The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential.

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms.

Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets.

Pilot Study on the Role of Circulating miRNAs for the Improvement of the Predictive Ability of the 2MACE Score in Patients with Atrial Fibrillation.

. Atrial fibrillation (AF) increases the risk for stroke but also for non-stroke major adverse cardiovascular events (MACE). The 2MACE score was recently proposed to predict these events.

Platelet activation and neutrophil extracellular trap (NET) formation in immune thrombocytopenia: is there an association?

No biological predictors for the increased risk of thrombosis in patients with immune thrombocytopenia (ITP) have been identified. The aim of the study was to investigate platelet and neutrophil activation as well neutrophil extracellular trap (NET) formation in 63 ITP patients and 30 healthy volunteers. Platelet and neutrophil activation was assessed during steady state using flow cytometry analysis, and NETs were evaluated by quantitation of cell free DNA (cfDNA), and citrullinated histone-3-DNA (CitH3-DNA).

First exploratory study on the metabolome from plasma exosomes in patients with paroxysmal nocturnal hemoglobinuria.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease in which patients are at increased risk of thrombosis. The mechanisms underlying the associated thrombosis risk are still poorly understood, although it is known that Eculizumab, the drug of choice for symptomatic patients, prevents thrombotic events. Exosomes are extracellular vesicles that can carry and disseminate genetic material, tumor biomarkers and inflammatory mediators.

Neutrophil extracellular trap components increase the expression of coagulation factors.

Neutrophil extracellular traps (NETs) represent an important link between inflammation and thrombosis. Here, the present study aimed to investigate the influence of the NET components, DNA and histone H4, on hemostatic gene expression. A further aim was to confirm the influence of H4 on the expression of tissue factor (TF) and investigate a potential effect of DNA, and to test the involvement of miR-17/92 and its paralog miR-106b-25 in this regulation.

Differential miRNA expression profile and proteome in plasma exosomes from patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal disease of blood cells caused by the lack of glycosyl phosphatidyl inositol anchored proteins bound to the cell membrane. In consequence, erythrocytes lead to intravascular hemolysis upon complement activation, which promotes high risk of thrombosis, intravascular hemolytic anemia, and bone marrow failure in patients. The mechanisms of thrombosis in PNH are still poorly understood.

miR-146a deficiency in hematopoietic cells is not involved in the development of atherosclerosis.

Background: Atherosclerosis involves activation of the IRAK1/TRAF6/NF-κB inflammatory cascade, which is negatively regulated by miR146a. Previous studies showed that the TT genotype of rs2431697, located near the miR-146a gene, drives lower miR-146a transcription and predicts adverse cardiovascular events in anticoagulated atrial fibrillation patients. Moreover, systemic miR-146a administration protects mice from atherosclerosis.

MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation.

Objective: Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known.

MiRNA-Based Regulation of Hemostatic Factors through Hepatic Nuclear Factor-4 Alpha.

MiRNAs have been reported as CIS-acting elements of several hemostatic factors, however, their mechanism as TRANS-acting elements mediated by a transcription factor is little known and could have important effects. HNF4α has a direct and important role in the regulation of multiple hepatic coagulation genes. Previous in vitro studies have demonstrated that miR-24-3p and miR-34a-5p regulate HNF4A expression.

Regulation of coagulation factor XI expression by microRNAs in the human liver.

High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver.

Prognostic role of MIR146A polymorphisms for cardiovascular events in atrial fibrillation.

There are few biomarkers able to forecast new thrombotic events in patients with AF. In this framework, microRNAs have emerged as critical players in cardiovascular biology. In particular, miR-146a-5p is recognised as an important negative regulator of inflammation.

Effect of VKORC1, CYP2C9 and CYP4F2 genetic variants in early outcomes during acenocoumarol treatment.

Aim: To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy.

Patients & Methods: Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed.

Results: VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.

Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations.

Control of post-translational modifications in antithrombin during murine post-natal development by miR-200a.

Background: Developmental haemostatic studies may help identifying new elements involved in the control of key haemostatic proteins like antithrombin, the most relevant endogenous anticoagulant.

Results: In this study, we showed a significant reduction of sialic acid content in neonatal antithrombin compared with adult antithrombin in mice. mRNA levels of St3gal3 and St3gal4, two sialyltransferases potentially involved in antithrombin sialylation, were 85% lower in neonates in comparison with adults.

Creating a genotype-based dosing algorithm for acenocoumarol steady dose.

Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.

miR-133a regulates vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the vitamin K cycle.

Regulation of key proteins by microRNAs (miRNAs) is an emergent field in biomedicine. Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is a relevant molecule for cardiovascular diseases, since it is the target of oral anticoagulant drugs and plays a role in soft tissue calcification. The objective of this study was to determine the influence of miRNAs on the expression of VKORC1.

Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy.

VKORC1 and CYP2C9 polymorphisms are used to predict the safe dose of oral anticoagulant therapy. A new variant of CYP4F2 (V433M) has recently been related to the required warfarin dose. We evaluated its influence in earliest response to acenocoumarol in 100 selected men who started anticoagulation (3 mg for 3 consecutive days).