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Congratulations to the winners!

Novo Nordisk Access to Insight Basic Research Grant

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

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

Winner:
Ingrid den Uijl
van Creveldkliniek
UMC Utrecht
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 Uijl^1,2, Arthur M. A. De Schepper³, Diederick E. Grobbee², Kathelijn Fischer^1,2
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

Winner:
Nadjoua Saidane, MD
Touhami Ibn-Flis University Hospital
Batna
Algeria

Training will be undertaken from October 2010 at: Hemophilia and Thrombosis Comprehensive Care Center, Edouard Herriot University Hospital, Lyon, France.

Supervised by: Prof. Dr. Claude Négrier

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

Winner:
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

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

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

AS-MO-024   PLATELET TISSUE FACTOR PATHWAY INHIBITOR (TFPI) PREVENTS HEPATIC AND CEREBRAL FIBRIN DEPOSITION IN MOUSE TISSUES AND LIMITS THROMBUS GROWTH

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

Winner:
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

Winner:
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.

http://bloodjournal.hematologylibrary.org/

Novo Nordisk Haemostasis Award 2005

Winner:
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

Winner:
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

Winner:
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.