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Background:  Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection., Objectives:  In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds., Methods:  Sixty-three patients (median [range] age, 28 [7-59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the "potentially effective trough level" for that bleed type. Kaplan-Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach)., Results:  Kaplan-Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds., Conclusion:  This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds., Competing Interests: All authors report nonfinancial (medical writing) support from Baxalta US Inc., a Takeda company, during the conduct of the study. P.C. has received consulting fees from Bayer, Baxalta*, Biogen, Biovertiv, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Shire*, Spark and Sobi; and research funding from CSL Behring, Novo Nordisk, and Pfizer. K.F. has received consulting fees from Bayer, Baxter*, Biogen, Freeline, Novo Nordisk, and Pfizer; research funding from Bayer, Baxter*, Novo Nordisk, and Wyeth/Pfizer; and has been a member of speaker bureaus for Bayer, Baxter*, Biotest Octapharma, CSL Behring, Novo Nordisk, and Pfizer. P.W.C. has received consulting fees from CSL Behring, Novo Nordisk, Shire*, and Sobi; research funding from CSL Behring; and has been a member of a speaker bureau for Shire*. At the time of the current study, A.C. was an employee of Baxalta Innovations GmbH, a member of the Takeda group of companies. B.A.K. has received consulting fees from BioMarin, Genentech, Sigilon, and Spark; and research funding from Bioverativ, Pfizer, Sangamo, Shire*, and Spark. V.B. has served as Chair of the International Prophylaxis Study Group (supported by grants to the Hospital for Sick Children Foundation, Toronto, Canada, from Bayer HealthCare, Bioverativ, Novo Nordisk, Pfizer, Shire*, and Spark); has served on data safety monitoring boards for Octapharma and Shire*; has served on speaker bureaus/advisory boards for Amgen, Bayer HealthCare, Novo Nordisk, Pfizer, and Shire*; and has received research support from Bayer HealthCare, Bioverativ, and Shire*. S.W.P. has received consulting fees from Apcintex, Bayer, BioMarin, Bioverativ, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sanofi, Shire*, Spark, and uniQure. E.B. has received research funding from Bayer, CSL Behring, Shire*, and Sobi; has been a member of speaker bureaus from Bayer, Octapharma, and Shire*; and has served on an advisory board for LFB. M.W. and W.E. are employees of Baxalta Innovations GmbH, a member of the Takeda group of companies, and are Takeda stock owners. At the time of the current study, G.S. was an employee of Baxalta US Inc, a member of the Takeda group of companies. *A member of the Takeda group of companies., (Georg Thieme Verlag KG Stuttgart · New York.)

Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis. Using data from the Haemophilia Growth and Development Study, we examined associations between 13,342 genetic markers and ROM scores measured at six-month intervals for up to seven years. As a first step, ordered logistic regression models were fit for each joint separately. A subset of SNP markers showing significant effects (p<0.01) on the right and left sides for at least two joints were included in a full model fit using a multivariate generalised linear mixed model assuming an ordinal response. The models contained all ROM scores obtained at all visits. Twenty-five markers analysed in the full model showed either increased or decreased risk of ROM abnormalities at the p<0.001 level. Several genes identified at either the first or second stage of the analysis have been associated with arthritis in a variety of large studies. Our results support the likelihood that risk for haemophilic arthropathy is associated with genetic factors, the identification of which holds promise for further advancing the individualisation of treatment.

Evaluation of factor F(V)III replacement in patients with haemophilia A undergoing surgery is critical for FVIII concentrates, yet large scale, multi-center prospective studies, particularly using continuous infusion, are generally lacking for new products. This study evaluated efficacy and safety of a newly developed recombinant FVIII (rAHF-PFM) administered by bolus or continuous infusion in haemophilia A patients undergoing surgery. Subjects > or =5 years of age with baseline FVIII:C < or =2%, and > or =150 prior FVIII exposure days were included in this prospective, international, open-label, uncontrolled clinical trial. rAHF-PFM was administered perioperatively by bolus infusion (BI) or continuous infusion (CI) according to the standard use at the center to prevent bleeding complication. Both the surgeon and haematologist rated efficacy during hospitalization. Fifty-eight subjects underwent 65 surgical procedures (22 major haemorrhagic risk; 35 minor, 8 dental procedures). Bolus infusion was used exclusively in 47 procedures and continuous infusion, with or without supplemental bolus infusions, in 18. Haemostatic efficacy was assessed as excellent or good for 100% of intraoperative ratings (17 CI, 44 BI, 61 total procedures), and 100% of postoperative ratings performed at time of discharge (18 CI, 44 BI, 62 total procedures). Median total consumption of rAHF-PFM during hospitalization was 822 IU/kg/surgery with CI and 910 IU/kg/surgery with BI. Overall rAHF-PFM was well tolerated, and FVIII inhibitors were not detected. In conclusion, rAHF-PFM administered via continuous infusion or bolus injections is safe, non-immunogenic, and effective for perioperative hemostatic management in previously treated haemophilia A patients.

The development of inhibitory antibodies to factor VIII is a serious complication of haemophilia. Two haemostatic agents with different bypassing mechanisms have been used in the treatment of patients with inhibitors: activated prothrombin complex concentrate (aPCC) and recombinant factor VIIa (rFVIIa). The objective was to compare cost and outcome of aPCC and rFVIIa in the treatment of joint bleeds. The analyses were based on the FENOC (FEIBA NovoSeven Comparative Study) crossover study where 48 patients used aPCC and rFVIIa to treat two joint bleeds. Incremental cost-effectiveness ratios were calculated for three outcome measures and the variation in cost was analyzed using two alternative regression methods. Results were subjected to sensitivity analyses. Key determinants of cost were prescribed dose, bodyweight and treatment in addition to protocol. The cost of aPCC was on average lower than rFVIIa. At all but one time point, patients rated slightly higher (but not statistically significantly) percentages of treatment efficacy and stopping of the bleed by aPCC. The reported reduction in pain from start of treatment up to 48 hours varied considerably among individuals. The different relative prices in the US, Turkey and Sweden mattered, but did not reverse the main results. In conclusion, the cost per episode was significantly lower for aPCC. The large individual-level variation in reduction of pain supports decisions that consider the individual patient's experience and that accept trade-offs between cost and reduction in pain rather than focusing on cost only.

To assess the potential roles of protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in venous thrombosis, their plasma levels were measured in 426 individuals with venous thrombosis and 471 control individuals participating in the Leiden Thrombophilia Study. A relationship between the level of PZ or ZPI and venous thrombosis was not detected in the overall case-control study. PZ and ZPI circulate as a complex and their plasma levels are interdependent. Both PZ and ZPI are increased with oral contraceptive use and reduced with oral anticoagulant therapy.