Tetherin/BST2, a physiologically and therapeutically relevant regulator of platelet receptor signalling.

The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells.

Pharmacodynamic Comparison of Ticagrelor Monotherapy Versus Ticagrelor and Aspirin in Patients After Percutaneous Coronary Intervention: The TEMPLATE (Ticagrelor Monotherapy and Platelet Reactivity) Randomized Controlled Trial.

Background To assess differences in platelet inhibition during ticagrelor monotherapy (TIC) or dual therapy with ticagrelor and aspirin (TIC+ASP) in patients after percutaneous coronary intervention using a comprehensive panel of functional tests. Methods and Results In a single-center parallel group, open label, randomized controlled trial, 110 participants were randomized to receive either TIC (n=55) or TIC+ASP (n=55) for 4 weeks. The primary outcome was the platelet aggregation response with 10 μmol/L thrombin receptor activation peptide-6 (TRAP-6).

TEG PlateletMapping assay results may be misleading in the presence of cold stored platelets.

Background: Viscoelastic tests (VETs) are used widely to monitor hemostasis in settings such as cardiac surgery. There has also been renewed interest in cold stored platelets (CSPs) to manage bleeding in this setting. CSPs are reported to have altered hemostatic properties compared to room temperature platelets (RTPs), including activation of GPIIb/IIIa.

Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia.

We report rare monoallelic variants of that alter intracellular trafficking and diminish thrombopoietin secretion. Affected cases have autosomal-dominant thrombocytopenia but no other hematological features.

Carbonic Anhydrase Inhibitors suppress platelet procoagulant responses and in vivo thrombosis.

Carbonic anhydrase (CA) inhibitors have a long history of safe clinical use as mild diuretics, in the treatment of glaucoma and for altitude sickness prevention. In this study, we aimed to determine if CA inhibition may be an alternative approach to control thrombosis. We utilized a high-resolution dynamic imaging approach to provide mechanistic evidence that CA inhibitors may be potent anti-procoagulant agents and effective anti-thrombotics .

Differential effects of direct factor IIa and factor Xa inhibitors in protein C-deficient plasma detected using thrombin generation and viscoelastometry assays.

Introduction: Protein C (PC) deficiency results in dysregulated thrombin generation and increases thrombosis risk.

Methods: In order to investigate the potential effects of anticoagulant drugs in PC deficiency, we evaluated the pharmacodynamic effect of selective direct factor (F) IIa inhibitors (dabigatran and argatroban), selective direct FXa inhibitors (rivaroxaban and apixaban) and an indirect FXa/FIIa inhibitor (enoxaparin) in commercial PC-deficient plasma using thrombin generation and viscoelastometry assays modified to reflect PC anticoagulant activity.

Results: Endogenous thrombin potential (ETP) and peak thrombin concentration (PTC) were increased in PC-deficient plasma but this corrected completely with PC concentrate.

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y receptor.

Genetic variations in G protein-coupled receptor (GPCR) genes can disrupt receptor function in a wide variety of human genetic diseases, including platelet bleeding disorders. Platelets are critical for haemostasis with inappropriate platelet activation leading to the development of arterial thrombosis, which can result in heart attack and stroke whilst decreased platelet activity is associated with an increased risk of bleeding. GPCRs expressed on the surface of platelets play key roles in regulating platelet activity and therefore function.

Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor.

Ticagrelor is a potent antagonist of the P2Y receptor (P2YR) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterize its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of adenosine 5'-diphosphate (ADP)-induced Ca release in washed platelets vs other P2YR antagonists.