The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector ...dose.
In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 10
vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10
vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII.
The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean ±SD factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval CI, -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year range, 0 to 43.0 before vector administration vs. 0.3 events per year range, 0 to 6.5 after vector administration).
Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).
Perioperative clotting factor replacement is administered to reverse the inherent haemostatic defect in persons with haemophilia (PWH), potentially increasing their risk for developing venous ...thromboembolism (VTE) postoperatively. It was our objective to determine the prevalence of VTE in PWH undergoing total hip or knee arthroplasty (THA, TKA). Patients with haemophilia A or B who underwent THA or TKA were enrolled in this prospective, multicentre observational cohort study. Lower extremity venous duplex ultrasound was performed prior to surgery and 4-6 weeks after surgery. Eleven centres enrolled 51 subjects, 46 of whom completed the study. Six subjects (13.0 %) were treated with bypass agents perioperatively; the remaining 40 subjects received factor VIII or IX replacement. Intermittent pneumatic compression devices were utilised postoperatively in 23 subjects (50 %), and four subjects (8.7 %) also received low-molecular-weight heparin prophylaxis. One subject (2.2 %) with moderate haemophilia A was diagnosed with symptomatic distal deep-vein thrombosis (DVT) on day 6 following TKA. One subject (2.2 %) with severe haemophilia A was diagnosed with pulmonary embolism on day 9 following bilateral TKA. No subjects had asymptomatic DVT. Eighteen subjects (39.1 %) had major bleeding, and three subjects (6.5 %) experienced minor bleeding. The observed prevalence of ultrasound-detectable, asymptomatic DVT in PWH following TKA or THA in this study was low, but the incidence of symptomatic VTE (4.3 %, 95 % CI, 0.5-14.8 %) appeared similar to the estimated incidence in the general population without thromboprophylaxis.
: Men and boys who present with bleeding associated with low factor VIII levels and normal von Willebrand studies are assumed to have hemophilia A until proven otherwise. However, routinely available ...coagulation assays cannot easily distinguish mild hemophilia A from the 2N variant of von Willebrand disease. We present a case that highlights the difficulties of recognizing this diagnosis, the role of genetic testing, and the identification of a 2N variant that has not been previously described.
•Limited data exist for use of DOACs for treatment of VTE in underweight patients.•We performed a multicenter retrospective study of DOACs vs warfarin in this population.•There was no difference in ...recurrent VTE between DOACs and warfarin in underweight patients.•There was no difference in major bleeding between DOACs and warfarin in underweight patients.
Background
Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function.
...Objectives
This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA).
Patients/Methods
We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24‐h period, or transfusion of two or more units of packed red blood cells.
Results
One hundred thirty‐one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non‐use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk.
Conclusions
The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.
Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia ...study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.
•CV risk factors are common in older men with hemophilia.•Although older men with hemophilia have less CV disease than comparable unaffected men, CV events do occur and require treatment.
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The effectiveness and safety of direct oral anticoagulants (DOAC) compared with warfarin remains uncertain in obese patients. We assessed the comparative effectiveness and safety of DOACs with ...warfarin for the treatment of VTE among obese patients. This multi-center retrospective cohort study included adults with a BMI ≥ 35 kg/m
2
or weight ≥ 120 kg prescribed either DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin for a VTE diagnosis. The primary outcome was the 12-month rate of recurrent VTE. The secondary outcome was the 12-month rate of major bleeding. Among 5626 patients, 67% were prescribed warfarin and 33% were prescribed a DOAC. The 12-month VTE recurrence rate was 3.6% (67/1823) for patients treated with DOAC compared with 3.8% (143/3664) for patients treated with warfarin odds ratio for recurrent VTE on warfarin versus DOAC (OR) (95% CI).07 (0.80, 1.45). The 12-month major bleeding rate was 0.5% (10/1868) for patients on DOAC versus 2.4% (89/3758) on warfarin OR 4.25 (2.19, 8.22). Similar proportions of recurrent VTE occurred across BMI thresholds on DOAC and warfarin: for BMI ≥ 35 kg/m
2
(N = 5412), 3.6% versus 3.8%, respectively OR 1.08 (0.80, 1.46); for BMI ≥ 40 kg/m
2
(N = 2321), 4.4% versus 3.5%, respectively OR 0.80 (0.51, 1.26); and for BMI ≥ 50 kg/m
2
(N = 560), 3.1% versus 3.7%, respectively OR 1.18 (0.39, 3.56). Similar proportions of recurrent VTE occurred in patients with obesity treated for VTE with DOACs and warfarin. DOACs were associated with lower major bleeding compared to warfarin in patients with obesity and VTE.
The majority of described DHSt cases result from gain-of-function mutations in the mechanosensitive cation channel gene PIEZO1, leading to an inappropriate increase in calcium influx. Less ...frequently, gain-of-function mutations have been identified in the Gardos channel gene, KCNN4, that alter calcium sensitivity and result in a more active channel. ...DHSt due to KCNN4 mutation is aptly termed a Gardos channelopathy 2–4. Though a complex compensatory mechanism has been proposed in those with KCNN4 mutations, the increased cation leak across the red blood cell membrane in cases with either PIEZO1 or KCNN4 mutations is accompanied by intracellular dehydration and the formation of stomatocytes 4. Since the first reports in 2015, to our knowledge, KCNN4 mutations have been identified in ten DHSt families 2–6. Genes screened included: ATP binding cassette subfamily G members (ABCG5 and ABCG8), ATPase phospholipid transporting 11c (ATP11c), collagen type IV alpha 1 chain (COL4A1), erythrocyte membrane protein band 4.1 (EPB41), potassium calcium-activated channel subfamily N member 4 (KCNN4), UDP glucuronosyltransferase family 1 member A6 and A7 (UGT1A6, UGTA17), X-linked Kx blood group (XK), glutathione peroxidase 1 (GPX1), glycophorin A (GYPA), glycophorin B (GYPB), CD47, adducin 1 (ADD1), adducin 2 (ADD2), atypical chemokine receptor 1 (ACKR1), ankyrin 1 (ANK1), dematin actin-binding protein (DMTN), kell system (KEL), intercellular adhesion molecule 4 (ICAM4), peroxiredoxin 2 (PRDX2), erythrocyte tropomodulin (TMOD1), tropomyosin 1 (TPM1), TRIO, and F-Actin binding protein (TRIOBP).
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