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January 2001 - May 2015
Publications
Publications (93)
Background: The recruitment of activated factor VIII (FVIII) at the surface of activated
Cerebral venous sinus thrombosis (CVST) is an uncommon venous thromboembolic event accounting for <1% of strokes resulting in brain parenchymal injuries. JAK2V617F mutation, the most frequent driving mutation of myeloproliferative neoplasms has been reported to be associated with worse clinical outcomes in patients with CVST. We investigated whethe...
The association between endometriosis and autoimmune diseases is well known, however no acquired platelet function defect has been described so far. We describe the case of two patients with endometriosis associated with an antiplatelet glycoprotein VI (anti-GPVI) antibody. The two women with deep pelvic endometriosis associated with secondary infe...
Background:
Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain "emergency hematopoiesis" and fuel the thromboinflammatory process.
Methods:
Using a murine m...
Platelet glycoprotein VI (GPVI) is attracting interest as a potential target for the development of new antiplatelet molecules with a low bleeding risk. GPVI binding to vascular collagen initiates thrombus formation and GPVI interactions with fibrin promote the growth and stability of the thrombus. In the present study we show that glenzocimab, a c...
Cerebral venous sinus thrombosis (CVST) is an uncommon cause of stroke resulting in parenchymal injuries associated with heterogeneous clinical symptoms and prognosis. Therefore, an experimental animal model is required to further study underlying mechanisms involved in CVST. This study is aimed at developing a novel murine model suitable and relev...
Background – Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome.
Objective – The aim of this study was to gain insights into the mechanisms underlying immediate reocclusion, and to evaluate the efficacy and safety of the glycoprotein II...
Background
Carboxypeptidase U (CPU, CPB2, TAFIa) is a potent attenuator of fibrinolysis. The inhibition of CPU is thus an interesting strategy for improving thrombolysis.
Objectives
The time course of CPU generation and proCPU consumption were assessed in an experimental rat model of acute ischemic stroke (AIS). In addition, the effects of the sel...
Objective
Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its...
Acquired deficiencies in platelet glycoprotein VI are rare and have not been found associated with other defects. Here we report the case of a 64-year old male patient presenting an immune GPVI deficiency associated to a mutation in the alpha-actinin gene and who has been treated with dual anti platelet therapy without bleeding.
Introduction: Glyco...
Background Ligneous conjunctivitis (LC) is a rare disorder associated with plasminogen deficiency characterized by chronic fibrin deposits in the eyelids. All patients with plasminogen deficiency do not develop LC, whose underlying mechanisms remain unknown.
Objective We investigated whether fibrinolytic activity was correlated with phenotype and/o...
Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Pegylated-interferon alpha (IFN) and hydroxyurea (HU) are commonly used to treat MPN, but their effect on hemostasis has not yet been studied. The aim of our study was to determine whether IFN and HU impact the biological hemostatic profile o...
Objectives:
Thrombi responsible for large vessel occlusion (LVO) in the setting of acute ischemic stroke (AIS) are characterized by a low recanalization rate after IV thrombolysis. To test whether AIS thrombi have inherent common features that limit their susceptibility to thrombolysis, we analyzed the composition and ultrastructural organization...
Objectives
Behçet’s disease (BD) is a chronic systemic vasculitis. Thrombosis is a frequent and life-threatening complication. The pathogenesis of BD is poorly understood and evidence supporting a role for primed neutrophils in BD-associated thrombotic risk is scant. To respond to inflammatory insults, neutrophils release web-like structures, known...
Heparin-induced thrombocytopenia (HIT) is due to immunoglobulin G (IgG) antibodies, which bind platelet factor 4 (PF4) modified by polyanions, such as heparin (H). IgG/PF4/polyanion complexes directly activate platelets via Fc gamma type 2 receptor A (FcγRIIA) receptors. A bacterial protease, IgG-degrading enzyme of Streptococcus pyogenes (IdeS), c...
Heparin-induced thrombocytopenia (HIT) is a severe drug-adverse event due to platelet-activating antibodies (Abs) directed against platelet factor 4 (PF4)/heparin (H) complexes. In most patients, HIT Abs are IgG that directly activate platelets and monocytes in the presence of heparin via FcγRIIA receptors. The interaction between the Fc fragment o...
Objective—
Despite the high clinical relevance of thrombolysis, models for its study in human flowing blood are lacking. Our objective was to develop a microfluidic model for comparative evaluation of thrombolytic therapeutic strategies.
Approach and Results—
Citrated human blood was supplemented with 3,3′-dihexyloxacarbocyanine iodide and Alexa F...
The ephrin transmembrane receptor (EPHR) family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in two siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2...
Background
Carboxypeptidase U (CPU, CPB2, TAFIa) is a basic carboxypeptidase that attenuates fibrinolysis. This characteristic raised interest in the scientific community and pharmaceutical industry for the development of inhibitors as profibrinolytic agents.
Objectives
Little is known about the contribution of CPU to clot resistance in more advan...
GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinog...
Background and purpose:
Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identified as major triggers and structural factors of thrombosis. A recent study designated extracellular DNA threads from NETs as a potential therapeutic targ...
Acute ischaemic stroke, myocardial infarction and pulmonary embolism are the main causes of mortality and morbidity worldwide. Thrombolysis by intravenous injection of recombinant tissue plasminogen activator (rtPA) remains the most common non-interventional treatment to recanalize occluded vessels. However, this procedure is limited by significant...
Background and purpose:
Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury.
Methods:
Normoglycemic and streptozotocin-treated...
Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Besides clinical factors (previous history of thrombosis, age > 60 years, cardiovascular risk factors), procoagulant phenotype, proadhesive properties of the endothelium and secretion of inflammatory cytokines, contribute to the pathogenesis...
Background and purpose:
Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral ar...
Unlabelled:
Exposure of platelets to collagen triggers the formation of a platelet clot. Pharmacological agents capable of inhibiting platelet activation by collagen are thus of potential therapeutic interest. Thrombus formation is initiated by the interaction of the GPIb-V-IX complex with collagen-bound vWF, while GPVI interaction with collagen t...
Platelets protect vascular integrity during inflammation. Recent evidence suggests that this action is independent of thrombus formation and requires the engagement of glycoprotein VI (GPVI), but it remains unclear how platelets prevent inflammatory bleeding. We investigated whether platelets and GPVI act primarily by preventing detrimental effects...
Fibrin, the coagulation end product, consolidates the platelet plug at sites of vascular injury and supports the recruitment of circulating platelets. In addition to integrin αIIbβ3, another as yet unidentified receptor is thought to mediate platelet interaction with fibrin. Platelet glycoprotein VI (GPVI) interacts with collagen and several other...
Background: Fibrin, the end product of the coagulation cascade, consolidates the platelet plug at site of thrombosis: polymerized fibrin supports platelet adhesion under low and high shear rate conditions (Hantgan RR et al., Thromb Haemost 1992) and triggers platelet procoagulant activity (Beguin S et al., Blood 1999). These responses are largely i...
CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction.
Here, we show that intact CD31 molecules, which are able to drive an inhi...
Platelets are not only central actors of hemostasis and thrombosis but also of other processes including inflammation, angiogenesis, and tissue regeneration. Accumulating evidence indicates that these "non classical" functions of platelets do not necessarily rely on their well-known ability to form thrombi upon activation. This suggests the existen...
The recent introduction of highly effective antiplatelet drugs has contributed to the significantly improve the treatment of acute coronary syndromes. However, limitations remain: recurrent adverse vascular events remain a problem and improved antithrombotic efficacy is offset by an increased risk of bleeding whose importance is critical in patient...
We have previously reported that intravenous injection of high-density lipoproteins (HDLs) was neuroprotective in an embolic stroke model. We hypothesized that HDL vasculoprotective actions on the blood-brain barrier (BBB) may decrease hemorrhagic transformation-associated with tissue plasminogen activator (tPA) administration in acute stroke.
We u...
. The treatment of acute coronary syndromes has been considerably improved in recent years with the introduction of highly efficient antiplatelet drugs. However, there are still significant limitations: the recurrence of adverse vascular events remains a problem, and the improvement in efficacy is counterbalanced by an increased risk of bleeding, w...
Infective endocarditis (IE) is characterized by septic thrombi (vegetations) attached on heart valves, consisting of microbial colonization of the valvular endocardium, that may eventually lead to congestive heart failure or stroke subsequent to systemic embolism. We hypothesized that host defense activation may be directly involved in tissue prote...
Flowchart of human heart valves illustrating type of experimental methods performed on the conditioned media and their distribution.
(TIF)
Immunostaining of eosinophils with anti-EMBP antibody with very few cells expressing positive staining.
(TIF)
Although intravital microscopy models of thrombosis in mice have contributed to dissect the mechanisms of thrombus formation and stability, they have not been well adapted to study long-term evolution of occlusive thrombi. Here, we assessed the suitability of the dorsal skinfold chamber (DSC) for the study of thrombolysis and testing of thrombolyti...
Glycoprotein VI (GPVI) has been proposed as a promising antiplatelet target, because its blockade prevents experimental thrombosis without impairing hemostasis. The objective of this study was to develop a preclinical tool to evaluate the role of human GPVI (hGPVI) in various models of thrombosis and to screen anti-GPVI compounds. A genetically mod...
The immune receptor homologue glycoprotein VI (GPVI)/FcR receptor γ chain complex is primarily responsible for platelet activation by collagen. There is growing evidence that optimal binding of GPVI to collagen depends on the assembly of GPVI dimers. The valence of GPVI on resting platelets needs to be clearly established because platelet avidity f...
Blood platelets play a key role in physiological hemostasis and in thrombosis. As a consequence, platelet functional analysis is widely used in the diagnosis of hemorrhagic disorders as well as in the evaluation of thrombosis risks and of the efficacy of antithrombotics. Glycoprotein (GP) VI is a platelet-specific collagen-signaling receptor. Clini...
Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets.
In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking...
3194
In the blood, platelets are normally prevented from activation by endothelial inhibitors (i.e. prostacycline, ectonucleotidase). Dysfunctional endothelial cells loose their protective properties and favor platelet adhesion to matrix proteins, platelet aggregation and thrombus growth. Collagen fibers are highly thrombogenic and the platelet Gly...
818
Fibrinolysis, a physiological process leading to clot resorbtion, is strictly controlled by fibrin-localized plasminogen activators (tPA and uPA) and by inhibitors like plasminogen activator type-1 (PAI-1). The serpin PAI-1 is a plasmatic serine protease inhibitor, that is also stored in platelets α-granules. PAI-1 inhibits both the action of u...
GPVI is a major platelet collagen signaling receptor. In rare cases of immune thrombocytopenic purpura (ITP), autoantibodies to GPVI result in receptor shedding. Objectives: To investigate a possible pathogenic role of plasma anti-GPVI antibody located in a woman with lupus nephritis.
Measured were (i) platelet aggregation to collagen and convulxin...
Various studies using proteomic approaches have shown that HDL can carry many proteins other than its constitutive apolipoprotein A-I (apoA-I). Using mass spectrometry and Western blotting, we showed the presence of alpha(1)-antitrypsin (AAT) (SERPINA1, serpin peptidase inhibitor, clade A, an elastase inhibitor) in HDL, isolated either by ultracent...
Objectif
La glycoprotéine VI est le récepteur d’activation des plaquettes par les collagènes de type I et de type III. Nous avons émis l’hypothèse que nous pourrions développer une sonde spécifique du collagène basée sur la spécificité de GPVI et que cette sonde permettrait de visualiser la fibrose in vivo par une méthode non invasive.
Méthodes
Un...
Fibrosis, which is characterized by the pathological accumulation of collagen, is recognized as an important feature of many chronic diseases, and as such, constitutes an enormous health burden. We need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in various disorders. Collagen targeting molecules are therefore of...
Glycoprotein VI (GPVI), the main receptor for platelet activation by collagen, has been shown to play an important role in thrombosis, vascular remodelling and atherothrombosis. GPVI which belongs to the immunoglobulin receptor family, binds to fibrillar type I and type III collagens of vascular as well as non-vascular origin. 9O12.2, a high affini...
Glycoprotein (GP)VI is an attractive target for the development of new antithrombotic drugs. Its deficiency protects animals in several models of thrombosis, arterial stenosis and ischemia--reperfusion while inducing no major bleeding tendency. The Fab fragment of one anti-GPVI monoclonal antibody (9O12.2) inhibits all GPVI functions in vitro. The...
The pathological remodeling of the arterial wall in atherosclerosis involves protease activities, which play a major role in complications, through plaque rupture. Here, we investigated the release of active proteases by human carotid plaques in relation to (1) the degree of lesion complexity and (2) their compartmentalization between cap, core and...
Glycoprotein (GP) VI, a key receptor for collagen-induced platelet activation, recently emerged as a major target for developing new antithrombotics. However, little is known about its functional domains, which is a disadvantage for the rational development of antagonists. Our aim was to identify the structures determining GPVI specificity. GPVI pr...
Protease nexin-1 (PN-1) is a non-circulating pericellular serpin expressed by vascular cells. PN-1 inhibits different proteases but when associated with glycosaminoglycans, its activity is mainly directed towards thrombin. Fucoidans are sulphated polysaccharides which can interact with several serpins and have antithrombotic and anticoagulant prope...
Coronary syndromes, stroke and other ischaemic arterial diseases are the leading cause of death in the world and will probably remain it at least until 2020. Cardiovascular diseases kill 17 million people each year with an expected increase to 20 million in 2020 and 24 million in 2030. The global impact of recurrence and death during the 6 months f...
Les accidents coronariens et cerebrovasculaires aigus sont la premiere cause de mortalite dans le monde et vont le rester au moins jusqu'en 2020. Les maladies cardiovasculaires (ischemie myocardique et cerebrale) tuent environ 17 millions de personnes par an avec un accroissement prevu a 20 millions par an en 2020 et 24 millions par an en 2030. L'i...
Background Lp(a), a major cardiovascular risk factor, contains a specific apolipoprotein, apo(a), which by virtue of structural homology with plasminogen inhibits the formation of plasmin, the fibrinolytic enzyme. A number of clinical reports support the role of Lp(a) as a cardiovascular or cerebral risk factor, and experimental data suggest that i...
Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes.
Recombinant apo(a) [r-apo(a)] prepar...
Monoclonal antibodies directed against recombinant apolipoprotein (a) (r-apo(a)) lacking plasminogen-like KIV-2 repeats were used to identify structurally related conformational epitopes in various members of the plasminogen-prothrombin gene family. A number of procedures including a fibrin-binding inhibition immunoassay and surface plasmon resonan...
The interaction of lipoprotein(a) [Lp(a)] with platelets is not well defined, particularly with regards to the individual contribution of the protein components of Lp(a), the apo B-100 and the apolipoprotein apo(a). This study investigated the binding of different recombinant apo(a) [r-apo(a)] isoforms, to human platelets and its effect on platelet...
A high plasma concentration of lipoprotein Lp(a) is now considered to be a major and independent risk factor for cerebro- and cardiovascular atherothrombosis. The mechanism by which Lp(a) may favour this pathological state may be related to its particular structure, a plasminogen-like glycoprotein, apo(a), that is disulfide linked to the apo B100 o...
Fibrinogen Bicêtre II is a dysfibrinogenemia in which there is a substitution of Lys for Asn at gamma 308. We have studied the polymerization of this abnormal fibrinogen by measurement of turbidity and have characterized clot structure by scanning electron microscopy, permeation, and viscoelastic measurements. The results of these studies demonstra...
Simultaneous natural changes in lipoprotein(a) [Lp(a)] and plasminogen occur in the nephrotic syndrome and offer a unique opportunity to investigate their effects on plasminogen activation under conditions fashioned in vivo. Plasminogen, Lp(a), and apolipoprotein(a) in plasma were characterized, and their competitive binding to carboxy-terminal lys...
In the present study we have investigated the effect of individual variations in the concentration of Lp(a) on plasmin formation at the surface of fibrin. The plasma Lp(a) concentrations from 20 nephrotic children were high at flare-up of the disease (0.43 ± 0.45 g/l) and decreased progressively with remission at both 6 weeks (0.28 ± 0.24 g/l) and...
Apolipoprotein[a] phenotyping is a critically important method to explore the role of kringle-4 repeat number as a modulator of lipoprotein[a]-associated cardiovascular risk. The availability of a kringle-4 number-based reference standard is therefore necessary for a reliable and generally accepted classification of apo[a] phenotypes. We propose he...
In the present study we have investigated the effect of individual variations in the concentration of Lp(a) on plasmin formation at the surface of fibrin. The plasma Lp(a) concentrations from 20 nephrotic children were high at flare-up of the disease (0.43 ± 0.45 g/l) and decreased progressively with remission at both 6 weeks (0.28 ± 0.24 g/l) and...
The fibrino(geno)lytic protein designated hementerin contained in crude extracts of the salivary complex of Haementeria depressa leeches was purified to apparent homogeneity by gel filtration, ion exchange chromatography and preparative SDS-PAGE. It is a single-chain 80 kDa, PhMeSO2F-resistant, calcium-dependent, metalloproteinase, which specifical...
The association between high plasma levels of lipropotein Lp(a) and cardiovascular risk may be explained by an anti-fibrinolytic effect based on the structural homology existing between apo(a), its specific apolipoprotein and plasminogen. Binding of plasminogen to lysine residues on a fibrin surface may thus be competitively inhibited by Lp(a). Suc...
Fibrinolysis triggered by t-PA bound to fibrin is one of the main antithrombotic mechanisms. Defects in the fibrinolytic system-decreased tissue-type plasminogen activator (t-PA) activity and elevated levels of plasminogen activator inhibitor (PAI-1), in patients with SLE have been associated with an increased tendency to thrombosis. In the present...
The association helween plasma levels of lipoproicin Lp(a) and cardiovascular risk may he explained hy an anti-lihrinolytic effect hased on the slruclural homology existing between apo(a), its specific apolipoprolcin ant) plasminogen. Binding of plasminogen to fibrin and monocylic cells may thus he competitively inhibited hy Lp(a). In order to iden...
The nephrotic syndrome constitules a unique model to study consequences on fihrinolysis of in vivo modifications in plasma levels of plasminogen and Lp(a). To explore this hypothesis, 49 children with nephrotic syndrome were studied during the flare up of the disease, and in 22 cases after ft months of remission. The molar concentration of these pr...
The present study was undertaken to explore the influence of natural variations in plasminogen and Lp(a) concentrations on the antifibrinolytic effect of Lp(a). Native plasmas containing 0.5 to 1.25 )jmol/l of plasminogen (Normal level 1.5-2 jimol/1) and high Lp(a) concentrations (0.5 to 1 g/1) were obtained from children with the nephrotic syndrom...
Abnormalities of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor have been described in some patients with systemic sclerosis (SSc). We studied 128 unselected SSc sera for the presence of autoantibodies to fibrin bound tPA.
A solid phase fibrin-tPA immunoassay utilized 500 IU/ml tPA bound to solid phase fibrin. Sera dilu...
Lipoprotein(a) is a major and independent genetic risk factor for atherosclerosis and cardiovascular disease. The essential difference between Lp(a) and low density lipoproteins (LDL) is apo(a), a glycoprotein structurally similar to plasminogen, the precursor of plasmin the fibrinolytic enzyme. This structural homology endows Lp(a) with the capaci...
A well characterized model of an intact and a degraded surface of fibrin that represents the states of fibrin during the initiation and the progression of fibrinolysis was used to quantitatively characterize the molecular interplay between tissue-type plasminogen activator (t-PA), plasminogen and fibrin. The molecular assembly of t-PA and plasminog...
High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evalua...
High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evalua...
High levels of histidine-rich glycoprotein (HRGP) and plasminogen activator inhibitor-1 (PAI-1) have been claimed to contribute to the hypofibrinolytic state observed in patients with venous thrombosis. These abnormalities were detected, respectively, in eight and 10 members of a family from which four of seven members with both abnormalities had v...
Background: Lp(a), a major cardiovascular risk factor, contains a specific apolipoprotein, apo(a), which by virtue of structural homology with plasminogen inhibits the formation of plasmin, the fibrinolytic enzyme. A number of clinical reports support the role of Lp(a) as a cardiovascular or cerebral risk factor, and experimental data suggest that...
Objective - Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes. Methods and Results - Re...
