Comparative Effects of Glenzocimab and Eptifibatide on Bleeding Severity in 2 Mouse Models of Intracranial Hemorrhage.

Background: Antiplatelet drugs represent potential candidates for protecting the penumbral microcirculation during cerebral ischemia and improving the benefits of arterial recanalization in ischemic stroke. Yet while the efficacy of such adjuvant strategies has been shown to be highly time dependent, antiplatelet therapy at the acute phase of ischemic stroke cannot be envisioned until the diagnosis of stroke and its ischemic nature have been confirmed because of the presumed risk of worsening bleeding in case of intracranial hemorrhage (ICH). Here, we investigated this risk for 2 antiplatelet drugs currently being tested in clinical trials for ischemic stroke, glenzocimab and eptifibatide, in 2 mouse models of ICH.

Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms.

Background: Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.

High factor VIII concentrations interfere with glycoprotein VI-mediated platelet activation in vitro.

Background: The recruitment of activated factor VIII (FVIII) at the surface of activated platelets is a key step toward the burst of thrombin and fibrin generation during thrombus formation at the site of vascular injury. It involves binding to phosphatidylserine and, possibly, to fibrin-bound αβ. Seminal work had shown the binding of FVIII to resting platelets, yet without a clear understanding of a putative physiological relevance.

Association between endometriosis, infertility and autoimmune antiplatelet glycoprotein VI antibodies in two patients.

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 infertility presented a mild bleeding tendency, a deficient platelet aggregation response to collagen, convulxin or CRP and a severe GPVI deficiency.

Thrombopoietin-Dependent Myelo-Megakaryopoiesis Fuels Thromboinflammation and Worsens Antibody-Mediated Chronic Renal Microvascular Injury.

Significance Statement: Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 μg auto-injector in healthy volunteers.

Aims: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 μg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 μg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females.

Intravenous abciximab as a rescue therapy for immediate reocclusion after successful mechanical thrombectomy in acute ischemic stroke patients.

Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome. 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 IIb/IIIa antagonist abciximab, for its treatment. Clinical data were collected from April 2015 to April 2019 in a monocentric prospective registry of AIS patients treated by MT.

A Novel Mouse Model for Cerebral Venous Sinus Thrombosis.

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 relevant for evaluating injury patterns during CVST and studying its clinical aspects.

Glenzocimab does not impact glycoprotein VI-dependent inflammatory haemostasis.

Not available.

Selective inhibition of carboxypeptidase U may reduce microvascular thrombosis in rat experimental stroke.

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).

Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin.

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 stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy.

Acute ischemic stroke thrombi have an outer shell that impairs fibrinolysis.

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 of AIS thrombi causing LVO.

Methods: A total of 199 endovascular thrombectomy-retrieved thrombi were analyzed by immunohistology and scanning electron microscopy (SEM) and subjected to ex vivo thrombolysis assay.

Cleavage of anti-PF4/heparin IgG by a bacterial protease and potential benefit in heparin-induced thrombocytopenia.

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 (IdeS), cleaves the hinge region of heavy-chain IgG, abolishing its ability to bind FcγR, including FcγRIIA.

Microfluidic Modeling of Thrombolysis.

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 Fluor 647 fibrinogen conjugate, recalcified, and perfused for 3 to 4 minutes at venous or arterial wall shear rate in microfluidic flow chambers coated with collagen and tissue factor to generate nonocclusive fluorescent thrombi.

Carboxypeptidase U (CPU, carboxypeptidase B2, activated thrombin-activatable fibrinolysis inhibitor) inhibition stimulates the fibrinolytic rate in different in vitro models.

Unlabelled: Essentials AZD9684 is a potent inhibitor of carboxypeptidase U (CPU, TAFIa, CPB2). The effect of AZD9684 on fibrinolysis was investigated in four in vitro systems. The CPU system also attenuates fibrinolysis in more advanced hemostatic systems.

Immobilized fibrinogen activates human platelets through glycoprotein VI.

Glycoprotein VI, a major platelet activation receptor for collagen and fibrin, is considered a particularly promising, safe antithrombotic target. In this study, we show that human glycoprotein VI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen was abolished in platelets from glycoprotein VI- deficient patients suggesting that fibrinogen activates platelets through glycoprotein VI.

Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke.

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 target for improving tissue-type plasminogen activator (tPA)-induced thrombolysis in acute coronary syndrome.