Plasmin drives burn-induced systemic inflammatory response syndrome

Gibson, Breanne; Wollenman, Colby C; Moore‐Lotridge, Stephanie N.; Keller, Patrick R.; Summitt, Joni; Revenko, Alexey R; Flick, Matthew J.; Blackwell, Timothy S.; Schoenecker, Jonathan G.

doi:10.1172/jci.insight.154439

Cited by 12 publications

(8 citation statements)

References 85 publications

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“…The authors concluded that the exhaustion of plasminogen and coagulation inhibitors was the principal mechanism leading to hypo brinolysis in the more severely ill patients and that the same mechanisms occurred with sepsis due to several different pathogens(8). Additional evidence for plasminogen consumption causing hypo brinolysis was obtained in burns patients with reduced plasminogen levels associating with the extent of burn injury and development of organ dysfunction (7). Plasmin is not only involved in intravascular brin degradation, but also in tissue repair and several aspects of the immune response (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmin is not only involved in intravascular brin degradation, but also in tissue repair and several aspects of the immune response (35,36). In fact, plasmin has been found to drive the early in ammatory response to tissue injury promoting cytokine release and in ammatory signalling (7).…”

Section: Discussionmentioning

confidence: 99%

“…Severe infection and tissue injury induce dynamic and interconnected responses in the in ammatory, coagulation and brinolytic systems (1,2). Signi cant perturbations in brinolysis may result in lifethreatening haemorrhage (hyper brinolysis) or fatal macro or micro-thrombosis (hypo brinolysis) (3)(4)(5)(6)(7), with several studies providing evidence that initial hyper brinolysis transitions to hypo brinolysis due to factor consumption (7,8). In critical conditions, such as sepsis, COVID-19 and non-COVID acute respiratory failure (ARF), and extensive trauma, hypo brinolysis has been associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1) (4)(5)(6)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Point-of-care Diagnosis and Monitoring of Hypofibrinolysis in the Critically Ill: Results from a Feasibility Study.

Coupland

Rabbolini

Schoenecker

et al. 2022

Preprint

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Background In critical conditions such as sepsis, severe trauma, COVID-19 and non-COVID acute respiratory failure, hypofibrinolysis is associated with multi-organ dysfunction syndrome and death. The mechanisms underpinning hypofibrinolysis may include reduced tissue plasminogen activator (t-PA) and/or plasmin effect due to elevated inhibitor levels, reduced expression and/or exhaustion. This study in critically ill patients with hypofibrinolysis aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis assessed by bedside viscoelastic testing (VET). Methods Prospective observational and interventional studies were undertaken in 28 critically ill patients identified as hypercoagulant and hypofibrinolytic using standard ClotPro VET. Hypercoagulation was defined as above normal values for clot amplitude on the EX-test (tissue factor (TF) activated coagulation) or FIB-test (TF activated coagulation with platelet inhibition). Hypofibrinolysis was defined as a clot lysis time > 300 seconds on the TPA-test (TF activated coagulation with t-PA accelerated fibrinolysis). In experimental VET, repeat TPA-tests were spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In a hypofibrinolytic patient, alteplase was administered intravenously over a 24-hr period with standard ClotPro VET repeated frequently throughout to monitor the effect on coagulation and fibrinolysis. Results In the ex-vivo studies, distinct response groups emerged with increased fibrinolysis observed following (i) additional t-PA supplementation only, or (ii) combined plasminogen and t-PA supplementation. A baseline TPA-test lysis time of > 1000 sec associated with the latter group. In the interventional study, alteplase administered as a 2-hr bolus (25 mg) followed by a 22-hr infusion (1 mg/hr) resulted in a gradual reduction in serial TPA-test lysis times. Conclusions ClotPro viscoelastic testing, the associated TPA-test and the novel spiked ex-vivo assays may be utilised to (i) investigate the potential mechanisms of hypofibrinolysis, (ii) guide corrective treatment, and (iii) monitor in real-time the treatment effect. Such a precision-medicine and personalised treatment approach to the management of hypofibrinolysis has the potential to increase treatment benefit, whilst minimising adverse events in hypofibrinolytic critically ill patients. Trial Registration: VETtiPAT ARF, a clinical trial evaluating the use of ClotPro-guided tissue plasminogen activator (alteplase) administration in hypofibrinolytic patients with acute respiratory failure is ongoing (ClinicalTrials.gov NCT05540834, registered 15 September 2022, retrospectively registered).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Point-of-care Diagnosis and Monitoring of Hypofibrinolysis in the Critically Ill: Results from a Feasibility Study.

Coupland

Rabbolini

Schoenecker

et al. 2022

Preprint

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“…Начальная фаза «отлива» гиперметаболического синдрома, развивающаяся в течение первых 1-3 дней после термической травмы, характеризуется снижением тканевой перфузии и временным снижением скорости метаболизма, сходным с кратковременной реакцией «бей или беги» [30]. В первые 24 часа уровни ИЛ-1, ИЛ-6, ИЛ-12, ФНО-α и других воспалительных цитокинов повышаются, и их уровни коррелируют с летальностью в первые 48 часов [7,28,30]. Ряд исследований показывает, что гипервоспалительный синдром, особенно повышение уровней ИЛ-6, ИЛ-8, ФНО-α среди других цитокинов, сдвигает гемостатический баланс в сторону коагуляции [14].…”

Section: основная частьunclassified

“…Еще один важный патофизиологический компонент -гипоперфузия [17,28,31]. Важная особенность ожогового шока -прогрессирующая во времени плазмопотеря, опережающая потерю клеточных элементов.…”

Section: основная частьunclassified

Coagulopathy in Patients with Severe Burn Injury: A Literature Review

Скакун¹,

Жилинский²,

Губичева³

et al. 2022

Хирургия. Восточная Европа

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Термическая травма связана со значительным уровнем заболеваемости и летальности и является одной из недооцененных причин травматизма. Данный вид травматизма имеет значительные социально-экономические последствия, которые затрагивают все социальные группы населения. Тяжелая термическая травма приводит к развитию ожоговой болезни, которая сопровождается нарушением функции различных органов и систем, иммунной и воспалительной реакцией, метаболическими изменениями и распределительным шоком, которые могут привести к полиорганной недостаточности и смерти. Одним из осложнений ожоговой болезни является системная коагулопатия. Развитие коагулопатии у пациентов с ожоговой травмой значительно усложняет и без того высокий уровень интенсивной терапии, необходимый для данной группы пациентов. Четкие руководящие принципы для лечения коагулопатии у пациентов с тяжелыми ожогами на данный момент отсутствуют, поэтому дальнейшее изучение данного феномена является перспективным. В этом обзоре рассмотрены современные патогенетические теории развития коагулопатий, связанных с термической травмой, рассмотрено текущее понимание изменения компонентов системы свертывания, системы фибринолиза и воспалительного ответа в остром и отсроченном периоде ожоговой травмы. Thermal trauma is associated with a significant level of morbidity and mortality and is one of the underestimated causes of injury. Severe thermal trauma leads to the development of burn disease, which is accompanied by impaired function of various organs and systems, immune and inflammatory reactions, metabolic changes and distributive shock, which can lead to multiple organ failure and death. One of the complications of burn disease is systemic coagulopathy. The development of coagulopathy in patients with burn injury significantly increases the already high level of intensive care required for this group of patients. Clear guidelines for the treatment of coagulopathy in patients with severe burns are currently lacking, therefore further study of this phenomenon is promising. In this review, the current pathogenetic theories of coagulopathies associated with thermal trauma are surveyed, and the current understanding of changes in coagulation system components, the fibrinolysis system, and the inflammatory response in the acute and delayed period of burn injury is examined.

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