As a social worker at Gulf States Hemophilia & Thrombophilia Treatment Center, I have the privilege of serving patients across their lifespan. I would like to initiate grass roots education about hemophilia in Houston, Texas, by offering educational programming to specialized health care professionals who work directly with the aging population in nursing homes and assisted living communities. This would include executive directors and administrators of these facilities as well as direct clinical staff.
Dr. Shi is a Professor of Pediatric Hematology at the Medical College of Wisconsin and an Investigator of Blood Research Institute at the BloodCenter of Wisconsin. She earned her MD from Fujian Medical University in China in 1990 and her Ph.D. in 1998. Dr. Shi’s research focus is to formulate innovative therapeutic approaches for the treatment of hemophilia A, a genetic bleeding disorder caused by a lack of the critical blood clotting protein, factor VIII (FVIII). One of her research programs funded by the National Institutes of Health, National Heart, Lung, and Blood Institute, is to develop platelet-specific gene transfer strategies for the treatment of hemophilia A and hemophilia A with neutralizing antibodies. In the project supported by the NHF Bridge Grant, Dr. Shi will investigate the potential effect of the FVIII carrier protein, von Willebrand factor, on FVIII immune responses in hemophilia A. Dr. Shi expects that results from her studies will aid the design of more effective protocols to prevent FVIII immune responses and to induce FVIII immune tolerance in patients with HA.
Objective:
The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.
Methods:
A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.
Summary:
Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.
Conclusions:
HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.
Objective:
We sought to explore real-world outcomes, such as annualized bleeding rate (ABR) and markers of adherence, in persons with hemophilia A (PwHA) or with hemophilia B (PwHB) who receive standard half-life (SHL) or extended half-life (EHL) factor VIII (FVIII) or factor IX (FIX) replacement products.
Methods:
We analyzed de-identified data from the Adelphi Disease Specific Programme (DSP) database, a patient health record–based survey of hematologists in the US and 5 European countries (France, Germany, Italy, Spain and the UK). Data were collected from May–November 2017 for male patients with moderate or severe HA or HB. Outcomes in the two groups of patients (SHL vs EHL) were compared and descriptive statistics were used to summarize results.
Summary:
A sample of 595 patients with HA or HB met the inclusion criteria (US, n=123; Europe, n=472). Age, weight, and body mass index (BMI) were similar between SHL and EHL groups for PwHA and PwHB on both continents. Higher ABR was noted consistently in Europe vs the US. Hemophilia A: Analysis included 101 patients from the US (SHL, n=64; EHL, n=37) and 360 patients from Europe (SHL, n=340; EHL, n=20). The ABR was similar between both groups on both continents (median: US, 1.0 SHL and 1.0 EHL; Europe, 1.0 SHL and 1.5 EHL; mean: US, 1.3 SHL and 1.2 EHL, P=0.68; Europe, 1.8 SHL and 1.7 EHL, P=0.76). The mean of the physician-reported ‘number of doses missed of the last 10 doses’ appeared to be numerically higher in the EHL vs the SHL group in the US (mean: 0.4 SHL and 1.6 EHL, P=0.13), whereas in Europe, the trend was reversed (mean: 0.7 SHL and 0.0 EHL, P=0.29). Hemophilia B: Analysis included 22 patients from the US (10 SHL; 12 EHL) and 112 patients from Europe (91 SHL; 21 EHL). The median ABR for PwHA and PwHB in the US was 1.0 (SHL) and 1.0 (EHL), and the mean was 1.6 SHL and 0.8 EHL (P=0.25); in Europe, the median ABR was 2.0 SHL and 1.0 EHL, and the mean was 2.2 SHL and 1.6 EHL, P=0.25. The mean of the physician-reported ‘number of doses missed of the last 10 doses’ was 0.8 SHL and 0.5 EHL (P=0.63) in the US and 0.6 SHL and 0.1 EHL (P=0.33) in Europe.
Conclusions:
These preliminary real-world data, unadjusted for treatment regimen and inclusive of US and ex-US sampling, showed no clinically meaningful difference in ABR or adherence markers in PwHA or PwHB who received SHL versus EHL FVIII or FIX products. These observations may challenge assumptions regarding adherence and or clinical outcomes associated with SHL/EHL product selection among PwHA and PwHB. Further analyses should be explored.
Dr. Megan Rost is a postdoctoral fellow at the University of Michigan. She received a B.S in biochemistry and biotechnology from Michigan State University, and her Ph.D. in molecular and developmental biology at the University of Cincinnati - Cincinnati Children's Hospital Medical Center. Her graduate work focused on understanding vascular endothelial development using zebrafish as a model organism. In July 2015, she joined the lab of Dr. Jordan Shavit in the Department of Pediatrics and Hematology/Oncology at University of Michigan. For her 2016 JGP research fellowship project, she will be using the zebrafish model to analyze blood clot structure and function in the presence and absence of von Willebrand Factor. In studying this, Dr. Rost will be elucidating how arterial thrombus formation occurs in the absence of VWF, aiding in uncovering possible new therapeutic targets for VWD treatment.
