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The medical research and training enterprise in the United States is complex in both its scope and implementation. Accordingly, adaptations to the associated workforce needs present particular challenges. This is particularly true for maintaining or expanding national needs for physician-scientists where training resource requirements and competitive transitional milestones are substantial. For the individual, these phenomena can produce financial burden, prolong the career trajectory, and significantly influence career pathways. Hence, when national data suggest that future medical research needs in a scientific area may be met in a less than optimal manner, strategies to expand research and training capacity must follow. This article defines such an exigency for research and training in nonneoplastic hematology and presents potential strategies for addressing these critical workforce needs. The considerations presented herein reflect a summary of the discussions presented at 2 workshops cosponsored by the National Heart, Lung, and Blood Institute and the American Society of Hematology.

Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.

The International Immune Tolerance Study was a multicenter, prospective, randomized comparison of high-dose (HD; 200 IU/kg/d) and low-dose (LD; 50 IU/kg 3 times/week) factor VIII regimens in 115 "good-risk," severe high-titer inhibitor hemophilia A subjects. Sixty-six of 115 subjects reached the defined study end points: success, n = 46 (69.7%); partial response, n = 3 (4.5%); and failure, n = 17 (25.8%). Successes did not differ between treatment arms (24 of 58 LD vs 22/57 HD, P = .909). The times taken to achieve a negative titer (P = .027), a normal recovery (P = .002), and tolerance (P = .116, nonsignificant) were shorter with the HD immune tolerance induction (ITI). Peak historical (P = .026) and on-ITI (P = .002) titers were correlated inversely with success, but only peak titer on ITI predicted outcome in a multivariate analysis (P = .002). LD subjects bled more often (odds ratio, 2.2; P = .0019). The early bleed rate/month was 0.62 (LD) and 0.28 (HD; P = .000 24), decreasing by 90% once negative titers were achieved. Bleeding was absent in 8 of 58 LD versus 21 of 57 HD subjects (P = .0085). One hundred twenty-four central catheter infections were reported in 41 subjects (19 LD); infection frequency did not differ between the treatment arms. Neither bleeding nor infection influenced outcome. Although it was stopped early for futility and safety considerations, this trial contributed valuable data toward evidence-based ITI practice.

The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.