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Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

ABSTRACT: Hypofibrinolysis is a recently-recognized risk factor for recurrent cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI), but the mechanistic determinants of this are not well understood. In patients with STEMI, we show that the effectiveness of endogenous fibrinolysis in whole blood is determined in part by fibrinogen level, high sensitivity C-reactive protein, and shear-induced platelet reactivity, the latter directly related to the speed of thrombin generation. Our findings strengthen the evidence for the role of cellular components and bidirectional crosstalk between coagulatory and inflammatory pathways as determinants of hypofibrinolysis.

SUBMITTER: Kanji R

PROVIDER: S-EPMC9849272 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

Kanji Rahim R Gue Ying X YX Farag Mohamed F MF Spencer Neil H NH Mutch Nicola J NJ Gorog Diana A DA

JACC. Basic to translational science 20220824 11

Hypofibrinolysis is a recently-recognized risk factor for recurrent cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI), but the mechanistic determinants of this are not well understood. In patients with STEMI, we show that the effectiveness of endogenous fibrinolysis in whole blood is determined in part by fibrinogen level, high sensitivity C-reactive protein, and shear-induced platelet reactivity, the latter directly related to the speed of thrombin genera ...[more]

PMID: 36687271

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Project description:This study sought to assess whether plasminogen, which is homologous to lipoprotein (a) [Lp(a)], contains proinflammatory oxidized phospholipids (OxPL) and whether this has clinical relevance.OxPL measured on apolipoprotein B-100 (OxPL/apoB), primarily reflecting OxPL on Lp(a), independently predict cardiovascular disease (CVD) events.The authors examined plasminogen from commercially available preparations and plasma from chimpanzees; gorillas; bonobos; cynomolgus monkeys; wild-type, apoE(-/-), LDLR(-/-), and Lp(a)-transgenic mice; healthy humans; and patients with familial hypercholesterolemia, stable CVD, and acute myocardial infarction (AMI). Phosphocholine (PC)-containing OxPL (OxPC) present on plasminogen were detected directly with liquid chromatography-mass spectrometry (LC-MS/MS) and immunologically with monoclonal antibody E06. In vitro clot lysis assays were performed to assess the effect of the OxPL on plasminogen on fibrinolysis.LC-MS/MS revealed that OxPC fragments were covalently bound to mouse plasminogen. Immunoblot, immunoprecipitation, density gradient ultracentrifugation, and enzyme-linked immunosorbent assay analyses demonstrated that all human and animal plasma samples tested contained OxPL covalently bound to plasminogen. In plasma samples subjected to density gradient fractionation, OxPL were present on plasminogen (OxPL/plasminogen) in non-lipoprotein fractions but on Lp(a) in lipoprotein fractions. Plasma levels of OxPL/apoB and OxPL/apo(a) varied significantly (>25×) among subjects and also strongly correlated with Lp(a) levels. In contrast, OxPL/plasminogen levels were distributed across a relatively narrow range and did not correlate with Lp(a). Enzymatic removal of OxPL from plasminogen resulted in a longer lysis time for fibrin clots (16.25 vs. 11.96 min, p = 0.007). In serial measurements over 7 months, OxPL/plasminogen levels did not vary in normal subjects or in patients with stable CVD, but increased acutely over the first month and then slowly decreased to baseline in patients following AMI.These data demonstrate that plasminogen contains covalently bound OxPL that influence fibrinolysis. OxPL/plasminogen represent a second major plasma pool of OxPL, in addition to those present on Lp(a). OxPL present on plasminogen may have pathophysiological implications in AMI and atherothrombosis.

Project description:AimsThere are limited contemporary data on the use of initial fibrinolysis in ST-segment elevation myocardial infarction cardiogenic shock (STEMI-CS). This study sought to compare the outcomes of STEMI-CS receiving initial fibrinolysis vs. primary percutaneous coronary intervention (PPCI).MethodsUsing the National (Nationwide) Inpatient Sample from 2009 to 2017, a comparative effectiveness study of adult (>18 years) STEMI-CS admissions receiving pre-hospital/in-hospital fibrinolysis were compared with those receiving PPCI. Admissions with alternate indications for fibrinolysis and STEMI-CS managed medically or with surgical revascularization (without fibrinolysis) were excluded. Outcomes of interest included in-hospital mortality, development of non-cardiac organ failure, complications, hospital length of stay, hospitalization costs, use of palliative care, and do-not-resuscitate status.ResultsDuring 2009-2017, 5297 and 110 452 admissions received initial fibrinolysis and PPCI, respectively. Compared with those receiving PPCI, the fibrinolysis group was more often non-White, with lower co-morbidity, and admitted on weekends and to small rural hospitals (all P < 0.001). In the fibrinolysis group, 95.3%, 77.4%, and 15.7% received angiography, PCI, and coronary artery bypass grafting, respectively. The fibrinolysis group had higher rates of haemorrhagic complications (13.5% vs. 9.9%; P < 0.001). The fibrinolysis group had comparable all-cause in-hospital mortality [logistic regression analysis: 28.8% vs. 28.5%; propensity-matched analysis: 30.8% vs. 30.3%; adjusted odds ratio 0.97 (95% confidence interval 0.90-1.05); P = 0.50]. The fibrinolysis group had comparable rates of acute organ failure, hospital length of stay, rates of palliative care referrals, do-not-resuscitate status use, and lesser hospitalization costs.ConclusionsThe use of initial fibrinolysis had comparable in-hospital mortality than those receiving PPCI in STEMI-CS in the contemporary era in this large national observational study.

Project description:BackgroundAortic valve sclerosis (AVSc) presents similar pathogenetic mechanisms to coronary artery disease and is associated with short- and long-term mortality in patients with coronary artery disease. Evidence of AVSc-specific pathophysiological traits in acute myocardial infarction (AMI) is currently lacking. Thus, we aimed to identify a blood-based transcriptional signature that could differentiate AVSc from no-AVSc patients during AMI.MethodsWhole-blood transcriptome of AVSc (n=44) and no-AVSc (n=66) patients with AMI was assessed by RNA sequencing on hospital admission. Feature selection, differential expression, and enrichment analyses were performed to identify gene expression patterns discriminating AVSc from no-AVSc and infer functional associations. Multivariable Cox regression analysis was used to estimate the hazard ratios of cardiovascular events in AVSc versus no-AVSc patients.ResultsThis cross-sectional study identified a panel of 100 informative genes capable of distinguishing AVSc from no-AVSc patients with 94% accuracy. Further analysis revealed significant mean differences in 143 genes, of which 30 genes withstood correction for age and previous AMI or coronary interventions. Functional inference unveiled a significant association between AVSc and key biological processes, including acute inflammatory responses, type I IFN (interferon) response, platelet activation, and hemostasis. Notably, patients with AMI with AVSc exhibited a significantly higher incidence of adverse cardiovascular events during a 10-year follow-up period, with a full adjusted hazard ratio of 2.4 (95% CI, 1.3-4.5).ConclusionsOur findings shed light on the molecular mechanisms underlying AVSc and provide potential prognostic insights for patients with AMI with AVSc. During AMI, patients with AVSc showed increased type I IFN (interferon) response and earlier adverse cardiovascular outcomes. Novel pharmacological therapies aiming at limiting type I IFN response during or immediately after AMI might improve poor cardiovascular outcomes of patients with AMI with AVSc.

Dataset Information

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

Publications

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

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