The fibrinolytic mechanism in haemostasis: A review

Stafford, Jane

doi:10.1136/jcp.17.5.520

Cited by 14 publications

(5 citation statements)

References 103 publications

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“…Therefore, a resuscitation strategy designed to the patient in a normal range of coagulation is logical. This was appreciated in the 1960’s in which it was suggested that coagulation is a physiologic process never intended to reach a physiologic endpoint (25). This attempt to correct hypercoagulability following injury is not new, as heparin based venous thromboembolic prophylaxis is advocated to start with 48 hours of injury (26, 27).…”

Section: Discussionmentioning

confidence: 99%

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

Moore

Liras

et al. 2017

The American Journal of Surgery

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Introduction The prevalence and impact of hypercoagulability(hypo) in severely injured patients early after injury remains unclear. We hypothesize that the predominant phenotype of postinjury coagulopathy is hypercoagulability(hyper) and it is associated with increased mortality. Material and Methods Blood samples from 141 healthy volunteers assayed with thrombelastography(TEG) were used to identify thresholds of hypo and hypercoagulability(above 95th/below the 5thpercentile) in four TEG indices. These cutoffs were subsequently evaluated in severely injured trauma patients(ISS>15) from two level 1 trauma centers. Results 2,540 patients with a median ISS of 25 were analyzed. Normal TEG was present in 36% of patients. Hyper was found in 38% of patients, with mixed(11%) and hypo(15%) being less common. Compared to normal coagulation patients and after controlling for age, sex, blood pressure, and injury hyper(0.013), mixed(p<0.001) and hypo(p<0.001) were all independent predictors of mortality. Conclusion These data support the ongoing need for goal directed resuscitation in trauma patients, it appears the optimal resuscitation strategy should be targeted towards normalization of coagulation status as both early hyper and hypocoagulability are associated with increased mortality.

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Section: Discussionmentioning

confidence: 99%

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

Moore

Liras

et al. 2017

The American Journal of Surgery

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“…6 In the 1960s a number of investigators hypothesized that fibrinolysis could be a protective physiologic process. In 1964, Stafford 7 proposed that “clotting is not episodic but a continuous process which is normally never allowed to program to a physiologic endpoint.” At the same time, Hardaway and Drake 8 hypothesized that irreversible shock occurred when microvascular flow ceased due to fibrin accumulation and subsequently documented experimentally that induced fibrinolysis prevented irreversible hemorrhagic shock. 9 Ultimately they conducted a Phase II trial showing tissue plasminogen activator (tPA) administration in the intensive care unit reduced acute lung injury in trauma patients.…”

Section: Historical Observationsmentioning

confidence: 99%

Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient

et al. 2016

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Postinjury fibrinolysis can manifest as three distinguishable phenotypes: 1) hyperfibrinolysis, 2) physiologic, and 3) hypofibrinolysis (shutdown). Hyperfibrinolysis is associated with uncontrolled bleeding due to clot dissolution; whereas, fibrinolysis shutdown is associated with organ dysfunction due to microvascular occlusion. The incidence of fibrinolysis phenotypes at hospital arrival in severely injured patients is: 1) hyperfibrinolysis 18%, physiologic 18%, and shutdown 64%. The mechanisms responsible for dysregulated fibrinolysis following injury remain uncertain. Animal work suggests hypoperfusion promotes fibrinolysis, while tissue injury inhibits fibrinolysis. Clinical experience is consistent with these observations. The predominant mediator of postinjury hyperfibrinolysis appears to be tissue plasminogen activator (tPA) released from ischemic endothelium. The effects of tPA are accentuated by impaired hepatic clearance. Fibrinolysis shutdown, on the other hand, may occur from inhibition of circulating tPA, enhanced clot strength impairing the binding of tPA and plasminogen to fibrin, or the inhibition of plasmin. Plasminogen activator inhibitor −1 (PAI-1) binding of circulating tPA appears to be a major mechanism for postinjury shutdown. The sources of PAI-1 include endothelium, platelets, and organ parenchyma. The laboratory identification of fibrinolysis phenotype, at this moment, is best determined with viscoelastic hemostatic assays (TEG, ROTEM). While D-dimer and plasmin antiplasmin (PAP) levels corroborate fibrinolysis, they do not provide real-time assessment of the circulating blood capacity. Our clinical studies indicate that fibrinolysis is a very dynamic process and our experimental work suggests plasma first resuscitation reverses hyperfibrinolysis. Collectively, we believe recent clinical and experimental work suggest antifibrinolytic therapy should be employed selectively in the acutely injured patient, and optimally guided by TEG or ROTEM.

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“…It has been recognized for decades that coagulation is never intended to reach a physiologic end point(1); ie clot formation and degradation are always occurring to prevent bleeding but keep the vasculature patent. In trauma, the extreme ends of the fibrinolytic system (hyperfibrinolysis and fibrinolysis shutdown) have been identified as predictors of mortality(2).…”

Section: Introductionmentioning

confidence: 99%

Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator

Moore

Huebner

et al. 2017

J Trauma Acute Care Surg

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Background Fibrinolysis shutdown(SD) is an independent risk factor for increased mortality in trauma. High levels of plasminogen activator inhibitor-1(PAI-1) directly binding tissue plasminogen activator(tPA) is a proposed mechanism for SD, however patients with low PAI-1 levels present to the hospital with a rapid TEG(rTEG) LY30 suggestive SD. We therefore hypothesized that two distinct phenotypes of SD exist, one, which is driven by tPA inhibition, while another is due to an inadequate tPA release in response to injury. Methods Trauma activations from our level-1 center between 2014 to 2016 with blood collected within an hour of injury were analyzed with r-TEG and a modified TEG assay to quantify fibrinolysis sensitivity using exogenous tPA(t-TEG). Using the existing rTEG thresholds for SD(<0.9%), physiologic(LY30 0.9–2.9%), and hyperfibrinolysis(LY30 >2.9%) patients were stratified into phenotypes. A t-TEG LY30 > 95th percentile of healthy volunteers(n=140) was classified as tPA hypersensitive and used to sub-divide phenotypes. A nested cohort had tPA and PAI-1 activity levels measured in addition to proteomic analysis of additional fibrinolytic regulators. Results This study included 398 patients (median NISS 18), tPA-Sen was present in 27% of patients. Shutdown had the highest mortality rate(20%) followed by hyperfibinolysis(16%) and physiologic(9% p=0.020). In the non-tPA hypersensitive cohort, SD had a 5-fold increase in mortality(15%) compared to non-SD patients(3% p=0.003 figure) which remained significant after adjusting for ISS and age (p=0.033). Overall tPA activity (p=0.002) PAI-1 (p<0.001) and tPA/PAI-1 complex levels (p=0.006) differed between the six phenotypes and 54% of fibrinolytic regulator proteins analyzed (n=19) were significantly different. Conclusion In conclusion, acute fibrinolysis shutdown is not caused by a single etiology, and is clearly associated with PAI-1 activity. The differential phenotypes require an ongoing investigation to identify the optimal resuscitation strategy for these patients.

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The fibrinolytic mechanism in haemostasis: A review

Cited by 14 publications

References 103 publications

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient

Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator

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