COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, we review the current understanding of the pathogenesis, epidemiology, management and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, and of those with preexisting thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155446/1/Bikdeli-2020-COVID-19 and Thrombotic or Thromb.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155446/3/DeepBluepermissions_agreement-CCBYandCCBY-NC_ORCID_Barnes.docxhttps://deepblue.lib.umich.edu/bitstream/2027.42/155446/4/license_rdf.rdfDescription of Bikdeli-2020-COVID-19 and Thrombotic or Thromb.pdf : ArticleDescription of DeepBluepermissions_agreement-CCBYandCCBY-NC_ORCID_Barnes.docx : Deep Blue sharing agreemen

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality among Patients with COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 � 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 �103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7) were included in the primary analysis (median interquartile range age, 62 50-71 years; 237 42.2% women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% 95% CI,-6.6% to 9.8%; odds ratio, 1.06 95% CI, 0.76-1.48; P =.70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% 1-sided 97.5% CI,-� to 3.4%; odds ratio, 1.83 1-sided 97.5% CI, 0.00-5.93), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% 95% CI, 0.4%-3.8%; P =.01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508. © 2021 American Medical Association. All rights reserved

Tissue-Engineered Endothelial Cells Induce Sustained Vascular Healing Through Early Induction of Vascular Repair

Abstract Background Perivascular implantation of tissue-engineered endothelial cells (TEEC) after vascular injury profoundly inhibits neointimal hyperplasia. However, the time course and mechanism by which this effect occurs remain unknown. By developing genetically modified TEEC that express a “suicide gene,” we can control the time during which the TEEC could exert their effect and determine the length of time TEEC need to be present following vascular injury to exert their inhibitory effect on long-term neointimal hyperplasia. Methods Bovine aortic endothelial cells (BAE) were transfected with the human herpes simplex virus thymidine kinase (tk) gene to render them sensitive to ganciclovir (GCV). These BAE+tk were grown to confluence on Gelfoam and shown to have the same growth kinetics and biologic potency as control cells but were sensitive to GCV at low concentrations. The BAE+tk were grown on Gelfoam and placed in the perivascular space around balloon-injured rat carotid arteries. Rats randomly received BAE-tk, BAE+tk, or nothing (control) after balloon injury. GCV was administered early (days 1–7), late (days 5–11), or not at all. Results Two weeks after injury, extensive neointimal hyperplasia was observed in control animals with an intima:media (I:M) area ratio of 0.80 ± 0.19. Early administration of GCV killed the BAE in constructs with TK sensitivity and eliminated the impact of TEEC regulation of intimal hyperplasia (0.45 ± 0.06). Intimal hyperplasia was still effectively reduced in animals with implants containing BAE-tk or BAE+tk which received GCV late (0.11 ± 0.04 and 0.19 ± 0.05). Immunohistochemistry demonstrated the lethal effect of GCV on TK-sensitive cells. Conclusions The application of perivascular TEEC for only the first few days after injury had a significant inhibitory effect on intimal hyperplasia. This is in contrast to the results obtained in this same animal model with the infusion of isolated anti-smooth muscle cell proliferative agents. This suggests that the mechanism of action of TEEC may be upstream from smooth muscle cell proliferation. Moreover, the use of this technique to further elucidate biologic mechanisms will prove invaluable in the tissue engineering field. Lay Summary We report a novel, genetically altered tissue-engineered endothelial cell (TEEC) implant that inhibits neointimal hyperplasia after experimental vascular injury. The viability of these implants can be carefully controlled and suggest a putative mechanism by which TEEC recapitulate control over the vascular response to injury

Taking paclitaxel coated balloons to a higher level: Predicting coating dissolution kinetics, tissue retention and dosing dynamics

© 2019 Elsevier B.V. Paclitaxel coated balloons (PCBs) are a promising non-implantable alternative to drug-eluting stents, whereby drug is delivered to the arterial wall in solid form as a semi-continuous solid coating or as micro drug depots. To date, it has been impossible to predict or even infer local tissue dosing levels and persistence, making it difficult to compare in vivo performance of different devices in healthy animals or to extrapolate such data to diseased human arteries. Here we derive and analyze a coupled reaction diffusion model that accounts for coating dissolution and tissue distribution, and predicts the concentration of dissolved drug in the tissue during and post dissolution. Time scale analysis and numerical simulations based on estimated diffusion coefficients in healthy animal and diseased human arteries both imply that dissolution of crystalline paclitaxel coating is mass transfer coefficient-limited, and can therefore be solved for independently of the tissue transport equations. Specifically, coating retention is predicted to follow piecewise linear kinetics, reflecting the differential and faster dissolution of lumenal versus tissue-embedded coating owing to a disparity in convective forces. This prediction is consistent with published data on a range of PCBs and allowed for the estimation of the associated dissolution rate-constants and the maximal soluble drug concentration in the tissue during coating dissolution. Maximal soluble drug concentration in the tissue scales as the product of the solubility and ratio of the dissolution and diffusion rate-constants. Thus, coatings characterized by micromolar solubilities give rise to nanomolar soluble concentrations in healthy animal arteries and ~0.1 micromolar in calcified atherosclerotic arteries owing to slower tissue diffusion. During dissolution, retention in porcine iliofemoral arteries is predicted to be dominated by solid coating, whereas post dissolution it is dominated by receptor-bound drug (3.7 ng receptors/g tissue). Paclitaxel coating dissolution and dosing kinetics can now be modeled based upon accepted principles of surface dissolution and tissue transport to provide insights into the dependence of clinical efficacy on device properties and the interplay of lesion complexity and procedural parameters

Patient‐Reported Outcomes in Venous Thromboembolism: A Systematic Review of the Literature, Current Challenges, and Ways Forward

Background Venous thromboembolism (VTE) affects >1.2 million Americans annually. Although the clinical outcomes and economic burdens of VTE have been well described, the impact of VTE on patients' health status has yet to be summarized. This systematic review summarizes how patient‐reported outcome measures (PROMs) have been used in VTE to date. Methods and Results PubMed/MEDLINE was queried for literature published through March 2023 using PROMs in a population of patients with VTE. Studies were excluded if the reference was an editorial, review, or case report, or if the study included patients with conditions other than VTE. Qualitative analyses were performed. After screening and exclusion, 136 references were identified; 5 described PROM development, 20 focused on PROM validation, and 111 used PROMs in outcomes research. The most used generic PROMs were the 36‐item Short‐Form Health Survey and EuroQol 5‐dimensional questionnaire, and the most common disease‐specific PROMs were the Venous Insufficiency Epidemiological and Economic Study–Quality of Life/Symptoms and the Pulmonary Embolism Quality of Life Questionnaire. PROMs were used to quantify the changes in health status after diagnosis, characterize the trajectory of subsequent improvement, and identify drivers of continued impairments in health status like postthrombotic syndrome and postpulmonary embolism syndrome. PROMs were also used to investigate the impact of novel treatment modalities on quality of life. Conclusions This review demonstrates the many benefits of PROM use, including quantifying changes in health status with treatment, capturing patients' experiences with the treatment itself, and identifying complications of VTE. Incorporating PROMs into VTE care will be an essential component of evaluating the effectiveness of novel therapies and should lead to improved shared decision‐making for patients with VTE

Redox Changes of Cultured Endothelial Cells and Actin Dynamics

Abstract —We studied the association between the production of reactive oxygen species, actin organization, and cellular motility. We have used an endothelial cell monolayer–wounding assay to demonstrate that the cells at the margin of the wound thus created produced significantly more free radicals than did cells in distant rows. The rate of incorporation of actin monomers into filaments was fastest at the wound margin, where heightened production of free radicals was detected. We have tested the effect of decreasing reactive oxygen species production on the migration of endothelial cells and on actin polymerization. The NADPH inhibitor diphenylene iodonium and the superoxide dismutase mimetic manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) virtually abolished cytochalasin D–inhibitable actin monomer incorporation at the fast-growing barbed ends of filaments. Moreover, endothelial cell migration within the wound was significantly retarded in the presence of both diphenylene iodonium and MnTMPyP. We conclude that migration of endothelial cells in response to loss of confluence includes the intracellular production of reactive oxygen species, which contribute to the actin cytoskeleton reorganization required for the migratory behavior of endothelial cells. </jats:p