Papers by Jean-Claude BORDET
Haematologica
Vascular homeostasis is impaired in various diseases thereby contributing to the progression of t... more Vascular homeostasis is impaired in various diseases thereby contributing to the progression of their underlying pathologies. The endothelial immediate early gene Apolipoprotein L domain-containing 1 (APOLD1) helps to regulate endothelial function. However, its precise role in endothelial cell biology remains unclear. We have localized APOLD1 to endothelial cell contacts and to Weibel-Palade bodies (WPB) where it associates with von Willebrand factor (VWF) tubules. Silencing of APOLD1 in primary human endothelial cells disrupted the cell junction-cytoskeletal interface, thereby altering endothelial permeability accompanied by spontaneous release of WPB contents. This resulted in an increased presence of WPB cargoes, notably VWF and angiopoietin-2 in the extracellular medium. Autophagy flux, previously recognized as an essential mechanism for the regulated release of WPB, was impaired in the absence of APOLD1. In addition, we report APOLD1 as a candidate gene for a novel inherited bl...
Acta Haematologica, 2020
Inherited thrombocytopenias correspond to a group of hereditary disorders characterized by a redu... more Inherited thrombocytopenias correspond to a group of hereditary disorders characterized by a reduced platelet count, platelet dysfunction, and a family history of thrombocytopenia. It is commonly associated with mucocutaneous bleeding. Thrombocytopenia results from mutations in genes involved in megakaryocyte differentiation, platelet formation, and clearance. Here we report on a patient presenting with severe syndromic inherited thrombocytopenia manifesting as spontaneous mucocutaneous bleeds, requiring frequent platelet transfusions. Thrombocytopenia was explained by the presence of 4 mutations in 3 hematopoietic transcription factor genes: FLI1, RUNX1, and ETV6. The patient was successfully treated with high-dose eltrombopag at 150 mg/day, an orally available non-peptide thrombopoietin receptor agonist. Since the start of treatment 23 months ago, the manifestations of bleeding have resolved, and no platelet transfusions or corticosteroids have been required. The patient has no cl...
Journal of Thrombosis and Haemostasis, 2021
Background 29 GATA1 is an essential transcription factor for both polyploidization and megakaryoc... more Background 29 GATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) 30 differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.
Genetics in Medicine, 2020
Purpose: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive b... more Purpose: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in ten different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in nonsyndromic or syndromic forms of albinism. Methods: Two hundred thirty albinism patients lacking a molecular diagnosis of albinism were screened for pathogenic variants in candidate genes with known links to pigmentation or HPS pathophysiology. Results: We identified two unrelated patients with distinct homozygous variants of the BLOC1S5 gene. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. Conclusion: Mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of Hermansky-Pudlak syndrome, HPS-11.
Platelets, 2020
Hermansky-Pudlak syndrome (HPS) is a rare form of syndromic oculocutaneous albinism caused by dis... more Hermansky-Pudlak syndrome (HPS) is a rare form of syndromic oculocutaneous albinism caused by disorders in lysosome-related organelles. Ten genes are associated with different forms of HPS. HPS type 9 (HPS-9) is caused by biallelic variants of BLOC1S6. To date, only three patients with HPS-9 have been reported. We described one patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. By reviewing the previous published cases we confirm the phenotype of HPS-9 patients. This patient is the only one described with dextrocardia and abnormal psychomotor development.
Revue Francophone des Laboratoires, 2020
Resume Les traitements antiplaquettaires les plus repandus utilisent aspirine et/ou des anti-P2Y1... more Resume Les traitements antiplaquettaires les plus repandus utilisent aspirine et/ou des anti-P2Y12 pour contenir l’agregation des plaquettes lors des traitements cardio-vasculaires. L’aspirine inhibe la voie de synthese des protaglandines-thromboxane, les anti-P2Y12 thienopyridines et pyrimidines bloquent le recepteur P2Y12 de l’ADP qui induit l’agregation stable des plaquettes. Une litterature abondante d’essais cliniques et de revues comparatives de ces essais sont recitees en partie dans ce document. Sauf en cas de suspicion de mauvais suivi des traitements, la recherche de resistance a ces types de traitements est variable, celle a l’aspirine, dont l’agoniste de choix est l’arachidonate, est bien consideree inutile a la quasi-unanimite, pour les anti-P2Y12, les positions ne sont pas tres claires, beaucoup de conclusions sont de ne pas encourager recherche et suivi du traitement au laboratoire pour methodes non standardisees, variabilites pre-analytiques, disparites des seuils des tests utilises. Du cout des traitements, le clopidogrel est toujours le plus utilise, c’est aussi le produit qui a ete decrit comme ayant le plus de cas avec resistance. Les methodes de suivi des anti-P2Y12 qui apparaissent les plus pertinentes utilisent un melange PGE1 + ADP pour evaluer cette resistance, elles sont encore a standardiser dans leur methodologie, du pre-analytique au postanalytique. Les societes savantes emettent une reserve pour les chirurgies lourdes et l’optimisation de leur mise en oeuvre et pour verifier l’observance des traitements de certains patients. En conclusion, au regard des methodes utilisees, le choix de methodes de references reste a etablir par les societes savantes avec des seuils tranches. De larges essais cliniques randomises sont a realiser suite a la definition de methodes de references.
Blood, 2018
Introduction Hemophilia is an X linked disorder characterized by an increased tendency to spontan... more Introduction Hemophilia is an X linked disorder characterized by an increased tendency to spontaneous bleeding resulting from profound compromise of the hemostatic response with delayed development of a clot and the formation of clots that are vulnerable to fibrinolysis. Optimization of clot stability by adding TXA to low concentrations of factor concentrates may be a way to improve prophylaxis in patients with severe hemophilia (sH) without substantially increasing the cost or the burden of more frequent infusions. Aims We proposed to study whether hemostasis is improved with the addition of TXA to low FVIII plasma concentrations (equivalent to trough levels in prophylactic setting). We specifically studied in vitro the clot stability in patients with sHA; and in vivo the hemostatic response to trauma-induced joint bleed and tail clip in FVIII knock-out (KO) mice. Methods After obtaining informed consent, blood samples of 12 adults with sHA were spiked in vitro to achieve final con...
Blood, 2014
RATIONAL/BACKGROUND: Venous thromboembolism (VTE) is a major complication of multiple myeloma (MM... more RATIONAL/BACKGROUND: Venous thromboembolism (VTE) is a major complication of multiple myeloma (MM). Mortality and morbidity related to VTE in multiple myeloma patients remain a challenging health problem. The incidence of deep venous thrombosis with thalidomide plus dexamethasone therapy is 15-17%. The reported incidence of thrombosis with lenalidomid treatment in MM is 9 – 17.5%. The risk is higher when lenalidomid is used in combination with high dose of dexamethasone. The guidelines therefore recommend thromboprophylaxis but serious uncertainties remain concerning the optimal thromboprophylaxis. The optimal dose of LMWH for thromboprophylaxis, the potential interest of aspirin as an alternative strategy in these patients have not been clearly established. Thus, antithrombotic prophylaxis remains underused also due to the lack of a laboratory assay which can reliably detect hypercoagulability and predict the VTE risk in each patient with MM. Thrombin generation assay is a global h...
Platelets, 2019
Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopen... more Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopenia with large platelets lacking α-granules. A long-term complication is myelofibrosis with pancytopenia. Hematopoietic stem cell transplant (HSCT) could be a curative treatment. We report a male GPS patient with severe pancytopenia, splenomegaly and a secondary myelofibrosis needing red blood cells transfusion. He received an HSCT from a 10/10 matched HLA-unrelated donor after a myeloablative conditioning regimen. Transfusion independence occurred at day+21, with a documented neutrophil engraftment. At day+ 180, we added ruxolitinib to cyclosporine and steroids for a moderate chronic graft versus host disease (GVHD) and persistent splenomegaly. At day+240 GVHD was controlled and splenomegaly reduced. Complete donor chimesrism was documented in blood and marrow and platelets functions and morphology normalized. At day+ 720, the spleen size normalized and there was no evidence of marrow fibrosis on the biopsy. In GPS, HSCT may be a curative treatment in selected patients with pancytopenia and myelofibrosis.
American Journal of Hematology, 2017
Rare gain-of-function mutations within the ITGA2B or ITGB3 genes have been recognized to cause ma... more Rare gain-of-function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, aIIbR995W, and a third family with an ITGB3 mutation, b3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of aIIb to b3 of the integrin aIIbb3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large a-granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with aIIbb3 intracytoplasmic mutations there is an abnormal maturation of a-granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the aIIb R995/b3 D723 salt bridge.
Blood, Jan 13, 2018
The ephrin transmembrane receptor (EPHR) family of tyrosine kinases is involved in platelet funct... more The ephrin transmembrane receptor (EPHR) family of tyrosine kinases is involved in platelet function. We report the first 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 gene. P1 and P2 were homozygous for this variant while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation and granule secretion induced by GPCR (G protein-coupled receptors) agonists and convulxin as well as in thrombus formation on collagen under flow. In contrast, clot retraction, flow-dependent platelet adhesion and spreading on fibrinogen were only mildly affected indicating limited effects on αIIbβ3 outside-in signaling. Most importantly, Lyn, Syk and FcRγ phosphorylation, the initial steps in GPVI platelet signaling were dr...
Blood Advances, 2017
Key Points A novel heterozygous ITGB3 Leu718del shows loss of synchronization between the intracy... more Key Points A novel heterozygous ITGB3 Leu718del shows loss of synchronization between the intracytoplasmic tail of β3 with that of αIIb. Decreased activation of αIIbβ3 accompanies enlarged platelets that contain giant granules and give a poor aggregation response.
Arteriosclerosis, thrombosis, and vascular biology, Jun 1, 2017
Dominant mutations of the X-linked filamin A (FLNA) gene are responsible for filaminopathies A, w... more Dominant mutations of the X-linked filamin A (FLNA) gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked FLNA allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: p.Ter2648SerextTer101). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most impor...
Thrombosis Research, 2017
Yesim , Pre-analytical effects of pneumatic tube system transport on routine haematology and coag... more Yesim , Pre-analytical effects of pneumatic tube system transport on routine haematology and coagulation tests, global coagulation assays and platelet function assays. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Tr(2016),
Thrombosis and haemostasis, Jan 21, 2016
The two most widely used antiplatelet drugs in the world are aspirin and clopidogrel. However, so... more The two most widely used antiplatelet drugs in the world are aspirin and clopidogrel. However, some patients on aspirin and/or clopidogrel therapy do not respond appropriately to either aspirin or clopidogrel. This phenomenon is usually called "aspirin/clopidogrel resistance". Several platelet function tests have been used in various studies for the assessment of aspirin and clopidogrel resistance in healthy individuals and patients admitted in cardiology departments. An accurate assessment of platelet response to aspirin/clopidogrel could benefit patients by proposing tailored-antiplatelet therapy based on test results. However, there is a clear lack of standardisation of such techniques and their analytical variability may induce misinterpretation. After a quick report of the mechanisms responsible for aspirin/clopidogrel resistance, we describe the pre-analytical aspects and the analytical performances of current platelet function tests (Light-transmission aggregometry,...
Blood, Aug 14, 2016
The role of the sarco-endoplasmic reticulum calcium (Ca(2+))ATPase (SERCA)3 in platelet physiolog... more The role of the sarco-endoplasmic reticulum calcium (Ca(2+))ATPase (SERCA)3 in platelet physiology remains poorly understood. Here, we show that SERCA3(-/-) mice exhibit prolonged tail bleeding time and re-bleeding. Thrombus formation was delayed both in arteries and venules in an in vivo ferric chloride-induced thrombosis model. Defective platelet adhesion and thrombus growth over collagen was confirmed in vitro ADP removal by apyrase diminished adhesion and thrombus growth of control platelets to the level of SERCA3(-/-) platelets. Aggregation, dense granule secretion and Ca(2+) mobilization of SERCA3(-/-) platelets induced by low collagen or low thrombin concentration were weaker than controls. Accordingly, SERCA3(-/-) platelets exhibited a partial defect in total stored Ca(2+), and in Ca(2+) store re-uptake following thrombin stimulation. Importantly ADP but not serotonin, rescued aggregation, secretion and Ca(2+) mobilization in SERCA3(-/-) platelets, suggesting specificity. De...
The Journal of biological chemistry, Jan 6, 2015
Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, is a novel gene that ... more Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, is a novel gene that positively regulates cancer cell motility, invasion, and metastasis through distinct biochemical and signaling pathways, but how MDA-9/syntenin is regulated in response to signals with the extracellular environment and promotes tumor progression is unclear. We now demonstrate that MDA-9/syntenin is dramatically up-regulated by a combination of rFVIIa and factor F(X) in malignant melanoma. Induction of MDA-9/syntenin in melanoma was found to occur in a thrombin-independent signaling pathway and involves the PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/c-Jun N-terminal kinase axis resulting in the activation of paxillin, NF-κB, and matrix metalloproteinase-2 (MMP-2). MDA-9/syntenin physically interacts with c-Src through its PDZ binding motif following stimulation of melanoma cells with rFVIIa and FX. We also document that induction of this signaling pathway is required for TF·FVIIa·Xa-induced c...
Haematologica, 2006
Recombinant factor VIIa (rFVIIa) has been shown to be efficient for the treatment of haemorrhages... more Recombinant factor VIIa (rFVIIa) has been shown to be efficient for the treatment of haemorrhages in patients with Glanzmann's thrombasthenia presenting anti-glycoprotein IIb-IIIa antibodies, but the mechanism of action is not well established and there is no routine laboratory test for the monitoring of rFVIIa. In this study, thrombin generation (TG) test was used to assess the efficacy of rFVIIa ex vivo in a Glanzmann patient with inhibitor, who had a surgery for cholesteatoma. The day before surgery, TG capacity in platelet rich plasma was significantly diminished (Endogenous thrombin potential = 637nM x min) in comparison with the normal control group (1338+/-353 nM x min). Thirty minutes after the first infusion of 90 microg/kg of rFVIIa, TG was increased by 59% (1010 nM x min). rFVIIa was administered as intravenous bolus injection of 90 microg/kg q x 2h during the first 24h, than 66microg/kg q x 2h during 24h and 53 microg/kg q x 2h on the post-operative day 3. Residual T...
Blood, Jan 18, 2014
The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high effici... more The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis man...
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Papers by Jean-Claude BORDET