DOAC compared with warfarin for VTE in patients with obesity: a retrospective cohort study conducted through the VENUS network.

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/m2 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/m2 (N = 5412), 3.6% versus 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥ 40 kg/m2 (N = 2321), 4.4% versus 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥ 50 kg/m2 (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.

Physician perceptions and use of reduced-dose direct oral anticoagulants for extended phase venous thromboembolism treatment.

Background: The direct oral anticoagulants (DOACs), apixaban and rivaroxaban, have been studied for extended-phase treatment of venous thromboembolism (VTE). Yet, scant evidence exists surrounding clinician practice and decision-making regarding dose reduction. Aims: Report clinician practice and characteristics surrounding dose reduction of DOACs for extended-phase VTE treatment. Methods: We conducted a 16-question REDCap survey between July 14, 2021, and September 13, 2021, among ISTH 2021 Congress attendees and on Twitter. We explored factors associated with dose reduction using logistic regression. We used k-means clustering to identify distinct groups of dose-reduction decision-making. Random forest analysis explored demographics with respect to identified groups. Results: Among 171 respondents, most were attending academic physicians from North America. Clinicians who treated larger volumes of patients had higher odds of dose reduction. We identified five clusters that showed distinct patterns of behavior regarding dose reduction. Cluster 1 rarely dose reduces and likely prescribes rivaroxaban over apixaban; cluster 2 dose reduces frequently, does not consider age when dose-reducing, is least likely to temporarily reescalate dosing, and prescribes apixaban and rivaroxaban equally; cluster 3 dose reduces <50% of the time, and temporarily reescalates dosing during increased VTE risk; cluster 4 dose reduces frequently, temporarily reescalates dosing, and is most likely to prescribe apixaban over rivaroxaban; and cluster 5 dose reduces most frequently, and takes the fewest risk factors into consideration when deciding to dose reduce. Conclusions: Most clinicians elect to dose-reduce DOACs for extended-phase anticoagulation. The likelihood of a clinician to dose reduce increases with volume of patients treated. Clinician prescribing patterns cluster around VTE risk factors as well as reescalation during high-risk periods.

Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study.

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.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

BACKGROUND: 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. METHODS: 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 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 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. RESULTS: 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). CONCLUSIONS: 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.).

A novel type 2N VWF gene mutation: a case report.

: 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.

A cross-sectional analysis of cardiovascular disease in the hemophilia population.

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.

Development of a novel automated screening method for detection of FVIII Inhibitors.

INTRODUCTION: Factor VIII activity is routinely determined by measuring the activated partial thromboplastin time (aPTT) of a patient plasma sample and determining percent activity from a standard curve. To maximize the detection of a clotting factor inhibitor, a subjective assessment of parallelism of a patient curve compared with a standard curve is performed. We developed and validated an automated objective method to assess parallelism as a rapid screening tool for detection of an inhibitor to factor VIII during routine FVIII assays. METHODS: We performed FVIII assays on a subset of FVIII-deficient patients with hemophilia A with and without inhibitors. Utilizing a ratio of the slopes from parallelism curves obtained by an independent Microsoft excel program in patients compared with a normal standard curve, we determined a cutoff ratio predictive for presence of an inhibitor. RESULTS: A cutoff ratio of patient to control slopes of <0.45 for the detection of an inhibitor to FVIII was 100% sensitive and 91.6% specific, with a positive predictive value of 92.3% and a negative predictive value of 100%. CONCLUSION: Utilizing a ratio of the slopes from parallelism curves in patients with and without an inhibitor, we developed and validated a rapid, automated, and objective method to assess parallelism as an added screening tool for detection of an inhibitor to factor VIII during routine FVIII assays on a STAGO-based coagulation platform. This simple automated method has the potential to detect inhibitors to other clotting factors.

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds.

Long term survival in persons with hemophilia and chronic hepatitis C: 40 year outcomes of a large single center cohort.

We studied the course of chronic HCV infections in a cohort of 222 persons with hemophilia (PWH) and von Willebrand disease followed at our center since 1973. Twenty two (10%) developed end stage liver disease (ESLD). Forty years after HCV infection, cumulative incidence of ESLD was 12.3% and overall survival was 45.5%. Those who were infected with HCV only (n = 100) had a survival of 75.2%, while those infected with HIV (n = 122) had a survival of 24% (P < 0.001). Survivals were significantly longer for those infected with HCV at younger age (< 15 years) compared to those infected over age 30 years (P = 0.014). Cause specific deaths for ESLD and bleeding were 8.8% and 8.3% respectively. For HIV negative subjects, the annual hazard of death from ESLD and bleeding was near zero for the first 10 years, and then rose slowly over the next 20 years to 0.4/100py for ESLD and 0.2/100py for bleeding. Sixty subjects completed 79 treatment episodes. Sustained viral response rates increased from 7/21 (33%) between 1990 and 2001, to 17/29 (58%) between 2002 and 2011, and to 27/29 (93%), since 2012 with the advent of the directly acting antiviral agents. These results confirm the very slow ESLD progression rate in HIV negative PWH. However, the risk of death from both ESLD and bleeding increases steadily with longer duration of HCV infection. More aggressive surveillance to detect those with early fibrosis is needed now that curative treatment is possible in >95% of individuals. Am. J. Hematol. 91:E335-E340, 2016. © 2016 Wiley Periodicals, Inc.

Prospective, multicenter study of postoperative deep-vein thrombosis in patients with haemophilia undergoing major orthopaedic surgery.

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.

Anemia and the Need for Intravenous Iron Infusion after Roux-en-Y Gastric Bypass.

The frequency of anemia, iron deficiency, and the long-term need for IV iron following Roux-en-y gastric bypass (RYGB) surgery has not been well characterized. Three-hundred and nineteen out of 904 consecutive subjects who underwent RYGB at Penn State Hershey Medical Center from 1999 to 2006 met the inclusion criteria for a preoperative complete blood count (CBC) and at least one CBC >6 months following surgery. Cumulative incidence of anemia 7 years post procedure was 58%. Menstruation status and presence of preoperative anemia were predictive of anemia by univariate analysis and multivariable Cox regression (P = 0.0014 and 0.044, respectively). Twenty-seven subjects, primarily premenopausal women, representing 8.5% of the cohort and 22% of the 122 anemic subjects, needed intravenous (IV) iron a mean of 51 months postoperatively for anemia unresponsive or refractory to oral iron. The risk for development of anemia necessitating IV iron therapy following RYGB is highest in menstruating women and continues to increase for many years, even in post-menopausal women. Well-designed prospective studies are needed to identify the incidence of iron deficiency anemia and the patient populations at increased risk for requiring IV iron replacement after RYGB surgery.

Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations.

BACKGROUND: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis. OBJECTIVES: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes. PATIENTS/METHODS: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence. RESULTS: Four cases had VWF:Ag < 3 IU dL(-1) and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL(-1) and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB. CONCLUSIONS: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy.