome was adherence to the prescribed prophylaxis regimen. RESULTS: The median (range of values [ROV]) weekly adherence to prophylaxis was 85.7% (37.4%-99.8%). The median (ROV) adherent weeks on steps 1 (weekly), 2 (twice weekly), and 3 (alternate-day) were 92.9% (50%-100%), 80.3 (32%-96%), and 72.6% (14%-98%); relative to step 1, subjects were less likely to be adherent on steps 2 and 3 (P < 0.00). On step 1, our cohort had higher adherence than previously reported rates. The median (ROV) adherence to the breakthrough bleeding protocol was 47.1% (0%-100%). At any given time, bleeding risk was reduced by 15% for each 10% increase in adherence during the preceding 12 weeks (hazard ratio, 0.85; 95% confidence interval, 0.81-0.90). CONCLUSION: This cohort had high rates of adherence to the prescribed prophylaxis regimen. Initiating prophylaxis with once-weekly infusions facilitated adherence to the prophylaxis regimen in this cohort of boys with severe hemophilia A started on primary prophylaxis at a very young age.

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

BACKGROUND: Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia. METHODS: In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344. FINDINGS: Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point during the study. INTERPRETATION: Tailored frequency-escalated prophylaxis leads to very little arthropathy and very good health outcomes within the WHO-ICF domains, and only uses a moderate amount of expensive clotting factor as compared with standard prophylaxis protocols. Some sequelae of bleeding were observed in our cohort, and future studies should consider a more stringent protocol of escalation. FUNDING: This study was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund. Subsequent renewals were funded by Bayer.

Enhanced thrombogenesis but not platelet activation is associated with transcatheter closure of patent foramen ovale in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: No studies have yet determined whether antiplatelet or anticoagulant therapy is the more appropriate treatment after transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. The objective of this study was to prospectively evaluate the presence, degree, and timing of activation of the platelet and coagulation systems after transcatheter closure of PFO in patients with cryptogenic stroke. METHODS: Twenty-four consecutive patients (mean age, 44+/-10 years; 11 men) with previous cryptogenic stroke who had undergone successful transcatheter closure of PFO were included in the study. Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin III (TAT) were used as markers of coagulation activation, and soluble P-selectin and soluble CD40 ligand were used as markers of platelet activation. Measurements of all hemostatic markers were taken at baseline just before the procedure and at 7, 30, and 90 days after device implantation. RESULTS: F1+2 and TAT levels increased from 0.41+/-0.16 nmol/L and 2.34+/-1.81 ng/mL, respectively, at baseline to a maximal value of 0.61+/-0.16 nmol/L and 4.34+/-1.83 ng/mL, respectively, at 7 days, gradually returning to baseline levels at 90 days (P<0.001 for both markers). F1+2 and TAT levels at 7 days after PFO closure were higher than those obtained in a group of 25 healthy controls (P<0.001 for both markers). Levels of soluble P-selectin and soluble CD40 ligand did not change at any time after PFO closure. CONCLUSIONS: Transcatheter closure of PFO is associated with significant activation of the coagulation system, with no increase in platelet activation markers. These findings raise the question of whether optimal antithrombotic treatment after PFO closure should be short-term anticoagulant rather than antiplatelet therapy.

Management of Loeffler's Endocarditis With Bivalvular Involvement and a FIP1L1/PDGFRA-Negative Mutation.

Hypereosinophilic syndromes (HESs) are a group of disorders characterized by end-organ damage caused by eosinophilic infiltration. We present a patient with idiopathic HES with severe tricuspid and mitral regurgitation secondary to Loeffler's endocarditis. In addition to prednisone, imatinib therapy initially helped control the eosinophil count. However, successful long-term remission was achieved with hydroxyurea therapy.