Fibrin to von Willebrand factor ratio in arterial thrombi is associated with plasma levels of inflammatory biomarkers and local abundance of extracellular DNA

Abstract

Introduction:The composition of thrombi determines their structure, mechanical stability, susceptibility to lysis, and consequently, the clinical outcome in coronary artery disease (CAD), acute ischemic stroke (AIS), and peripheral artery disease (PAD). Fibrin forms the primary matrix of thrombi intertwined with DNA, derived from neutrophil extracellular traps (NETs), and von Willebrand factor (VWF) bridging DNA and platelets. Here we examined the relative content of fibrin, DNA and VWF in thrombi and analyzed their interrelations and quantitative associations with systemic biomarkers of inflammation and clinical characteristics of the patients. Patients, methods: Thrombi extracted from AIS (n = 17), CAD (n = 18) or PAD (n = 19) patients were processed for scanning electron microscopy, (immune)stained for fibrin, VWF and extracellular DNA. Fibrin fiber diameter, cellular components, fibrin/DNA and fibrin/VWF ratios were measured. Results: Patients' age presented as a strong explanatory factor for a linear decline trend of the VWF content relative to fibrin in thrombi from CAD (adjusted-R 2 = 0.43) and male AIS (adjusted-R 2 = 0.66) patients. In a subgroup of CAD and PAD patients with dyslipidemia and high (above 80%) prevalence of atherothrombosis a significant correlation was observed between the VWF and DNA content in thrombi (adjusted-R 2 = 0.40), whereas a 3.7-fold lower linear regression coefficient was seen in AIS patients, in whom the fraction of thrombi of atherosclerotic origin was 57%. Independently of anatomical location, in patients with atherosclerosis the VWF in thrombi correlated with the plasma C-reactive protein levels. Conclusions: The observed interrelations between thrombus constituents and systemic inflammatory biomarkers suggest an intricate interplay along the VWF/NET/fibrin axis in arterial thrombosis.

Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis

“…Consistent with this notion, neutrophil activation and the formation of neutrophil extracellular traps (NETs) have been found to be involved in thromboinflammatory response to COVID-19 [124] , [125] , [126] . VWF interacts with NETs to provide a scaffold for platelet/leukocyte adhesion thus promoting thrombus formation and inflammation [28] , [127] , which also observed in patients with COVID-19 [24] , [128] . In addition, Ackermann et.al [89] reported an unexpected new vessel growth within lungs of COVID-19 patients through a mechanism of intussusceptive angiogenesis, and speculated that it is because of endothelialitis and thrombosis in the lungs.…”

Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path

“…The underlying mechanism proposed is that as inflammatory cells, especially neutrophils, present higher rates of oxygen consumption due to interplaque hemorrhage, they may trigger neovascularization and thus potentially increase hemorrhage [ 31 ]. Of note, interesting data from recent studies linked increased plasma NET levels in patients with stroke risk factors, such as atrial fibrillation [ 41 ], dyslipidemia [ 44 ] and essential hypertension [ 45 ].…”

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“…Investigations have revealed correlations between vWF levels and other signs of inflammation, as well as the great quantity of extracellular DNA in arterial thrombi [65]. Endotheliopathy, which is defined by high vWF antigen concentrations, has been linked to poor prognoses in COVID-19 patients, thus confirming the medical importance of vWF in ARDS and similar medical conditions [66].…”