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.

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.

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.

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.

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.

C-X-C Ligand 16 Is an Independent Predictor of Cardiovascular Death and Morbidity in Acute Coronary Syndromes.

OBJECTIVE: The chemokine CXCL16 (C-X-C motif ligand 16) is a scavenger receptor for OxLDL (oxidized low-density lipoproteins) and involved in inflammation at sites of atherosclerosis. This study aimed to investigate the association of CXCL16 with clinical outcome in patients with acute coronary syndrome. Approach and Results: Serial measurements of CXCL16 were performed in a subgroup of 5142 patients randomized in the PLATO trial (Platelet Inhibition and Patient Outcome). Associations between CXCL16 and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and the individual components were assessed by multivariable Cox regression analyses. The hazard ratio per 50% increase in admission levels of CXCL16 analyzed as continuous variable was 1.64 (95% CI, 1.44-1.88), P<0.0001. This association remained statistically significant after adjustment for randomized treatment, clinical variables, CRP (C-reactive protein), leukocytes, cystatin C, NT-proBNP (N-terminal pro-brain natriuretic peptide), troponin T, GDF-15 (growth differentiation factor 15), and other biomarkers; hazard ratio 1.23 (1.05-1.45), P=0.0126. The admission level of CXCL16 was independently associated with cardiovascular death (1.50 [1.17-1.92], P=0.0014) but not with ischemic events alone, in fully adjusted analyses. No statistically independent association was found between CXCL16 measured at 1 month, or change in CXCL16 from admission to 1 month, and clinical outcomes. CONCLUSIONS: In patients with acute coronary syndrome, admission level of CXCL16 is independently related to adverse clinical outcomes, mainly driven by an association to cardiovascular death. Thus, CXCL16 measurement may enhance risk stratification in patients with this condition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Admission Levels of DKK1 (Dickkopf-1) Are Associated With Future Cardiovascular Death in Patients With Acute Coronary Syndromes.

Objective- The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes. Approach and Results- We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20-1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02-1.10), P=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00-1.09]; P=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04-1.17]; P=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis. Conclusions- In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.

Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels.

Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. To overcome these limitations, we developed a novel anti-vWF aptamer, called DTRI-031, that selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. Finally, DTRI-031 activity is rapidly (<5 min) and completely reversed by AO administration in a murine saphenous vein hemorrhage model, and murine toxicology studies indicate the aptamer is well tolerated. These findings suggest that targeting vWF with an antidote-controllable aptamer potentially represents an effective and safer treatment for thrombosis patients having platelet-rich arterial occlusions in the brain, heart, or periphery.

COVID-19-associated vasculitis and vasculopathy.

The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.

Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common cardiac condition caused primarily by sarcomeric protein mutations with several distinct phenotypes, ranging from asymmetric septal hypertrophy, either with or without left ventricular outflow tract obstruction, to moderate left ventricular dilation with or without apical aneurysm formation and marked, end-stage dilation with refractory heart failure. Sudden cardiac death can occur at any stage. The phenotypic variability observed in HCM is the end-result of many factors, including pre-load, after-load, wall stress and myocardial ischemia stemming from microvascular dysfunction and thrombosis; however, tissue level inflammation to include leukocyte-derived extracellular traps consisting of chromatin and histones, apoptosis, proliferation of matrix proteins and impaired or dysfunctional regulatory pathways contribute as well. Our current understanding of the pathobiology, developmental stages, transition from hypertrophy to dilation and natural history of HCM with emphasis on the role of tissue-level inflammation in myocardial fibrosis and ventricular remodeling is summarized.

Bridging Anticoagulation with Mechanical Heart Valves: Current Guidelines and Clinical Decisions.

PURPOSE OF REVIEW: The management of patients with mechanical heart valves who require surgery or invasive procedures is a common clinical scenario in contemporary practice. The risk of thromboembolism versus the risk of bleeding is the foundation of optimal patient care. RECENT FINDINGS: Randomized, controlled trials are not available; yet, there is a wealth of experience to guide best practice. Current guidelines represent a compilation of data from trials of atrial fibrillation and expert opinion. Results from the PERI-OP trial of patients with either a mechanical heart valve, atrial fibrillation, or atrial flutter requiring interruption of oral anticoagulant therapy for surgery will inform clinical practice. Patient-specific factors and valve-specific factors are paramount when deciding whether a period of anticoagulant therapy interruption is safe. Similarly, the safety and efficacy of bridging anticoagulant therapy and the optimal time after surgery for restarting oral anticoagulants is vital to optimal patient care.