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Dive into the research topics where Alexandre Kauskot is active.

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Featured researches published by Alexandre Kauskot.


Blood | 2011

Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome

Paquita Nurden; Najet Debili; Isabelle Coupry; Marijke Bryckaert; Ibtissam Youlyouz-Marfak; Guilhem Solé; Anne-Cécile Pons; Eliane Berrou; Frédéric Adam; Alexandre Kauskot; Jean-Marie Daniel Lamazière; Philippe Rameau; Patricia Fergelot; Caroline Rooryck; Dorothée Cailley; Benoit Arveiler; Didier Lacombe; William Vainchenker; Alan T. Nurden; Cyril Goizet

Filaminopathies A caused by mutations in the X-linked FLNA gene are responsible for a wide spectrum of rare diseases including 2 main phenotypes, the X-linked dominant form of periventricular nodular heterotopia (FLNA-PVNH) and the otopalatodigital syndrome spectrum of disorders. In platelets, filamin A (FLNa) tethers the principal receptors ensuring the platelet-vessel wall interaction, glycoprotein Ibα and integrin αIIbβ3, to the underlying cytoskeleton. Hemorrhage, coagulopathy, and thrombocytopenia are mentioned in several reports on patients with FLNA-PVNH. Abnormal platelet morphology in 2 patients with FLNA-PVNH prompted us to examine a third patient with similar platelet morphology previously diagnosed with immunologic thrombocytopenic purpura. Her enlarged platelets showed signs of FLNa degradation in Western blotting, and a heterozygous missense mutation in FLNA was detected. An irregular distribution of FLNa within the total platelet population was shown by confocal microscopy for all 3 patients. In vitro megakaryocyte cultures showed an abnormal differentiation, including an irregular distribution of FLNa with a frayed aspect, the presence of enlarged α-granules, and an abnormal fragmentation of the cytoplasm. Mutations in FLNA may represent an unrecognized cause of macrothrombocytopenia with an altered platelet production and a modified platelet-vessel wall interaction.


Blood | 2010

Platelet JNK1 is involved in secretion and thrombus formation

Frédéric Adam; Alexandre Kauskot; Paquita Nurden; Eric Sulpice; Marc Hoylaerts; Roger J. Davis; Jean-Philippe Rosa; Marijke Bryckaert

The role of c-Jun NH(2)-terminal kinase 1 (JNK1) in hemostasis and thrombosis remains unclear. We show here, with JNK1-deficient (JNK1(-/-)) mice, that JNK1 plays an important role in platelet biology and thrombus formation. In tail-bleeding assays, JNK1(-/-) mice exhibited longer bleeding times than wild-type mice (396 +/- 39 seconds vs 245 +/- 32 seconds). We also carried out in vitro whole-blood perfusion assays on a collagen matrix under arterial shear conditions. Thrombus formation was significantly reduced for JNK1(-/-) platelets (51%). In an in vivo model of thrombosis induced by photochemical injury to cecum vessels, occlusion times were 4.3 times longer in JNK1(-/-) arterioles than in wild-type arterioles. Moreover, in vitro studies carried out in platelet aggregation conditions demonstrated that, at low doses of agonists, platelet secretion was impaired in JNK1(-/-) platelets, leading to altered integrin alphaIIbbeta3 activation and reduced platelet aggregation, via a mechanism involving protein kinase C. JNK1 thus appears to be essential for platelet secretion in vitro, consistent with its role in thrombus growth in vivo. Finally, we showed that ERK2 and another isoform of JNK affect platelet aggregation through 2 pathways, one dependent and another independent of JNK1.


Journal of Biological Chemistry | 2007

Protease-activating Receptor-4 Induces Full Platelet Spreading on a Fibrinogen Matrix INVOLVEMENT OF ERK2 AND p38 AND Ca2+ MOBILIZATION

Alexandra Mazharian; Séverine Roger; Eliane Berrou; Frédéric Adam; Alexandre Kauskot; Paquita Nurden; Martine Jandrot-Perrus; Marijke Bryckaert

Although the involvement of protease-activating receptor PAR1 and PAR4 is well established in platelet aggregation, their role in platelet adhesion and spreading has yet to be characterized. We investigated platelet adhesion and spreading on a fibrinogen matrix after PAR1 and PAR4 stimulation in correlation with the activation of two MAPKs, ERK2 and p38. Of the two PAR-activating peptides (PAR-APs), PAR1-AP and PAR4-AP, which both induce adhesion, only PAR4-AP induced full platelet spreading. Although both PAR1-AP and PAR4-AP induced ADP secretion, which is required for platelet spreading, only PAR4-AP induced sustained Ca2+ mobilization. In these conditions of PAR4 induction, ERK2 and p38 activation were involved in platelet spreading but not in platelet adhesion. p38 phosphorylation was dependent on ADP signaling through P2Y12, its receptor. ERK2 phosphorylation was triggered through integrin αIIbβ3 outside-in signaling and was dependent on the Rho pathway. ERK2 and p38 activation induced phosphorylation of the myosin light chain and actin polymerization, respectively, necessary for cytoskeleton reorganization. These findings provide the first evidence that thrombin requires PAR4 for the full spreading response. ERK2 and p38 and sustained Ca2+ mobilization, involved in PAR4-induced platelet spreading, contribute to the stabilization of platelet thrombi at sites of high thrombin production.


Journal of Biological Chemistry | 2007

Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

Alexandre Kauskot; Frédéric Adam; Alexandra Mazharian; Nadine Ajzenberg; Eliane Berrou; Arnaud Bonnefoy; Jean-Philippe Rosa; Marc Hoylaerts; Marijke Bryckaert

The involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase-1 (JNK1) has never been investigated in hemostasis and thrombosis. Using two JNK inhibitors (SP600125 and 6o), we have demonstrated that JNK1 is involved in collagen-induced platelet aggregation dependent on ADP. In these conditions, JNK1 activation requires the coordinated signaling pathways of collagen receptors (α2β1 and glycoprotein (GP)VI) and ADP. In contrast, JNK1 is not required for platelet adhesion on a collagen matrix in static or blood flow conditions (300–1500 s–1) involving collagen receptors (α2β1 and GPVI). Importantly, at 1500 s–1, JNK1 acts on thrombus formation on a collagen matrix dependent on GPIb-von Willebrand factor (vWF) interaction but not ADP receptor activation. This is confirmed by the involvement of JNK1 in shear-induced platelet aggregation at 4000 s–1. We also provide evidence during rolling and adhesion of platelets to vWF that platelet GPIb-vWF interaction triggers αIIbβ3 activation in a JNK1-dependent manner. This was confirmed with a Glanzmann thrombastenic patient lacking αIIbβ3. Finally, in vivo, JNK1 is involved in arterial but not in venular thrombosis in mice. Overall, our in vitro studies define a new role of JNK1 in thrombus formation in flowing blood that is relevant to thrombus development in vivo.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2013

Heterogeneity of Platelet Functional Alterations in Patients With Filamin A Mutations

Eliane Berrou; Frédéric Adam; Marilyne Lebret; Patricia Fergelot; Alexandre Kauskot; Isabelle Coupry; Martine Jandrot-Perrus; Alan T. Nurden; Rémi Favier; Jean-Philippe Rosa; Cyril Goizet; Paquita Nurden; Marijke Bryckaert

Objective—We examined platelet functions in 4 unrelated patients with filaminopathy A caused by dominant mutations of the X-linked filamin A (FLNA) gene. Methods and Results—Patients P1, P2, and P4 exhibited periventricular nodular heterotopia, heterozygozity for truncating FLNA mutations, and thrombocytopenia (except P2). P3 exhibited isolated thrombocytopenia and heterozygozity for a p.Glu1803Lys FLNA mutation. Truncated FLNa was undetectable by Western blotting of P1, P2, and P4 platelets, but full-length FLNa was detected at 37%, 82%, and 57% of control, respectively. P3 FLNa (p.Glu1803Lys and full-length) was assessed at 79%. All patients exhibited a platelet subpopulation negative for FLNa. Platelet aggregation, secretion, glycoprotein VI signaling, and thrombus growth on collagen were decreased for P1, P3, and P4, but normal for P2. For the 2 patients analyzed (P1 and P4), spreading was enhanced and, more markedly, in FLNa-negative platelets, suggesting that FLNa negatively regulates cytoskeleton reorganization. Platelet adhesion to von Willebrand factor under flow correlated with platelet full-length FLNa content: markedly reduced for P1 and P4 and unchanged for P2. Interestingly, von Willebrand factor flow adhesion was increased for P3, consistent with a gain-of-function effect enhancing glycoprotein Ib-IX-V/von Willebrand factor interaction. These results are consistent with a positive role for FLNa in platelet adhesion under high shear. Conclusion—FLNA mutation heterogeneity correlates with different platelet functional impacts and points to opposite regulatory roles of FLNa in spreading and flow adhesion under shear.


Thrombosis and Haemostasis | 2012

Fibrin formation by staphylothrombin facilitates Staphylococcus aureus -induced platelet aggregation

Thomas Vanassche; Alexandre Kauskot; Jan Verhaegen; Willy Peetermans; J. van Ryn; Olaf Schneewind; Marc Hoylaerts; Peter Verhamme

Interactions of Staphylococcus aureus (S. aureus) and platelets play an important role in the pathogenesis of intravascular infections such as infective endocarditis (IE). A typical feature of S. aureus is the ability to generate thrombin activity through the secretion of two prothrombin activating molecules, staphylocoagulase and von Willebrand factor-binding protein (vWbp), which bind to human prothrombin to form the enzymatically active staphylothrombin complex. The role of staphylothrombin in the interaction between S. aureus and platelets has not yet been studied. We found that in contrast with thrombin, staphylothrombin did not directly activate human platelets. However, the staphylothrombin-mediated conversion of fibrinogen to fibrin initiated platelet aggregation and secondary activation and facilitated S. aureus-platelet interactions. Both the genetic absence of staphylocoagulase and vWbp and pharmacological inhibition of staphylothrombin increased the lag time to aggregation, and reduced platelet trapping by S. aureus in high shear stress conditions. The combined inhibition of staphylothrombin and immunoglobulin binding to platelets completely abolished the ability of S. aureus to aggregate platelets in vitro. In conclusion, although staphylothrombin did not directly activate platelets, the formation of a fibrin scaffold facilitated bacteria-platelet interaction, and the inhibition of staphylothrombin resulted in a reduced activation of platelets by S. aureus.


Journal of Clinical Investigation | 2013

von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3

Caterina Casari; Eliane Berrou; Marilyne Lebret; Frédéric Adam; Alexandre Kauskot; Regis Bobe; Céline Desconclois; Edith Fressinaud; Olivier D. Christophe; Peter J. Lenting; Jean-Philippe Rosa; Cécile V. Denis; Marijke Bryckaert

von Willebrand disease type 2B (vWD-type 2B) is characterized by gain-of-function mutations in von Willebrand factor (vWF) that enhance its binding to the glycoprotein Ib-IX-V complex on platelets. Patients with vWD-type 2B have a bleeding tendency that is linked to loss of vWF multimers and/or thrombocytopenia. In this study, we uncovered evidence that platelet dysfunction is a third possible mechanism for bleeding tendency. We found that platelet aggregation, secretion, and spreading were diminished due to inhibition of integrin αIIbβ3 in platelets from mice expressing a vWD-type 2B-associated vWF (vWF/p.V1316M), platelets from a patient with the same mutation, and control platelets pretreated with recombinant vWF/p.V1316M. Impaired platelet function coincided with reduced thrombus growth. Further, αIIbβ3 activation and activation of the small GTPase Rap1 were impaired by vWF/p.V1316M following exposure to platelet agonists (thrombin, ADP, or convulxin). Conversely, thrombin- or ADP-induced Ca2+ store release, which is required for αIIbβ3 activation, was normal, indicating that vWF/p.V1316M acts downstream of Ca2+ release and upstream of Rap1. We found normal Syk phosphorylation and PLCγ2 activation following collagen receptor signaling, further implying that vWF/p.V1316M acts directly on or downstream of Ca2+ release. These data indicate that the vWD-type 2B mutation p.V1316M is associated with severe thrombocytopathy, which likely contributes to the bleeding tendency in vWD-type 2B.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2011

Progression of the Prothrombotic State in Aging Bmal1-Deficient Mice

Bianca Hemmeryckx; Cor E. Van Hove; Paul Fransen; Jan Emmerechts; Alexandre Kauskot; Hidde Bult; H. Roger Lijnen; Marc Hoylaerts

Objective—The goal of this study was to examine the functional relationship between aging endothelium and thrombogenicity in a mouse model of premature aging. Methods and Results—Coagulation tests and factors, blood cell counts, aorta endothelial function, aorta gene expression, and FeCl3-induced thrombosis in mesenteric blood vessels were analyzed in 10- to 30-week-old brain and muscle ARNT-like protein-1 (Bmal1)–deficient (knockout [KO]) mice and wild-type littermates. Ten-week-old KO mice manifested shortened prothrombin times (9.7 versus 11.3 seconds in wild-type) and elevated plasma fibrinogen (264 versus 172 mg/dL). At 30 weeks, factor VII (198% versus 149%), and platelet counts (2049 versus 1354 K/&mgr;L) were increased in KO mice. Gene deficiency reduced the vasoactive nitric oxide production at 10 and 30 weeks and tended to reduce and increase the protein expression of thrombomodulin and von Willebrand factor, respectively, with aging. Shortened venular and arteriolar occlusion times on FeCl3-induced injury in 10-week-old KO mice confirmed higher thrombogenicity, culminating in priapism, observed in 60% of 25- to 30-week-old KO males. Conclusion—Endothelial dysfunction and a hypercoagulable state cause early arterial and venous thrombogenicity in Bmal1 KO mice. With aging, progressive endothelial dysfunction, rising platelet counts, and high factor VII further enhance thrombogenicity, provoking priapism.


Frontiers in Bioscience | 2008

Hemostatic effects of recombinant DisBa-01, a disintegrin from Bothrops alternatus.

Alexandre Kauskot; Márcia Regina Cominetti; Oscar H. P. Ramos; Iga Bechyne; Jean-Marie Renard; Marc Hoylaerts; Michel Crépin; Chantal Legrand; Heloisa S. Selistre-de-Araujo; Arnaud Bonnefoy

A monomeric RGD-disintegrin was recently identified from a cDNA library from the venom gland of Bothrops alternatus. The corresponding 12 kDa-recombinant protein, DisBa-01, specifically interacted with alpha(v)beta3 integrin and displayed potent anti-metastatic and anti-angiogenic properties. Here, the interaction of DisBa-01 with platelet alphaIIb beta3 integrin and its effects on hemostasis and thrombosis were investigated. DisBa-01 bound to Chinese Hamster Ovary (CHO) cells expressing beta3 or alphaIIb beta3 and promoted their adhesion and the adhesion of resting platelets onto glass coverslips. The disintegrin inhibited the binding of FITC-fibrinogen and FITC-PAC-1 to ADP-stimulated platelets and inhibited ADP-, TRAP- and collagen-induced aggregation of murine, rabbit or human platelets. In a flow chamber assay, DisBa-01 inhibited and reverted platelet adhesion to immobilized fibrinogen. DisBa-01 inhibited the phosphorylation of FAK following platelet activation. The intravenous injection of DisBa-01 in C57Bl6/j mice, prolonged tail bleeding time as well as thrombotic occlusion time in mesenteric venules and arterioles following vessel injury with FeCl3. In conclusion, DisBa-01 antagonizes the platelet alphaIIb beta3 integrin and potently inhibits thrombosis.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2014

Elastin-Derived Peptides Are New Regulators of Thrombosis

Charlotte Kawecki; Nathalie Hézard; Olivier Bocquet; Gaël Poitevin; Fanja Rabenoelina; Alexandre Kauskot; Laurent Duca; Sébastien Blaise; Béatrice Romier; Laurent Martiny; Philippe Nguyen; Laurent Debelle; Pascal Maurice

Objective— Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. Approach and Results— We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappa-elastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. Conclusions— These results highlight the complex nature of the mechanisms governing thrombus formation and reveal an unsuspected regulatory role for circulating EDP in thrombosis.

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Marc Hoylaerts

Katholieke Universiteit Leuven

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Paquita Nurden

Centre national de la recherche scientifique

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Peter Verhamme

Katholieke Universiteit Leuven

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Márcia Regina Cominetti

Federal University of São Carlos

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Alan T. Nurden

Centre national de la recherche scientifique

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