Rationale:: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. Objective:: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. Methods and Results:: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. Conclusions:: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.

Objective—: Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results—: Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions—: In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.

Background: Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. Methods and Results: We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension ( CTEPH ), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte–platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine‐enriched phospholipids specifically inhibited endothelial proliferation and sprouting. Conclusions: After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in CTEPH .

Background: Recent evidence suggested levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and AST/ALT ratio (De-Ritis ratio) were associated with a worse outcome after acute myocardial infarction (AMI). However, their value for predicting long-term prognosis remained unknown. Therefore, we investigated the prognostic potential of transaminases on patient outcome after AMI from a long-term perspective. Methods: Data of a large AMI registry including 1355 consecutive patients were analyzed. The Cox regression hazard analysis was used to assess the impact of transaminases and the De-Ritis ratio on long-term mortality. Results: The median De-Ritis ratio for the entire study population was 1.5 (interquartile range [IQR]: 1.0–2.6). After a median follow-up time of 8.6 years, we found that AST (crude hazard ratio (HR) of 1.19 per 1-SD [95% confidence interval (CI): 1 .09–1.32; p < 0.001]) and De-Ritis ratio (crude HR of 1.31 per 1-SD [95% CI: 1.18–1.44; p < 0.001]), but not ALT (p = 0.827), were significantly associated with long-term mortality after AMI. After adjustment for confounders independently, the De-Ritis ratio remained a strong and independent predictor for long-term mortality in the multivariate model with an adjusted HR of 1.23 per 1-SD (95% CI: 1.07–1.42; p = 0.004). Moreover, the De-Ritis ratio added prognostic value beyond N-terminal pro-B-Type Natriuretic Peptide, Troponin T, and Creatine Kinase. Conclusion: The De-Ritis ratio is a strong and independent predictor for long-term mortality after AMI. As a readily available biomarker in clinical routine, it might be used to identify patients at risk for fatal cardiovascular events and help to optimize secondary prevention strategies after AMI.

To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients. A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees. In total, 176 MPM patients (mean age: 63.5 years±10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (390 mg dl⁻¹) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (627 mg dl⁻¹) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5–23.7 months) when compared with those with high level (OS 8.5; CI 6.2–10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23–2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl⁻¹) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS). Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.