Funded by Foundation

Hemophilia causes repetitive bleeding episodes throughout the musculoskeletal system, primarily into joints, such as knees and ankles. This leads to significant joint damage resulting in increased pain reproduction, decreased functional abilities, such as walking, and negatively impacts quality of life. Traditionally the extend of joint damage has been examined via clinical assessments, such as the Hemophilia Joint Health Scores, x-rays, MRIs, and more recently musculoskeletal ultrasound (MSKUS). However, these modalities fail to establish the global impact of joint damage on the entire body of a person with hemophilia and their functional abilities. Analyzing joint motion and forces acting upon the joint during walking has been a widely established technique to gain understanding of abnormal three-dimensional movements and is a key factor in clinical decision making-processes. With the overall goal of establishing better treatment approaches for persons with hemophilia it is vital to understand the underlying functional joint limitations. Therefore, the purpose of this study is to investigate characteristics of damaged joints, joint motion and control as well as forces acting upon the joint during walking in persons with hemophilia.

The hemophilia and thrombosis centers in Tucson and Phoenix would like to join efforts to make a meaningful contribution to our understanding of the mental health profile of our pediatric population. This knowledge could contribute to a more tailored approach when designing clinics and programming, and, by identifying mental health issues, inform the development of targeted interventions. We hope to look at the prevalence of depression and anxiety in children with bleeding disorders including hemophilia, von Willebrand disease, and other congenital coagulopathies. We expect that the existence of a chronic health condition could affect a child's psychological development. We're also aware of the critical impact of family culture so our survey will include data on the mental health of the participants’ primary caretakers as well as other significant socioeconomic markers.

Moanaro Biswas, PhD, is currently an Assistant Professor in the Gene and Cell Therapy Program at the Herman B Wells Center for Pediatric Research at Indiana University, Indianapolis. She was appointed to this position in May 2018. She received her Masters and PhD in Biotechnology from India. She joined the University of Florida in 2013 as a Postdoctoral Research Associate and was subsequently appointed a faculty position in the department of Pediatrics at UF in 2017. She is mentored by Dr. Roland W. Herzog, a distinguished professor with extensive expertise in gene therapy for hemophilia. While at the University of FLorida, she received the Henry A. Kokomoor Award for excellence in Pediatric Research in 2017. Dr. Biswas has been the recipient of an early career investigator award from Bayer in 2016. Dr. Biswas is interested in studying cell and gene therapy-based treatments for combating inhibitor formation in hemophilia, As the 2018 recipient of the NHF/Novo Nordisk Career Development Award, which is made possible by a generous gift from Novo Nordisk, Dr. Biswas will be researching engineered Treg therapy for tolerance induction in hemophilia A. Chimeric antigen receptor (CAR) expressing Tregs, made specific for FVIII, will be tested in a murine model of hemophilia A. She will explore at the cellular and molecular level, interactions between antigen-specific CAR-Tregs and immune cell types involved in the development of inhibitors to FVIII.

Dr. Laura Haynes received her PhD in biochemistry from the University of Vermont where she studied how flow conditions throughout the vasculature affect thrombin generation, as well as the role of the platelet membrane in modulating the structure/function of the platelet associated prothrombinase complex. Dr. Haynes is currently a research fellow with Dr. David Ginsburg at the University of Michigan. During her JGP fellowship, she will use phage-display technology coupled with high throughput DNA sequencing to make an exhaustive index of the mutations in plasminogen activator inhibitor-1 (PAI-1) that prolong its half-life while not being deleterious in the inhibition of its canonical targets urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). In doing so, she hopes to identify a PAI-1 variant that can downregulate the fibrinolytic process. Dr. Haynes will also implement similar technology to engineer a PAI-1 variant that inhibits activated protein C (APC), thereby prolonging thrombin generation. She hopes that this research will lead to potential therapeutic agents to treat hemophilia and other bleeding disorders.

Dr. Kari Lavik is a postdoctoral fellow at the University of Michigan in the laboratory of Dr. Jordan Shavit. She received a B.A. in biology from Case Western Reserve University, and her Ph.D. in Biomedical Sciences from The University of Toledo. Her graduate work focused on the study of cancer motility and metastasis through which she became interested in using zebrafish as a model for human disease. In February of 2017, Dr. Lavik joined the Shavit Laboratory in the Department of Pediatrics at the University of Michigan to use zebrafish for the study of bleeding and clotting disorders. For her 2018 JGP fellowship project, she will model hemophilia in the zebrafish, looking for novel species-specific regulators of hemostasis. By delving deeper into the genetic mechanisms that underlie the intrinsic pathway in zebrafish, Dr. Lavik will look for novel gene interactions that can be therapeutically targeted in patients with hemophilia.

This study will evaluate hemophilia treatment center (HTC) services provided to women with hemophilia A or B (Factor VIII or Factor IX level [ 50%). The American Thrombosis and Hemostasis Network (ATHN) maintains a confidential national database for patients with bleeding and clotting disorders. Utilizing this existing ATHNdataset, the study will analyze the effect of gender on the delivery of comprehensive care in patients with hemophilia A and B. The project will focus on how gender impacts three specific components of care: identification of patients with factor VIII or IX deficiency, inclusion of patients in the comprehensive care model, and monitoring of joint bleeding as a key component of comprehensive care provided by HTCs. Demonstrating gender-based disparities in comprehensive care would provide evidence for making changes to improve the clinical care provided to women with hemophilia. This study will add to the knowledge regarding the care of women with hemophilia, helping to inform future studies of this under-researched population.

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.

The National Hemophilia Foundation (NHF) is pleased to announce Christopher J. Ng, MD, Assistant Professor of Pediatrics, University of Colorado Denver, as the recipient of the 2017 NHF/Novo Nordisk Career Development Award (CDA). The overall objectives of the CDA are to advance bleeding disorders research by promoting the development of innovative studies among established investigators. The award funds basic, pre-clinical or clinical research approaches to yielding scientific information or answers contributing to better treatments for inheritable bleeding disorders.

Dr. Ng's CDA project is on "von Willebrand Factor (VWF) regulation in blood outgrowth endothelial cells from individuals with altered VWF levels”. By using blood outgrowth endothelial cells, Ng will identify the transcriptional and epigenetic modifiers that play a role in the regulation of VWF levels. He will also be utilizing novel assays for characterizing the effects. The proposed studies should shed light on our molecular understanding of VWD, advance other areas of investigation and potentially lead to better diagnostic and prediction algorithms for bleeding in VWD. Ng will be mentored on this award by Jorge DiPaola, MD, Director of Basic and Translational Research in Pediatric Hemostasis and Thrombosis at University of Colorado Denver.

Dr. Ng received his medical degree in 2008 from the Keck School of Medicine at the University of Southern California and completed his pediatric residency at the University of Washington–Seattle Children’s Hospital. Dr. Ng has the distinction of having received a several previous awards from NHF and others during the early stages in his career. He is a former NHF-Shire Clinical Fellow, having received the award in 2013 while training under the mentorship of Dr. Marilyn Manco-Johnson, Director of the Hemophilia and Thrombosis Center at UCD and Dr. DiPaola (see below). Ng has been the recipient of NHF’s Judith Graham Pool Postdoctoral Research Fellowship in 2015 for his project on a “Multi-system evaluation of von Willebrand factor function in Type 1 von Willebrand disease mutations” (see below). Ng also received a 2013 HTRS Mentored Research Award, the CSL Behring Professor Heimburger Award and the Hemophilia Association of New York Research Award.

Ng’s immediate focus is to continue building his career as a physician-scientist, through basic and translational studies on VWF for enhancing knowledge of hemostatic and thrombotic disorders while continuing to treat patients and providing clinical leadership at the University of Colorado Denver’s Hemophilia and Thrombosis Center. For the longer term, Ng hopes to one day have an independent, NIH-funded laboratory studying VWF and the biological factors that lead to varied clinical phenotypes in hemophilia and VWD.

Through the CDA, Ng will receive $70,000 per year for up to three years. This award was selected through a process of peer review conducted by NHF's Research Review Committee. This volunteer committee is made up of highly experienced and respected physicians and researchers working in the field of hematology. NHF wishes to thank the reviewers as well as Novo Nordisk, Inc. for their very generous support of this research award.

Dr. Esther Cooke received her Ph.D. from the Leeds Institute of Cardiovascular and Metabolic Medicine at the University of Leeds, U.K., where she studied the role of fibrinogen phosphorylation in thrombosis. Dr. Cooke is currently a postdoctoral fellow in the laboratory of Dr. Annette von Drygalski, at the University of California San Diego, and in collaboration with the laboratory of Dr. Laurent Mosnier at the Scripps Research Institute. Dr. Cook's JGP Fellowship project will focus on pathological mechanisms associated with joint bleeding, re-bleeding, and the development of hemophilic arthropathy. Dr. Cooke will perform comprehensive gene expression analyses to explore key molecular markers and pathways that drive soft tissue inflammation and vascular changes in joints after bleeding. In this way, she hopes to identify new therapeutic targets and develop novel treatment strategies to down-regulate these processes, thereby reducing re-bleeding tendency and slowing the progression of hemophilic arthropathy.

Dr. Jill Johnsen is scientist and physician at the Washington Center for Bleeding Disorders in Seattle, WA.  She is an Associate Member at the Bloodworks Research Institute and also an Associate Professor of Medicine in the Division of Hematology at the University of Washington. Her research focuses on the study of hereditary and acquired modifiers of blood traits, with particular emphasis on the genetics and biology of variation in blood group and coagulation factors such as factor VIII, factor IX, and von Willebrand Factor.  Dr. Johnsen is honored by this award and grateful for this support that will further the development of a test to enable patients and providers to determine factor levels much more quickly without needing to send blood to a lab.

Swimming is an important life skill that benefits hemophilia patients medically and psychosocially. The goal of this project is to provide inner city children and teenagers the opportunity to learn how to swim. The swim program will be held at the Detroit Medical Center, where a team of professionals will teach the basics of swimming with the goal of independent swimming by the end of the program. The team will measure the children's progress medically and psychosocially throughout the program. This program will provide children and teenagers at our HTC with an amazing opportunity and also a very important life skill. We will also be using adult hemophilia patients to teach the children how to swim, which will provide them with work experience and community involvement.

Dr. Satish Nandakumar is currently a postdoctoral fellow in the laboratory of Dr. Vijay Sankaran at the Boston Children's Hospital. Previously, he did his graduate work at the St. Jude's Children's Research Hospital in Memphis, Tennessee. In his JGP Fellowship project, Dr. Nandakumar aims to develop a novel gene therapy approach for hemophilia that involves activation of the endogenous factor VIII or IX genes within hematopoietic stem cells by taking advantage of the CRISPR/Cas9 gene activation system. This work has the potential to benefit patients with mild hemophilia mutations.

Dr. Meeks is an Associate Professor of Pediatrics in the Department of Pediatrics at the Emory University School of Medicine and the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. She obtained a Bachelor of Science in Mathematics from Duke University where she was elected to Phi Beta Kappa. After earning her medical degree from the University of Mississippi, she completed her clinical training at the University of Virginia and Emory University. Dr. Meeks has a basic, translational, and clinical research interest in the development of inhibitors in hemophilia A. Her work has focused on the early immune response to factor VIII and the diversity of the B-cell response to factor VIII. She is a former NHF clinical fellow who currently has funding to pursue these projects from the Hemostasis and Thrombosis Research Society and the National Institutes of Health.

The purpose of this project is to request support for the development of a Virtual Reality Environment (VRE) study program for pediatric patients diagnosed with hemophilia. The VRE program proposed was developed and created for children and includes interactive imagery, character avatars and colorful visual environments. This VRE program will be deployed by the child in a clinical setting and is proposed to help decrease, anxiety and needle phobia during intravenous factor infusions. Outcome measures will include an anxiety scale before and after each infusion, collection of biophysiologic data, pain score and visual analogue evaluation. The expected result of this nursing project is to monitor the use of a VRE in the pediatric population with a reduction of fear, anxiety and pain experienced with intravenous factor infusions.

Preliminary work done by Dr. Riten Kumar and colleagues has documented that moderate intensity exercise is associated with a significant improvement in multiple coagulation parameters in post-adolescent males with mild-moderate hemophilia A. As a continuation to our previous work, we now hope to compare the impact of moderate intensity exercise to DDAVP on laboratory coagulation parameters in post-adolescent males with mild hemophilia A. We also hope to investigate the impact of sequentially administering these interventions on hemostatic indices. Our over-arching hypothesis is that increase in coagulation parameters (particularly FVIII:C) with moderate intensity aerobic exercise would be non-inferior to DDAVP. We additionally hypothesize that we will appreciate an additive effect of sequentially administering clinical implications for patients with MHA. It may negate the use of DDAVP pre- exercise and could potentially lead to clinicians advising patients to appropriately warm-up (e g running), to raise their FVIII/VWF levels prior to undertaking more rigorous sports. It will also lay the foundation for future studies investigating the interaction between aerobic exercise and hemostasis in subjects with bleeding disorders these interventions. Should our hypothesis be correct, our study would have significant clinical implications for patients with MHA. It may negate the use of DDAVP pre-exercise and could potentially lead to clinicians advising patients to appropriately warm-up to raise their FVIII/VWF levels prior to undertaking more rigorous sports. It will also lay the foundation for future studies investigating the interaction between aerobic exercise and hemostasis in subjects with bleeding disorders.