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Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.

ABSTRACT: BACKGROUND:Both hyperfibrinolysis and fibrinolysis shutdown can occur after severe trauma. The subgroup of trauma patients with fibrinolysis shutdown resistant to tissue plasminogen activator (t-PA)-mediated fibrinolysis have increased mortality. Fibrin polymerization and structure may influence fibrinolysis subgroups in trauma, but fibrin architecture has not been characterized in acutely injured subjects. We hypothesized that fibrin polymerization measured in situ will correlate with fibrinolysis subgroups. METHODS:Blood samples were collected from trauma patients and noninjured controls. We selected samples across a range of fibrinolysis phenotypes (shutdown, physiologic, hyperfibrinolysis) and t-PA sensitivities (sensitive, physiologic, resistant) determined by thrombelastography. Plasma clots were created in situ with fluorescent fibrinogen and imaged using confocal microscopy for analysis of clot architecture in three dimensions. For each clot, we quantified the fiber resolvability, a metric of fiber distinctness or clarity, by mapping the variance of fluorescence intensity relative to background fluorescence. We also determined clot porosity by measuring the size and distribution of the gaps between fibrin fibers in three-dimensional space. We compared these measures across fibrinolysis subgroups. RESULTS:Fiber resolvability was significantly lower in all trauma subgroups compared with controls (n = 35 and 5, respectively; p < 0.05). We observed markedly different patterns of fibrin architecture among trauma patients stratified by fibrinolysis subgroup. Subjects with t-PA-resistant fibrinolysis shutdown exhibited abnormal, densely packed fibrin clots nearly devoid of pores. Individuals with t-PA-hypersensitive fibrinolysis shutdown had highly irregular clots with pores as large as 2500 ?m to 20,000 ?m, versus 78 ?m to 1250 ?m in noninjured controls. CONCLUSION:Fiber resolvability was significantly lower in trauma patients than controls, and subgroups of fibrinolysis differ in the porosity of the fibrin clot structure. The dense fibrin network in the t-PA-resistant group may prevent access to plasmin, suggesting a mechanism for thrombotic morbidity after injury.

SUBMITTER: Dow N

PROVIDER: S-EPMC7546039 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.

Dow Nathan N Coleman Julia R JR Moore Hunter H Osborn Zachary T ZT Sackheim Adrian M AM Hennig Grant G Butenas Saulius S Nelson Mark T MT Moore Ernest E EE Freeman Kalev K

The journal of trauma and acute care surgery 20200201 2

<h4>Background</h4>Both hyperfibrinolysis and fibrinolysis shutdown can occur after severe trauma. The subgroup of trauma patients with fibrinolysis shutdown resistant to tissue plasminogen activator (t-PA)-mediated fibrinolysis have increased mortality. Fibrin polymerization and structure may influence fibrinolysis subgroups in trauma, but fibrin architecture has not been characterized in acutely injured subjects. We hypothesized that fibrin polymerization measured in situ will correlate with f ...[more]

PMID: 31999655

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Project description:Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.

Project description:BACKGROUND:Morbid obesity is associated with an increased risk of thrombotic events, which has been attributed to increased thrombotic activity. Multiple mechanisms have been proposed to explain this increased risk, including an inflammatory state with upregulation of procoagulant and antifibrinolytic proteins. We therefore hypothesize that patients with morbid obesity are hypercoagulable and will revert to normal after bariatric surgery. OBJECTIVES:To evaluate changes in the hypercoagulable state after bariatric surgery. SETTING:University Hospital, Bariatric Center of Excellence, United States. METHODS:Thromboelastography (TEG) data were collected on 72 subjects with morbid obesity, with 36 who had 6 months of follow-up after bariatric surgery. TEG data of 75 healthy subjects (HS) without obesity, recent trauma or surgery, acute infection, or chronic conditions (e.g., liver, cardiovascular, or kidney disease; cancer; diabetes; autoimmune or inflammatory disorders; and disorders of coagulation) were used for comparison. TEG was performed alone and with the addition of 75 and 150 ng/mL tissue plasminogen activator (tPA) to quantify fibrinolysis resistance (tPA-challenged TEG). RESULTS:The bariatric surgery cohort had a median age of 40.5 years, a median body mass index of 44.6 kg/m2, and 90% female patients. Median body mass index reduced significantly 6 months post surgery but remained elevated compared with the HS group (31.4 versus 25.4 kg/m2, P < .0001). At 6 months post surgery, subjects had longer reaction time (mean difference, 1.3; P = .02), lower maximum amplitude (-2.4, P = .01), and increased fibrinolysis with low-dose (3.1, P < .0001) and high-dose tPA-challenged TEG (9, P < .0001). Compared with HS, the postsurgery TEG values were still more likely to be abnormal (all P < .05). CONCLUSIONS:Patients with morbid obesity form stronger clots more rapidly and are more resistant to fibrinolysis than subjects without obesity. Bariatric surgery significantly improved the hypercoagulable profile and fibrinolysis resistance of morbid obesity.

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Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.

Publications

Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.

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