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Novo Nordisk Access to Insight Clinical Research Grant 2023

Lize van Vulpen
University Medical Center Utrecht, Center for Benign Hematology, Thrombosis and Haemostasis, Van Creveldkliniek, Utrecht University, Utrecht
The Netherlands

Project title:
Synovial proliferation on routine ultrasound: active or inactive? A prospective study


Improved treatment for patients with severe haemophilia reduced joint bleeding and improved joint health. However, joint bleeding still cannot be prevented totally, resulting in (sub)clinical inflammation and degeneration. The introduction of point-of-care ultrasound makes it possible to routinely screen joint status and detect preclinical alterations. We recently demonstrated at our center that 44% of the patients with severe haemophilia A have subclinical synovial proliferation on ultrasound. From MRI studies, we know that synovial proliferation predicts joint bleeding and deterioration of joint health. However, it is unknown whether these routinely found synovial abnormalities alter over time, are static remnants of previous (unnoticed) bleeds or still active tissue changes that can be adapted.
We hypothesize that subclinical synovial proliferation can be either ‘inactive fibrotic’ or ‘active inflammatory’ changes ultimately resulting in joint damage progression. In this study we will prospectively investigate subclinical synovial proliferation found on routine ultrasound screening. Patients will be offered a COX-2 inhibitor and followed by ultrasound and physical examination. Additionally, we will explore whether baseline characteristics and MRI findings can predict whether the synovial proliferation will change over time.
With this study we aim to better understand the clinical impact of findings at routine ultrasound screening and provide a basis for further studies investigating treatments to prevent (repeated) joint bleeding and joint damage progression in haemophilia.

Novo Nordisk Access to Insight Basic Research Grant 2023

Anne Angelillo-Scherrer
Bern University Hospital / University of Bern, Bern

Project title:
Role of protein S in bone health & remodeling after hemarthrosis in the context of hemophilia A


An understanding of the mechanisms of decreased bone mineral density (BMD) leading to a higher risk of fractures in people with haemophilia A (PwH) is an unmet need. In this context, a better understanding of the effect of non-factor replacement therapies (NFRTs) on BMD may help to select further indications for these treatments beyond bleeding control.
Our group has reported that targeting PS rebalances coagulation in haemophilia. Targeting the PS gene (Pros1) in haemophilia A (F8-/-) mice protects them from bleeding, particularly when it occurs intra-articularly. However, the mechanism by which targeting the PS gene confers protection against haemarthrosis and its complications is not fully understood.
Our group therefore performed bulk RNA sequencing of synovial tissue isolated from wild-type (WT), F8-/- and F8-/-Pros1-/- mice to assess differential gene expression in the steady state and after haemarthrosis. In the steady state, mRNAs encoding proteins involved in bone resorption were decreased while those encoding markers of bone formation were increased in F8-/-Pros1-/- mice compared with F8-/- mice. Following haemarthrosis, F8-/-Pros1-/- mice show an increase in genes involved in bone regeneration and tissue remodelling.
In this project, we will determine the involvement of PS signalling in BMD in the context of HA by taking advantage of the above-mentioned mouse models. In parallel, we aim to translate our project to humans by conducting a pilot study using PwH samples in on-demand therapy and prophylaxis with factor VIII or NFRT.
Our research pathway aims to identify therapeutic targets for BMD in PwH and to provide further mechanistic insights into NFRT, including PS targeting.

Novo Nordisk Access to Insight Clinical Research Grant 2022

Paul McLaughlin
Katharine Dormandy Haemophilia Centre, Royal Free London NHS Foundation Trust

Project title:
Gap analysis investigating healthcare professionals’ skills and knowledge for pain management in PwH – a qualitative study


Pain associated with haemophilia is a burdensome and life interrupting to those experiencing it. Clinical guidelines such as those from the World Federation of Haemophilia make broad recommendations for pain management, but people with haemophilia continue to report that pain is poorly managed by their haemophilia centres. Through a qualitative inquiry, this project aims to identify what deficits exist in knowledge and skills of haemophilia clinicians that present barriers to effective pain management input, and to better understand what clinicians understand of their roles and responsibilities in pain management.
This project is motivated by an urgent need for pain management approaches to be better employed in day-to-day clinical practice. Previous research from our group appeared to suggest that whilst haemophilia clinicians are confident in their haemophilia care provision, they feel uncertain about their own knowledge and ability to implement good pain management. The confidence of clinicians to better assess and manage pain (and what support they may need) may well be a key component in establishing better pain management pathways.
The qualitative inquiry approach informed by a focus group method is an excellent way to collate and analyse the views, beliefs and opinions of a broad range of specialist clinicians. Profession specific focus groups will help encourage open discussion, whilst data analysis across all groups will help identify issues (themes) that exist across all professions as well as any that may be unique to one profession. I have significant experience in this methodological approach and have the necessary skills to collate and present findings that will inform the development of a education/skills framework for use by haemophilia clinicians.
Understanding the key role that haemophilia clinicians have in providing pain management and being able to inform how this may be offered to people with haemophilia, should help bridge the gap between broad clinical guidelines and person centred care. More confident and skilled clinicians should enable a change in better outcomes relating to pain management.

Novo Nordisk Access to Insight Basic Research Grant 2022 (3)

Axel Schlagenhauf
Department of General Pediatrics and Adolescent Medicine
Medical University of Graz, Graz

Project title:
Investigating the role of clotting factors on osteoclastogenesis in-vitro


Several studies indicate that specific coagulation proteins exert additional moonlighting functions as regulators of bone density. Correspondingly, dysfunction or absence of these proteins does not only result in bleeding disorders but also leads to potential impairments in bone health. Recent publications suggest reduced bone density in mice with hemophilia A and B. We have developed an in-vitro method to investigate the impact of various clotting factors on osteoclast differentiation. Preliminary data show a regulating role of von Willebrand factor but not factor VIII. Hence, increased bone resorption observed in hemophilia A models is more likely to be caused by reduced generation of downstream proteases (e.g. thrombin and FXa).
We aim to investigate the role of thrombin, factor Xa, and PAR1/2/4-activating peptides on osteoclast differentiation using our established workflow. Additionally, we want to mimic the setting of hemophilia by supplementing osteoclast differentiation medium with factor VIII/IX/II/X-depleted plasma in comparison to standard human plasma. We hypothesize that thrombin or FXa regulate osteoclastogenesis and that a lack thereof leads to augmented osteoclast formation.
This study provides a biochemical basis for future studies investigating bone health in patients with hemophilia and von Willebrand syndrome.

Novo Nordisk Access to Insight Basic Research Grant 2022 (2)

Patrick Ellsworth
University of North Carolina at Chapel Hill
Chapel Hill, NC

Project title:
Mechanistic Investigation of Factor IX/IXa Synergy with Emicizumab


Approximately 25-30% of patients with severe hemophilia A develop inhibitors, the primary complication of treatment in the current era, rendering factor therapy ineffective. Bypassing agents and the non-factor therapy emicizumab are the therapeutic mainstays for these patients.

Emicizumab (Genentech) is a bispecific, monoclonal antibody which binds activated Factor IX (FIXa) and Factor X (FX), mimicking activated FVIII (FVIIIa) to enable FX activation, even in the presence of FVIII inhibitors. While emicizumab drastically reduces bleeding frequency, thrombosis and thrombotic microangiopathy (TMA) were observed in clinical trials, invariably associated with concurrent use of activated prothrombin complex concentrate (aPCC). The mechanism of thrombosis and TMA is uncertain and recombinant factor VIIa (rFVIIa) is the only bypassing agent considered safe for breakthrough bleeding during emicizumab therapy. However, rFVIIa is ineffective in 10-20% of cases. As TMA is thought to occur on damaged endothelium, I have investigated the activity of these agents on endothelium using a novel, in vitro microfluidic model, to elucidate the mechanism of TMA and effective rescue therapies.

My preliminary data have shown that factor X is more readily activated by factor IXa and emicizumab on endothelium that has been activated by tumor necrosis factor alpha compared to unstimulated endothelium, potentially in a phosphatidylserine-independent manner. My specific aims going forward are to:

  1. Determine the emicizumab-dependent mechanism of Xa and thrombin generation on activated endothelium and determine whether this is dependent on emicizumab binding to surface ligand(s) on the endothelial surface.
  2. Demonstrate synergy of emicizumab and FIX/FIXa on endothelium to normalize thrombin generation in a purified system and with commercially available factor IX products to predict their utility as a safe and effective alternative to rFVIIa in the management of breakthrough bleeding, major surgery, and trauma in hemophilia A patients with inhibitors.

Novo Nordisk Access to Insight Basic Research Grant 2022 (1)

Dario Balestra
Department of Life Sciences and Biotechnology
University of Ferrara

Project title:
Prime Editing of DNA as new therapeutic option for Hemophilia A


Treatment of hemophilia is commonly based on infusion of concentrates of the missing coagulation factor, either plasma derived or recombinant, but still has significant drawbacks. These limitations boosted research and led to several alternative strategies that are under development but not optimized yet. Recently, an innovative genome editing strategy, named Prime Editing (PE) and able to introduce all 12 possible types of changes, small insertions and deletions at distances (>30 bp) from the site of Cas9 targeting, has been developed. In this project we propose the exploitation of PE to revert and correct splicing mutations, which are frequently associated with the severest form of human genetic disorder, including coagulation factor deficiencies. By considering the requirements of PE editors, an inspection of the HA mutation database revealed that virtually all mutations in the 5’ss or 3’ss of all F8 exons (from exon 2 to exon 25) can be rescued by the PE approach, with a therapeutic implication for a high number of HA severe patients.
Overall, the prime editing strategy, by fulfilling the longstanding aspiration of the life sciences to make virtually any targeted change in the genome of any living cell or organism, has the potential to advance the study and correction of the vast majority of pathogenic alleles.

Novo Nordisk Access to Insight Basic Research Grant 2021(2)

Alessio Branchini
Department of Life Sciences and Biotechnology
University of Ferrara

Project title:
Insights into the contribution of tailored collagen binding to half-life of designed factor IX fusion proteins


Several strategies have allowed the improvement of coagulation factor IX (FIX) half-life for therapeutic purposes, including human serum albumin (HSA) fusion (FIX-HSA). While it is known that FIX binds to extra-vascular collagen IV, which contribute to FIX bioavailability, the contribution of this mechanism to the biological properties of chimeric molecules has been poorly addressed.
Here we propose to detail and provide novel in-vitro and in-vivo information on the contribution of collagen IV binding on pharmacokinetics, haemostatic potential and tissue distribution of FIX-HSA molecules by taking advantage of our previously designed fusion proteins as scaffolds.
We expect to provide new experimental insights into the contribution of differential collagen binding to the overall biological properties of FIX-HSA fusion proteins, thus adding relevant knowledge to this field of research even in terms of design of novel long-acting proteins.

Novo Nordisk Access to Insight Basic Research Grant 2021

Kohei Tatsumi
Nara Medical University

Project title:
Development of a stem cell-based allogenic cell sheet therapy for hemophilia A


Gene- or cell-based therapies aimed at creating delivery systems for FVIII protein have emerged as promising options for hemophilia A (HA) treatment. Previously, we reported the long-term therapeutic efficacy of autologous cell therapy for HA, in which HA mice-derived cells were transduced with FVIII gene ex vivo, and transplanted as cell sheets into subcutaneous space of HA mice. For rendering this type of cell therapy applicable for all HA patients, we will try to develop an allogenic cell therapy for HA. For that, we focus on differentiating stem cells, including induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs), to enough number of liver sinusoidal endothelial cells (LSECs), because the main cell type responsible for FVIII production is LSECs. Next, cell sheets composed of the FVIII-producing LSECs will be fabricated by utilizing temperature-responsive culture dishes, and then transplanted to HA mice. I believe that by optimizing all the protocols for cell differentiation, cell sheet fabrication, and the transplantation technique, long-term cell engraftment that renders robust and sustainable FVIII production can be achieved.

Novo Nordisk Access to Insight Clinical Research Grant 2021

Rungrote Natesirinilkul
Faculty of Medicine
Chiang Mai University
Chiang Mai

Project title:
Cultural adaptation and validation of a Thai version of Canadian Hemophilia Outcomes – Kids’ Life Assessment Tool version 3.0 (CHO-KLATv3.0) and the Hemophilia Family Impact Tool (H-FIT): a prospective, multi-centre study


The value of patient-reported outcome measures (PROMs) is of increasing importance, particularly when evaluating expensive treatments for people with hemophilia (PWH). Canadian experts recently revised the Canadian Hemophilia Outcomes-Kids Life Assessment Tool, CHO-KLAT version(v)3.0, and developed a new Hemophilia Family Impact Tool (H-FIT) to evaluate PWH and parents/guardians of those boys. The CHO-KLATv3.0 and H-FIT require cultural adaptation for use in Thailand.


  1. To translate and validate CHO-KLATv3.0 and H-FIT questionnaires for use in Thailand
  2. To assess the measurement properties of the Thai-CHO-KLATv3.0 and H-FIT tools
  3. To assess the ability of the CHO-KLATv3.0 and H-FIT to differentiate between groups based on disease severity, age, and type of treatment in the four hemophilia treatment centers (HTCs) which are the representatives of each region of Thailand


  1. Validated versions of the Thai-CHO-KLATv3.0 and H-FIT
  2. Measurement properties of the Thai-CHO-KLATv3 and H-FIT
  3. Differences in the mean scores on the CHO-KLATv3.0 and H-FIT between patient groups


The data obtained will provide objective evidence of hemophilia-specific health-related quality of life (HRQoL) and impact/burden on families of boys with hemophilia resulting from limited access to clotting factor concentrates (CFCs) for effective prophylaxis for boys with hemophilia in Thailand in the future.

Novo Nordisk Access to Insight Basic Research Grant 2020

Mettine H.A. Bos
Leiden University Medical Center
The Netherlands

Project title:
Novel strategies towards blood coagulation factor IX that functions independently of the cofactor VIIIa


We propose to develop a novel factor IX protein that is capable of functioning independently from its cofactor VIIIa through specific modifications that mimic those induced by cofactor binding. We are currently expanding the biochemical characterization of previously designed factor IX variants that are already capable of cofactor-independent functioning to some extent. Additional and/or novel modifications could further improve the cofactor-independent factor IX activity. By employing in silico modelling strategies based on findings obtained for homologous serine proteases, we will identify novel targets and substitutions to introduce these gain-of-function characteristics in factor IX. Subsequent detailed biochemical characterization of the generated factor IX variants will allow for evaluation of potential for hemostatic efficacy. As a consequence of cofactor-independent functioning, the novel factor IX variants may prove efficient to restore hemostasis in hemophilia A patients suffering from inhibitory antibodies targeting factor VIII.

Novo Nordisk Access to Insight Clinical Research Grant 2020 (1)

Merel Timmer
van Creveldkliniek,
University Medical Center Utrecht,
Heidelberglaan 100,
Utrecht, 3508 GA
The Netherlands

Project title:
Primary care physiotherapy for persons with haemophilic arthropathy


Joint bleeds in haemophilia cause a disabling haemophilic arthropathy (HA). Persons with HA experience limitations in activities and participation and are less active than their healthy peers. The first choice for treatment of persons with HA is conservative management, including pain medication and physiotherapy. Access to physiotherapy is therefore one of the conditions to become a European Haemophilia Comprehensive Care Center (HCCC). Unfortunately, many PWH live too far from their HCCC to receive regular physiotherapy treatment by an experienced physiotherapist located at the HCCC. Although several studies have investigated physiotherapy for persons with HA performed by experienced physiotherapists located at the HCCC, little is known about physiotherapy for persons with HA performed in primary care.
The objectives of the proposed study are therefore to 1) give insight into the content (treatment modality, duration, frequency etc.) of physiotherapy for persons with HA in primary care, 2) determine feasibility of physiotherapy for persons with HA in primary care and 3) determine effectiveness of physiotherapy for persons with HA in primary care.

Novo Nordisk Access to Insight Clinical Research Grant 2020 (2)

Cecilia Augustsson
Coagulation (Clinical chemistry and pharmacology, Region Skane),

Project title:
Laboratory monitoring of modified haemophilia products


During the past years new recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have been introduced in the treatment of haemophilia patients. The EHL products have a great potential to increase the quality of life for the patients. The products have an increased half-life and fewer injections are needed for the patient. This is accomplished by e.g. fusion of the molecules to Fc portion of immunoglobulin, albumin or addition of polyethylene glycol (PEG) group. Effective treatment requires correct measurement of the potency after administration, which is a challenge with the new EHL products. Both over- and underestimation have been shown for different products using different assays. The assays used in laboratory monitoring of factor VIII and factor IX are either one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). There is also a need to further understand how global assays can be used for monitor of haemophilia patients.
For haemophilia patients, the new EHL modified haemophilia products are a significant improvement in quality of life. However, this presupposes that the effect of drugs can be measured with high precision to set the right dose. Adjustment and monitoring the right dose is a prerequisite for cost effective drug use. The project can identify new methods for clinical follow-up of haemophilia patients. There are currently large variations in instrument and reagent set-up in the coagulation laboratories around the world and the methods are often very time-consuming to set up. Although we have access to both CSA and OSA methods for FVIII and FIX, the included reagents in the methods can contribute to measurements in patient samples with drugs underestimating or overestimating the effect patients have on their treatment and therefore also the development of inhibitors. It is a potential patient safety risk. It is difficult for an individual laboratory to produce all the information needed to be able to measure each new preparation on the market. The information will be used to adapt the analysis range and possibly also produce more accessible automated methods. In addition, the data will create insight how to use thrombin generation as a global assay for monitoring. There is a great news value in this because several new preparations have now become available. More publications are needed to facilitate analysis choices and our hope is also that we can gain an increased understanding of what causes the differences.

Novo Nordisk Access to Insight Clinical Research Grant 2020 (3)

Chioma Ejezie
University of Nigeria Teaching Hospital,

Project title:
Thrombin activatable fibrinolysis inhibitor and annualized bleeding rate in a cohort of Nigerians with moderate to severe Haemophilia A & B


Background: Haemophilia A is the commonest X-linked bleeding disorder with a global prevalence of 1:5000 while that of haemophilia B is 1:20000. Apart from factor deficiency, it has been hypothesized that bleeding in people living with haemophilia may also be due to unregulated fibrinolysis. This may account for the heterogeneity in the annualized bleeding rates seen in people living with haemophilia A or B. Thrombin activatable fibrinolysis inhibitor (TAFI) provides a link between coagulation and fibrinolysis. Activated TAFI plays a role in inhibiting fibrinolysis where it changes the fibrin structure and makes it less susceptible to fibrinolysis. Aim: This study proposes to assess the relationship between plasma levels of TAFI and annualized bleeding rates in people living with moderate or severe haemophilia A and B.
Methods: This will be a cross-sectional study of 80 (pediatric and adult) subjects with moderate or severe haemophilia A and B attending comprehensive haemophilia treatment centres in Nigeria. Convenience sampling technique will be used to recruit consenting subjects. Data on disease characteristics mainly annualized bleeding rate (ABR), presence of target joints will be collected. APTT mixing studies(inhibitor screening) and one stage factor assay will be done for each subject. Plasma TAFI levels would also be evaluated using an invitro enzyme linked immunosorbent assay (ELISA) technique. Assessment of QoL using ED 5Q will be done. Data analysis will be done using SPSS version 17. Continuous variables will be analyzed using appropriate statistical models based on the distribution of the data. Associations between discrete variables will be determined using chi-square or Fisher’s exact tests and statistical significance will be determined using odds ratio, confidence intervals, and statistical significance will be inferred at a p < 0.05. Ethical clearance will be obtained from the ethics committee of the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu.

Expected outcomes: The study will have the following deliverables:

  • To generate data on annualised bleeding rate in PWLH in Nigeria
  • Values of plasma levels of TAFI in persons with moderate or severe haemophilia
  • Associations if any between plasma levels of TAFI and the annualized bleeding rate
  • Associations if any between TAFI and the Quality of life of subjects

Significance of the study: Fibrinolysis has long been seen as a possible therapeutic intervention in the management of bleeding episodes in PLWH. TAFI is a potential target for developing novel therapeutic agents. This study offers the opportunity to evaluate TAFI levels in Nigerians with haemophilia and assess any possible association with ABR.

Novo Nordisk Access to Insight Basic Research Grant 2019

Tsukasa Ohmori
Jichi Medical University

Project title:
Development of a patient-specific genome-editing approach for haemophilia


Hemophilia is considered suitable for gene therapy because it is caused by a single gene abnormality. Of note, permanent repair of the gene responsible for haemophilia is a worthwhile goal for medical science. We have developed a gene-editing approach for haemophilia B using the CRISPR/Cas9 system. However, the disease-specific mutation cannot be effectively treated owing to the lower frequencies of homology-directed repair. Furthermore, the induction of double strand break (DSB) in the chromosomal DNA by DNA-cutting enzyme could create large deletions and shuffle genes, possibly resulting in unnecessary adverse effects. Accordingly, an alternative approach to correct disease-specific mutations without DSB will be indispensable. This study aims to develop a novel base-editing technology to enhance the flexibility of the base-editing tool to repair various mutations in haemophilia. We believe that our study provides an important advance in gene therapy approaches for haemophilia patients. Therefore, the results should be of considerable interest not only to basic scientists and clinicians, but also haemophilia patients.

Novo Nordisk Access to Insight Clinical Research Grant 2019

Brigitte Tardy
Haemophilia Treatment Centre / Centre d’Investigation Clinique – CHU Saint Etienne
Saint Priest en Jarez

Project title:
Identification of Physiopathological Mechanisms of Haemophilia-Related Osteoporosis


Osteoporosis in haemophilic patients is a true (even still underestimated) underlying comorbidity. However, definite conclusion regarding exact pathogenesis of haemophilia-associated osteoporosis cannot be drawn yet. Further investigations are needed to guide appropriate screening and treatment of haemophilia-related osteoporosis. To date, 2 studies appear to be in favour of a role of fVIII or fIX deficiency in abnormal bone metabolism. However, neither of these studies answered the question whether fVIII or fIX deficiency in itself has a direct impact on bone metabolism or whether thrombin generation impairment (as a consequence of fVIII or fIX deficiency) is responsible for the reduction in bone density. In order to cover the question, we plan to conduct a study that aims to evaluate, in haemophilic patients, the correlation of fVIII, fIX or thrombin levels with the osteoporosis degree.
Unlike previous clinical studies focusing on bone density in haemophilic patients, our study will classify patients in terms of their fVIII/fIX and thrombin generation levels. This will allow evaluation of the direct impact of fVIII/fIX and thrombin levels on BMD.

Novo Nordisk Access to Insight Basic Research Grant 2018

Philip M. Zakas
Lillicrap Laboratory
Molecular Hemostasis Research Group
Queen’s University
Kingston ON, Canada

Project title:
Gene delivery of large nucleic acid cassettes via foamy viral vectors for the treatment of hemophilia A


Hemophilia A, is an ideal candidate for somatic cell-based gene therapy, however, current clinical trials have required high viral vector doses of adeno-associated viral (AAV) vectors and have resulted in variable levels of FVIII. Limitations of the AAV vector platform include its packaging capacity and pre-existing immunity to the viral capsid in ~50% of potential gene therapy recipients. There is a critical need for a safe and effective alternative viral vector with a larger packaging capacity that could incorporate larger FVIII constructs with enhanced biotherapeutic properties. Foamy viruses are non-pathogenic retroviruses currently being explored in pre-clinical gene therapy settings for β-thalassemia, Wiskott–Aldrich syndrome, and chronic granulomatous disease. Foamy viral vectors (FVVs) have distinct advantages over current AAV and lentiviral vector systems including enhanced transduction efficiency, reduced genotoxicity and clonal dominance, and the lack of pre-existing immunity in the population. Critically, FVVs have a substantially larger packaging capacity than either AAV or lentivirus, enabling the development of larger transgene cassettes. This gene therapy platform will allow development of therapies with improved safety features previously disregarded due to transgene size limitations and will enable the use of engineered FVIII sequences with modified B-domains and/or VWF fragment molecules provided in cis. This proposal will investigate the safety and efficacy of FVVs for the treatment of hemophilia A.

Novo Nordisk Access to Insight Clinical Research Grant 2018(1)

Wouter Foppen
University Medical Centre Utrecht
The Netherlands

Project title:
Detecting Subclinical Bleeding and Subclinical Joint Changes in Adolescent Hemophilia Patients on Prophylaxis


Several studies in children have suggested that occult/subclinical bleeding in ankles occurs in up to 63% of severe haemophilia patients on prophylaxis. Others have challenged these findings and have questioned the occurrence of subclinical bleeding. After a joint bleed, intra-articular blood directly induces chondrocyte apoptosis before being cleared by the synovial tissue. Therefore, the first changes are expected to be observed in the synovial tissue. Subclinical bleeding may be detected by biomarkers for changes in joint tissues and inflammation, as well as sensitive imaging modalities (Magnetic Resonance Imaging (MRI) and ultrasound). Especially in patients treated with intermediate-dose prophylaxis, the detection of occult bleeding is important, as it may warrant intensification of treatment. However, subclinical bleeds are difficult to establish. The subclinical bleeding theory is based on (presumably blood-induced) joint changes, although the presence of intra-articular blood in the absence of a clinical bleed has not observed yet. Although standard MRI settings are unable to detect limited amounts of intra-articular blood, dedicated MRI settings are potentially useful to detect low concentrates of blood in synovial fluid. These dedicated MRI setting can be used in addition to a standard MRI protocol for blood-induced joint damage as a non-invasive test to support or reject the likelihood of subclinical bleeding. In this project we aim to verify the subclinical bleeding theory using biomarkers and sensitive imaging modalities. In addition we aim to establish the occurrence of subclinical joint changes in patients on intermediate-dose prophylaxis and evaluate potential biochemical markers for synovial changes and cartilage changes on MRI.

Novo Nordisk Access to Insight Clinical Research Grant 2018(2)

Bram Peters
Amsterdam UMC, University of Amsterdam
Emma Children's Hospital, Pediatric Hematology
The Netherlands

Project title:
iCHEC: Refining the Pediatric Bleeding Assessment Tool


The evaluation of bleeding symptoms in children may be challenging as symptoms can be subtle and children face less hemostatic challenges in comparison to adults. However, the accurate assessment of the bleeding history of a child is very important, as unrecognized subtle cues may delay diagnosis and lead to severe bleeding complications.

Previous studies have standardized bleeding histories by means of standardized questionnaires called “Bleeding Assessment Tools” (BATs). In children such scoring systems are of limited value because scoring is restricted to the most severe episode and therefore lacks sensitivity to pick up subtle cues. Moreover, the existing BATs are inflexible to changes in the bleeding phenotype of the developing child.

In this observational study we have developed a comprehensive iCHEC (Identifying Children with HEreditary coagulation disorders) questionnaire, to use as the baseline item bank for measurement in our study. The iCHEC questionnaire is based on the ISTH-BAT and Pediatric Bleeding Questionnaire (PBQ). Following a thorough literature review and consultation with experts, we added pediatric-specific bleeding items and qualitative questions. To increase the flexibility we incorporated the time dependency of bleeding symptoms and we adapted the questionnaire to be a self-administered.

The items of this questionnaire will be analyzed for diagnostic accuracy in 200 children attending pediatric hematology clinics. Based on the results we expect to select the most informative items for a refined new pediatric BAT that will be a more sensitive, efficient and flexible screening tool for inherited bleeding disorders in children presenting with bleeding symptoms.

Novo Nordisk Access to Insight Scholarship 2018

Ines Vaide
North Estonian Medical Centre

Training will be undertaken at:
A twelve-month training period is planned at Helsinki CCC Thrombosis and Hemostasis Centre, Helsinki, Finland, including some time spent at another centre in Europe.

Supervised by: Prof. Riitta Lassila and Dr. Anna-Elina Armstrong

The focus of the 12-month training period will be on:

  1. Training at a specialized hemostaseology laboratory.
  2. Care of children with bleeding disorders in an out-patient setting.
  3. Management and consultation of patients with acute bleeds.
  4. Carrier consulting and preparation for obstetrical care of women with bleeding disorders.
  5. Management of bleeds and transfusions and their monitoring in the intensive care unit or emergency settings.
  6. Management and consultations of patients with combined coagulation deficiencies suffering from both bleedings and thrombosis, anticoagulation of thrombosis patients and their care of anticoagulation-induced bleeds.
  7. Acquiring deep insight and understanding of age-related conditions and comorbidities in patients with bleeding disorders - orthopedic, surgical, cardiovascular diseases and multidisciplinary cooperation with specific specialists.
Estonia is still developing comprehensive care for patients with bleeding disorders. My training is very important to this process. The main aim of my training is for me to become a specialist in Estonia who is experienced in both coagulation pathologies - bleeding disorders and thrombosis. My training would also help my scientific research, characterizing bleeding disorders in Estonia.

Novo Nordisk Access to Insight Basic Research Grant 2017

Lacramioara Ivanciu
The Children’s Hospital of Philadelphia

Project title:
Fibrinolysis Inhibition as Novel Adjuvant Therapy for Hemophilia


Hemophilia therapy aims to control bleeding by inducing and facilitating thrombin generation. It involves infusion of factor VIII or IX plasma-derived or recombinant proteins, or bypassing agents, such as FVIIa in cases complicated by the presence of antibodies to either FVIII or FIX. However, for certain individuals the clinical response can be variable. The reasons are likely multifactorial but include underlying joint/tissue damage as well as variable half-lives among the patients. Further, due to the high cost of this therapy, only 20% of patients worldwide have regular access to treatment with those located in the developing countries have little to no access. Thus, there is a global unmet medical need to develop novel therapies that could be accessible to a larger patient population. The overall goal of this proposal is to better understand the extent to which fibrinolysis influences clot stability at the site of the vascular injury in hemophilia and, to determine whether down-regulating fibrinolysis could benefit the currently available hemostatic agents in hemophilia and potentially reduce the therapeutic doses of the hemophilia therapy.

Novo Nordisk Access to Insight Clinical Research Grant 2017

David James Stephensen
Haemophilia Centre, Royal London Hospital
Barts Health NHS Trust

Project title:
Home ultrasound - Empowering the haemophilia patient with inhibitors to distinguish between bleeding and non-bleeding episodes


Joint bleeding is the typical manifestation of haemophilia and the presence of an inhibitor increases the incidence of haemarthrosis. Long-term consequence of repeated haemarthrosis is chronic arthropathy, a pattern of disabling joint pain, stiffness, muscle weakness, atrophy and reduced mobility. Overuse of an arthropathic joint may cause inflammation of the joint, together with pain and limited movement, symptoms similar to that of a joint bleed but without the presence of intra-articular blood, i.e. non-bleeding episode. To offer appropriate treatment and, in turn, regain optimal functional ability, accurate diagnosis is essential. Currently, diagnosis of haemarthrosis is made empirically by patients who treat themselves at home based on clinical presentations. However, there are no standard diagnostic criteria available and the overlap in symptoms between joint arthropathy and haemarthrosis make it challenging to differentiate between the two conditions. People with haemophilia have for many years been successfully trained to self-administer intravenous treatment at home and we plan to explore whether they could similarly be trained to self-administer ultrasound imaging at home to better manage their condition by accurately differentiating between joint bleeding and non-bleeding episodes. We will develop and trial a training programme to educate haemophilia patients on how to use point of care US for the assessment and interpretation of joint bleeding in the home setting. The primary outcome will be the patient’s perception of the use of home ultrasound to assist in differentiating between bleeding and non-bleeding episodes. Secondary outcomes will include; annual bleeding rates (ABR), use of bypassing agent (frequency and amount), clinical symptoms, joint or muscle fluid/ effusion, Haemophilia Joint Health Score, health-related quality of life, confidence to self-manage.

Novo Nordisk Access to Insight Ulla Hedner Haemostasis Award 2017

Iris van Moort
Erasmus University Medical Center
Sophia Childen's Hospital
The Netherlands

Project title:
Current PK tools differ in prophylactic dosing advice of factor VIII concentrate in hemophilia A patients

Special Issue: Res Pract Thromb Haemost 2017;1(Suppl. 1):1-1451.
Abstract number ASY 27.3 (page 32)

Novo Nordisk Access to Insight Scholarship 2017

Gianfranco Di Prinzio
Université Catholique de Louvain

Training will be undertaken at:
Universitätsklinikum, Bonn, Germany
Supervised by: Prof. Oldenburg

The focus of the 12-month training period will be on:

  1. Ultrasound ankle, knee and elbow joints of patients coming to routine visits.
  2. Doing this in severe but also moderate and mild haemophilia.
  3. Documenting results from the findings as there might be clinical silent synovitis, early defects of the cartilage.
  4. Evaluating the findings with respect to regimen, concentrate consumption and trough levels.
  5. Documenting actions that are taken from the findings, e. g. intensifying early prophylaxis .
  6. Focusing on ankles as the leading joint.
  7. Developing strategies for long term joint protection (e. g. early intensive prophylaxis with trough levels of 3-5%, early MRT (6-8 YoA) of ankles .
  8. Accompanying this project with genetic lab work e.g. correlating the findings to genetic variants known to be important for rheumatic disease, joint disease progression in haemophilia with the scores of US, HJHS, Petterson Score with respect to time on prophylaxis and degree of joint disease.
  9. Taking part in the routine care of patients with haemophilie and other disorders of Thrombosis and Haemostasis.

Novo Nordisk Access to Insight Basic Research Grant 2016

Christian Kastrup
University of British Columbia
2185 East Mall

Project title:
Enhancing the Adhesion of Clots by FXIIIa to Treat Hemorrhage


Uncontrolled bleeding is a leading cause of death, pervading all socioeconomic and geographical backgrounds. Halting hemorrhage is particularly challenging for patients with coagulopathies, such as hemophilia or trauma-induced coagulopathy (TIC). Mortality from hemorrhage remains high, and the most severe, intractable cases of hemorrhage cannot be adequately managed with current treatment options, such as intravenous recombinant proteins, transfusions of whole blood or platelet concentrates, fluid resuscitation, external hemostatic agents and compression of wounds. This project will foster new insight into the mechanisms limiting effective hemostasis during coagulopathy and use them to develop new strategies for reducing bleeding-related morbidity and mortality. Intravenous coagulation factor XIII (FXIII) may be a potential option for hemorrhage management, but is not regularly used. FXIII, when activated, increases clot firmness, adhesion, and resistance to fibrinolysis to prevent rebleeding episodes. However, the extent to which FXIII may reduce the burden of primary hemorrhage during coagulopathies has not been investigated. We hypothesize that coagulopathies may interfere with the adhesion and stabilization of clots by activated coagulation factor XIIIa (FXIIIa), and that this is one of the limiting factors to achieving effective hemostasis during intractable hemorrhage. Two questions will we address in this project are whether FXIIIa activity is reduced in TIC due to hyperfibrinolysis, and whether restoring FXIIIa increases clot adhesion to reduce hemorrhage. The expected short-term output will be determining the importance of FXIIIa and clot adhesion in TIC and hemophilia. The long-term output is a potential strategy to increase the adhesive strength of clots and reduced mortality and morbidity from hemorrhage associated with coagulopathies.

Novo Nordisk Access to Insight Clinical Research Grant 2016

Andrea Doria
The Hospital for Sick Children
Department of Diagnostic Imaging

Project title:
Can Ultrasound “See” What Clinicians Cannot in Hemophilic Arthropathy? Point-of-Care Ultrasound and Physical Examination Perspectives


Early accurate detection of reversible soft tissue changes (including synovial hypertrophy, hemarthrosis and hemosiderin deposition) and determination of etiology of pain (hemarthrosis vs arthropathy) are paramount in the care of persons with hemophilia (PWH). Perception of pain etiology can be unreliable by physical examination alone. There is an urgent need to overcome limitations of isolated clinical tools for detection/measurement of changes that characterize pathology in PWH. Point-of-care ultrasound (POCUS) refers to the use of US at the patient’s bedside to facilitate diagnosis, holding exciting potential for complementing physical examination and improving cost-effectiveness of diagnostic tests using a “one-stop-shop” approach.

In this study we will determine: 1.Any change in diagnosis of individual joint components of children (7-18 years) with hemophilia which resulted from the use of MRI in joints that were previously evaluated by POCUS (either by a trained physiotherapist/nurse or by an experienced sonographer), by 3600 full US (by experienced sonographer) and by physical examination (by experienced physiotherapist), and the reason for change in diagnosis. 2. The diagnostic accuracy and levels of agreement between POCUS (by trained physiotherapist/nurse or experienced sonographer) and physical examination; and between full US and physical examination for different joint components, in different scenarios that are independently compared with MRI (reference standard).

Expected Results
Investigators will prepare an algorithm indicating further steps in diagnostic management according to agreements/disagreements between diagnostic tests (POCUS, full US and physical examination). Wide Bland-Altman limits of agreement (beyond 2 standard deviations from mean difference score between diagnostic tests in a given scenario) will suggest the need for further imaging (MRI) of the given joint.

Results of this research should optimize POCUS protocols and development of competence training standards for POCUS by national and international board certification organizations. It is hoped that POCUS becomes a bedside outcome measure that could lead to implementation of strategies (e.g. intensification of prophylaxis) that would protect joints with early subclinical arthropathy from progressing to more severe/clinically evident disease.

Novo Nordisk Access to Insight Harold R. Roberts Haemostasis Award 2016

Lisette M. Schütte
Erasmus University Medical Center
Sophia Childen's Hospital
the Netherlands

Project title:
A pharmacokinetic model for the response to desmopressin in mild hemophilia A patients (“DAVID” studies)

Haemophilia (2016), 22 (Suppl. S4), 1—152. (page 99)

Novo Nordisk Access to Insight Scholarship 2016

Dhwanee Shardul Thakkar
Fortis Memorial Research Institute
122002 Gurgaon

Training will be undertaken at:
The Edinburgh Haemophilia and Thrombosis Comprehensive Care Centre, Scotland
Supervised by: Angela Thomas

My expectations of the six-month training period:
India has a high burden of haemophiliacs and patients with coagulopathies and thrombophilias, and the physicians trained in this field are too few to cater to these huge numbers. Due to lack of training and awareness regarding coagulation disorders and platelet function defects, these disorders are underdiagnosed/missed. Also not many laboratories are so well developed as to carry out coagulation factor assays, platelet function studies, inhibitor assay, etc. Many of the states also do not have a Comprehensive Hemophilia Care centre.

Also, there are several barriers to optimal care of the patients with Hemophilia viz. lack of implementation of uniform protocols for dose and frequency of factor administration, ease of availability of factor for replacement, screening for inhibitors, etc. There is a lack of knowledge, awareness as well as advocacy for resource allocation for provision of free/subsidised factor for these patients. There is a need for change in the policies for resource allocation for availing recombinant factor at subsidised rates and build advocacy groups for improving the quality of care of these patients.

I believe that after an intensive training at a pioneering centre in Hemostasis and thrombophilias, where I would get to be a part of the diagnosis and management of a large number of patients with bleeding and thrombotic disorders, I would be able to confidently diagnose and manage patients of Hemophilia with/without inhibitors, other rare coagulation disorders, platelet number & function defects and thrombophilias; and help to improve their quality of life. I can share the knowledge and experience acquired from the training with my colleagues and peers. I believe that I can motivate and further train more people in this field.

During my training programme, I wish to be actively involved in:

  • Evaluation and management of patients presenting with suspected bleeding disorder.
  • Attend clinics for follow-up visits of patients with Hemophilia, vWD, rare bleeding disorders, thrombophilias, etc. who are on prophylaxis or Immune tolerance induction and also attend clinics that address their co-morbidities.
  • Management of in-patients and patients admitted for other ailments/posted for surgery and need consultation/opinion pertaining to coagulopathies/thrombophilias.
  • Counselling sessions for families regarding the disease, genetic counselling and prenatal diagnosis process.
  • Attend Hemostasis laboratory (observe the coagulation studies, platelet function studies, factor assays, inhibitor assay, genetic/molecular diagnosis).

This training experience would help me deliver on above stated objectives and work to provide holistic care for these patients. I believe that this formal training would help me bring a change in the current scenario of management of these patients in India.

Novo Nordisk Access to Insight Scholarship 2016

Zainab Salim Al-Hosni
Oman Medical Speciality board (OMSB)
123 Muscat

My expectations of the twelve-month training period:
The one-year training period at a renown Haemophilia Treatment centre will provide me with an excellent opportunity to deepen my knowledge and expertise in the field of acquired and congenital bleeding disorders and to be part of state-of-the-art research.

Currently I work at the Oman Medical Specialty Board (OMSB) as a haematopathology resident. During my studies the subject ‘haematology’ was of special interest to me and I am highly interested in haemostasis and bleeding disorders. While working in different haematology units and attending a number of internships in Oman and abroad I have already experienced the benefits of learning from specialists in the field. This is why I believe that I will greatly benefit from my one-year training.

I am interested in gaining further insights into diagnostics and laboratory tests used to identify common and rare bleeding disorders and I am looking forward to increase my knowledge on quality control in haemostasis testing to provide a high quality service to my patients. In addition, I hope to be able to serve as a consultant for other physicians after the training.

My overall goal is to learn as much as possible from the experts during my Access to Insight-sponsored training. The expertise that I will take home will improve the care for patients with acquired and congenital bleeding disorders in my home country. I aim to become one of the leading specialists in the field of haematology in Oman and would like to combine clinical work, research and teaching.

Novo Nordisk Access to Insight Basic Research Grant 2015

Dr Peter Lenting
Institut national de la santé et de la recherche médicale (Inserm)
U1176 Hémostase Inflammation Thrombose
Le Kremlin-Bicêtre

Project title:
Platelet-targeted factor VIIa as a novel approach for haemophilia treatment


Among the FVIII-bypassing agents, recombinant factor VIIa (rFVIIa) has shown to be an efficient agent in the treatment of haemophilia-inhibitor patients. Unfortunately, rFVIIa is characterized by a relatively short half-life (2-3 h). Given the proven efficacy of rFVIIa in haemophilia treatment, it is an attractive candidate for the development of next-generation long-acting variants. The maximal prolongation obtained so far is insufficiently long to allow regular prophylactic treatment. Furthermore, prolonged exposure of rFVIIa in the circulation may potentially increase its thrombotic side effects.

By using a novel peptide-targeting peptide (PTP), we will develop a FVII-fusion protein (FVIIa-PTP) that permits its targeting to platelet α-granules. Preliminary experiments using PTP fused to mNeonGreen, revealed that up to 55 % of the platelets had incorporated mNeonGreen-PTP when expressed in wt-mice.

Uptake of FVIIa in platelets will shield FVIIa from plasma during the normal circulation, and allows its release for haemostatic action upon platelet activation. Potential benefits of this approach will be a superior half-life similar to that of platelets combined with reduced thrombogenicity and immunogenicity.

Novo Nordisk Access to Insight Clinical Research Grant 2015

Víctor Jiménez-Yuste, MD, PhD
Universitary Hospital La Paz

Project title:
Tailoring prophylaxis in children with severe haemophilia: impact of the trough procoagulant state on the incidence of breakthrough bleeding


Prophylaxis is a proven method to prevent bleedings in patients with severe haemophilia. However, its highly expensive costs restrain its use in patients in developing countries and compel accurate individualized prophylaxis in developed countries to optimize the benefit/cost ratio. Factors that influence prophylaxis efficacy are poorly understood and therefore complicate the optimization of prophylaxis tailoring. The principal aim of this study is to determine the influence of the trough procoagulant state on the incidence of breakthrough bleeding in children with severe haemophilia under prophylactic treatment. To achieve this goal we will determine the correlation between the incidence of breakthrough bleeding and the trough procoagulant state in a cohort of children under prophylaxis treatment. In addition, the trough activity levels of FVIII/FIX, physical activity, time spent under 1% of FVIII/FIX and joint status will be analyzed to determine their interaction and their relative importance on the incidence of breakthrough bleeding in this group of patients. We hypothesize that determining the procoagulant effect of trough levels of FVIII/FIX will allow a better tailoring of prophylaxis in children with haemophilia. This will improve both the quality of patients’ care and the cost of prophylaxis’ schemes in children and adolescents with severe haemophilia.

Novo Nordisk Access to Insight Ulla Hedner Haemostasis Award 2015

Dott Daniela Scalet
University of Ferrara

Project title:
Correction of aberrant splicing causing haemophilia B through the combination of compensatory U1snRNAs and antisense oligonucleotides

The work has been published in the following publication:

Balestra D, Barbon E, Scalet D, et al. Regulation of a strong F9 cryptic 5'ss by intrinsic elements and by combination of tailored U1snRNAs with antisense oligonucleotides. Hum Mol Genet 2015.

Novo Nordisk Access to Insight Scholarship 2015

Oliver Grottke, MD, PhD, Priv.-Doz.
RWTH Aachen University Hospital
Department of Anaesthesiology

Training will be undertaken at:
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany.
Supervised by: Prof. J. Oldenburg

My expectations of the six-month training period:
Perioperative haemostasis and thrombosis is an evolving topic of great relevance to anaesthesiologists and our patients, because patient outcomes are highly dependent on treatment decisions. Perioperative coagulopathies are highly heterogeneous, and optimal management can reduce the risk of severe adverse events such as massive blood loss, arterial or venous thromboembolism, and death.

During my training I am hoping to increase my clinical knowledge of rare coagulation disorders such as haemophilia A, haemophilia B and von Willebrand disease, to gain a deeper understanding of the diagnosis and treatment of these conditions. I have a particular interest in learning about the best approaches to laboratory analysis and their application to patient management. From the clinical rotation I hope to improve my competence in:

  1. characterizing the patient’s condition and deciding which laboratory tests to request;
  2. initiating the appropriate diagnostic or therapeutic processes based on established protocols and full understanding of the laboratory tests, with correct referral routes and patient consultations;
  3. independent decision-making for the treatment of bleeding and haemorrhagic conditions.

To acquire these competencies, I hope to be involved in the daily procedures of treating and consulting with in-patients and out-patients. I would also be available on-call. From my experience as an anaesthesiologist and intensivist, I am used to treating patients with acquired coagulation disorders. Such patients require special attention throughout the perioperative period to minimize the risk of bleeding complications which, should they occur, are best managed through an interdisciplinary approach. I hope the rotational programme will enhance my skills so that the patients I treat receive the best possible level of care. I would proactively share the knowledge and expertise gained from the rotation with my existing colleagues, providing a valuable opportunity to improve overall patient care at RWTH Aachen University hospital.

I strongly believe that the combination of anaesthesiology, intensive care medicine and clinical training in rare coagulation disorders is key to optimising modern perioperative care. This is especially important at medical centres which have no or limited access to physicians with training in inherited bleeding disorders.

Novo Nordisk Access to Insight Scholarship 2015

Dr Giorgia Sacullo
Università degli Studi di Palermo
Policlinico Paolo Giaccone

Project title:
N.A. (6 month scholarship; planned HTC: Sheffield)

Novo Nordisk Access to Insight Basic Research Grant 2014

Mirko Pinotti, PhD
University of Ferrara
Department of Life Sciences and Biotechnology

Project title:
Altered mRNA processing and FVIII biosynthesis/function as determinants of phenotype variability in the frequent Arg2016Trp Haemophilia A patients


The relationship between the molecular defect, the coagulation and the clinical phenotype in Haemophilia is often unclear. While the association of the so-called “null mutations” with severe forms is well-established, that of missense mutations, frequent in Haemophilia A (HA) and largely predominant in Haemophilia B (HB), with the phenotype is elusive. Missense mutations are candidate to affect protein biosynthesis/function but might also impair pre-mRNA splicing, an emerging mechanism whose pathophysiological impact is still poorly investigated. The interplay between these mechanisms might concur to factor VIII/IX levels and to HA/HB severity.

As an ideal model to investigate this issue, we propose the frequent F8 c.6046C>T mutation that has been found in severe and moderate HA patients with different degrees of bleeding tendency. The mutation is candidate to affect FVIII protein biology, and preliminary data suggest it alters F8 pre-mRNA splicing.

To elucidate the pathogenic mechanisms of the frequent F8 p.Arg2016Trp (c.6046C>T) mutation and define the underlying residual factor VIII levels, thus identifying determinants of phenotypic variability of Haemophilia A.

Expected results
By investigation at the protein and mRNA level in several p.Arg2016Trp patients and with recombinant FVIII variants we expect to define the contribution of impaired mRNA splicing and/or protein biosynthesis/function to FVIII expression. This will provide insights into a poorly known, and largely underestimated feature of missense mutations, which are frequent cause of Haemophilia and of the other rare coagulation factor disorders, and could boost the investigation of mRNA splicing patterns in patients with missense mutations to help interpretation of the related coagulation and clinical phenotypes.

We believe that our findings on the frequent F8 c.6046C>T mutation could help clinicians in the patient’s diagnosis and treatment.

Novo Nordisk Access to Insight Clinical Research Grant 2014

Dr Kevin Deschamps
Katholieke Universiteit Leuven

Project title:
Non-invasive in-vivo measurement of foot joints loading in children with haemophilia during walking


Primary prophylaxis has radically decreased the incidence of arthropathy in patients with haemophilia (PwH). However, the ankle joint seems to be an exception to the rule, as PwH treated with primary prophylaxis still experience ankle arthropathy. As such, the ankle now is the main affected joint in PwH under the age of 20.

In the current project, we will aim at determining aetiologic/contributing factors associated to the ankle arthropathy pathophysiological cascade in children with haemophilia (CwH). To achieve this goals, we will first develop and subsequently introduce a 3D Multisegment Foot Kinetic Model within the population of CwH. The major objective of this model is to quantify accurately (in-vivo and in a non-invasive manner) joint loading at the tibiotalar joint, the midfoot and forefoot. Secondly, we will aim at developing a classification system based on these kinetic data. Finally, we will assess the relationship between the newly developed classification system and the degree of ankle joint structural integrity (MRI). The current project involves an intensive collaboration between the two biggest belgian haemophilia centers (Haemophilia Centre of UZ Leuven (Prof. K. Peerlinck) and the Haemophilia Centre of UCL (Brussels- Prof. C. Hermans).

Novo Nordisk Access to Insight Harold R. Roberts Award 2014

Lize F.D. van Vulpen, MD
University Medical Center Utrecht
The Netherlands

Project title:
Interleukin-1 beta is essential for blood-induced cartilage damage in vitro

Haemophilia (2014), 20 (Suppl. 3), 1—186. (page 71)

Novo Nordisk Access to Insight Scholarship 2014

Ana Lilia Hernández Moreno
UMAE Centro Médico Nacional La Raza
México, D.F

Training will be undertaken at:
Hospital Universitario La Paz, Madrid, Spain
Supervised by: Dr. Víctor Jiménez Yuste

My expectations of the training:

My expectations in the one-year training period at the Hematology department in the centre of Dr. Jiménez Yuste in Madrid, Spain, will provide benefit for my patients at the Medical Center La Raza in México City where I take care of around 170 hemophilic children and patients with other bleeding disorders. This requires physicians and specialists to continue training and to assist further education courses to provide the best care to all patients. In the last few years, our institution has been ranked first in México for the treatment of patients with the diseases mentioned above.

It is remarkable to mention that the Mexican population is about 112 million people, while, on the other hand, there are only 600 hematologists. Furthermore, only 5% of these physicians are trained experts in hemophilia. For these reasons, I would like to continue my training to become a leading hematologist in my country and the world.

For my training at the Hospital Universitario La Paz, my main goal is to acquire the best possible expertise in the management of hemostasis and rare bleeding disorders, inherited platelet disorders and thrombosis. Currently, in México and in our hospital as well, there is a lack of professionals in this field.

In detail, I would like to focus my training on the following objectives:
  1. To improve my clinical assessment skills in hemophilia, including orthopedic assistance and rehabilitation programs.
  2. To increase my expertise in patients with coagulation factor inhibitors, in immune tolerance induction (ITI) and in treatments involving bypass-clotting agents.
  3. To increase my clinical skills in the management of thrombosis, congenital and acquired factor deficiencies and other rare bleeding disorders, which nowadays entail a great challenge in hematology.
  4. To complete the hematological team of thrombosis and thrombophilia, taking care of these two conditions which are related to cancer and the central venous which require immediate diagnosis and assistance.
  5. To get a better understanding of the main laboratory tests and analysis of the bleeding disorders and, in the end, improve the diagnosis of these diseases.
    I also want to increase my knowledge in the laboratory routine involving: a) the procedures for the genetic diagnosis of hemophilia and the diagnosis of female hemophilia carriers, including the genetic study to determine the domain of inhibitors (influences of Immuno-Genetic and Haemophilia Treatment factors) b) platelet analysis and aggregation tests.
  6. To take an active role in lectures, discussions and work rounds sessions with the doctors and professors of the Hospital Univesitario La Paz.
  7. I will also offer to teach my colleagues back here in México, in order to further improve the assistance and to increase the number of hematologists who are dedicated to hemophilia, thrombosis and other rare bleeding disorders.

In conclusion, I would like to improve my skills managing the bleeding disorders mentioned above and therefore become a much better physician treating all these diseases that are developing in my country. With my training and the experience that I will acquire I will benefit Mexican children, and possibly patients in other Latin American Countries.

Novo Nordisk Access to Insight Scholarship 2014

Dr Mehran Karimi
Hematology Research Center of Shiraz University of Medical Sciences

My expectations of the training at a renowned HTC:

I am working in a major referral hospital that is responsible for hemophilia care. It is located in the southern Iran as an emerging/developing country where consanguineous marriage is common. In our area, hemophilia and rare bleeding disorders (RBDs) are not uncommon and many cases are undiagnosed, especially in the field of RBDs, VWD and platelet disorders. In this training, I want to gain experience in both laboratory and clinical management of bleeding disorders.

I expect to learn more about:
  1. Established inhibitor tests in RBDs and VWD and updated inhibitor tests for patients with hemophilia A and B.
  2. Appropriate methods of diagnosis, management and prophylaxis of RBDs as well as platelet disorders which are not uncommon in our area.
  3. Appropriate diagnosis and treatment of women with bleeding disorders specially menorrhagia which is a common undiagnosed problem in our area.
  4. Management of hemophilia patients with inhibitors in surgery. I want to learn how to manage and monitor these patients during and after surgery which is challenging in my country because of a shortage of factor concentrates.
  5. I would like to learn about musculoskeletal disorders in hemophilia (when should we manage musculoskeletal disorders in hemophilia and how to monitor them during physiotherapy. When should surgery be performed).
  6. ITI management in patients with inhibitors.
  7. Upgrade and update our laboratory for diagnosis of RBDs, platelet disorders and VWD.
  8. Diagnosis and management of RBDs such as acquired hemophilia.

Furthermore, I hope to participate in clinical trials about RBDs and hemophilia. I also hope to establish a center for prenatal diagnosis (PND) especially for hemophilia A, B and RBDs because abortion is legal before 16 weeks of gestational age in Iran. At the end of training, I hope I will be able to have comprehensive laboratory, PND test as well as hemophilia treatment center experience in order to help the patients with better management and prophylaxis regimens. I plan to have educational programs for physicians, patients and their parents. I also plan to use the best and accurate scientific treatment for patients with inhibitors, patients with RBDs and platelet disorders.
Increased quality of life (QOL) of patients with inhibitors, RBDs and women with bleedings, specially menorrhagia, is another aim in my treatment strategy. Finally, I believe the patients and my colleagues in our area will gain considerable benefits from my training and will assist me in improving the QOL for patients with hemophilia, RBDs and platelet disorders.
Also, the training will be of unparalleled help for my future career and enable me having more researches in the field of hemostasis/hemophilia and provide a high quality clinical service.

Novo Nordisk Access to Insight Basic Research Grant 2013

Dr Christina Baumgartner
BloodCenter of Wisconsin
Wisconsin, USA

Project description:
Thrombosis risk of platelet targeted FVIII gene therapy in murine Hemophilia A

Hemophilia is an ideal target for gene therapy due to its monogenic nature and the urgent requirement to improve quality of life for patients and potentially reduce costs of hemophilia care.

Our lab has developed a very successful gene therapy approach for hemophilia A, in which FVIII expression is targeted to platelets. Platelet expressed FVIII (2bF8) protects hemophilic mice from lethal blood loss upon vessel injury. Most importantly this therapy does not induce inhibitory antibodies against FVIII and is even successful in mice with pre-existing high titer inhibitors. Therefore this approach is the first to hold promise for patients with inhibitory antibodies against FVIII. Although hemostasis is successfully restored, pathological consequences in conjunction with 2bF8 therapy have not been studied. Because FVIII is usually not expressed in platelets and local FVIII levels might dramatically increase at the site of injury, the aim of this study is to evaluate the risk for thrombosis of 2bF8. Our lab has generated transgenic mice expressing different levels of 2bF8 (as much as 20-fold increase). Using a variety of in vitro hemostasis assays and an in vivo thrombus formation model we will evaluate the thrombosis risk in 2bF8-transgenic mice compared with wild-type mice under the following thrombogenic conditions: 1) inflammation 2) increased levels of VWF and 3) genetic prothrombotic pre-deposition (TMpro and FVLeiden).

Determining the thrombosis risk of platelet expressed FVIII will provide important insights into 2bF8 gene therapy and thereby add further evidence that this therapy might represent a safe and clinically feasible approach.

Novo Nordisk Access to Insight Ulla Hedner Haemostasis Award 2013

Dr Mettine H. A. Bos
Leiden University Medical Center
The Netherlands

Abstract title:
APC-resistant factor V restores impaired coagulation resulting from deficient factor XI-mediated feedback activation

Novo Nordisk Access to Insight Scholarship 2013

Dr Moe Hein
Mandalay General Hospital

Training will be undertaken at:

Katharine Dormandy Haemophilia Centre and Thrombosis Unit Royal Free Hampstead, London, United Kingdom.
Supervised by: Dr T. Yee

My expectations of the six-month training period:

The World Federation of Haemophilia (WFH) estimates that worldwide, approximately 70% of patients with hemophilia are under diagnosed and untreated. Most live in developing countries.

My country, Union of Myanmar, is one of the emerging/developing countries with population of approximately 60 million. According to WFH, The United Kingdom, with a population of 60 million, has 6078 registered cases, whereas Myanmar has well less than 100 identified cases.

The majority of patients with hemophilia remain undiagnosed and per capita usage of FVIII is negligible. This leads to poor quality of life and little chance of survival into adulthood for the majority of patients.

In Myanmar, Hemophilia is perceived as being a rare disorder, so it is not a priority in country's basic health priorities, such as nutrition, immunization, sanitation, family planning, and the treatment of infectious diseases such as tuberculosis, HIV and malaria.

The treatment infrastructure is weak but possesses very basic laboratory diagnostic facilities for hemophilia A&B. There is, however, no treatment center (HTC) to provide comprehensive hemophilia treatment.

A Hemophilia Treatment Center (HTC), as described by WFH, provides comprehensive care that addresses all issues related to the bleeding disorder, as well as education about the disorder. The team consists of physicians (hematologists), nurses, social workers, physical therapists, and other health care providers who specialize in the care of people with bleeding disorders. Most importantly, care is provided regardless of race, religion, culture, or ability to pay.

By undertaking the Haemophilia training with the Novo Nordisk training scholarship my foremost expectation is to learn how these cutting edge HTCs are organized and how they function and by doing so I expect to acquire a certain level of expertise in the diagnosis and management of Hemophilia. Ultimately, I expect to be able to setup a hemophilia treatment center in upper Myanmar which will be run by dedicated clinicians and a comprehensive care team with a specific interest in hemophilia (for Care Delivery). This HTC will collaborate with other upcoming centers in the country to compile data for a national Hemophilia registry. It will also help ensure an accepted standard for hemophilia care based on the WFH models, throughout the country.

There is inadequate knowledge and awareness about hemophilia among doctors, healthcare workers, and patients with hemophilia and their families in Myanmar. Through learning in Haemophilia training with the Novo Nordisk training scholarship I expect to be able to formulate techniques for educating and training clinicians, laboratory technologists, and other healthcare professionals essential to ensure adequate expertise in diagnosis and treatment.

A strong patient organization as suggested by WFH is needed to improve and maintain hemophilia care. It is extremely difficult for such an organization to get legally registered in Myanmar. One possibility of getting functional organization is to encourage hemophilia patients and their families to write to MPs of respective constituencies. The aim is to carry the matter into the House of Representatives and ultimately to get a legislature for national hemophilia healthcare program.

The blood transfusion services (at least in 2 tertiary centers Yangon & Mandalay) are fast improving in Myanmar. They can produce most basic blood products, albeit insufficient, for treatment of hemophilia, such as plasma and cryoprecipitate from screened donors. By improving production and storage capacity and by supporting basic materials (like triple blood collecting bags) for blood products will encourage the long-term availability of replacement therapy on an economically sustainable basis.

In Myanmar (Burma) Russell's vipers are responsible for 90% of cases of snake bite. In 1991, there were 14,000 bites with 1,000 deaths and in 1997, 8,000 bites with 500 deaths. Almost all of them are paddy farmers. Under-reporting is estimated at 12%. Coagulation abnormalities and renal failure are the most common causes of death. The problem, thus, is considered the top priority occupational health hazard in Myanmar. Learning in Haemophilia training with the Novo Nordisk training scholarship, I expect, will give me an opportunity help solve coagulation problems encountered in Russell's viper bites in my country.

In conclusion, Haemophilia training with the Novo Nordisk training scholarship is expected to help me acquire necessary knowledge and expertise to start establish a very basic HTC for Hemophilia patients in Myanmar and ultimately lead to start a national hemophilia healthcare program for improved care of Myanmar Hemophilia patients.

Novo Nordisk Access to Insight Scholarship 2013

Dr Martin Hendelmeier

Training will be undertaken at:

Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany.
Supervised by: Prof. J. Oldenburg

My expectations of the six-month training period:

In this training I want to gain experience in both laboratory and clinical management of bleeding disorders.

During my training in Bonn, I expect to participate in the daily clinical duties of the haemophilia treatment centre. This implies consultative service in the area of haemostasis and thrombosis and other medical, surgical, and obstrectric specialities incl. management of bleeding episodes and aspects on dental care and prevention of complications. Furthermore I would like to undergo a diagnostic coagulation laboratory training, that teaches about quality control of laboratory and community based testings among other topics. Finally, I expect to learn more about the genetics behind haemophilia, incl. genetic and environmental risk factors in the development of inhibitors to FVIII and FIX.

I hope that upon finalization of the training I will have improved my competence in performance, interpretation, and understanding limitations of diagnostic methods, incl. genetic and molecular diagnosis, inheritance, and genetic counseling. Furthermore my knowledge in epidemiology, immunology, and of the molecular basis of inhibitors to FVIII and FIX will have improved and I will have learned more about the special aspects of acquired haemophilia including the characterization of FVIII and FIX inhibitors, the use of by-passing-agents and therapeutic options aiming to eradicate the inhibitor and to achieve immune tolerance induction.

If I can reach these goals during my training in Bonn, it will assist me in my future career and - more specifically - I will be able to do research and teaching in the area of haemostasis/haemophilia to provide a high quality clinical service.

Personally, this training will help me to further develop my professional competence in the field of haemostasis/haemophilia and give me an opportunity to identify practice areas for clinical research.

Overall, it is my belief that the training will assist me in improving the quality of life for patients with haemophilia.

Novo Nordisk Access to Insight Scholarship 2013

Dr Datta Waman Dharmadhikari
National Health Laboratory and Princess Marina Hospital

Training will be undertaken at:

University of the Witwatersrand, Johannesburg, South Africa.
Supervised by: Prof. J.N. Mahlangu

My expectations of the six-month training period:

In this training I want to gain experience in both laboratory and clinical management of bleeding disorders.

I expect to learn more about:

  • Establishing new laboratory tests and their use to diagnose and monitor patients
  • Diagnosing and managing patients with suspected FVIII inhibitors
  • Diagnosing and managing rare conditions like acquired haemophilia
  • Managing and monitoring prophylactic/home therapy
  • Haematological management of surgery in patients with FVIII inhibitors
  • Translational research in bleeding disorders
  • Physiotherapy and occupational rehabilitation in cases of joint deformities due to haemophilia
  • Managing bleeding disorders associated with platelet function defects

Also, I hope to participate in clinical trials about bleeding and clotting disorders.

After I return to Botswana, I want to share my experience and knowledge with my haemophilia care team and with the patients and the Haemophilia Society. I will try to apply some of the insights, which will benefit the patients. The implementation of new laboratory tests and improved management plans will also reduce the referral of patients to South Africa.

Finally, this opportunity will help me to reach to my goal of helping children with Haemophilia and other bleeding disorders.

Novo Nordisk Access to Insight Basic Research Grant 2012

Dr Karin Fijnvandraat
Amsterdam Hemophilia Treatment Center
Academic Medical Center
The Netherlands

Abstract title:
RISE: Response to DDAVP In mild Hemophilia A patients, in Search for dEterminants

In most individuals with mild hemophilia A, factor VIII coagulant activity (FVIII:C) levels increase to a hemostatic range after DDAVP administration. This decreases the need for FVIII concentrates, thereby reducing costs of treatment and exposure to FVIII concentrates with the associated risk of inhibitor development. However, a yet undetermined proportion of patients fail to respond or have a partial response. Understanding the determinants for DDAVP response may enable better prediction and optimal clinical use of DDAVP.

The aim of this study is to investigate the association between both clinical factors (age, FVIII:C, ABO blood group, family history of DDAVP response) and genetic factors (F8 genotype, genes that influence VWF release or FVIII pharmacokinetics) and the DDAVP response.

Patients with mild hemophilia are derived from the hemophilia treatment centers (HTCs) participating in the INSIGHT project, in which we have collected demographic, clinical and laboratory data on 2700 moderate and mild hemophilia A patients from 34 HTCs in 11 countries. DNA samples are presently collected in a subgroup of the patients.

The proposed study will help to predict the response to DDAVP in patients with mild hemophilia A. This will allow for efficient and rational use of this treatment. Identifying genetic predictors of DDAVP response might also help to understand biological mechanisms associated with the release of von Willebrand Factor and rise in FVIII:C. This knowledge could help to develop new treatment approaches.

Novo Nordisk Access to Insight Harold R. Roberts Award 2012

Dr Yesim G. Dargaud
University of Lyon
Hopital Edouard Herriot

Abstract title:
The potential role of synovial thrombomodulin in the pathophysiology of joint bleeds in haemophilia

The work has been published in the following publication:

Dargaud Y, Simpson H, Chevalier Y, et al. The potential role of synovial thrombomodulin in the pathophysiology of joint bleeds in haemophilia. Haemophilia : the official journal of the World Federation of Hemophilia 2012.

Novo Nordisk Access to Insight Scholarship 2012

Dr Zahra Badiei
Mashhad University of Medical Sciences
Haemophilia-Thalassamia Center (Sarvar Clinic)
Khorasan Razavy

My expectations of the six-month training period at a renowned HTC:

I expect to have duties in relation to approaching new cases (being involved in discussions about clinical aspects, laboratory diagnosis, preparing treatment programs and follow up) and in the management of previous cases with different complications, such as arthropathy, inhibitors and blood born infections in both out- and inpatient care. Furthermore I expect to gain insights in the management of emergency conditions, home treatment, prophylaxis treatment in different hemorrhagic disorders and prenatal diagnosis.

There are about 100 cases of different kinds of Rare Bleeding Disorders in our centre in Iran and we have a lot of experience in different aspects of working with them. I believe that sharing this experience with my colleagues in the training centre can be of value for both sides.

It is very important for me to learn more about the management of women with bleeding disorders and the many problems they face. In general I hope to increase my knowledge about bleeding disorders, especially in the field of laboratory diagnosis, bleeding score, prophylactic treatment, home therapy, inhibitor management, arthropathy and its treatment and safe products. I also wish to learn about how a comprehensive Haemophilia care centre is organized and works in the daily routine.

For me it is clear that I – being a physician who works with haemophilic patients and related disorders – need to be up-to-date not only regarding the diagnosis and treatment of these patients, but also in terms of organization of HTCs and cooperation with peripheral units. The centre I work for in my home country is a model for other countries in our state and I feel a special obligation because of that.

I think the training program has the potential to increase life expectancy and quality of life of my patients and can decrease the direct medical cost of treatments (with standard use of products). Furthermore it will promote centralized care in haemophilia field.

UPDATE: Though Dr. Badiei successfully applied and was recipient of the scholarship grant in 2012 she unfortunately could not initiate her training.

Novo Nordisk Access to Insight Scholarship 2012

Dr Majid Naderi
Research Center For Children And Adolescents Health [RCCAH],
Zahedan University of Medical Sciences
Zahedan, 9813643353
Sistan and Balochestan

My expectations of the six-month training period at a renowned HTC:

The hospital I work for is based in the city of Zahedan, Iran. Zahedan is about 1800 km away from Tehran and many of my patients can not afford the cost of travelling to other cities for treatment. I take pride in working in this region for the disadvantaged patients.

In my unit we see rare diseases such as haemophilia A and B, rare bleeding disorders (RBD) and especially factor XIII deficiencies because of consanguinity marriages. As a paediatric haematologist oncologist I am obliged to treat a wide variety of haematologic patients such as patients with deficiencies of factor IX, VIII or XIII.

During the scholarship I expect to learn about:

  • Appropriate methods to diagnose and treat common and rare coagulation disorders.
  • Managing haemophilia patients who are candidates for surgery and delivery.
  • Managing musculoskeletal disorder in patient with haemophilia.
  • Performing ITI.

Furthermore I hope to gain experience in:
  • High level science and clinical practise of my training centre.
  • Establishing a centre for prenatal diagnosis (PND) (especially for factors IX, VIII and XIII)
  • Understanding the managing of inhibitor in patients with haemophilia.

It is noteworthy that at present we have 230 patients with XIII factor deficiency who have diagnostic and therapeutic problems, and suffer from neurological problems which are caused by brain haemorrhage (CNS bleeding) or bleeding in other vital organs.

At the completion of this training I hope I will be able to:

  • Help haemophilia A and B patients to have the minimum musculoskeletal disorder and have high quality of life, experience in therapy and/or prophylaxis for patients with haemophilia and prevent from inhibitors.
  • Use the best and most accurate academic treatment for patients with inhibitor. I am interested to learn about accurate records of treatment methods, complications and services for these patients in other centres.
  • Understand appropriate laboratory and diagnostic skills about RBD and decide on the most appropriate treatment if complications happen.
  • Establish a comprehensive clinic which includes PND diagnosis for patient with haemophilia.
  • Transfer my experience of diagnosis and treatment of women with bleeding disorders and patients with rare bleeding disorders.
  • Participate in ongoing clinical trials in bleeding and clotting disorders, so as to have an opportunity to participate in global clinical trials in the future for example FACTOR XIII.

I believe that the patients who live in the area of my hospital will benefit strongly from my training. Cooperation with colleagues in other centres can only be of advantage to them, because the valuable experience of other haematologists can support me.

Novo Nordisk Access to Insight Basic Research Grant 2011

Dr John P. Sheehan
University of Wisconsin

Abstract title:
Protease Exosites Regulate the Clearance and Activity of Human Factor IX(a)

The pharmacokinetics of recombinant factor IX are characterized by limited recovery and a volume of distribution that suggests a large non-circulating “pool” of factor IX bound to vascular and/or extravascular sites. Additionally, a large proportion of injected zymogen is sequestered in the liver. Antithrombin is the principal plasma inhibitor of the factor IXa protease, and this inhibition is markedly accelerated by heparin/heparan sulfate. Furthermore, heparin oligosaccharides directly inhibit factor X activation by the intrinsic tenase complex (factor IXa-factor VIIIa). Understanding the specific molecular interactions that contribute to physiologic regulation of factor IX(a) will allow the design of proteins with enhanced in vivo activity.

We hypothesize that exosites on human factor IX critically regulate intravascular distribution, clearance, and in vivo protease activity. Plasma-based and in vivo studies demonstrate the importance of the factor IXa heparin-binding exosite for regulation of hemostasis and thrombosis.  Likewise, mutagenesis and crystallographic studies suggest that a distinct exosite is critical to recognition of factor IXa by antithrombin, particularly in the presence of heparin. The aims of this study are to define the contribution of: 1) the factor IX heparin-binding exosite to zymogen recovery and clearance in hemophilia B mice, and 2) the factor IX(a) antithrombin- and heparin-binding exosites to regulation of thrombin generation in human plasma and clearance in hemophilia B mice. The rationale for these studies is that mutagenesis of factor IX can reduce heparin binding while preserving cofactor affinity, and reduce antithrombin binding while preserving factor X affinity. Factor IX with decreased heparin and antithrombin affinity will demonstrate increased circulating levels, half-life, and in vivo activity; enhancing therapeutic effects in protein replacement and gene therapy for hemophilia B.

Novo Nordisk Access to Insight Ulla Hedner Haemostasis Award 2011

Dr Rezan A. Kadir
The Royal Free Hospital
United Kingdom

Abstract title:
Non-invasive prenatal diagnosis of haemophilia by microfluidics digital PCR analysis of maternal plasma DNA
(Please click on the link and download the PDF for Wednesday, 27 July 2011. Go to 'O-WE-005' for the award-winning poster-abstract)

Novo Nordisk Access to Insight Scholarship 2011

Dr Baolai Hua
Peking Union Medical College Hospital (PUMCH)

Training will be undertaken at: Harold R. Roberts Comprehensive Hemophilia Diagnostic and Treatment Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Supervised by: Prof. Nigel Key

My expectations of the one-year training period at the selected HTC:
I will undertake my scholarship at the University of North Carolina at Chapel Hill under the tutelage of Prof. Nigel Key. My goals are to refine my clinical skills and further my experience in the diagnosis and management of patients with bleeding and clotting disorders. At the completion of this training, I hope I will be able to:

  • Understand the laboratory tests used in the clinic to diagnose or monitor patients, especially cutting-edge diagnostic approaches;
  • Understand the options for outpatient therapy and/or prophylaxis for patients with haemophilia;
  • Understand and gain experience in the management of inhibitors in patients with haemophilia;
  • Interpret coagulation tests, with special emphasis on what may cause false positive and false negative tests;
  • Gain experience in the diagnosis and treatment of women with bleeding disorders and patients with rare bleeding disorders;
  • Participate in ongoing clinical trials in bleeding and clotting disorders, so as to have an opportunity to participate in global clinical trials in the future;
  • If possible, prepare a manuscript for submission to a peer-reviewed journal;
  • Establish and maintain a long term relationship with experts in host center;
  • Observe some of the translational research opportunities in hemophilia available in Chapel Hill, including the Gene Therapy Center and the Frances Owen Blood Labs that house dogs with hemophilia A and B, as well as von Willebrand disease.

Upon my return, I would convey these clinical skills and new concepts to my home center and apply them in severing patients with hemophilia and other bleeding disorders. Sharing the experience and skills with colleagues is my second goal. My experiences will definitely benefit other centers in China, as we share the same problems and barriers. I plan to conduct seminars, workshops, and case presentations.

Previous recipients:

Novo Nordisk Access to Insight Basic Research Grant 2010

Roger J. S. Preston, PhD
Institute of Molecular Medicine
Trinity College Dublin
St James' Hospital Campus

Project description:
Molecular Determinants of EPCR-Dependent Coagulation Protease Cell Signaling: Generation of Recombinant Activated Factor VII Variants With Novel Therapeutic Properties

Vitamin K-dependent proteins that promote and regulate blood clot formation can also mediate cell signalling via interactions with receptors expressed on the surface of the vasculature. The endothelial cell protein C receptor (EPCR) is a vitamin K-dependent protein receptor that promotes coagulation protease signalling via protease-activated receptors (PARs) on endothelial and innate immune cells. EPCR-dependent PAR1 signalling by the anticoagulant vitamin K-dependent protease activated protein C (APC) has been shown to be anti-inflammatory, anti-apoptotic and contribute to maintenance of vascular integrity.

We have previously identified coagulation factor VII(a) as a ligand for EPCR. Factor VII(a) binds EPCR with similar affinity to protein C or APC, using the same EPCR binding motif. Consequently, high-dose recombinant factor VIIa administration to attenuate bleeding may elevate factor VIIa plasma concentration such that factor VIIa competes with protein C/APC for EPCR binding. Disruption of the EPCR-dependent anticoagulant and cytoprotective properties of protein C/APC represents a potential mechanism by which recombinant factor VIIa promotes thrombus formation.

Although the physiological function of the factor VII(a)-EPCR interaction is unknown, previous studies have indicated that factor VII(a) binding to EPCR does not promote APC-like cytoprotective signalling on endothelial cells. In this study, novel recombinant APC and factor VII(a) variants will be utilized to probe the molecular basis of divergent EPCR-dependent signal transduction by APC and factor VII(a). The aims of this study are to delineate the specific molecular requirements for cytoprotective signalling by vitamin K dependent proteins, and generate recombinant factor VII(a) variants with novel cytoprotective properties and enhanced therapeutic potential.

Novo Nordisk Access to Insight Harold R. Roberts Award 2010

Ingrid den Uijl
van Creveldkliniek
UMC Utrecht
The Netherlands

Abstract presented at the XXIX INTERNATIONAL CONGRESS OF THE WORLD FEDERATION OF HEMOPHILIA, July 10-14, 2010 - Buenos Aires, Argentina

den Uijl I et al. Haemophilia 2010; 16 (suppl 4): 22P25.

Assessing the Value of MRI Diagnostics in Haemophilic Arthropathy

INTRODUCTION: The value of Magnetic Resonance Imaging (MRI) in haemophilic arthropathy is not yet defined; especially clinical relevance of subtle changes on MRI and its applicability to evaluate treatment are unknown.

METHODS: A prospective study was performed to determine the association of MRI with joint function and X-ray findings. Knees and ankles of 20 patients with severe or moderate haemophilia (aged 12-25) and very little arthropathy were assessed using 3Tesla MRI, in a short protocol to minimize patient burden. MRI score (Lundin scale, max. 20 points/joint), X-ray (Pettersson score (PS), max. 13 points/joint) and HJHS (max. 22 points/joint) were used to calculate Pearsons' correlations at joint level.

RESULTS: Mean age was 20 years, 70% had severe haemophilia. Seven joints showed abnormalities on X-ray (PS 1-9), 22 joints had reduced clinical function (HJHS 1-11 points). MRI scores correlated with PS (r=0.60, p=0.00), but not with HJHS (r=0.04 p=0.75) or lifetime cumulative number of bleeds (r=0.06 p=0.60).
In 4 joints (8%) without changes on X-ray, MRI showed minor changes (score 1-2), while in 2 joints (4%), despite changes on X-ray (PS 1-9), MRI score was 0. MRI scores were 0 in 58 joints (73%), including 42 (72%) with recorded bleeds. In 3 joints (4%) without documented bleeds MRI showed minor changes (MRI score 1-3). Scanning time was shortened to 60 minutes for 4 joints, while preserving high quality images.

CONCLUSION: Changes detected with MRI correlate with X-ray findings, but not with clinical function or bleeds. MRI could be used to evaluate treatment.

Ingrid E. M. den Uijl1,2, Arthur M. A. De Schepper3, Diederick E. Grobbee2, Kathelijn Fischer1,2
1 van Creveldkliniek, dept haematology, UMC Utrecht, the Netherlands.
2 Julius Center for health sciences and primary care, UMC Utrecht, the Netherlands,
3 Department of Radiology, University Hospital Antwerp, Belgium.

Novo Nordisk Access to Insight Scholarship 2010

Nadjoua Saidane, MD
Touhami Ibn-Flis University Hospital

Training will be undertaken from June 2012 at: Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK.

Supervised by: Dr. Michael Makris

My expectations of the one-year training period at the selected HTC:

I expect from this training as a first goal to convey the experience of a well qualified Haemophilia Treatment Center to my home institution, especially because we are on the way to construct our own Haemophilia Treatment Center in the University Hospital of Batna. I want it to be based on a solid ground ensuring an ideal management to the patients.

I would like to add that during my medical studies in my country, I noted that the majority of Algerian haemophiliacs have important skeletal deformations in addition to all other kinds of haemophilia complications. Also the recent retrospective study that I did during my few months at the University Hospital of Batna about 104 haemophiliacs living in the region of Batna and its neighbourhood had led to same results. That situation pushed me to think seriously about more education and more training outside Algeria in modern world countries to decrease such complications.

In fact, I am attracted by the field of haemostatic disorders and I really intend to continue my career in it, so that I hope that this training will prepare me to be a good expert.
As a programmer engineer and researcher in the field of medical informatics, I always dream to use my computer science skills to improve haemostatic exploration techniques. In Algeria, I found a lot of difficulties to make my dream come true and I hope that I can carry on with this dream during the training.

Novo Nordisk Access to Insight Basic Research Grant 2009

Ton Lisman, PhD
Surgical Research Laboratory
Department of Surgery
University Medical Center Groningen
The Netherlands

Project description:
The role of platelet glycoprotein Iba in supporting coagulation reactions on the activated platelet surface – relevance for haemophilia treatment?

Traditionally it was believed that coagulation reactions take place on a negatively charged phospholipid surface provided by a cellular surface such as activated platelets. Although it has long been thought that a negatively charged surface is required and sufficient for coagulation reactions, recent data have indicated that multiple coagulation factors, including factor VIIa, factor IX(a), and activated protein C (APC) not only interact with the lipid surface of a platelet, but in addition can bind to glycoprotein Ibα (GPIbα) on the platelet surface. We have shown modulation of coagulation reactions by GPIbα on activated platelets in experiments using the GPIbα-cleaving protease OSE. The negative surface thus seems required but not sufficient in physiological coagulation.

In this study, we will use nanodisc technology to study modulation of coagulation by GPIbα on a molecular level. Nanodiscs are nanoscale phospholipid bilayers, which can be tailored to accommodate a predefined number of lipid molecules per leaflet. Moreover, proteins can be incorporated into these lipid bilayers. We will create nanodiscs with a single molecule of GPIbα per disc, and different compositions and sizes of the lipid bilayer. We will study the effect of GPIbα on multiple coagulation reactions including Xa or IXa generation via rFVIIa, Xa generation via IXa/VIIIa, or FVIIIa inactivation by APC on nanodiscs with variable lipid content.

The results of this study will expand our knowledge of the biochemistry of platelet-mediated coagulation, which is of direct interest for the treatment of bleeding and thrombotic disorders.

Novo Nordisk Access to Insight Ulla Hedner Haemostasis Award 2009

Susan A. Maroney, DVM, PhD
Blood Research Institute
Blood Centre of Wisconsin
Milwaukee, WI

Abstract presented at the XXII ISTH congress, July 11-16, 2009 in Boston, MA, USA


To read the abstract, please refer to the journal’s website:

Journal of Thrombosis and Haemostasis, Volume 7, Issue s2

Novo Nordisk Access to Insight Scholarship 2009

Sonata S. Trakymiene, MD
Vilnius University Children’s Hospital
Vilnius, Lithuania

Training will be undertaken at: Centre for Haemophilia and Thrombosis, University Hospital Skejby, Aarhus, Denmark
Supervised by: Prof. Dr. Jørgen Ingerslev

My expectations of the one-year training period at the selected HTC:

I expect to become a physician dedicated to treating patients with haemophilia and other inherited bleeding or thrombotic disorders. One way to do so is through education and training at qualified bleeding disorder centres. During the one-year training, I hope to extend my knowledge and strengthen my skills in diagnostic methods (laboratory methodology that does not exist in my country as well as molecular biological techniques), optimal management (especially introduction of prophylactic treatment in children with haemophilia and overcoming existing barriers), new imaging evaluation techniques, orthopaedics, physical therapy, musculoskeletal status measurements and education of patients and their families. I am especially interested in the musculoskeletal outcome and the quality of life of patients with bleeding disorders receiving different treatment regimens.
I feel that this training will provide me with modern world-class training in the field of haemostasis/haemophilia and would help to further improve care of coagulation disorders in Lithuania.

Novo Nordisk Haemostasis Award 2007

Cees Weeterings
Department of Clinical Chemistry and Haematology
UMC Utrecht
Utrecht, The Netherlands

Presented at the XXI ISTH congress, July 6-12, 2007 in Geneva, Switzerland

Weeterings C, Adelmeijer J, de Groot PG, Lisman T. Glycoprotein IB-alpha contributes to tissue factor-independent thrombin generation by recombinant factor VIIA on the activated platelet surface. J Thromb Haemost 2007; 5 Supplement 2: O-S-042.

Introduction: Recombinant factor VIIa (rFVIIa) is able to activate factor X on an activated platelet via an interaction with negatively charged phospholipids, independent of tissue factor (TF). We hypothesized that besides the negatively charged surface, a receptor on the activated platelet surface is involved in this process. Methods: We examined the binding of rFVIIa to GPIb-alpha in three different ways. First, we investigated whether the purified proteins were able to interact with each other. Furthermore, we tested whether cells expressing GPIb-alpha could adhere to rFVIIa. Finally, we investigated whether GPIb-alpha contributed to the formation of factor Xa. Results: Here, we show that a purified extracellular fragment of GPIb-alpha (glycocalicin) binds to immobilized rFVIIa. This binding could be shown both by using an ELISA setup as by using surface plasmon resonance. In addition, Chinese Hamster Ovary (CHO) cells transfected with the GPIb-IX-V complex (CHO-Ib) were able to adhere to immobilized rFVIIa, whereas wild-type CHO cells were not. This interaction was unaffected by the presence of TF or an inhibitory antibody against TF. Furthermore, platelets could adhere to immobilized rFVIIa under static conditions and this adhesion increased when platelets were stimulated with SFLLRN, a PAR1-activating peptide, or collagen. Platelet adhesion was inhibited by using the snake venom Nk, which cleaves GPIb-alpha from the platelet surface. In addition, rFVIIa-mediated Xa generation on the activated platelet surface was substantially reduced by cleaving GPIb-alpha from the platelet surface. Conclusions: In summary, three lines of evidence show that rFVIIa interacts with GPIb-alpha, and this interaction appears to enhance rFVIIa-mediated thrombin generation on the platelet surface independent of TF. The rFVIIa-GPIb- alpha interaction might contribute to cessation of bleeding by administration of rFVIIa to patients with hemophilia or other bleeding disorders.

Full publications:
Weeterings C, de Groot PG, Adelmeijer J, Lisman T. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor VIIa on the activated platelet surface. Blood 2008;112:3227-33 and

Hoffman M. FVIIa: you've come a long way, baby! Blood 2008;112:3002-3.

Novo Nordisk Haemostasis Award 2005

Kirstin M. Seré
Department of Biochemistry
Cardiovascular Research Institute Maastricht
University of Maastricht
Maastricht, The Netherlands

Hackeng TM, Seré KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A. 2006;103(9):3106-11.

Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer. In this article we uncover a mechanism in which protein S, which is well known as the cofactor of activated protein C, specifically inhibits TF activity by promoting the interaction between full-length TF pathway inhibitor (TFPI) and factor Xa (FXa). The stimulatory effect of protein S on FXa inhibition by TFPI is caused by a 10-fold reduction of the Ki of the FXa/TFPI complex, which decreased from 4.4 nM in the absence of protein S to 0.5 nM in the presence of protein S.

Novo Nordisk Haemostasis Award 2003

H. Versteeg
Academisch Medisch Centrum (AMC)
Amsterdam, The Netherlands

Presented at the XIX ISTH congress, July 12-18, 2003, Birmingham, UK

Versteeg H. Tissue factor/factor Vlla interaction induces activation of the pro-inflammatory JAK/STAT pathway. J Thromb Haemost 2003; 1 Supplement: S19.

Abstract not available

Novo Nordisk Haemostasis Award 2001

Ton Lisman
Thrombosis and Haemostasis Laboratory,
Department of Haematology, Institute of Biomembranes,
Van Creveldkliniek, University Medical Centre, Utrecht University, The Netherlands

Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP, Meijers JC, Nieuwenhuis HK, de Groot PG. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 2002; 99(1): 175-9.

Recombinant factor VIIa (rFVIIa) is a novel prohemostatic drug for patients with hemophilia who have developed inhibitory antibodies. The postulation has been made that hemophilia is not only a disorder of coagulation, but that hyperfibrinolysis due to a defective activation of thrombin activatable fibrinolysis inhibitor (TAFI) might also play a role. In this in vitro study, the potential of rFVIIa to down-regulate fibrinolysis via activation of TAFI was investigated. rFVIIa was able to prolong clot lysis time in plasmas from 17 patients with severe hemophilia A. The prolongation of clot lysis time by rFVIIa was completely abolished by addition of an inhibitor of activated TAFI. The concentration of rFVIIa required for half maximal prolongation of clot lysis time (C(lys 1/2)-VIIa) varied widely between patients (median, 73.0 U/mL; range, 10.8-250 U/mL). The concentration of rFVIIa required for half maximal reduction of clotting time (C(clot 1/2)-VIIa) was approximately 10-fold lower than the C(lys 1/2)-VIIa value (median, 8.4 U/mL; range, 1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody significantly decreased C(lys 1/2)-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas C(clot 1/2)-VIIa values did not change (median, 7.2 U/mL; range, 2.2-22.5 U/mL). On addition of 100 ng/mL recombinant full-length TFPI, a nonsignificant increase of C(lys 1/2)-VIIa values was observed (median, 119.2 U/mL; range, 12.3-375.0 U/mL), whereas C(clot 1/2)-VIIa values did not change (median, 8.8 U/mL; range, 2.6-34.6 U/mL). In conclusion, this study shows that rFVIIa both accelerates clot formation and inhibits fibrinolysis by activation of TAFI in factor VIII-deficient plasma. However, a large variability in antifibrinolytic potential of rFVIIa exists between patients.



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