Regulation of Fibrinolysis in Plasma by TAFI and Protein C Is Dependent on the Concentration of Thrombomodulin

Mosnier, Laurent O.; Meijers, Joost C. M.; Bouma, Bonno N.

doi:10.1055/s-0037-1612655

Cited by 110 publications

(6 citation statements)

References 45 publications

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“…30 In vitro data suggest that low-dose rTM stimulates thrombin-activatable fibrinolysis inhibitor (TAFI) activation, which could be beneficial in aiding the reduction of hyperfibrinolysis in early TIC. 24,31 An optimised dose of rTM for traumatic shock should be based on TAFI vs protein C activation in future studies. Of note, we used human TM in this model, which might activate mouse protein C less efficiently than murine TM.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock

Sloos¹,

Maas²,

Meijers³

et al. 2023

British Journal of Anaesthesia

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Section: Discussionmentioning

confidence: 99%

“…rTM activates protein C in a dosedependent manner. 24 A dose of 0.01 mg g À1 was chosen because it did not trigger fibrinolysis and was associated with the lowest mortality compared with other dosages (Supplementary Table S3).…”

Section: Doseeresponse Studiesmentioning

confidence: 99%

Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock

Sloos¹,

Maas²,

Meijers³

et al. 2023

British Journal of Anaesthesia

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“…Thrombomodulin can also stabilize clots by facilitating TAFI activation. The relative contribution of thrombomodulin to anticoagulant or antifibrinolytic pathways depend, in part, on its concentration, 31–33 which may change dynamically during trauma and subsequent treatment. Plasmin generated in response to trauma may activate factor V and enhance procoagulant activity 34 .…”

Section: Discussionmentioning

confidence: 99%

Plasma-based assays distinguish hyperfibrinolysis and shutdown subgroups in trauma-induced coagulopathy

Lawson

Holle

Dow

et al. 2022

J Trauma Acute Care Surg

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BACKGROUND:Trauma patients with abnormal fibrinolysis have increased morbidity and mortality. Knowledge of mechanisms differentiating fibrinolytic phenotypes is important to optimize treatment. We hypothesized that subjects with abnormal fibrinolysis identified by whole blood viscoelastometry can also be distinguished by plasma thrombin generation, clot structure, fibrin formation, and plasmin generation measurements. METHODS:Platelet-poor plasma (PPP) from an observational cross-sectional trauma cohort with fibrinolysis shutdown (% lysis at 30 minutes [LY30] < 0.9, n = 11) or hyperfibrinolysis (LY30 > 3%, n = 9) defined by whole blood thromboelastography were studied. Noninjured control subjects provided comparative samples. Thrombin generation, fibrin structure and formation, and plasmin generation were measured by fluorescence, confocal microscopy, turbidity, and a fluorescence-calibrated plasmin assay, respectively, in the absence/presence of tissue factor or tissue plasminogen activator (tPA). RESULTS:Whereas spontaneous thrombin generation was not detected in PPP from control subjects, PPP from hyperfibrinolysis or shutdown patients demonstrated spontaneous thrombin generation, and the lag time was shorter in hyperfibrinolysis versus shutdown. Addition of tissue factor masked this difference but revealed increased thrombin generation in hyperfibrinolysis samples. Compared with shutdown, hyperfibrinolysis PPP formed denser fibrin networks. In the absence of tPA, the fibrin formation rate was faster in shutdown than hyperfibrinolysis, but hyperfibrinolysis clots lysed spontaneously; these differences were masked by addition of tPA. Tissue plasminogen activator-stimulated plasmin generation was similar in hyperfibrinolysis and shutdown samples. Differences in LY30, fibrin structure, and lysis correlated with pH. CONCLUSION:This exploratory study using PPP-based assays identified differences in thrombin generation, fibrin formation and structure, and lysis in hyperfibrinolysis and shutdown subgroups. These groups did not differ in their ability to promote tPA-triggered plasmin generation. The ability to characterize these activities in PPP facilitates studies to identify mechanisms that promote adverse outcomes in trauma. (

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“…The protein C system, an important anticoagulation system, is associated with the development and progression of many thromboembolic diseases, and decreased protein C activity is a risk factor for VTE. 41,42 TM has both anticoagulant and antifibrinolytic properties and is a cofactor in the activation of protein C. 15 When thrombosis occurs in the body, the anticoagulant and anti-inflammatory responses lead to a depleting decrease in protein C levels in the body, which in turn weakens the anticoagulant effect, increases thrombus formation, aggravates vascular endothelial cell damage, and promotes the release of soluble TM. 9 Impaired endothelial cell function leads to TM release into the blood, which in turn weakens the activation of protein C. This leads to an anticoagulation-coagulation-fibrinolysis imbalance, ultimately promoting thrombosis and increased protein C consumption.…”

Section: Discussionmentioning

confidence: 99%

“…13 In addition, the Thrombin-TM complex can also activate thrombin-activated fibrinolytic inhibitors. 14 Low concentrations of TM enhance activation of thrombin-activated fibrinolytic inhibitors, while high concentrations of TM enhance activation of protein C. 15 Therefore, there is a link between TM and the occurrence of VTE.…”

Section: Introductionmentioning

confidence: 99%

Effect of thrombomodulin gene polymorphisms on venous thromboembolism: An analysis of evidence involving 6,629 patients

et al. 2022

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Backgroud The association between thrombomodulin gene (THBD) c.1418 C>T polymorphisms and the risk of venous thromboembolism (VTE) is controversial. The purpose of this meta-analysis was to evaluate THBD c.1418 C>T polymorphisms and the risk of VTE. Methods Computer searches were performed on the CNKI, Wanfang database, VIP database, PubMed, Embase, Web of Science, and Cochrane Library databases. The retrieval time limit was from the establishment of the database to June 2022. Case-control studies and cohort studies of THBD c.1418 C>T polymorphisms associated with VTE were included. The literature was screened according to inclusion and exclusion criteria, data extraction and literature quality evaluation. Meta-analysis was performed using STATA 14.0 software. Results A total of 12 literature were included, including 2980 cases in the case group and 3649 cases in the control group. The meta-analysis results showed no significant association of the THBD c.1418 C> T polymorphisms with the occurrence of VTE (T vs C: OR = 1.17, 95%CI = 0.93–1.48; TT vs CT+CC: OR = 1.00, 95%CI = 0.75–1.33; TT+CT vs CC: OR = 1.22, 95%CI = 0.94–1.59). Subgroup analyses revealed an increased risk of VTE in Asian populations due to THBD c.1418 C>T polymorphisms (T vs C: OR = 1.48, 95%CI = 1.06–2.07; TT vs CT+CC: OR = 1.80, 95%CI = 1.13–2.85; TT+CT vs CC: OR = 1.58, 95%CI = 1.07–2.32). THBD c.1418 C>T polymorphisms increased the risk of DVT (T vs C: OR = 1.51, 95%CI = 1.24–1.85; TT vs CT+CC: OR = 1.85, 95%CI = 1.10–3.12; TT+CT vs CC: OR = 1.64, 95%CI = 1.28–2.11). THBD c.1418 C>T polymorphisms reduced the risk of VTE in non-Asian populations (TT vs CT+CC: OR = 0.66, 95%CI = 0.45–0.98). Conclusion THBD c.1418 C>T polymorphisms is associated with VTE in Asian population, which may be a factor in the occurrence of VTE in Asian population. THBD c.1418 C>T polymorphisms increases the risk of DVT. Given the limitations of this meta-analysis, the conclusions require being further supported by large-scale and high-quality studies.

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Regulation of Fibrinolysis in Plasma by TAFI and Protein C Is Dependent on the Concentration of Thrombomodulin

Cited by 110 publications

References 45 publications

Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock

Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock

Plasma-based assays distinguish hyperfibrinolysis and shutdown subgroups in trauma-induced coagulopathy

Effect of thrombomodulin gene polymorphisms on venous thromboembolism: An analysis of evidence involving 6,629 patients

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