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Abstract-ADP plays a key role in hemostasis and thrombosis. Despite its early identification in 1961 as the first known aggregating agent, the molecular basis of ADP-induced platelet activation is only beginning to be understood. The present review proposes a model of 3 purinergic receptors contributing separately to the complex process of ADP-induced platelet aggregation: the P2X 1 ionotropic receptor, responsible for rapid influx of ionized calcium into the cytosol; the P2Y 1 metabotropic receptor, responsible for mobilization of ionized calcium from internal stores, which initiates aggregation; and an as-yet-unidentified P2Y receptor coupled to G ␣i2 , which is essential for the full aggregation response to ADP. It is probable that this as-yet-unidentified receptor is the molecular target of the ADP-selective antiaggregating drugs ticlopidine and clopidogrel. In addition, it is probably defective in patients with a bleeding diathesis that is characterized by selective impairment of platelet responses to ADP. Key Words: adenosine diphosphate Ⅲ purino receptors Ⅲ platelets Ⅲ bleeding disorders Ⅲ thrombosis A DP, the first known low-molecular-weight, plateletaggregating agent, was initially identified after observations that a small molecule derived from red blood cells stimulated platelet adhesion to glass and induced platelet aggregation. 1,2 Adenine nucleotides, which originate from platelet dense granules and damaged cells, especially red blood cells and endothelial cells, interact with P2 receptors to regulate a broad range of physiological processes. P2 receptors are widely distributed in many different cell types. These receptors are divided into 2 main groups: the G proteincoupled, or "metabotropic," superfamily termed P2Y and the ligand-gated ion channel, or "ionotropic," superfamily termed P2X. 3 Seven subtypes of P2X and 11 subtypes of P2Y receptor have been identified to date.Several lines of evidence indicate that ADP plays a key role in the formation of the hemostatic plug and in the pathogenesis of arterial thrombi: (1) ADP is contained at high concentrations in the platelet dense granules and is released when platelets are stimulated by other agents, such as thrombin or collagen, thus reinforcing platelet aggregation 4 ; (2) inhibitors of ADP-induced platelet aggregation are effective antithrombotic drugs 5,6 ; and (3) patients with defects of ADP receptors or those lacking ADP in platelet granules have a bleeding diathesis. 4,7 ADP-Induced Platelet ActivationAddition of exogenous ADP to washed human platelets results in shape change, reversible aggregation at physiological concentrations of ionized calcium in the external medium, and finally, desensitization. In a minority of individuals, the close platelet-to-platelet contact brought about by the aggregation process triggers the formation of trace amounts of thromboxane A 2 , which stimulates platelet secretion and reinforces aggregation. 8 This effect is greatly enhanced 9 and can be observed in most individuals 8 when the concentration of ion...

Open systems of coupled qubits are ubiquitous in quantum physics. Finding a suitable master equation to describe their dynamics is therefore a crucial task that must be addressed with utmost attention. In the recent past, many efforts have been made toward the possibility of employing local master equations, which compute the interaction with the environment neglecting the direct coupling between the qubits, and for this reason may be easier to solve. Here, we provide a detailed derivation of the Markovian master equation for two coupled qubits interacting with common and separate baths, considering pure dephasing as well as dissipation. Then, we explore the differences between the local and global master equation, showing that they intrinsically depend on the way we apply the secular approximation. Our results prove that the global approach with partial secular approximation always provides the most accurate choice for the master equation when Born-Markov approximations hold, even for small inter-system coupling constants. Using different master equations we compute the stationary heat current between two separate baths, the entanglement dynamics generated by a common bath, and the emergence of spontaneous synchronization, showing the importance of the accurate choice of approach.the case for most of the applications of the two-qubit problem, we will consider memory-less reservoirs, that is to say, we will study a Markovian master equation.Our detailed derivation allows us to establish the validity of the so-called local approach for the master equation in comparison with a global one in a rather general setting. The global approach arises naturally when deriving the master equation from a microscopic model considering the full system Hamiltonian, i.e. in presence of interactions between its subsystems (here the two qubits), while the local one follows from the approximation which neglects these interactions. Recently, the problem of characterizing the range of applicability of the local rather than global master equation has received much interest [25][26][27][28][29], mostly related to the consistency of this decription in quantum thermodynamics. It is our aim to show here that an accurate application of the secular approximation in the global approach always leads to a correct Markovian master equation, independently of the value of the coupling constant between the subsystems. The deep interconnection between a correct application of the secular approximation and the local versus global issue is discussed starting from the first principles of the derivation of the master equation. Deviations from the most accurate (global partial secular) approximation are illustrated by looking at the open system dynamics as well as the steady state. Moreover, we observe how the steady state heat current, the entanglement dynamics and the presence of quantum beats or quantum synchronization vary when using distinct master equations, so as to corroborate the validity (or inaccuracy) of each approach according to physical con...

Abstract-Two unrelated patients with a congenital bleeding diathesis associated with a severe defect of the platelet ADP receptor coupled to adenylate cyclase (P2 CYC ) have been described so far. In one of them, platelet secretion was shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granule stores, thromboxane A 2 production, and ADP-induced primary wave of aggregation) have a moderate defect of P2 CYC . Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for normal platelet secretion, and PSD patients may be heterozygotes for the congenital severe defect of P2 CYC .In this study, we describe 2 new related patients with a severe defect of P2 CYC and the son of one of them, who is to be considered an obligate heterozygote for the defect. The 2 patients with the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack of inhibition of adenylate cyclase by ADP, and a deficiency of platelet-binding sites for

Platelet aggregation by ADP plays a major role in the development and extension of arterial thrombosis. The antithrombotic thienopyridine compounds ticlopidine and clopidogrel have proved useful tools to investigate the mechanisms of ADP-induced platelet activation. In essence, although clopidogrel has been shown to completely and selectively block ADP-induced platelet aggregation, G protein activation and inhibition of adenylyl cyclase, this drug does not affect shape change and Ca2+ influx. Binding studies, using the non-hydrolysable ligand [33P]2MeSADP, have shown that human platelets contain about 600 high-affinity binding sites for 2MeSADP (Kd approximately 5 nM). These sites present pharmacological characteristics of a P2T receptor. Clopidogrel treatment reduces the number of sites by 70% on rat platelets (from 1200 to 450) and leaves the residual binding sites resistant to clopidogrel. Moreover, patients with congenital impairment of ADP-induced platelet aggregation but normal shape change display very low levels of [33P]2MeSADP binding sites. The current data thus strongly suggest the presence of two ADP receptors, one responsible for shape change and rapid Ca2+ influx and the other a Gi protein-coupled receptor responsible for Ca2+ mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation.

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed. Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and Study acronym or PI Trial ID Source registry Countries Date of registration Estimated study completion date COVID-HEP NCT04345848 ClinicalTrials.gov Switzerland

The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction.

This study characterizes a congenital hemorrhagic disorder caused by a platelet function defect with the following features: (1) severely impaired platelet aggregation and fibrinogen or von Willebrand factor (vWF) binding induced by adenosine diphosphate (ADP); (2) defective aggregation, release reaction, and fibrinogen or vWF binding induced by other agonists; (3) normal aggregation and release reaction induced by high concentrations of thrombin or collagen; (4) no further inhibition by ADP scavengers of aggregation, release reaction, and fibrinogen or vWF binding, comparable with those observed for normal platelets in the presence of ADP scavengers; (5) normal membrane glycoprotein (GP) composition and normal binding of the anti-GP IIb/IIIa monoclonal antibody 10E5; (6) no acceleration by ADP of binding of the anti-GP IIb/IIIa monoclonal antibody 7E3; (7) normal platelet-fibrin clot retraction if induced by thrombin or reptilase plus epinephrine, absent if induced by reptilase plus ADP; (8) no inhibition by ADP of the prostaglandin E1-induced increase in platelet cyclic adenosine monophosphate, but normal inhibition by epinephrine; (9) defective mobilization of cytoplasmic Ca2+ by ADP; (10) normal binding of 14C-ADP to fresh platelets, but defective binding of [2–3H]-ADP to formalin- fixed platelets. This congenital platelet function defect is characterized by selective impairment of platelet responses to ADP, caused by either decreased number of platelet ADP receptors or abnormalities of the signal-transduction pathway of platelet activation by ADP.