Simon F De Meyer

Publications of Simon F De Meyer

• von Willebrand factor: an emerging target in stroke therapy.

  Authors: Simon F De Meyer, Guido Stoll, Denisa D Wagner, Christoph Kleinschnitz

  Stroke; a journal of cerebral circulation. 12/2011; 43(2):599-606.

  Thrombus formation is of paramount importance in the pathophysiology of acute ischemic stroke. Current antithrombotics used to treat or prevent cerebral ischemia are only moderately effective or bearThrombus formation is of paramount importance in the pathophysiology of acute ischemic stroke. Current antithrombotics used to treat or prevent cerebral ischemia are only moderately effective or bear an increased risk of severe bleeding. von Willebrand factor (VWF) has long been known to be a key player in thrombus formation at sites of vascular damage. While the association between VWF and coronary heart disease has been well studied, knowledge about the role of VWF in stroke is much more limited. However, in recent years, an increasing amount of clinical and preclinical evidence has revealed the critical involvement of VWF in stroke development. This review summarizes the latest insights into the pathophysiologic role of VWF-related processes in ischemic brain injury under experimental conditions and in humans. Potential clinical merits of novel inhibitors of VWF-mediated platelet adhesion and activation as powerful and safe tools to combat thromboembolic disorders including ischemic stroke are discussed. Preclinical and clinical evidence illustrates an important role of VWF in ischemic stroke, suggesting that VWF could become a promising target in stroke therapy.

• Blood platelet biochemistry.

  Authors: Katleen Broos, Simon F De Meyer, Hendrik B Feys, Karen Vanhoorelbeke, Hans Deckmyn

  Thrombosis research. 11/2011; 129(3):245-9.

  Defects in platelet function or formation increase the risk for bleeding or thrombosis, which indicates the crucial role for platelets in maintaining haemostasis in normal life. Upon vascular injury,Defects in platelet function or formation increase the risk for bleeding or thrombosis, which indicates the crucial role for platelets in maintaining haemostasis in normal life. Upon vascular injury, platelets instantly adhere to the exposed extracellular matrix which results in platelet activation and aggregation and the formation a haemostatic plug that stops bleeding. To prevent excessive platelet aggregate formation that eventually would occlude the vessels, this self-amplifying process nevertheless requires a tight control. This review intends to give a comprehensive overview of the currently established main mechanisms in platelet function.

• Platelet glycoprotein Ibα is an important mediator of ischemic stroke in mice.

  Authors: Simon F De Meyer, Tobias Schwarz, Daphne Schatzberg, Denisa D Wagner

  Experimental & translational stroke medicine. 09/2011; 3:9.

  ABSTRACT: Platelets play an important role in ischemic stroke. GPIbα is a major platelet receptor that is critical for platelet adhesion to exposed subendothelial matrix components at sites ofABSTRACT: Platelets play an important role in ischemic stroke. GPIbα is a major platelet receptor that is critical for platelet adhesion to exposed subendothelial matrix components at sites of vascular damage. In this study, we used transgenic mice in which the extracellular part of GPIbα is replaced by human interleukin 4-receptor (GPIbα/IL4Rα). We observed normal brain vasculature in these mice. We compared infarct size in GPIbα/IL4Rα and wild-type (WT) mice 23 hours after 1-hour transient middle cerebral artery occlusion (tMCAO). In addition, the functional outcome was evaluated using a modified Bederson score. We found a significantly smaller infarct size in GPIbα/IL4Rα mice compared to WT mice (38.0 ± 6.5 mm3 vs. 74.2 ± 8.6 mm3, p < 0.001). The decrease in infarct size was functionally relevant as indicated by a significantly better functional Bederson score in GPIbα/IL4Rα mice compared to WT animals (1.3 ± 0.4 vs. 2.7 ± 0.3, p < 0.05). Our data illustrate and further confirm the important role of platelet GPIbα in ischemic stroke, suggesting that targeted inhibition of this receptor may open new avenues in stroke treatment.

• Local elongation of endothelial cell-anchored von Willebrand factor strings precedes ADAMTS13 protein-mediated proteolysis.

  Authors: Karen De Ceunynck, Susana Rocha, Hendrik B Feys, Simon F De Meyer, Hiroshi Uji-i, Hans Deckmyn, Johan Hofkens, Karen Vanhoorelbeke

  The Journal of biological chemistry. 09/2011; 286(42):36361-7.

  Platelet-decorated von Willebrand factor (VWF) strings anchored to the endothelial surface are rapidly cleaved by ADAMTS13. Individual VWF string characteristics such as number, location, andPlatelet-decorated von Willebrand factor (VWF) strings anchored to the endothelial surface are rapidly cleaved by ADAMTS13. Individual VWF string characteristics such as number, location, and auxiliary features of the ADAMTS13 cleavage sites were explored here using imaging and computing software. By following changes in VWF string length, we demonstrated that VWF strings are cleaved multiple times, successively shortening string length in the function of time and generating fragments ranging in size from 5 to over 100 μm. These are larger than generally observed in normal plasma, indicating that further proteolysis takes place in circulation. Interestingly, in 89% of all cleavage events, VWF strings elongate precisely at the cleavage site before ADAMTS13 proteolysis. These local elongations are a general characteristic of VWF strings, independent of the presence of ADAMTS13. Furthermore, large elongations, ranging in size from 1.4 to 40 μm, occur at different sites in space and time. In conclusion, ADAMTS13-mediated proteolysis of VWF strings under flow is preceded by large elongations of the string at the cleavage site. These elongations may lead to the simultaneous exposure of many exosites, thereby facilitating ADAMTS13-mediated cleavage.

• Platelets at work in primary hemostasis.

  Authors: Katleen Broos, Hendrik B Feys, Simon F De Meyer, Karen Vanhoorelbeke, Hans Deckmyn

  Blood reviews. 07/2011; 25(4):155-67.

  When platelet numbers are low or when their function is disabled, the risk of bleeding is high, which on the one hand indicates that in normal life vascular damage is a rather common event and thatWhen platelet numbers are low or when their function is disabled, the risk of bleeding is high, which on the one hand indicates that in normal life vascular damage is a rather common event and that hence the role of platelets in maintaining a normal hemostasis is a continuously ongoing physiological process. Upon vascular injury, platelets instantly adhere to the exposed extracellular matrix resulting in platelet activation and aggregation to form a hemostatic plug. This self-amplifying mechanism nevertheless requires a tight control to prevent uncontrolled platelet aggregate formation that eventually would occlude the vessel. Therefore endothelial cells produce inhibitory compounds such as prostacyclin and nitric oxide that limit the growth of the platelet thrombus to the damaged area. With this review, we intend to give an integrated survey of the platelet response to vascular injury in normal hemostasis.

• Letter by De Meyer et al regarding article "High von Willebrand factor levels increase the risk of stroke: the Rotterdam study".

  Authors: Simon F De Meyer, Guido Stoll, Christoph Kleinschnitz

  Stroke; a journal of cerebral circulation. 03/2011; 42(3):e41.

• Binding of von Willebrand factor to collagen and glycoprotein Ibalpha, but not to glycoprotein IIb/IIIa, contributes to ischemic stroke in mice--brief report.

  Authors: Simon F De Meyer, Tobias Schwarz, Hans Deckmyn, Cécile V Denis, Bernhard Nieswandt, Guido Stoll, Karen Vanhoorelbeke, Christoph Kleinschnitz

  Arteriosclerosis, thrombosis, and vascular biology. 10/2010; 30(10):1949-51.

  To unravel crucial von Willebrand factor (VWF) interactions that are detrimental in stroke development. VWF(-/-) mice received gene transfer to express mutants of VWF defective either in binding toTo unravel crucial von Willebrand factor (VWF) interactions that are detrimental in stroke development. VWF(-/-) mice received gene transfer to express mutants of VWF defective either in binding to fibrillar collagen, glycoprotein (GP)Ibα or GPIIb/IIIa, and underwent 60 minutes of transient middle cerebral artery occlusion. In VWF(-/-) mice reconstituted with VWF mutants defective in binding to collagen or GPIbα, protection against stroke was sustained, whereas VWF lacking the GPIIb/IIIa binding site restored full susceptibility similar to normal VWF. VWF-collagen and VWF-GPIbα (but not VWF-GPIIb/IIIa) interactions are instrumental in thrombus formation after transient middle cerebral artery occlusion, and their inhibition could be a promising target for stroke treatment.

• von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models.

  Authors: Alexander Brill, Tobias A Fuchs, Anil K Chauhan, Janie J Yang, Simon F De Meyer, Maria Köllnberger, Thomas W Wakefield, Bernhard Lämmle, Steffen Massberg, Denisa D Wagner

  Blood. 10/2010; 117(4):1400-7.

  Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, theDeep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF(-/-) mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF(-/-) mice. Infusion of GPG-290, a mutant glycoprotein Ibα-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF(-/-) IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis.

• Human platelets produced in NOD/SCID mice upon transplantation of human cord blood CD34+ cells are functionally active in an ex vivo flow model of thrombosis.

  Authors: Isabelle I Salles, Tim Thijs, Christine Brunaud, Simon F De Meyer, Johan Thys, Karen Vanhoorelbeke, Hans Deckmyn

  Blood. 10/2009;

  Xenotransplantation systems have been used with increasing success to better understand human hematopoiesis and thrombopoiesis. We here demonstrate that production of human platelets in nonobeseXenotransplantation systems have been used with increasing success to better understand human hematopoiesis and thrombopoiesis. We here demonstrate that production of human platelets in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice after transplantation of unexpanded cord-blood CD34(+) cells was detected within 10 days post-transplantation with the number of circulating human platelets peaking at 2 weeks (up to 87x10(3)/microL). This rapid human platelet production was followed by a second wave of platelet formation 5 weeks post-transplantation, with a population of 5% still detected after 8 weeks, attesting for long-term engraftment. Platelets issued from human hematopoietic stem cell progenitors are functional as assessed by increased CD62P expression and PAC1 binding in response to collagen-related peptide and TRAP (Thrombin-Receptor-Activating Peptide) activation and their ability to incorporate into thrombi formed on a collagen-coated surface in an ex vivo flow model of thrombosis. This interaction was abrogated by addition of inhibitory monoclonal antibodies against human GPIbalpha and GPIIb/IIIa. Thus, our mouse model with production of human platelets may be further explored to study the function of genetically modified platelets but also to investigate the effect of stimulators or inhibitors of human thrombopoiesis in vivo.

• ADAMTS13's tail tale.

  Authors: Karen Vanhoorelbeke, Hendrik B Feys, Simon F De Meyer

  Blood. 06/2009; 113(21):5039-40.

• Von Willebrand factor: drug and drug target.

  Authors: Simon F De Meyer, Bauke De Maeyer, Hans Deckmyn, Karen Vanhoorelbeke

  Cardiovascular & hematological disorders drug targets. 04/2009; 9(1):9-20.

  One of the key players in many thrombotic complications is von Willebrand factor (VWF), a large, multimeric glycoprotein that is present in plasma where it fulfils a crucial role in haemostasis.One of the key players in many thrombotic complications is von Willebrand factor (VWF), a large, multimeric glycoprotein that is present in plasma where it fulfils a crucial role in haemostasis. First, VWF recruits platelets to vascular lesions by acting as a linker molecule between the exposed collagen and free-flowing platelets in the circulation. Second, by serving as a carrier protein for the coagulation factor VIII, VWF protects this anti-haemophilic factor from rapid degradation. Quantitative or qualitative defects in VWF result in the most common bleeding disorder in man, known as von Willebrand disease, illustrating the central role of VWF in haemostasis. On the other hand, a thrombotic risk emerges when over-reactive VWF molecules can bind spontaneously to platelets. It is clear that because of its pivotal role in maintaining the fine balance between bleeding and thrombosis, VWF is an attractive but delicate drug target. This review focuses on the role of VWF in both haemostasis and thrombosis with special attention to the molecule as drug and drug target respectively.

• Von Willebrand factor to the rescue.

  Authors: Simon F De Meyer, Hans Deckmyn, Karen Vanhoorelbeke

  Blood. 04/2009;

  Von Willebrand factor (VWF) is a large multimeric adhesive glycoprotein with complex roles in thrombosis and hemostasis. Abnormalities in VWF give rise to a variety of bleeding complications, knownVon Willebrand factor (VWF) is a large multimeric adhesive glycoprotein with complex roles in thrombosis and hemostasis. Abnormalities in VWF give rise to a variety of bleeding complications, known as von Willebrand disease (VWD), the most common inherited bleeding disorder in man. Current treatment of VWD is based on the replacement of the deficient or dysfunctional protein either by endogenous release from endothelial Weibel-Palade bodies or by administration of plasma-derived VWF concentrates. During the last years, several efforts have been made to optimize existing therapies for VWD, but also to devise new approaches, such as inducing endogenous expression with interleukin-11, administering exogenous recombinant VWF, or introducing the protein via gene delivery. Clearly, the efficacy of any strategy will depend on several factors, including, for example, the quantity, activity and stability of the delivered VWF. The inherent complexity of VWF biosynthesis, which involves extensive post-translational processing, may be limiting in terms of producing active VWF outside of its native cellular sources. This review summarizes recent progress in the development of different treatment strategies for VWD, including those that are established, and those that are at the experimental stage. Potential pitfalls and benefits of each strategy are discussed.

• The novel S527F mutation in the integrin beta 3 chain induces a high affinity alpha IIbbeta 3 receptor by hindering adoption of the bent conformation.

  Authors: Karen Vanhoorelbeke, Simon F De Meyer, Inge Pareyn, Chantal Melchior, Sebastien Plançon, Christiane Margue, Olivier Pradier, Pierre Fondu, Nelly Kieffer, Timothy A. Springer, Hans Deckmyn

  The Journal of biological chemistry. 04/2009;

  Three heterozygous mutations were identified in the genes encoding the platelet integrin receptor alphaIIbbeta3 in a patient with an ill-defined platelet disorder: one in the beta3 gene (S527F) andThree heterozygous mutations were identified in the genes encoding the platelet integrin receptor alphaIIbbeta3 in a patient with an ill-defined platelet disorder: one in the beta3 gene (S527F) and two in the alphaIIb gene (R512W and L841M). Five stable CHO cell lines were constructed expressing recombinant alphaIIbbeta3 receptors bearing either the individual R512W, L841M or S527F mutations, both the R512W and the L841M mutations, or all three mutations. All receptors were expressed on the cell surface and mutations R512W and L841M had no effect on integrin function. Interestingly, the beta3-S527F mutation produces a constitutively active receptor. Indeed, both fibrinogen and the ligand mimetic antibody PAC-1 bound to non-activated alphaIIbbeta3 receptors carrying the S527F mutation, indicating that the conformation of this receptor was altered and corresponded to the high affinity ligand binding state. In addition, the conformational change induced by S527F was evident from basal anti-LIBS antibody binding to the receptor. A molecular model bearing this mutation was constructed based on the crystal structure of alphaIIbbeta3 and revealed that the S527F mutation, situated in the third integrin epidermal growth factor-like (I-EGF3) domain, hinders the alphaIIbbeta3 receptor from adopting a wild-type like bent conformation. Movement of I-EGF3 into a cleft in the bent conformation may be hampered both by steric hindrance between Phe-527 in beta3 and the calf-1 domain in alphaIIb, and by decreased flexibility between I-EGF domains 2 and 3.

• Deficiency of von Willebrand factor protects mice from ischemic stroke.

  Authors: Christoph Kleinschnitz, Simon F De Meyer, Tobias Schwarz, Madeleine Austinat, Karen Vanhoorelbeke, Bernhard Nieswandt, Hans Deckmyn, Guido Stoll

  Blood. 01/2009;

  We recently demonstrated that blockade of the platelet adhesion receptor glycoprotein(GP)Ibalpha protects mice from ischemic stroke. Although von Willebrand factor (VWF) is the major ligand forWe recently demonstrated that blockade of the platelet adhesion receptor glycoprotein(GP)Ibalpha protects mice from ischemic stroke. Although von Willebrand factor (VWF) is the major ligand for GPIbalpha, GPIbalpha can engage other counterreceptors on endothelial cells, platelets and leukocytes (e.g. Mac-1 or P-selectin) potentially involved in stroke outcome. To further analyze whether VWF is of particular relevance for stroke development, VWF(-/-) mice underwent 60 min of middle cerebral artery occlusion. After 24 h, VWF(-/-) mice had significantly smaller infarctions (p<0.05) and less severe neurological deficits (p<0.01) compared to controls. This effect was sustained after 1 week and intracranial bleeding was absent in VWF(-/-) mice as revealed by serial magnetic resonance imaging. Hydrodynamic injection of a VWF-encoding plasmid restored the susceptibility for stroke in VWF(-/-) mice. This study indicates that VWF is critically involved in cerebral ischemia. Hence, targeted inhibition of the GPIbalpha-VWF pathway might become a promising therapeutic option.

• Restoration of Plasma von Willebrand Factor Deficiency Is Sufficient to Correct Thrombus Formation After Gene Therapy for Severe von Willebrand Disease.

  Authors: Simon F De Meyer, Nele Vandeputte, Inge Pareyn, Inge Petrus, Peter J Lenting, Marinee K L Chuah, Thierry Vandendriessche, Hans Deckmyn, Karen Vanhoorelbeke

  Arteriosclerosis, thrombosis, and vascular biology. 07/2008;

  OBJECTIVE: Gene therapy for severe von Willebrand disease (vWD) seems an interesting treatment alternative with long-term therapeutic potential. We investigated the feasibility of targeting the liverOBJECTIVE: Gene therapy for severe von Willebrand disease (vWD) seems an interesting treatment alternative with long-term therapeutic potential. We investigated the feasibility of targeting the liver for ectopic expression of physiologically active von Willebrand factor (vWF). METHODS AND RESULTS: The capacity of transgene-encoded murine vWF to restore vWF function was studied in a mouse model of severe vWD after liver-specific gene transfer by hydrodynamic injection. By using a hepatocyte-specific alpha1 antitrypsin promoter, a considerably higher and longer-lasting vWF expression was obtained when compared with a cytomegalovirus promoter, reaching maximum vWF plasma levels that are 10+/-1 times higher than the wild-type level. Liver-expressed vWF showed the full range of multimers, including the high molecular weight multimers, and restored factor VIII plasma levels, consistent with correction of the bleeding time 3 but not 7 days after gene transfer. Importantly, transgene encoded plasma vWF restored proper platelet adhesion and aggregation in a FeCl3 induced thrombosis model. CONCLUSIONS: High ectopic expression of transgene encoded plasma vWF can be obtained after gene transfer to the liver. Liver-expressed vWF was fully multimerized and able to restore proper platelet plug formation in severe vWD. The liver therefore seems an attractive target for gene therapy for severe vWD.

• Inherited traits affecting platelet function.

  Authors: Isabelle I Salles, Hendrik B Feys, Brecht F Iserbyt, Simon F De Meyer, Karen Vanhoorelbeke, Hans Deckmyn

  Blood reviews. 06/2008; 22(3):155-72.

  Inherited platelet disorders constitute a large group of diseases involving a wide range of genetic defects that can lead to bleeding symptoms of varying severity. They are associated with defects inInherited platelet disorders constitute a large group of diseases involving a wide range of genetic defects that can lead to bleeding symptoms of varying severity. They are associated with defects in surface membrane glycoproteins resulting in e.g. Bernard Soulier Syndrome and Glanzmann Thrombasthenia causing defects in platelet adhesion and aggregation, respectively, as well as in receptors for agonists (a.o. P2Y(12), TXA(2)) disrupting platelet signalling. Defects affecting platelet granules can be characterised by abnormalities of alpha-granules as in the Gray platelet syndrome or dense granules as in Hermansky-Pudlak and Chediak-Higashi syndromes, the latter two also altering other cytoplasmic organelles such as melanosomes and therefore not restricted to platelets. Finally, defects in proteins essential to signalling pathways (a.o. in Wiskott-Aldrich syndrome) or in platelet-derived procoagulant activity (Scott and Stormorken syndromes) also impair platelet function. For most of the above disorders mouse knockout models have been generated, that allowed to confirm the genotype-phenotype relationship and to further unravel the molecular causes of the disease and the mechanisms underlying primary haemostasis. More recently, interest has been growing in the effects of the more common polymorphisms that are found in the platelet glycoproteins as possible risk factors for thrombotic disorders. The new era of platelet genomics and proteomics will increase our knowledge on platelet disorders that will improve their diagnosis, but also will provide basis for new antithrombotic therapies.

• Antiplatelet drugs.

  Authors: Simon F De Meyer, Karen Vanhoorelbeke, Katleen Broos, Isabelle I Salles, Hans Deckmyn

  British journal of haematology. 06/2008;

  Platelets play a major role in thromboembolic diseases, and so antiplatelet therapy remains crucial in treatment and prophylaxis. Upon vascular injury, platelets rapidly adhere to the exposedPlatelets play a major role in thromboembolic diseases, and so antiplatelet therapy remains crucial in treatment and prophylaxis. Upon vascular injury, platelets rapidly adhere to the exposed subendothelial matrix, after which they become activated, resulting in the recruitment of additional platelets from the circulation to eventually form a stable arterial platelet plug. Although controlled plug formation is desired for the prevention of excessive blood loss and for promoting wound healing, several pathological conditions may result in the formation of occlusive thrombi leading to severe clinical complications, including myocardial infarction and ischaemic stroke. Many antiplatelet approaches have been investigated, interfering with one or more of the different stages in thrombus formation. This review discusses antiplatelet agents that interfere with the three principal phases in thrombus formation: platelet adhesion, amplification of platelet activation and platelet aggregation. For each stage, novel experimental targets and clinically established antiplatelet strategies will be reviewed. Limitations and possible benefits will be discussed for each target.

• Coronary artery in-stent stenosis persists despite inhibition of the von Willebrand factor--collagen interaction in baboons.

  Authors: Simon F De Meyer, Stephanie Staelens, Philip N Badenhorst, Henry Pieters, Seb Lamprecht, Jan Roodt, Stefan Janssens, Muriel Meiring, Karen Vanhoorelbeke, André Bruwer, Stephen Brown, Hans Deckmyn

  Thrombosis and haemostasis. 01/2008; 98(6):1343-9.

  Revascularization techniques, such as angioplasty and stent implantation, frequently lead to restenosis due to the formation of neointima after platelet activation and the concomitant release ofRevascularization techniques, such as angioplasty and stent implantation, frequently lead to restenosis due to the formation of neointima after platelet activation and the concomitant release of various smooth muscle cell mitogenic and attractant factors. We here investigate whether inhibition of initial platelet adhesion after stent implantation can decrease neointima formation in a clinically relevant baboon model of in-stent stenosis using standard treatment with aspirin, clopidogrel and heparin. Inhibition of platelet adhesion was established by administration of the anti-von Willebrand factor (VWF) monoclonal antibody 82D6A3, which inhibits VWF binding to collagen. Administration of 82D6A3 resulted in a complete inhibition of VWF binding to collagen during the first three days after stent implantation. No thrombocytopenia or prolongation of the bleeding time was observed. Our results show that the formation of neointima was not affected in the group of baboons where primary platelet adhesion was abolished with 82D6A3 when compared to the control group. Vascular injury scores were the same in both groups. Inhibition of platelet adhesion during the first three days after stenting, on top of standard treatment with aspirin, clopidogrel and heparin, had no effect on neo-intima formation in a baboon model of in-stent stenosis. During the last decade, attempts to translate seemingly effective therapies based on smaller animal experimentation to the clinic have consistently failed. This study, using a non-human primate model that more closely resembles the clinical situation, presents a model that may be of further clinical interest for studying the prevention of restenosis.

• The A/T1381 polymorphism in the A1-domain of von Willebrand factor influences the affinity of von Willebrand factor for platelet glycoprotein Ibalpha.

  Authors: Tímea Szántó, Agota Schlammadinger, Stephanie Staelens, Simon F De Meyer, Kathleen Freson, Inge Pareyn, Stephan Vauterin, Jolán Hársfalvi, Hans Deckmyn, Karen Vanhoorelbeke

  Thrombosis and haemostasis. 08/2007; 98(1):178-85.

  Many polymorphisms in vonWillebrand factor (VWF) have been reported and their association with VWF plasma levels or cardiovascular diseases has been investigated. The aim of this study was to examineMany polymorphisms in vonWillebrand factor (VWF) have been reported and their association with VWF plasma levels or cardiovascular diseases has been investigated. The aim of this study was to examine whether the amino acid polymorphism A/T1381 in the VWF A1-domain would affect VWF binding to platelet GPIbalpha. Sixty-one normal individuals were genotyped at the A/T1381 locus. Twenty-one A/A1381 homozygotes, 30 A/T1381 heterozygotes and 10 T/T1381 homozygotes were identified. Remarkably, when compared to VWF of A/T1381 and A/A1381 individuals, VWF of individuals carrying the T/T1381 variant showed an increased affinity for its platelet receptor GPIbalpha under static conditions, as reflected by an increased sensitivity to low concentrations of ristocetin or botrocetin. In addition, also the rVWF-T1381 demonstrated a higher affinity for GPIbalpha than rVWF-A1381. Interestingly, this enhanced affinity of the T/T variant over the A/T and A/A variant was, however, too subtle to affect platelet adhesion under physiological flow conditions, which fully corroborates the normal haemostatic phenotype of all individuals. We demonstrate that the VWF A/T1381 polymorphism plays an important role in inter-individual variability of the affinity of VWF for GPIbalpha, with T/T variants having a higher affinity than A/A and A/T variants, at least under static conditions in vitro. Further genetic linkage and association studies are necessary to establish whether the A/T1381 polymorphism could correlate with an increased risk of thrombotic events.

• Correction of the bleeding time in von Willebrand factor (VWF)-deficient mice using murine VWF.

  Authors: Peter J Lenting, Philip G de Groot, Simon F De Meyer, Karen Vanhoorelbeke, Cynthia Pruss, David Lillicrap, Isabelle Marx, Cécile V Denis

  Blood. 04/2007; 109(5):2267-8.