Thrombosis Cascade Research Articles

ACUTE DIGITAL GANGRENE TRIGGERED BY COVID-19 COAGULOPATHY

ACUTE DIGITAL GANGRENE TRIGGERED BY COVID-19 COAGULOPATHY

Stent malapposition generates stent thrombosis: Insights from a thrombosis model

BackgroundCurrently, there exists differing conclusions on the role of acute stent malapposition and its role in stent thrombosis (ST). The European Association of Percutaneous Cardiovascular Interventions (EAPCI) consensus recommends that acute malapposition <0.4 mm with longitudinal extension <1 mm need not be corrected since there is no clear correlation of malapposition with adverse clinical outcomes. However, malapposition was identified as the main mechanism of ST in the Bern and PESTO registries, and one of the three leading mechanism in the PRESTIGE study. MethodsIn this study, a validated perfused benchtop thrombosis model was deployed to evaluate the role of both stent under-expansion (UE) and acute stent malapposition (MA) on thrombus formation in vitro in a controlled reproducible environment. ResultsThe results showed that UE alone did not result in acute thrombus formation, but UE together with MA did. The data suggested that a MA distance of 0.25 mm led to significant thrombus formation; and a positive correlation exists between the longitudinal extension of the MA and the thrombus volume formed. ConclusionExperiments in this in vitro model demonstrated that platelets and a thrombosis cascade were activated and developed around large segments of malapposed stent. This was significantly more thrombus formation than in the under-expanded stent region.

Optimization of sulfonated polyethyleneimine zwitterionic coating mediated by polydopamine for poly(vinyl chloride) antifouling

AbstractAlthough poly(vinyl chloride) (PVC) has been widely used as blood‐contacting materials in extracorporeal circuits and indwelling medical devices, its hydrophobicity also is a limitation due to the adsorption of plasma proteins and the immediately followed thrombosis cascade and bacterial infections. Herein, we developed a mild and simple strategy for improving the hydrophilicity and antifouling properties of the surface via mussel‐inspired chemistry. Different amounts of 1,3‐Propanesultone (1,3‐PS) were attached onto the polyethyleneimine (PEI), so as to modify it into the zwitterion, called PESX. Two layer‐by‐layer approaches about PESX grafting on PVC substrates were designed. One strategy was by coating PESX after coating polydopamine (PDA) on PVC surface, obtaining PDA‐PESX coatings. The other was by grafting PESX after co‐deposition treatment of PDA and PESX with appropriate feeding ratio on PVC, obtaining PDA/PESX‐PESX coatings. The study results indicated that the PDA/PES0.5‐PES0.5 coatings with optimized PEI molecular weight and sulfonation degree, presented about 2.5–3 times reduction in BSA adsorption (0.77 μg/cm2) compared with PDA/PES0.5 (1.93 μg/cm2) and PDA‐PES0.5 (2.26 μg/cm2), and kept long time antifouling stability. Moreover, the more excellent antifouling performance of PDA/PES0.5‐PES0.5 was also seen on fibrinogen (Fg), γ‐globulin (γ‐GL), and the mixture of these proteins. Meanwhile, PDA/PES0.5‐PES0.5 could prevent the adhesion of blood components and bacteria on the surface as well as maintain excellent hemocompatibility and cytocompatibility. We had hopes that our simple and mild strategy will find practical application in surface engineering of clinical use in blood‐contacting medical devices.

Functional Layer-by-Layer Thin Films of Inducible Nitric Oxide (NO) Synthase Oxygenase and Polyethylenimine: Modulation of Enzyme Loading and NO-Release Activity.

Nitric oxide (NO) release counteracts platelet aggregation and prevents the thrombosis cascade in the inner walls of blood vessels. NO-release coatings also prevent thrombus formation on the surface of blood-contacting medical devices. Our previous work has shown that inducible nitric oxide synthase (iNOS) films release NO fluxes upon enzymatic conversion of the substrate l-arginine. In this work, we report on the modulation of enzyme loading in layer-by-layer (LbL) thin films of inducible nitric oxide synthase oxygenase (iNOSoxy) on polyethylenimine (PEI). The layer of iNOSoxy is electrostatically adsorbed onto the PEI layer. The pH of the iNOSoxy solution affects the amount of enzyme adsorbed. The overall negative surface charge of iNOSoxy in solution depends on the pH and hence determines the density of adsorbed protein on the positively charged PEI layer. We used buffered iNOSoxy solutions adjusted to pHs 8.6 and 7.0, while saline PEI solution was used at pH 7.0. Atomic force microscopy imaging of the outermost layer shows higher protein adsorption with iNOSoxy at pH 8.6 than with a solution of iNOSoxy at pH 7.0. Graphite electrodes with PEI/iNOSoxy films show higher catalytic currents for nitric oxide reduction mediated by iNOSoxy. The higher enzyme loading translates into higher NO flux when the enzyme-modified surface is exposed to a solution containing the substrate and a source of electrons. Spectrophotometric assays showed higher NO fluxes with iNOSoxy/PEI films built at pH 8.6 than with films built at pH 7.0. Fourier transform infrared analysis of iNOSoxy adsorbed on PEI at pH 8.6 and 7.0 shows structural differences of iNOSoxy in films, which explains the observed changes in enzymatic activity. Our findings show that pH provides a strategy to optimize the NOS loading and enzyme activity in NOS-based LbL thin films, which enables improved NO release with minimum layers of PEI/NOS.

Enzyme-Based Nitric Oxide (NO) Releasing Surfaces: Nitric Oxide Synthase As a Source of Catalytic NO Release in Polymeric Films and in Electrospun Fibers

Nitric oxide (NO) is a key player at multiple physiologic fronts including the body’s immune response, neurotransmission, and cardiovascular processes. Among other effect on the cardiovascular system, NO is known to counteract platelet aggregation, and therefore has the ability to prevent the thrombosis cascade on the surface of blood-contacting medical implants and vascular grafts. Capitalizing on this property, NO-releasing surfaces have been proposed to counteract thrombosis on the surface of implanted devices or devices used as part of cardiovascular procedures. However, previous proposals using organic or inorganic sources of NO face the challenge that the amount of available NO is finite, which limits the long-term viability of implanted devices. We proposed the use of NOS enzymes, in alternating layer-by-layer thin film architecture, as the catalytic source of NO released using substrates of the NOS reaction in blood or plasma. We will summarize the performance of thin based on polyethyleneimine (PEI) including the effect of fabrication conditions on enzyme and loading and enzyme activity and subsequent effect on counteracting platelet adhesion from platelet-rich plasma. We will also describe and characterize membranes of electrospun fibers embedding nitric oxide synthase as a catalytic source of NO release. The NO-releasing membrane is to be used as a biocompatible platform for medical applications such as support-scaffolds for internal wounds. We will describe the process of formation of these NOS-based NO-releasing fibers. We will discuss the characterization of such material with methods including atomic force microscopy and enzymatic activity assay of encapsulated enzyme by monitoring levels of NO released over time. We will compare and contrast the results of PEI-based thin films with embedded NOS enzyme and electrospun fibers with encapsulated NOS.

Depression in vascular pathologies: the neurologist's point of view

The coexistence of depression and cardiovascular disease (CVD) is regularly discussed, and much debated. There is strong evidence that there are pathophysiological mechanisms, particularly endothelial dysfunction, altered platelet aggregation, and hyperactivation of the thrombosis cascade, which coexist with hypothalamic-pituitary-adrenocortical axis dysfunction, and link depression to CVD. Therefore, depression should not be automatically considered to be a consequence of life impairment due to myocardial infarction or major stroke. Probably, it should be considered as one of the many other stressful events, or “genetic reactions to life”, which are risk factors for CVD development. This review will examine the significance of depression in clinical daily practice, its pathophysiology as a determinant in vascular events, and its real importance in, before, and after many CVD events.

The Heparin Rebound Phenomenon-Does It Offer Insights Toward Understanding the Pathobiology of Coronary Thrombosis and Its Treatment?

The heparin rebound phenomenon is a poorly characterized event occurring in patients treated with heparin. The pathobiology appears to be thrombin related; however, a primary platelet abnormality or a combination of coagulation and platelet-mediated events must also be considered. It seems likely that the initial event, in most instances plaque rupture and intracoronary thrombosis, is involved directly by establishing a procoagulant environment. The available evidence suggests further that thrombin and platelet activity are increased in most patients both locally and systemically despite heparin administration (Table 1). Several major questions remain unanswered: 1. Is heparin rebound truly a “rebound” phenomenon or is a recrudescence of procoagulant substrate following a relatively brief period of incomplete anticoagulation a more accurate description? 2. Does treatment aimed at thrombin, a near final step in the coagulation process, allow or foster a buildup of procoagulant substrate more proximally positioned in the cascade of thrombosis? 3. Do the level of anticoagulation, consistency, duration, and/or route of administration influence procoagulant events following the discontinuation of heparin? 4. Are platelets involved primarily or secondarily?