Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (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 fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

Fibrinolysis Resistance After Injury Is a Risk Factor for a Hospital-Acquired Pneumonia-Like Disease Pattern.

Background: Pneumonia is associated with increased morbidity and costs in the intensive care unit (ICU). Its early identification is key for optimal outcomes, but early biomarkers are lacking. Studies suggest that fibrinolysis resistance (FR) after major abdominal surgery is linked to an increased risk of infection. Patients and Methods: Patients in a randomized controlled trial for hemorrhagic shock were evaluated for FR. Fibrinolysis resistance was quantified by thrombelastography with exogenous tissue plasminogen activator (tPA-TEG) at 24- and 48-hours post-injury and measuring LY30 (%). A receiver-operating characteristics (ROC) curve analysis was used to identify a cutoff for increased risk of pneumonia, which was then validated in ICU patients at risk for venous thromboembolism (VTE). Multivariable logistic regression was used to control for confounders. Results: Forty-nine patients in the hemorrhagic shock cohort had tPA-TEGs at 24- and 48-hours (median ISS, 27; 7% pneumonia). A composite tPA-TEG LY30 of less than 4% at 24 and 48 hours was found to be the optimal cutoff for increased risk of pneumonia. This cohort had a seven-fold increased rate of pneumonia (4% vs. 28%; p = 0.048). Eighty-eight patients in the VTE cohort had tPA-TEGs at 24 and 48 hours post-ICU admission (median ISS, 28; 6% pneumonia). The tPA-TEG LY30 of less than 4% was associated with a 10-fold increased rate of pneumonia (19% vs. 1.5%; p = 0.002). In patients with traumatic brain injury, the same association was found (33% vs. 3.2%; p = 0.006). Adjusting for confounders, the tPA-TEG persisted as a substantial risk factor for pneumonia (adjusted odds ratio [OR], 35.7; 95% confidence interval [CI], 1.9-682; p = 0.018). Conclusions: Fibrinolysis resistance quantified by tPA-TEG within 48 hours of ICU admission is associated with an increased risk of pneumonia in patients in hemorrhagic shock and those at risk for VTE. Prospective validation of the tPA-TEG LY30 optimal cutoff for pneumonia and further investigation into whether endogenous FR is a cause of an altered immunity is warranted.

Fibrinolysis resistance after liver transplant as a predictor of early infection.

BACKGROUND: Infection is a leading cause of morbidity in liver transplant (LT). Considering that the fibrinolytic system is altered in sepsis, we investigated the relationship between fibrinolysis resistance (FR) and post-transplant infection. METHODS: Fibrinolysis was quantified using thrombelastography (TEG) with the addition of tPA to quantify FR. FR was defined as LY30 = 0% and stratified as transient if present on POD1 or POD5 (tFR), persistent (pFR) if present on both, or no FR (nFR) if absent. RESULTS: 180 LT recipients were prospectively enrolled. 52 (29%) recipients developed infection. 72 had tFR; 37 had pFR; and 71 had nFR. Recipients with pFR had significantly greater incidence of infections (51% vs. 26% tFR vs. 20% nFR, p = 0.002). pFR was independently associated with increased odds of post-transplant infection (adjusted OR 3.39, p = 0.009). CONCLUSIONS: Persistent fibrinolysis resistance is associated with increased risk of post-transplant infection.

Peroxynitrite may affect fibrinolysis via the reduction of platelet-related fibrinolysis resistance and alteration of clot structure.

We tested the hypothesis that in vitro peroxynitrite (ONOO(-), a product of activated inflammatory cells) may affect fibrinolysis in human blood through the reduction of platelet-related fibrinolysis resistance. It was found that ONOO(-) (25-300 µM) accelerated lysis of platelet-fibrin clots (in PRP) dose-dependently, whereas fibrinolysis of platelet-free clots was slightly inhibited by ≥ 1000 µM stressor. Concentrations of ONOO(-) affecting the lysis of platelet-rich clots, inhibited clot retraction (CR) in a dose-dependent manner. Thromboelastometry (ROTEM) measurements performed in PRP showed that treatment with ONOO(-) (threshold conc. 100 µM) prolongs clotting time, and reduces alpha angle, and clot formation velocity parameters indicating for reduced thrombin formation rate. In PRP, ONOO(-) (threshold conc. 100 µM) reduced the collagen-evoked exposure of phosphatidylserine (PS) on platelets' plasma membrane, the shedding of platelet-derived microparticles (PMP), and inhibited platelet-dependent thrombin generation (measured in artificial system), dose-dependently. As judged by confocal microscopy, similar ONOO(-) concentrations altered the architecture of clots formed in collagen-treated PRP. Clots formed in the presence of ONOO(-) were less dense and were composed of thicker fibers, which make them more susceptible to lysis. In platelet-depleted plasma, ONOO(-) (up to milimolar concentration) did not alter clot structure. Blockage of PS exposed on platelets resulted in an alteration of clot architecture toward more prone to lysis. ONOO(-), at lysis-affecting concentrations, inhibited the collagen-evoked secretion of fibrinolytic inhibitors from platelets. We conclude that physiologically relevant ONOO(-) concentrations may accelerate the lysis of platelet-fibrin clots predominantly via downregulation of platelet-related mechanisms including: platelet secretion, clot retraction, platelet procoagulant response, and the alteration in clot architecture associated with it.