Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

Hijazi, Nuha; Fanne, Rami Abu; Abramovitch, Rinat; Yarovoi, Serge; Higazi, Muhamed; Abdeen, Suhair; Basheer, Maamon; Maraga, Emad; Cines, Douglas B.; Higazi, Abd Al‐Roof

doi:10.1182/blood-2014-08-588442

Cited by 116 publications

(118 citation statements)

References 50 publications

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“…70 As expected, uPA and tPA knockout mice had reduced intracranial hemorrhage (ICH) after TBI compared with wild type, whereas PAI-1 knockout mice had worse ICH. As mentioned earlier, CSF and brain parenchyma levels of tPA peaked several hours before uPA levels; in this context, early TXA reduced ICH, whereas late TXA exacerbated it.…”

Section: Trauma-induced Coagulopathy 1045mentioning

confidence: 80%

“…One explanation may be the differential effect of TXA on tPA-vs uPA-mediated fibrinolysis combined with time-varying expression of these plasminogen activators: although the TXA-induced conformational change on plasminogen reduces tPA-mediated activation, it actually accelerates uPA-mediated activation, 69 and Hijazi et al recently demonstrated in a mouse model of isolated TBI that cerebrospinal fluid (CSF) and brain parenchyma levels of tPA peaked within 3 hours, whereas uPA levels peaked at 8 hours: after tPA levels had already decreased. 70 Although this finding plausibly explains the time-dependent effect of TXA on bleeding in CRASH-2, confirmation is required in human studies.…”

Section: Trauma-induced Coagulopathy 1045mentioning

confidence: 99%

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Advances in the understanding of trauma-induced coagulopathy

Chang

Cardenas

Wade

et al. 2016

Blood

246

225

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Ten percent of deaths worldwide are due to trauma, and it is the third most common cause of death in the United States. Despite a profound upregulation in procoagulant mechanisms, one-quarter of trauma patients present with laboratory-based evidence of trauma-induced coagulopathy (TIC), which is associated with poorer outcomes including increased mortality. The most common causes of death after trauma are hemorrhage and traumatic brain injury (TBI). The management of TIC has significant implications in both because many hemorrhagic deaths could be preventable, and TIC is associated with progression of intracranial injury after TBI. This review covers the most recent evidence and advances in our understanding of TIC, including the role of platelet dysfunction, endothelial activation, and fibrinolysis. Trauma induces a plethora of biochemical and physiologic changes, and despite numerous studies reporting differences in coagulation parameters between trauma patients and uninjured controls, it is unclear whether some of these differences may be “normal” after trauma. Comparisons between trauma patients with differing outcomes and use of animal studies have shed some light on this issue, but much of the data continue to be correlative with causative links lacking. In particular, there are little data linking the laboratory-based abnormalities with true clinically evident coagulopathic bleeding. For these reasons, TIC continues to be a significant diagnostic and therapeutic challenge.

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Section: Trauma-induced Coagulopathy 1045mentioning

confidence: 80%

Section: Trauma-induced Coagulopathy 1045mentioning

confidence: 99%

Advances in the understanding of trauma-induced coagulopathy

Chang

Cardenas

Wade

et al. 2016

Blood

246

225

View full text Add to dashboard Cite

show abstract

“…In isolated TBI without major bleeding, brain-derived TF-induced consumptive coagulopathy 129 and the release of plasminogen activators result in local and systemic fibrinolysis, intracerebral hemorrhage and the development of acute traumatic coagulopathy 130 . In addition, after TBI, the complement system has been shown to be locally and systemically activated in the acute phase and in a prolonged manner 131 .…”

Section: Cerebral and Extracerebral Challenges To The Innate Immune Smentioning

confidence: 99%

Innate immune responses to trauma

2018

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Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.

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“…This figure was adapted from [33] with permission from Wolters Kluwer Health, Inc. [54]. Many other studies reported the presence of D-dimer and FDP in not only cases of isolated head trauma [54,[56][57][58][59] but also torso trauma regardless of shock [6,12,16]. Furthermore, another investigation reported that hyper-fibrino(geno)lysis in severe head trauma is not directly related to shock [60].…”

Section: Coagulation Activation-induced Fibrino(geno)lysismentioning

confidence: 99%

“…In severe trauma, elevations in D-dimer and FDP levels are frequently observed and are complicated with coagulopathy, regardless of severe shock [6,12,16,[54][55][56][57][58][59]. Although severe head trauma is not generally complicated with shock, trauma-induced coagulopathy is frequently observed with this type of injury [54,[56][57][58].…”

Section: Coagulation Activation-induced Fibrino(geno)lysismentioning

confidence: 99%

Dynamics of fibrinogen in acute phases of trauma

Hayakawa

2017

j intensive care

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Fibrinogen is a unique precursor of fibrin and cannot be compensated for by other coagulation factors. If plasma fibrinogen concentrations are insufficient, hemostatic clots cannot be formed with the appropriate firmness. In severe trauma patients, plasma fibrinogen concentrations decrease earlier and more frequently than other coagulation factors, predicting massive bleeding and death. We review the mechanisms of plasma fibrinogen concentration decrease, which include coagulation activation-induced consumption, hyper-fibrino(geno)lysis-induced degradation, and dilution by infusion/transfusion. Understanding the mechanisms of plasma fibrinogen concentration decrease in severe trauma patients is crucial.

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Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

Abstract: Key Points Closed head trauma sequentially releases tPA followed by uPA from injured brain. Increased uPA is responsible for delayed intracerebral hemorrhage, which is prevented by a tPA variant that inhibits uPA activity.

Cited by 116 publications

References 50 publications

Advances in the understanding of trauma-induced coagulopathy

Advances in the understanding of trauma-induced coagulopathy

Innate immune responses to trauma

Dynamics of fibrinogen in acute phases of trauma

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