Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

OBJECTIVES: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. METHODS: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. RESULTS: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. CONCLUSIONS: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Factor XI: structure, function and therapeutic inhibition.

Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide. Traditional anticoagulants like heparin and vitamin K antagonists (VKAs) have shown efficacy in preventing and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants (DOACs), targeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern. Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI (FXI), has attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding. Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease (ESRD), myocardial infarction, and ischemic stroke. Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints. Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlights the rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.

The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease and related conditions characterized by a heightened risk for thrombosis. Acute coronary syndrome, chronic coronary syndrome, ischemic stroke, and atrial fibrillation are the most common. In addition to their proclivity for thrombosis, each of these four conditions is also characterized by local and systemic inflammation, endothelial/endocardial injury and dysfunction, oxidative stress, impaired tissue-level reparative capabilities, and immune dysregulation that plays a critical role in linking molecular events, environmental triggers, and phenotypic expressions. Knowing that cardiovascular disease and thrombosis are complex and dynamic, can the scientific community identify a common pathway or specific point of interface susceptible to pharmacological inhibition or alteration that is likely to be safe and effective? The contact factors of coagulation may represent the proverbial "sweet spot" and are worthy of investigation. The following review provides a summary of the fundamental biochemistry of factor XI, its biological activity in thrombosis, inflammation, and angiogenesis, new targeting drugs, and a pragmatic approach to managing hemostatic requirements in clinical trials and possibly day-to-day patient care in the future.

Commentary: Value of information case study strongly supports use of the Threshold of Toxicological Concern (TTC).

A Value of Information (VOI) analysis can play a key role in decision-making for adopting new approach methodologies (NAMs). We applied EPA's recently developed VOI framework to the Threshold of Toxicological Concern (TTC). Obtaining/deriving a TTC value for use as a toxicity reference value (TRV) for substances with limited toxicity data was shown to provide equivalent or greater health protection, immense return on investment (ROI), greater net benefit, and substantially lower costs of delay (CoD) compared with TRVs derived from either traditional human health assessment (THHA) chronic toxicity testing in lab animals or the 5-day in vivo EPA Transcriptomic Assessment Product (ETAP). For all nine exposure scenarios examined, the TTC was more economical terms of CoD and ROI than the ETAP or the THHA; expected net benefit was similar for the TTC and ETAP with both of these more economical than the THHA The TTC ROI was immensely greater (5,000,000-fold on average) than the ROI for THHA and the ETAP ROI (100,000-fold on average). These results support the use of the TTC for substances within its domain of applicability to waive requiring certain in vivo tests, or at a minimum, as an initial screening step before conducting either the ETAP or THHA in vivo studies.

Evaluating chest pain in patients with post COVID conditions permission to think outside of the box.

Chest pain is among the most common symptoms of post-COVID-19 Conditions (PCC) that prompts medical attention. Because the SARS-CoV-2 virus has proclivity for many organs and organ systems in the chest, ranging from the heart, lungs, great vessels, lymphatics, and peripheral nerves, clinicians evaluating patients with chest pain must consider a broad differential diagnosis and take a comprehensive approach to management.

Best practices for exposure model peer review - A SciPinion advisory panel report.

The extent and rigor of peer review that a model undergoes during and after development influences the confidence of users and managers in model predictions. A process for determining the breadth and depth of peer review of exposure models was developed with input from a panel of exposure-modeling experts. This included consideration of the tiers and types of models (e.g., screening, deterministic, probabilistic, etc.). The experts recommended specific criteria be considered when evaluating the degree to which a model has been peer reviewed, including quality of documentation and the model peer review process (e.g., internal review with a regulatory agency by subject matter experts, expert review reports, formal Scientific Advisory Panels, and journal peer review). In addition, because the determination of the confidence level for an exposure model's predictions is related to the degree of evaluation the model has undergone, irrespective of peer review, the experts recommended the approach include judging the degree of model rigor using a set of specific criteria: (1) nature and quality of input data, (2) model verification, (3) model corroboration, and (4) model evaluation. Other key areas considered by the experts included recommendations for addressing model uncertainty and sensitivity, defining the model domain of applicability, and flags for when a model is used outside its domain of applicability. The findings of this expert engagement will help developers as well as users of exposure models have greater confidence in their application and yield greater transparency in the evaluation and peer review of exposure models.

Quantitative Structure Use Relationships: Highlights from a technical summit meeting.

The Quantitative Structure Use Relationship (QSUR) Summit, held on November 2-4, 2022, focused on advancing the development, refinement, and use of QSURs to support chemical substance prioritization and risk assessment and mitigation. QSURs utilize chemical structures to predict the function of a chemical within a formulated product or an industrial process. This presumed function can then be used to develop chemical use categories or other information necessary to refine exposure assessments. The invited expert meeting was attended by 38 scientists from Canada, Finland, France, the UK, and the USA, representing government, business, and academia, with expertise in exposure science, chemical engineering, risk assessment, formulation chemistry, and machine learning. Workshop discussions emphasized the importance of collection and sharing of data and quantification of relative chemical quantities to progress QSUR development. Participants proposed collaborative approaches to address key challenges, including mechanisms for aggregating information while still protecting proprietary product composition and other confidential business information. Discussions also led to proposals for applications beyond exposure and risk modeling, including sustainable formulation discovery. In addition, discussions continue to construct, conduct, and circulate case studies tied to various specific problem formulations in which QSURs supply or derive information on chemical functions, concentrations, and exposures.

Electronic health record-embedded decision support to reduce stroke risk in patients with atrial fibrillation - Study protocol.

BACKGROUND: Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder and is a powerful common risk factor for stroke. Randomized trials have demonstrated that anticoagulation can reduce the risk of stroke in patients with AF. Yet, there continues to be widespread underutilization of this therapy. To address this practice gap locally and improve efforts to reduce the risk of stroke for patients with AF in our health system, we have designed a study to implement and evaluate the effectiveness of an Atrial Fibrillation Decision Support Tool (AFDST) embedded within our electronic health record. METHODS: Our intervention is provider-facing and focused on decision support. The clinical setting is ambulatory patients being seen by primary care physicians. Patients include those with both incident and prevalent AF. This randomized, prospective trial will enroll 800 patients in our University of Cincinnati Health System who are currently receiving less than optimal anticoagulation therapy as determined by the AFDST. Patients will be randomized to one of two arms - 1) usual care, in which the AFDST is available for use; 2) addition of a best practice advisory (BPA) to the AFDST notifying the clinician that their patient stands to gain a significant benefit from a change in their current thromboprophylactic therapy. RESULTS: The primary outcome is effectiveness of the BPA measured by change to "appropriate thromboprophylaxis" based on the AFDST recommendation at 3 months post randomization. Secondary endpoints include Reach and Adoption, from the RE-AIM framework for implementation studies. Sample size is based upon an improvement from inappropriate to appropriate anticoagulation therapy estimated at 4% in the usual care arm and ≥10% in the experimental arm. CONCLUSION: Our goal is to examine whether addition of a BPA to an AFDST focused on primary care physicians in an ambulatory care setting will improve "appropriate thromboprophylaxis" compared with usual care. Results will be examined at 3 months post randomization and at the end of the study to evaluate durability of changes. We expect to complete patient enrollment by the end of June 2022. TRIAL REGISTRATION: Clinicaltrials.gov NCT04099485.

Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy.

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x109/L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x109/L, at 6 months vs 7.56 (2.28) x109/L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.

Rivaroxaban versus warfarin in patients with atrial fibrillation enrolled in Latin America: Insights from ROCKET AF.

BACKGROUND: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW). METHODS: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region. RESULTS: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77). CONCLUSIONS: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted.

COVID-19 and its sequelae: a platform for optimal patient care, discovery and training.

COVID-19- related patient care and research have focused on short-term outcomes, particularly among those with underlying or preexisting medical conditions. A major focus has been on mortality rates. Broadening the dialogue is neither meant nor intended to disparage the near-term devastation felt globally each day, but rather to begin preparation for optimally caring for and addressing the needs of survivors. The sequelae of COVID-19 includes acute, subacute and chronic stages of the condition. If one applies current World Health Organization (WHO) statistics to calculate the global burden of disease, there are 98,000,000 COVID-19 survivors. The following editorial focuses on post-COVID sequelae as a continuum of patient care needs, as well as discovery and training opportunities in an academic setting.

Factor Xa inhibitors: critical considerations for clinical development and testing.

The selection of factor (F) X and its activated protease FXa for targeted inhibition to prevent and treat thrombotic conditions is based on an understanding of coagulation biochemistry, sequential steps that occur on tissue factor bearing cells and the interface of coagulation proteins, platelets, mononuclear cells and the nuclear constituents of inflammatory cells. The goal for developing direct oral FXa inhibitors was to achieve rapid, selective, predictable, safe and effective anticoagulation across a broad group of patients expected to derive benefit. The history and development in patient care are exemplars of knowledge, translation and collaboration between the public and private sectors.

Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.

COVID-19 and biomarkers of thrombosis: focus on von Willebrand factor and extracellular vesicles.

COVID-19, caused by the SARS-CoV-2 virus, is responsible for a pandemic of unparalleled portion over the past century. While the acute phase of infection causes significant morbidity and mortality, post-acute sequelae that can affect essentially any organ system is rapidly taking on an equally large part of the overall impact on human health, quality of life, attempts to return to normalcy and the global economy. Herein, we summarize the potential role of von Willebrand Factor and extracellular vesicles toward understanding the pathophysiology, clinical presentation, duration of illness, diagnostic approach and management of COVID-19 and its sequelae.

Point-of-care platelet function tests: relevance to arterial thrombosis and opportunities for improvement.

Studies using whole blood platelet aggregometry as a laboratory research tool, provided important insights into the mechanism and modulators of platelet aggregation. Subsequently, a number of point-of-care (POC) platelet function tests (PFTs) were developed for clinical use, based on the concept that an individual's thrombotic profile could be assessed in vitro by assessing the response to stimulation of platelet aggregation by specific, usually solo agonists such as adenosine diphosphate (ADP), collagen and thrombin. However, adjusting antiplatelet medication in order to improve the results of such POC PFTs has not translated into a meaningful reduction in cardiovascular events, which may be attributable to important differences between the POC PFT techniques and in vivo conditions, including patient-to-patient variability. Important limitations of most tests include the use of citrate-anticoagulated blood. Citrate directly and irreversibly diminishes platelet function and even after recalcification, it may result in altered platelet aggregation in response to ADP, epinephrine or collagen, and interfere with thrombin generation from activated platelets. Furthermore, most tests do not employ flowing blood and therefore do not assess the effect of high shear forces on platelets that initiate, propagate and stabilize arterial thrombi. Finally, the effect of endogenous thrombolysis, due to fibrinolysis and dislodgement, which ultimately determines the outcome of a thrombotic stimulus, is mostly not assessed. In order to accurately reflect an individual's predisposition to arterial thrombosis, future tests of thrombotic status which overcome these limitations should be used, to improve cardiovascular risk prediction and to guide pharmacotherapy.

Evaluating management options to reduce Lake Erie algal blooms using an ensemble of watershed models.

Reducing harmful algal blooms in Lake Erie, situated between the United States and Canada, requires implementing best management practices to decrease nutrient loading from upstream sources. Bi-national water quality targets have been set for total and dissolved phosphorus loads, with the ultimate goal of reaching these targets in 9-out-of-10 years. Row crop agriculture dominates the land use in the Western Lake Erie Basin thus requiring efforts to mitigate nutrient loads from agricultural systems. To determine the types and extent of agricultural management practices needed to reach the water quality goals, we used five independently developed Soil and Water Assessment Tool models to evaluate the effects of 18 management scenarios over a 10-year period on nutrient export. Guidance from a stakeholder group was provided throughout the project, and resulted in improved data, development of realistic scenarios, and expanded outreach. Subsurface placement of phosphorus fertilizers, cover crops, riparian buffers, and wetlands were among the most effective management options. But, only in one realistic scenario did a majority (3/5) of the models predict that the total phosphorus loading target would be met in 9-out-of-10 years. Further, the dissolved phosphorus loading target was predicted to meet the 9-out-of-10-year goal by only one model and only in three scenarios. In all scenarios evaluated, the 9-out-of-10-year goal was not met based on the average of model predictions. Ensemble modeling revealed general agreement about the effects of several practices although some scenarios resulted in a wide range of uncertainty. Overall, our results demonstrate that there are multiple pathways to approach the established water quality goals, but greater adoption rates of practices than those tested here will likely be needed to attain the management targets.

Aptamers as Therapeutics.

Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.

Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.

Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN: PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY: PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin.

The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay.

Chemical risk assessment relies on toxicity tests that require significant numbers of animals, time and costs. For the >30,000 chemicals in commerce, the current scale of animal testing is insufficient to address chemical safety concerns as regulatory and product stewardship considerations evolve to require more comprehensive understanding of potential biological effects, conditions of use, and associated exposures. We demonstrate the use of a multi-level new approach methodology (NAMs) strategy for hazard- and risk-based prioritization to reduce animal testing. A Level 1/2 chemical prioritization based on estrogen receptor (ER) activity and metabolic activation using ToxCast data was used to select 112 chemicals for testing in a Level 3 human uterine cell estrogen response assay (IKA assay). The Level 3 data were coupled with quantitative in vitro to in vivo extrapolation (Q-IVIVE) to support bioactivity determination (as a surrogate for hazard) in a tissue-specific context. Assay AC50s and Q-IVIVE were used to estimate human equivalent doses (HEDs), and HEDs were compared to rodent uterotrophic assay in vivo-derived points of departure (PODs). For substances active both in vitro and in vivo, IKA assay-derived HEDs were lower or equivalent to in vivo PODs for 19/23 compounds (83%). Activity exposure relationships were calculated, and the IKA assay was as or more protective of human health than the rodent uterotrophic assay for all IKA-positive compounds. This study demonstrates the utility of biologically relevant fit-for-purpose assays and supports the use of a multi-level strategy for chemical risk assessment.

Translational Implications of Platelets as Vascular First Responders.

Platelets play a vital role in normal hemostasis to stem blood loss at sites of vascular injury by tethering and adhering to sites of injury, recruiting other platelets and blood cells to the developing clot, releasing vasoactive small molecules and proteins, and assembling and activating plasma coagulation proteins in a tightly regulated temporal and spatial manner. In synchrony with specific end products of coagulation, primarily cross-linked fibrin, a stable thrombus quickly forms. Far beyond physiological hemostasis and pathological thrombosis, emerging evidence supports platelets playing a pivotal role in vascular homeostasis, inflammation, cellular repair, regeneration, and wide range of autocrine and paracrine functions. In essence, platelets play both structural and functional roles as reporters, messengers, and active transporters surveying the vasculature for cues of environmental or developmental stimuli and participating as first responders.1 In this review, we will provide a contemporary perspective of platelet physiology, including fundamental, translational, and clinical constructs that apply directly to human health and disease.