Pharmacologic targeting of coagulation factors XII and XI by monoclonal antibodies reduces thrombosis in nitinol stents under flow.

BACKGROUND: Cardiovascular implantable devices, such as vascular stents, are critical for the treatment of cardiovascular diseases. However, their success is dependent on robust and often long-term antithrombotic therapies. Yet, the current standard-of-care therapies often pose significant bleeding risks to patients. Coagulation factor (F)XI and FXII have emerged as potentially safe and efficacious targets to safely reduce pathologic thrombin generation in medical devices. OBJECTIVES: To study the efficacy of monoclonal antibody-targeting FXII and FXI of the contact pathway in preventing vascular device-related thrombosis. METHODS: The effects of inhibition of FXII and FXI using function-blocking monoclonal antibodies were examined in a nonhuman primate model of nitinol stent-related thrombosis under arterial and venous flow conditions. RESULTS: We found that function-blocking antibodies of FXII and FXI reduced markers of stent-induced thrombosis in vitro and ex vivo. However, FXI inhibition resulted in more effective mitigation of thrombosis markers under varied flow conditions. CONCLUSION: This work provides further support for the translation of contact pathway of coagulation inhibitors for their adjunctive clinical use with cardiovascular devices.

Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia.

Background: Hyperlipidemia is associated with chronic inflammation and thromboinflammation. This is an underlying cause of several cardiovascular diseases, including atherosclerosis. In diseased blood vessels, rampant thrombin generation results in the initiation of the coagulation cascade, activation of platelets, and endothelial cell dysfunction. Coagulation factor (F) XI represents a promising therapeutic target to reduce thromboinflammation, as it is uniquely positioned at an intersection between inflammation and thrombin generation. Objectives: This study aimed to investigate the role of FXI in promoting platelet and endothelial cell activation in a model of hyperlipidemia. Methods: Nonhuman primates (NHPs) were fed a standard chow diet (lean, n = 6) or a high-fat diet (obese, n = 8) to establish a model of hyperlipidemia. Obese NHPs were intravenously administered a FXI blocking antibody (2 mg/kg) and studied at baseline and at 1, 7, 14, 21, and 28 days after drug administration. Platelet activation and inflammatory markers were measured using fluorescence-activated cell sorting or enzyme-linked immunosorbent assay. Molecular imaging was used to quantify vascular cell adhesion molecule 1 (VCAM-1) expression at the carotid bifurcation. Results: Obese NHPs demonstrated increased sensitivity for platelet P-selectin expression and phosphatidylserine exposure in response to platelet GPVI or PAR agonists compared with lean NHPs. Obese NHPs exhibited elevated levels of C-reactive protein, cathepsin D, and myeloperoxidase compared with lean NHPs. Following pharmacological inhibition of FIX activation by FXIa, platelet priming for activation by GPVI or PAR agonists, C-reactive protein levels, and endothelial VCAM-1 levels were reduced in obese NHPs. Conclusion: FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

Sintomatología Depresiva y Bienestar en Personas Mayores de Concepción, Chile: Rol moderador del apoyo social

Antecedentes: La población sobre 60 años va en aumento y es relevante tener más conocimiento sobre los factores que inciden en su bienestar y salud mental. Objetivo: Este estudio busca comprender la relación entre bienestar, apoyo social y sintomatología depresiva en personas mayores de la provincia de Concepción. Método: 538 adultos mayores fueron seleccionados aleatoriamente de 15 Centros de Salud Primaria de la provincia de Concepción, Chile. Se midieron sus niveles de bienestar (con el Pemberton Happiness Index), de apoyo Social (con la Escala Multidimensional de Percepción de Apoyo Social de Zimet) y de sintomatología depresiva (mediante el Patient Health Questionnaire-9). Resultados: Los adultos mayores mostraron un puntaje elevado (M=8,54; DE = 1,34) en bienestar, sin diferencias por sexo (t(536) = −1,065, p = 0,288 > 0,05). En los análisis de regresión lineal, el apoyo social (β =0,463, p<0,001) y la sintomatología depresiva (β =-1,585, p<0,001) aparecen como influyentes en el bienestar de las personas mayores; y el apoyo social actúa como un factor moderador (β=0,049, p=0,007, IC =0,021; 0,077) en la relación entre sintomatología depresiva y bienestar. Conclusiones: Las personas mayores muestran elevado bienestar. Los resultados refuerzan la relevancia del apoyo social como un factor protector en las personas mayores. Ello corrobora la importancia del fomento de este aspecto en los programas promocionales y preventivos destinados al bienestar y salud mental de adultos mayores.

Background: The population over 60 years of age is increasing. Aim: This research aims to understand the relationship between well-being, social support, and depressive symptoms in older Chilean people. Method: 538 older adults were randomly selected from 15 Primary Health Centers in the province of Concepción, Chile, 341 women and 197 men. Well-being was measured with the Pemberton Happiness Index, Social Support with the Zimet Multidimensional Scale of Perceived Social Support, and Depressive Symptomatology using the Patient Health Questionnaire-9. Results: Older adults showed a high mean score (M=8.54; SD=1.34) in well-being, with no differences by sex (t(536) = −1.065, p = .288 > .05.) In linear regression analyses, social support (β =0,463, p<0,001) and depressive symptomatology (β =-1,585, p<0,001) influence the well-being of the elderly, and social support acts as a moderating factor (β=0.049, p=0.007, CI =0.021; 0.077) in the relationship between social support and well-being. Conclusions: Older people show high well-being. The results reinforce the relevance of social support as a protective factor for the positive mental health of older adults. This corroborates the importance of including this aspect in promotional and preventive mental health programs for older adults.

Life satisfaction, positive affect, depression and anxiety symptoms, and their relationship with sociodemographic, psychosocial, and clinical variables in a general elderly population sample from Chile.

Background: This study aims to describe the relationship between life satisfaction, positive affect, depression and anxiety symptoms with sociodemographic, psychosocial and clinical variables, and to identify the relative importance of these predictor groups. Methods: We evaluated life satisfaction (SWLS), positive affect (PANAS), depressive (PHQ-9), and anxiety (GAI) symptoms and their association with sociodemographic, psychosocial and clinical variables in a multistage, random general population sample of fully functioning individuals aged 60-80 years from the Concepción province and Gran Santiago, Chile (n = 396). We performed weighted multiple regression analysis, considering the complex sample structure with age group, sex, and geographical area, complemented with general and conditional dominance analyses to estimate the relevance of the predictor groups. Results: We found significant associations with the geographical area, sex, age, education level, household members, having a partner, employment status, caregiver status, economic satisfaction, presence of chronic diseases, medication use, and alcohol use. Satisfaction with health was the most important predictor for positive affect (p < 0.001), depressive (p < 0.001), and anxiety (p < 0.001) symptoms, while alcohol use was the most significant predictor for life satisfaction (p < 0.001). Conclusion: Simultaneously studying the positive and negative dimensions of wellbeing and mental health in older adults allows for a more comprehensive perspective on the challenges faced during this stage of life. This study accounts for previously unknown associations and contributes to the identification of common and specific predictors in both dimensions.

How can we use proteomics to learn more about platelets?

Proteomics tools provide a powerful means to identify, detect, and quantify protein-related details in studies of platelet phenotype and function. Here, we consider how historical and recent advances in proteomics approaches have informed our understanding of platelet biology, and, how proteomics tools can be used going forward to advance studies of platelets. It is now apparent that the platelet proteome is comprised of thousands of different proteins, where specific changes in platelet protein systems can accompany alterations in platelet function in health and disease. Going forward, many challenges remain in how to best carry out, validate and interpret platelet proteomics experiments. Future studies of platelet protein post-translational modifications such as glycosylation, or studies that take advantage of single cell proteomics and top-down proteomics methods all represent areas of interest to profiling and more richly understanding platelets in human wellness and disease.

What is the context?Platelets are well known as cellular mediators of hemostasis and drivers of thrombosis and inflammation. Thousands of different proteins come together to make up the molecular structure of platelets and support their functions in health and disease.What is new?"Proteomics" refers to laboratory approaches that study many proteins simultaneously to provide details on proteomes and the biology of a given system of interest. Many different high-throughput biochemical methods can be considered as proteomics, including mass spectrometry analysis.What is the impact?Proteomics has already identified more than 5,000 individual proteins in human platelets and provided important insights into how platelets may serve as biomarkers or therapeutic targets in human health and disease. In coming years, advances in proteomics technologies will likely help to characterize additional proteins and molecular systems in platelets to shed light on platelet-mediated mechanisms of physiology and pathology that have been largely unapproachable with other methods.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup'ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis.

BACKGROUND: Obesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. OBJECTIVES: The aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. METHODS: In total, 571 Yup'ik Alaska Native adults (18-87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). RESULTS: In this Yup'ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. CONCLUSIONS: Intake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup'ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

Role of single-dose intravenous iron therapy for the treatment of anaemia after orthopaedic trauma: protocol for a pilot randomised controlled trial.

INTRODUCTION: Orthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this perioperative anaemia is an opportunity to impact outcomes in orthopaedic trauma surgery. The primary outcome of this pilot study is feasibility for a large randomised controlled trial (RCT) to evaluate intravenous iron therapy (IVIT) to improve patient well-being following orthopaedic injury. Measurements will include rate of participant enrolment, screening failure, follow-up, missing data, adverse events and protocol deviation. METHODS AND ANALYSIS: This single-centre, pilot, double-blind RCT investigates the use of IVIT for acute blood loss anaemia in traumatically injured orthopaedic patients. Patients are randomised to receive either a single dose infusion of low-molecular weight iron dextran (1000 mg) or placebo (normal saline) postoperatively during their hospital stay for trauma management. Eligible subjects include adult patients admitted for lower extremity or pelvis operative fracture care with a haemoglobin of 7-11 g/dL within 7 days postoperatively during inpatient care. Exclusion criteria include history of intolerance to intravenous iron supplementation, active haemorrhage requiring ongoing blood product resuscitation, multiple planned procedures, pre-existing haematologic disorders or chronic inflammatory states, iron overload on screening or vulnerable populations. We follow patients for 3 months to measure the effect of iron supplementation on clinical outcomes (resolution of anaemia and functional iron deficiency), patient-reported outcomes (fatigue, physical function, depression and quality of life) and translational measures of immune cell function. ETHICS AND DISSEMINATION: This study has ethics approval (Oregon Health & Science University Institutional Review Board, STUDY00022441). We will disseminate the findings through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05292001; ClinicalTrials.gov.

Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity.

Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.

The role of oral iron in the treatment of adults with iron deficiency.

Iron deficiency is the most common nutrient deficiency in the world, affecting over 20% of premenopausal women worldwide. Oral iron supplementation is often the first-line treatment for the acute and chronic management of iron deficiency due to its ease and accessibility. However, there is no consensus on the optimal formulation or dosing strategy, or which patients should be preferentially treated with intravenous iron. Management of iron deficiency is complicated by the hepcidin-ferroportin iron regulatory pathway, which has evolved to prevent iron overload and thereby creates an inherent limit on gastrointestinal iron uptake and efficacy of oral iron. Unabsorbed iron propagates many of the side effects that complicate oral iron use including dyspepsia and constipation, all of which can thus be exacerbated by excessive oral iron doses. Daily low dose and every other day dosing protocols have attempted to bypass this physiologic bottleneck to allow for effective absorption and limit side effects; however, this approach has still resulted in low fractional iron absorption. In the following manuscript, we review the pathophysiology of iron absorption and current evidence for various preparations of oral iron. Lastly, we highlight opportunities for further study to advance the care of individuals affected by iron deficiency.

Xanthohumol microbiome and signature in adults with Crohn's disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial.

BACKGROUND: Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn's disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states. METHODS: A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn's Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks. DISCUSSION: We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD. TRIAL REGISTRATION: ClinialTrials.gov NCT04590508. Registered on October 19, 2020.

The incidence, complications, and treatment of iron deficiency in pregnancy.

Iron deficiency and/or iron deficiency anemia (IDA) complicate nearly 50% of pregnancies globally, negatively impacting both maternal and fetal outcomes. Iron deficiency can cause a range of symptoms that range from aggravating to debilitating including fatigue, poor quality of life, pagophagia, and restless leg syndrome. Iron deficiency and IDA are also associated with maternal complications including preterm labor, increased rates of cesarean delivery, postpartum hemorrhage, and maternal death. Fetal complications include increased rates of low birth weight and small for gestational age newborns. Prenatal maternal anemia has also been associated with autism spectrum disorders in the neonate, although causation is not established. Deficiency in the newborn is associated with compromised memory, processing, and bonding, with some of these deficits persisting into adulthood. Despite the prevalence and consequences associated with iron deficiency in pregnancy, data show that it is routinely undertreated. Due to the physiologic changes of pregnancy, all pregnant individuals should receive oral iron supplementation. However, the bioavailability of oral iron is poor and it is often ineffective at preventing and treating iron deficiency. Likewise, it frequently causes gastrointestinal symptoms that can worsen the quality of life in pregnancy. Intravenous iron formulations administered in a single or multiple dose series are now available. There is increasing data suggesting that newer intravenous formulations are safe and effective in the second and third trimesters and should be strongly considered in pregnant individuals without optimal response to oral iron repletion.

Platelets and tyrosine kinase inhibitors: clinical features, mechanisms of action, and effects on physiology.

Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of target-directed, small molecule inhibitors used to treat hematologic malignancies, inflammatory diseases, and autoimmune disorders. Recently, TKIs have also gained interest as potential antiplatelet-directed therapeutics that could be leveraged to reduce pathologic thrombus formation and atherothrombotic complications, while minimally affecting platelet hemostatic function. This review provides a mechanistic overview and summarizes the known effects of tyrosine kinase inhibitors on platelet signaling and function, detailing prominent platelet signaling pathways downstream of the glycoprotein VI (GPVI) receptor, integrin αIIbß3, and G protein-coupled receptors (GPCRs). This review focuses on mechanistic as well as clinically relevant and emerging TKIs targeting major families of tyrosine kinases including but not limited to Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (Syk), Src family kinases (SFKs), Janus kinases (JAK), and signal transducers and activators of transcription (STAT) and evaluates their effects on platelet aggregation and adhesion, granule secretion, receptor expression and activation, and protein phosphorylation events. In summation, this review highlights current advances and knowledge on the effects of select TKIs on platelet biology and furthers insight on signaling pathways that may represent novel druggable targets coupled to specific platelet functional responses.

Ibrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression In Vitro and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion In Vivo.

Introduction: Inflammatory activation of the vascular endothelium leads to overexpression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), contributing to the pro-thrombotic state underpinning atherogenesis. While the role of TEC family kinases (TFKs) in mediating inflammatory cell and platelet activation is well defined, the role of TFKs in vascular endothelial activation remains unclear. We investigated the role of TFKs in endothelial cell activation in vitro and in a nonhuman primate model of diet-induced atherosclerosis in vivo. Methods and Results: In vitro, we found that ibrutinib blocked activation of the TFK member, BMX, by vascular endothelial growth factors (VEGF)-A in human aortic endothelial cells (HAECs). Blockade of BMX activation with ibrutinib or pharmacologically distinct BMX inhibitors eliminated the ability of VEGF-A to stimulate VCAM-1 expression in HAECs. We validated that treatment with ibrutinib inhibited TFK-mediated platelet activation and aggregation in both human and primate samples as measured using flow cytometry and light transmission aggregometry. We utilized contrast-enhanced ultrasound molecular imaging to measure platelet GPIbα and endothelial VCAM-1 expression in atherosclerosis-prone carotid arteries of obese nonhuman primates. We observed that the TFK inhibitor, ibrutinib, inhibited platelet deposition and endothelial cell activation in vivo. Conclusion: Herein we found that VEGF-A signals through BMX to induce VCAM-1 expression in endothelial cells, and that VCAM-1 expression is sensitive to ibrutinib in vitro and in atherosclerosis-prone carotid arteries in vivo. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.

Effects of ex vivo blood anticoagulation and preanalytical processing time on the proteome content of platelets.

BACKGROUND: Ex vivo assays of platelet function critically inform mechanistic and clinical hematology studies, where effects of divergent blood processing methods on platelet composition are apparent, but unspecified. OBJECTIVE: Here, we evaluate how different blood anticoagulation options and processing times affect platelet function and protein content ex vivo. METHODS: Parallel blood samples were collected from healthy human donors into sodium citrate, acid citrate dextrose, EDTA or heparin, and processed over an extended time course for functional and biochemical experiments, including platelet proteome quantification with multiplexed tandem mass tag (TMT) labeling and triple quadrupole mass spectrometry (MS). RESULTS: Each anticoagulant had time-dependent effects on platelet function in whole blood. For instance, heparin enhanced platelet agonist reactivity, platelet-monocyte aggregate formation and platelet extracellular vesicle release, while EDTA increased platelet α-granule secretion. Following platelet isolation, TMT-MS quantified 3357 proteins amongst all prepared platelet samples. Altogether, >400 proteins were differentially abundant in platelets isolated from blood processed at 24 h versus 1 h post-phlebotomy, including proteins pertinent to membrane trafficking and exocytosis. Anticoagulant-specific effects on platelet proteomes included increased complement system and decreased α-granule proteins in platelets from EDTA-anticoagulated blood. Platelets prepared from heparinized blood had higher levels of histone and neutrophil-associated proteins in a manner related to neutrophil extracellular trap (NET) formation and platelet:NET interactions in whole blood ex vivo. CONCLUSION: Our results demonstrate that different anticoagulants routinely used for blood collection have varying effects on platelets ex vivo, where methodology-associated alterations in platelet proteome may influence mechanistic, translational and biomarker studies.

Analysis of Adverse Events and Intravenous Iron Infusion Formulations in Adults With and Without Prior Infusion Reactions.

Importance: Although iron deficiency is common, it remains unclear which iron repletion strategy is associated with the lowest rate of infusion-related adverse events, and how patients with history of infusion reaction should be managed. Objective: To evaluate rates of infusion reactions among 4 commonly used intravenous iron repletion strategies and determine how readministration was managed in patients with history of reaction. Design, Setting, and Participants: This cohort study included all patients receiving intravenous iron infusion from January 1, 2015, to September 7, 2021, at 6 centers in Portland, Oregon. Participants included a total of 12 237 patients with iron deficiency, not restricted by etiology. Statistical analysis was performed from September to October 2021. Exposures: Type of intravenous iron formulation and concurrent administration of diphenhydramine, epinephrine, famotidine, and/or hydrocortisone, used as surrogate maker of infusion reaction. Main Outcomes and Measures: Incidence of adverse events, including severe events requiring epinephrine, stratified by type of iron formulation, and in patients who received premedication or with history of infusion-related reaction receiving subsequent doses. Results: Among 35 737 unique iron infusions (12 237 patients [9480 (77.5%) women; 717 (5.9%) Black; 10 250 (83.7%) White; mean (SD) age of 51 (20) years]), comprising 22 309 iron sucrose doses, 9067 iron dextran total doses (1771 preceded by test dose, 56 test doses alone), 3147 ferumoxytol doses, and 1214 ferric carboxymaltose doses, incidence of adverse events was 3.9% (n = 1389; 95% CI, 3.7%-4.1%). Rate of infusion events differed among iron formulations: 4.3% (n = 970; 95% CI, 4.1%-4.6%) iron sucrose, 3.8% (n = 345, 95% CI: 3.4%-4.2%) iron dextran (test and full doses or test dose alone), 1.8% (n = 57; 95% CI, 1.4%-2.3%) ferumoxytol, and 1.4% (n = 17, 95% CI, 0.8%-2.3%) ferric carboxymaltose (P < .001). Severe adverse events were exceedingly rare with only 2 documented epinephrine administrations, both associated with iron dextran. Incidence of adverse events among those who received premedication was 23-fold higher compared with those who did not (38.6% vs 1.7%, χ21 = 7324.8; P < .001). Among 873 patients with history of infusion reaction who underwent readministration, the majority received the same formulation, which was associated with significantly higher reaction rate particularly if premedication was administered (68% [95% CI, 64%-72%] vs 32% [95% CI, 26%-41%], respectively), compared with those who received an alternate formulation (21% [95% CI, 11%-35%] vs 5% [95% CI, 2%-12%], respectively) (P < .001). Conclusions and Relevance: These data, and the preponderance of published evidence, suggest that intravenous iron is generally well tolerated with exceedingly low risk of severe reaction, use of premedication and test doses are unnecessary, and that optimal prevention and management of infusion-related reactions warrant further study.