Thrombin: Coagulation's master regulator of innate immunity

Conway, Edward M.

doi:10.1111/jth.14586

Cited by 17 publications

(10 citation statements)

References 50 publications

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“…The activation of IL-1α by thrombin is another mechanism that connects coagulation and the recruitment of leukocytes [44]. IL-1α is an essential inflammatory cytokine ubiquitously produced and maintained on the surface of eukaryotic cells as an inactive pro-protein (pro-IL-1α) [45]. By cleaving pro-IL-1α and releasing active IL-1α, thrombin recruits and activates PMNs, potentially contributing to the proinflammatory effect of coagulation [45].…”

Section: Polymorphonuclear Cells (Pmns)mentioning

confidence: 99%

“…IL-1α is an essential inflammatory cytokine ubiquitously produced and maintained on the surface of eukaryotic cells as an inactive pro-protein (pro-IL-1α) [45]. By cleaving pro-IL-1α and releasing active IL-1α, thrombin recruits and activates PMNs, potentially contributing to the proinflammatory effect of coagulation [45]. Importantly, PMNs are also recognized for their ability to reinforce coagulation.…”

Section: Polymorphonuclear Cells (Pmns)mentioning

confidence: 99%

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Coagulome and the tumor microenvironment: an actionable interplay

et al. 2022

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Section: Polymorphonuclear Cells (Pmns)mentioning

confidence: 99%

Section: Polymorphonuclear Cells (Pmns)mentioning

confidence: 99%

Coagulome and the tumor microenvironment: an actionable interplay

et al. 2022

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“…The observed effects were thought to have led to the preservation of the glycocalyx, maintenance of the microcirculation, and the prevention of subsequent organ dysfunction. Thrombin is thought to be the key mediator in sepsis [42], and the observed effects were considered to be expressed through inhibition of the coagulation cascades since APTT and fibrinogen levels were better maintained in the high-dose group. However, as the direct evidence of thrombin inhibition was not proven in this study, it should be further confirmed.…”

Section: Discussionmentioning

confidence: 99%

Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

Iba

Levy

Aihara

et al. 2020

IJMS

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(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

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“…Back in 1986, it was reported that IL-1 administration in rabbits upregulates tissue factor and induces fibrin formation while suppressing thrombomodulin [63]. Several different models support this finding by showing that IL-1α rapidly activates endothelial cells via NF-κB pathways and promotes thrombosis [62].…”

Section: Thrombin Can Directly Activate Interleukin-1αmentioning

confidence: 95%

“…While these results show that thrombin can promote inflammation via direct activation IL-1α, evidence also suggests IL-1α drives coagulation to form a circle of interaction between inflammation and coagulation [62]. Back in 1986, it was reported that IL-1 administration in rabbits upregulates tissue factor and induces fibrin formation while suppressing thrombomodulin [63].…”

Section: Thrombin Can Directly Activate Interleukin-1αmentioning

confidence: 97%

The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

Garton

Hua

et al. 2020

Transl. Stroke Res.

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Thrombin is increased in the brain after hemorrhagic and ischemic stroke primarily due to the prothrombin entry from blood either with a hemorrhage or following blood-brain barrier disruption. Increasing evidence indicates that thrombin and its receptors (protease-activated receptors (PARs)) play a major role in brain pathology following ischemic and hemorrhagic stroke (including intracerebral, intraventricular, and subarachnoid hemorrhage). Thrombin and PARs affect brain injury via multiple mechanisms that can be detrimental or protective. The cleavage of prothrombin into thrombin is the key step of hemostasis and thrombosis which takes place in every stroke and subsequent brain injury. The extravascular effects and direct cellular interactions of thrombin are mediated by PARs (PAR-1, PAR-3, and PAR-4) and their downstream signaling in multiple brain cell types. Such effects include inducing blood-brain-barrier disruption, brain edema, neuroinflammation, and neuronal death, although low thrombin concentrations can promote cell survival. Also, thrombin directly links the coagulation system to the immune system by activating interleukin-1α. Such effects of thrombin can result in both short-term brain injury and longterm functional deficits, making extravascular thrombin an understudied therapeutic target for stroke. This review examines the role of thrombin and PARs in brain injury following hemorrhagic and ischemic stroke and the potential treatment strategies which are complicated by their role in both hemostasis and brain.

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Thrombin: Coagulation's master regulator of innate immunity

Cited by 17 publications

References 50 publications

Coagulome and the tumor microenvironment: an actionable interplay

Coagulome and the tumor microenvironment: an actionable interplay

Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

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