Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses

Lund, Mikael; Macwan, Ankit S.; Tunströmer, Kjersti; Lindahl, Tomas; Boknäs, Niklas

doi:10.3389/fcvm.2021.717835

Cited by 7 publications

(3 citation statements)

References 39 publications

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“…NETs have direct endothelial cell death induction and cytotoxicity mediated by histone and MPO. Under inflammatory conditions, NETs trigger the production of O 2and NO, increase the formation of peroxynitrite (ONOO -) [21] , induce increased mitochondrial outer membrane permeability, and efflux various pro-apoptotic signaling molecules. Peroxynitrite can also induce DNA damage and then activate the DNA repair enzyme PARP-1.…”

Section: Apoptosis Leads To Increased Permeabilitymentioning

confidence: 99%

Research progress of NETs-mediated endothelial cell dysfunction in sepsis

2023

MEDSC

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Neutrophil extracellular traps (NETs), a network of DNA, histone, myeloperoxidase, and other particles released by activated neutrophils, can effectively capture circulating pathogens. Inappropriate neutrophil activation and NETs release in sepsis induce endothelial cells to turn to an inflammatory cascade, degrade the glycocalyx on the surface of endothelial cells, and increase endothelial cell permeability, leading to microcirculation disorders, tissue hypoperfusion and life-threatening organ dysfunction in the later stages of sepsis. This article summarizes the formation of NETs and elaborates the mechanism of nets-mediated endothelial cell dysfunction in sepsis, so as to provide a new direction for targeted therapy of sepsis.

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Section: Apoptosis Leads To Increased Permeabilitymentioning

confidence: 99%

Research progress of NETs-mediated endothelial cell dysfunction in sepsis

2023

MEDSC

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“…Previously, heparin and bivalirudin were successfully used as inhibitors of thrombin. [ 3 ] The major role of heparin is to activate antithrombin to stop the clotting process. [ 4 ] Bivalirudin was latterly reported as an alternative drug for anticoagulation therapy by directly inhibiting thrombin.…”

Section: Introductionmentioning

confidence: 99%

Discovering peptide inhibitors of thrombin as a strategy for anticoagulation

Zhen,

Wang,

et al. 2024

Medicine

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Unusual blood clots can cause serious health problems, such as lung embolism, stroke, and heart attack. Inhibiting thrombin activity was adopted as an effective strategy for preventing blood clots. In this study, we explored computational-based method for designing peptide inhibitors of human thrombin therapeutic peptides to prevent platelet aggregation. The random peptides and their 3-dimentional structures were generated to build a virtual peptide library. The generated peptides were docked into the binding pocket of human thrombin. The designed strong binding peptides were aligned with the native binder by comparative study, and we showed the top 5 peptide binders display strong binding affinity against human thrombin. The 5 peptides were synthesized and validated their inhibitory activity. Our result showed the 5-mer peptide AEGYA, EVVNQ, and FASRW with inhibitory activity against thrombin, range from 0.53 to 4.35 μM. In vitro anti-platelet aggregation assay was carried out, suggesting the 3 peptides can inhibit the platelet aggregation induced by thrombin. This study showed computer-aided peptide inhibitor design can be a robust method for finding potential binders for thrombin, which provided solutions for anticoagulation.

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“…Bivalirudin is a direct and specific thrombin inhibitor which is successfully used for anticoagulation in patients undergoing PCI for MI. 43 In vitro data suggest that on top of mere anticoagulation, bivalirudin leads to reduced thrombin-dependent platelet PAR activation 44 and may exert an anti-inflammatory effect via a reduction of soluble CD40 ligand (sCD40L) during PCI. 45 In a mouse study, the inhibition of thrombin generation through the TF pathway ameliorated I/R by decreasing chemokine expression and leukocyte infiltration.…”

Section: Introductionmentioning

confidence: 99%

Platelets in Myocardial Ischemia/Reperfusion Injury

et al. 2022

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Coronary artery disease, including myocardial infarction (MI), remains a leading cause of global mortality. Rapid reperfusion therapy is key to the improvement of patient outcome but contributes substantially to the final cardiac damage. This phenomenon is called “ischemia/reperfusion injury (IRI).” The underlying mechanisms of IRI are complex and not fully understood. Contributing cellular and molecular mechanisms involve the formation of microthrombi, alterations in ion concentrations, pH shifts, dysregulation of osmolality, and, importantly, inflammation. Beyond their known action as drivers of the development of coronary plaques leading to MI, platelets have been identified as important mediators in myocardial IRI. Circulating platelets are activated by the IRI-provoked damages in the vascular endothelium. This leads to platelet adherence to the reperfused endothelium, aggregation, and the formation of microthrombi. Furthermore, activated platelets release vasoconstrictive substances, act via surface molecules, and enhance leukocyte infiltration into post-IR tissue, that is, via platelet–leukocyte complexes. A better understanding of platelet contributions to myocardial IRI, including their interaction with other lesion-associated cells, is necessary to develop effective treatment strategies to prevent IRI and further improve the condition of the reperfused myocardium. In this review, we briefly summarize platelet properties that modulate IRI. We also describe the beneficial impacts of antiplatelet agents as well as their mechanisms of action in IRI beyond classic effects.

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Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses

Cited by 7 publications

References 39 publications

Research progress of NETs-mediated endothelial cell dysfunction in sepsis

Research progress of NETs-mediated endothelial cell dysfunction in sepsis

Discovering peptide inhibitors of thrombin as a strategy for anticoagulation

Platelets in Myocardial Ischemia/Reperfusion Injury

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