Role of Membrane Lipid Rafts in MRP4 (ABCC4) Dependent Regulation of the cAMP Pathway in Blood Platelets.

Background: Platelet cytosolic cyclic adenosine monophosphate (cAMP) levels are balanced by synthesis, degradation, and efflux. Efflux can occur via multidrug resistant protein-4 (MRP4; ABCC4) present on dense granule and/or plasma membranes. As lipid rafts have been shown to interfere on cAMP homeostasis, we evaluated the relationships between the distribution and activity of MRP4 in lipid rafts and cAMP efflux.

Comparative Study of Various α-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal.

Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y 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 α-adrenoreceptors.

Epinephrine restores platelet functions inhibited by ticagrelor: A mechanistic approach.

Ticagrelor, an antagonist of the platelet adenosine diphosphate (ADP)-P2Y receptor is recommended for patients with acute coronary syndromes. However, ticagrelor exposes to a risk of bleeding, the management of which is challenging because platelet transfusion is ineffective, and no antidote is yet available. We hypothesized that the vasopressor drug epinephrine could counter the antiplatelet effects of ticagrelor and restore platelet functions.

Pain assessment and factors influencing pain during bone marrow aspiration: A prospective study.

Although bone marrow aspiration (BMA) is still considered a painful procedure, pain level remains poorly documented. We therefore conducted a prospective study intended to evaluate pain level in adult patients undergoing BMA at the sternal or iliac crest site to identify factors associated with pain. We enrolled a total of 448 patients who underwent 461 BMA and asked those patients to score their pain intensity after BMA using numerical pain rating scale (NPRS).

Evaluation of commonly used tests to measure the effect of single-dose aspirin on mouse hemostasis.

Discrepancies in preclinical studies of aspirin (ASA) antiplatelet activity in mouse models of bleeding and arterial thrombosis led us to evaluate commonly reported methods in order to propose a procedure for reliably measuring the effects of single dose ASA on mouse hemostasis. FVB and C57Bl6 mice received 100 mg/kg of ASA or vehicle orally 30 min or 3 h prior to investigate either hemostasis using the tail bleeding assay or carotid thrombosis induced by FeCl, or to blood sampling for isolated platelet aggregation and TXB generation. Expected inhibition of COX1 by ASA was ascertained by a strong decrease in TXB production, and its effect on platelet function and hemostasis, by decreased collagen-induced aggregation and increased bleeding time, respectively.

Platelet-mapping assay for monitoring antiplatelet therapy during mechanical circulatory support in children: A retrospective observational study.

Introduction: The complex hemostatic changes associated with Berlin Heart (BH) implantation in children require a challenging antithrombotic treatment. The aim of this retrospective analysis was to evaluate the thromboelastography (TEG)-platelet mapping (PM) assay to monitor antiplatelet therapy in children implanted with a BH.

Methods: TEG-PM was performed in 4 BH-implanted patients receiving dipyridamole and aspirin, and 9 healthy volunteers.

Beta-1,4-galactosyltransferase 2 c.909C>T gene variant is predictive of on-clopidogrel platelet reactivity.

CYP2C19 genotype influences clopidogrel response but only accounts for a small part of the variability in platelet reactivity. Recently, exome sequencing identified a variant of the gene encoding B4GALT2 as a potential candidate implicated in on-treatment platelet reactivity. Carriers of the B4GALT2 c.

MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease.

This review focuses on multidrug resistance protein 4 (MRP4 or ABCC4) that has recently been shown to play a role in cAMP homeostasis, a key-pathway in vascular biology and in platelet functions. In vascular system, recent data provide evidence that inhibition of MRP4 prevents human coronary artery smooth muscle cell proliferation in vitro and in vivo, as well as human pulmonary artery smooth muscle cell proliferation in vitro and pulmonary hypertension in mice in vivo. In the heart, MRP4 silencing in adult rat ventricular myocytes results in an increase in intracellular cAMP levels leading to enhanced cardiomyocyte contractility.

Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice.

Molecules that reduce the level of cyclic adenosine 5'-monophosphate (cAMP) in the platelet cytosol, such as adenosine 5'-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. In this study, we evaluated the role of multidrug resistance protein 4 (MRP4, or ABCC4), a nucleotide transporter, in platelet functions in vivo and in vitro by investigating MRP4-deficient mice.