Papers by Pascale Gaussem
at: is onlineArteriosclerosis, Thrombosis, and Vascular Biology Information about subscribing to ... more at: is onlineArteriosclerosis, Thrombosis, and Vascular Biology Information about subscribing to Subscriptions:
International Journal of Molecular Sciences, 2021
For more than 10 years, direct oral anticoagulants (DOACs) have been increasingly prescribed for ... more For more than 10 years, direct oral anticoagulants (DOACs) have been increasingly prescribed for the prevention and treatment of thrombotic events. However, their use in immunothrombotic disorders, namely heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS), is still under investigation. The prothrombotic state resulting from the autoimmune mechanism, multicellular activation, and platelet count decrease, constitutes similarities between HIT and APS. Moreover, they both share the complexity of the biological diagnosis. Current treatment of HIT firstly relies on parenteral non-heparin therapies, but DOACs have been included in American and French guidelines for a few years, providing the advantage of limiting the need for treatment monitoring. In APS, vitamin K antagonists are conversely the main treatment (+/− anti-platelet agents), and the use of DOACs is either subject to precautionary recommendations or is not recommended in severe APS. While some randomized...
International Journal of Molecular Sciences, 2021
Endoglin (Eng) is an endothelial cell (EC) transmembrane glycoprotein involved in adhesion and an... more Endoglin (Eng) is an endothelial cell (EC) transmembrane glycoprotein involved in adhesion and angiogenesis. Eng mutations result in vessel abnormalities as observed in hereditary hemorrhagic telangiectasia of type 1. The role of Eng was investigated in endothelial functions and permeability under inflammatory conditions, focusing on the actin dynamic signaling pathway. Endothelial Colony-Forming Cells (ECFC) from human cord blood and mouse lung/aortic EC (MLEC, MAEC) from Eng+/+ and Eng+/− mice were used. ECFC silenced for Eng with Eng-siRNA and ctr-siRNA were used to test tubulogenesis and permeability +/− TNFα and +/− LIM kinase inhibitors (LIMKi). In silico modeling of TNFα–Eng interactions was carried out from PDB IDs 5HZW and 5HZV. Calcium ions (Ca2+) flux was studied by Oregon Green 488 in epifluorescence microscopy. Levels of cofilin phosphorylation and tubulin post-translational modifications were evaluated by Western blot. F-actin and actin–tubulin distribution/co-localiza...
International Journal of Molecular Sciences, 2021
Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have s... more Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of ...
OncoImmunology, 2020
Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well... more Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well as endogenous danger-associated molecular patterns to trigger innate immune responses by myeloid cells. A single nucleotide polymorphism, rs867228 (allelic frequency 19-20%), in the gene coding for FPR1 accelerates the manifestation of multiple carcinomas, likely due to reduced anticancer immunosurveillance secondary to a defect in antigen presentation by dendritic cells. Another polymorphism in FPR1, rs5030880 (allelic frequency 12-13%), has been involved in the resistance to plague, correlating with the fact that FPR1 is the receptor for Yersinia pestis. Driven by the reported preclinical effects of FPR1 on lung inflammation and fibrosis, we investigated whether rs867228 or rs5030880 would affect the severity of coronavirus disease-19 (COVID-19). Data obtained on patients from two different hospitals in Paris refute the hypothesis that rs867228 or rs5030880 would affect the severity of COVID-19.
Journal of Clinical Medicine, 2020
Extracorporeal membrane oxygenation (ECMO) is an extracorporeal circulation used to manage patien... more Extracorporeal membrane oxygenation (ECMO) is an extracorporeal circulation used to manage patients with severe circulatory or respiratory failure. It is associated with both high bleeding and thrombosis risks, mainly as a result of biomaterial/blood interface phenomena, high shear stress, and complex inflammatory response involving the activation of coagulation and complement systems, endothelial cells, leukocytes, and platelets. Besides their critical role in hemostasis, platelets are important players in inflammatory reactions, especially due to their ability to bind and activate leukocytes. Hence, we reviewed studies on platelet function of ECMO patients. Moreover, we addressed the issue of platelet–leukocyte aggregates (PLAs), which is a key step in both platelet and leukocyte activation, and deserves to be investigated in these patients. A reduced expression of GPIb and GPVI was found under ECMO therapy, due to the shedding processes. However, defective platelet aggregation is...
Journal of Clinical Medicine, 2020
Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y12 receptor antagonist, increases the ... more Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y12 receptor antagonist, increases the risk of bleeding. Its management is challenging because platelet transfusion is ineffective and no specific antidote is currently available. Epinephrine, a vasopressor catecholamine prescribed during shock, restores platelet functions inhibited by ticagrelor through stimulation of α2A-adrenoreceptors. It subsequently inhibits cyclic adenosine monophosphate (cAMP) pathway and PI3K signaling. However, since epinephrine may expose a patient to deleterious hemodynamic effects, we hypothesized that other α2-adrenoreceptor agonist drugs used in clinical practice with fewer side effects could reverse the antiplatelet effects of ticagrelor. We compared in vitro the efficacy of clonidine, dexmedetomidine, brimonidine, and norepinephrine with epinephrine to restore ADP- and PAR-1-AP-induced washed platelet aggregation inhibited by ticagrelor, as well as resulting platelet cAMP levels. In ticagrelo...
International Journal of Molecular Sciences, 2020
The P2Y12 receptor is a key player in platelet activation and a major target for antithrombotic d... more The P2Y12 receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y12 receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y12 receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y12 receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y12-mediated inflammation, including cytokine release, platelet–leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y12 antagonists during var...
Thrombosis Research, 2019
Introduction: Lupus Anticoagulant (LA) testing using dilute Russell Viper Venom Time (dRVVT) is c... more Introduction: Lupus Anticoagulant (LA) testing using dilute Russell Viper Venom Time (dRVVT) is challenging in patients receiving Direct Oral AntiCoagulants (DOAC) due to potential false positive results. In a multicenter study, we evaluated the in vitro removal of DOAC by activated charcoal (DOAC remove ®), allowing reliable dRVVT testing. Materials and Methods: Patient samples were analyzed before and after treatment with DOAC remove ® : 49 apixaban, 48 rivaroxaban, 24 dabigatran and 30 none. DOAC plasma concentrations were measured using anti-Xa or anti-IIa diluted thrombin time assays. In a subset of 28 samples, DOAC concentrations were also measured using HPLC-MS/MS following treatment with DOAC remove ®. DRVVT was performed using STA-Staclot dRVVT Screen ® /Confirm ® (Stago) or LAC-Screening ® /Confirm ® (Siemens). Results: Baseline median [min-max] concentrations were 94 [<20-479] for apixaban, 107 [<20-501] for rivaroxaban and 135 ng/mL [<20-792] for dabigatran; dRVVT screen ratio /confirm normalized ratio was positive in 47, 90 and 42 % of apixaban, rivaroxaban and dabigatran samples. Treatment with DOAC remove ® did not affect dRVVT results in non-DOAC patients while it resulted in DOAC concentrations < 20 ng/mL in 82, 98 and 100 % of samples, respectively. Concentrations were < 5 ng/mL with HPLC-MS/MS in 5 out of 10, 8 out of 10 and 7 out of 8 samples, respectively. DOAC remove ® corrected DOAC interference with dRVVT assays allowed excluding LA in 76, 85 and 95 % of the patients, respectively. without affecting dRVVT results in non-DOAC patients. Conclusion: For dRVVT testing in DOAC patients, we suggest the use of DOAC remove ® for every rivaroxaban sample, whereas it might only be used in positive apixaban and dabigatran samples. A residual DOAC interference cannot be ruled out in case of persisting dRVVT positive results after treatment with DOAC remove ®. For those with persisting positive results, LA-diagnosis using dRVVT remains questionable.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2019
PloS one, 2018
This prospective observational study was designed to analyze platelet functions across time in 50... more This prospective observational study was designed to analyze platelet functions across time in 50 patients scheduled for liver transplantation (LT) secondary to decompensated cirrhosis or hepatocellular carcinoma. Platelet functions were assessed before LT (pre-LT), one week (D7) and 1 month (D28) after LT. Platelet count significantly increased from pre-LT time to day 28 as well as circulating CD34+hematopoietic stem cells. To avoid any influence of platelet count on assays, platelet function was evaluated on platelet-rich-plasma adjusted to pre-LT platelet count. Although platelet secretion potential did not differ between time-points, as evaluated by the expression of CD62P upon strong activation, platelet aggregation in response to various agonists significantly increased along time, however with no concomitant increase of circulating markers of platelet activation: platelet microvesicles, platelet-leukocyte complexes, soluble CD40L and soluble CD62P. In the multivariate analysi...
Cellular and molecular life sciences : CMLS, Apr 28, 2017
Complex interactions between platelets and activated endothelium occur during the thrombo-inflamm... more Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also...
Circulation research, Jan 30, 2016
Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascu... more Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear. To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood e...
Cellular and molecular life sciences : CMLS, Jan 8, 2015
The circulatory system is walled off by different cell types, including vascular mural cells and ... more The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng (+/-) mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, ...
Blood, Jan 27, 2015
Molecules that reduce the level of cyclic adenosine monophosphate (cAMP) in the platelet cytosol,... more Molecules that reduce the level of cyclic adenosine monophosphate (cAMP) in the platelet cytosol, such as adenosine diphosphate (ADP) secreted from dense granules, trigger platelet activation. Therefore, any change in the distribution and/or availability of cyclic nucleotides or ADP may interfere with platelet reactivity. Here we evaluated the role of multidrug resistance protein 4 (MRP4, ABCC4), a nucleotide transporter, in platelet functions in vivo and in vitro by investigating MRP4 deficient mice. MRP4 deletion resulted in a slight increase in platelet count but had no impact on platelet ultrastructure. In MRP4-deficient mice, the arterial occlusion was delayed and the tail bleeding time was prolonged. In a model of platelet depletion and transfusion mimicking a platelet specific KO, mice injected with MRP4-/- platelets also showed a significant increase in blood loss compared to mice injected with WT platelets. Defective thrombus formation and platelet activation were confirmed...
Archives of Cardiovascular Diseases Supplements, 2015
Small, medium but not large arteries are involved in digital ulcers associated with systemic scle... more Small, medium but not large arteries are involved in digital ulcers associated with systemic sclerosis
Archives of Cardiovascular Diseases Supplements, 2015
New England Journal of Medicine, 2015
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Papers by Pascale Gaussem