Geometrical and Hemodynamic Variables for Thrombotic Risk Stratification in Kawasaki Disease

Objectives Thrombosis is a major adverse outcome for coronary artery aneurysms (CAA) in Kawasaki disease (KD). We investigated the geometric and hemodynamic abnormalities in patients with CAA and identified the risk factors for thrombosis by computational fluid dynamics (CFD) simulation. Methods We retrospectively studied 27 KD patients with 77 CAAs, including 20 CAAs with thrombosis in 12 patients. Patient-specific anatomic models obtained from cardiac magnetic resonance imaging (CMRI) were constructed to perform a CFD simulation. From the simulation results, we produced local hemodynamic parameters comprising of time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI) and relative resident time (RRT). The CAA’s maximum diameter (Dmax) and Z-score were measured on CMRI. Results Giant CAAs tended to present with more severe hemodynamic abnormalities. Thrombosed CAAs exhibited lower TAWSS (1.551 ± 1.535 vs. 4.235 ± 4.640dynes/cm2, p = 0.002), higher Dmax (10.905 ± 4.125 vs. 5.791 ± 2.826mm, p = 0.008), Z-score (28.301 ± 13.558 vs. 13.045 ± 8.394, p = 0.002), OSI (0.129 ± 0.132 vs. 0.046 ± 0.080, p = 0.01), and RRT (16.780 ± 11.982s vs. 9.123 ± 11.770s, p = 0.399) than the non-thrombosed group. An ROC analysis for thrombotic risk proved that all of the five parameters had area under the ROC curves (AUC) above 0.7, with Dmax delineating the highest AUC (AUCDmax = 0.871) and a 90% sensitivity, followed by Z-score (AUCZ−score = 0.849). Conclusions It is reasonable to combine the geometric index with hemodynamic information to establish a severity classification for KD cases.

Thrombotic risk determined by protein C receptor (PROCR) variants among middle-aged and older adults: a population-based cohort study

Background: The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the protein C receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives: This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequencies (MAF) < 0.1%. Results: Resequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2584 VTE exomes), 11 synonymous, 22 missense and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio of 1.5 (95%CI 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF=0.004) showed an increased VTE risk (HR=1.3; 95%CI 1.0-1.9). Conclusions: Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.

Could the PARIS Risk Scores Be Useful for the Choice of Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention?

Introduction. Current guidelines recommend dual antithrombotic therapy (DAT) for the majority of patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) and suggest a short course of triple antithrombotic therapy (TAT) for those at very high thrombotic risk (TR) but low bleeding risk (BR). Methods. We analyze if the PARIS ischemic-hemorrhagic scale could be useful for the choice of antithrombotic strategy in patients with acute coronary syndromes (ACS) and AF treated with coronary stenting enrolled in the prospective, observational, nationwide MATADOR-PCI study. Results. Among the 588 patients discharged alive, a TAT was prescribed in 381 (64.8%) and DAT in 52 (8.8%) patients. According to the PARIS scoring system, 142 (24.2%) were classified as low, 244 (41.5%) as intermediate and 292 (34.3%) as high TR. In parallel, 87 (14.8%) were categorized in the low, 260 (44.2%) in the intermediate and 241 (41.0%) in the high-risk stratum for major bleedings. Crossing the various strata of the two PARIS risk scores, the largest group of patients consisted of those at high TR and BR (n=130, 22%), followed by those at intermediate risk according to both scores (n=122, 21%). At discharge, TAT was mainly used in patients at intermediate to high BR, while DAT in those at intermediate to high TR but low BR, according to the PARIS score. Conclusion. Our data suggest that some variables associated with increased TR or BR are poorly considered in the daily practice while the use of PARIS scales could help in the implementation of guidelines' recommendations.

Identification of Thrombosis-Related Genes in Patients with Advanced Gastric Cancer: Data from AGAMENON-SEOM Registry

Advanced gastric cancer is one of the most thrombogenic neoplasms. However, genetic mechanisms underlying this complication remain obscure, and the molecular and histological heterogeneity of this neoplasm hinder the identification of thrombotic biomarkers. Therefore, our main objective was to identify genes related to thrombosis regardless of Lauren subtypes. Furthermore, in a secondary exploratory study, we seek to discover thrombosis-associated genes that were specific to each TCGA molecular subtype. We designed a nested case-control study using the cohort of the AGAMENON national advanced gastric cancer registry. Ninety-seven patients were selected—48 with and 49 without venous thromboembolism (using propensity score matching to adjust for confounding factors)—and a differential gene expression array stratified by Lauren histopathological subtypes was carried out in primary tumor samples. For the secondary objective, the aforementioned differential expression analysis was conducted for each TCGA group. Fifteen genes were determined to be associated with thrombosis with the same expression trend in both the intestinal and diffuse subtypes. In thrombotic subjects, CRELD1, KCNH8, CRYGN, MAGEB16, SAA1, ARL11, CCDC169, TRMT61A, RIPPLY3 and PLA2G6 were underexpressed (adjusted-p < 0.05), while PRKD3, MIR5683, SDCBP, EPS8 and CDC45 were overexpressed (adjusted-p < 0.05), and correlated, by logistic regression, with lower or higher thrombotic risk, respectively, in the overall cohort. In each TCGA molecular subtype, we identified a series of genes differentially expressed in thrombosis that appear to be subtype-specific. We have identified several genes associated with venous thromboembolism in advanced gastric cancer that are common to Lauren intestinal and diffuse subtypes. Should these genetic factors be validated in the future, they could be complemented with existing clinical models to bolster the ability to predict thrombotic risk in individuals with advanced gastric adenocarcinoma.

Treatment of MIS-C in Children and Adolescents

Purpose of Review Different treatment approaches have been described for the management of COVID-19-related multisystem inflammatory syndrome in children (MIS-C), the pathogenesis of which has not yet been fully elucidated. Here, we comprehensively review and summarize the recommendations and management strategies that have been published to date. Recent Findings MIS-C patients are treated with different regimens, mostly revolving around the use of immunomodulatory medications, including IVIG and glucocorticoids as first-tier therapy. Refractoriness to IVIG and glucocorticoids warrants a step-up of immunomodulatory therapy to biologic agents such as anakinra, tocilizumab, and infliximab. Summary We review the current evidence regarding the use of monotherapy versus combination therapy, as well as the current recommendations for assessing thrombotic risk and administering antiplatelet and anticoagulant therapy. We anticipate that future studies will provide evidence for management plans that maximize short- and long-term outcomes.

Endovascular Treatment of Renal Artery Thrombosis in Living-Donor Kidney Transplant Recipient With Severe COVID-19 Disease

Purpose: Coronavirus disease 2019 (COVID-19) patients have a higher prevalence of micro-and macrovascular thrombotic events. However, the underlying mechanism for the increased thrombotic risk is not completely understood. Solid organ transplant recipients infected with SARS-CoV-2 may have an exponential increase in thrombotic risk and the best management strategy is unknown. Case Report: A female kidney transplant recipient presented with allograft’s renal artery thrombosis after a recent COVID-19 infection. Due to the risk of kidney failure or exclusion, catheter directed thrombolysis was performed. Residual thrombus was excluded using an endoprosthesis with an excellent result. There were no adverse events and kidney function improved. Conclusion: This paper reports the endovascular treatment of renal artery thrombosis in a living-donor kidney transplant recipient with severe COVID-19 disease.

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Antiplatelet and Antithrombotic Therapy in Type I Diabetes Mellitus: Update on Current Data.

Diabetes mellitus type 1 (T1DM) is an autoimmune disease characterized by a markedly elevated cardiovascular (CV) risk due to premature atherosclerosis. Previous studies have shown that intense glycemic control reduces the incidence of CV disease. Antiplatelet therapy is considered to be a very important therapy for secondary prevention of recurrent atherothrombotic events in patients with DM, while it may be considered for primary prevention in individuals with T1DM with additional CV risk factors.The aim of the present review is to summarize existing literature data regarding the thrombotic risk in T1DM patients and discuss current treatment strategies.