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

Abstract

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).

Thromboelastometry-Guided Individualized Fibrinolytic Treatment for COVID-19-Associated Severe Coagulopathy Complicated by Portal Vein Thrombosis: A Case Report

“…The novel ClotPro system has the potential to evaluate the fibrinolysis shutdown phenomenon via the TPA assay containing 600 ng of rtPA. The TPA assay will result in complete fibrinolysis if the fibrinolytic activity is preserved; in contrast, both prolonged lysis time (LT > 300 s) and / or incomplete lysis (ML < 100%) indicate fibrinolysis resistance [ 19 ].…”

Concentration–effect relationship for tranexamic acid inhibition of tissue plasminogen activator-induced fibrinolysis in vitro using the viscoelastic ClotPro® TPA-test

“… 12 In brief, coagulation is initiated in citrated whole blood samples by recalcification and the addition of either tissue factor (EX-test), tissue factor and cytochalasin (FIB-test), or tissue factor and tissue plasminogen activator (tPA; TPA-test) with a final tPA concentration of 650 ng mL − 1 . 14 Changes in sample viscoelasticity are measured for 1 h as clot amplitude (mm) over time (s). The resulting curve can be examined visually, and the following parameters are extracted by the ClotPro software: clotting time (CT [s]; defined as duration from starting the test until an amplitude of 2 mm is reached), clot formation time (CFT [s]; defined as duration from reaching 2 mm amplitude until 20 mm amplitude is measured), amplitude at 5, 10, 20, and 30 min after reaching an amplitude of 2 mm (A5, A10, A20, and A30 [all in mm]), maximum clot firmness (MCF [mm]; i.e.…”

Impaired Whole-Blood Fibrinolysis is a Predictor of Mortality in Intensive Care Patients

“…24 ML was significantly lower in sepsis patients than in nonsepsis patients (23 [8-90] vs. 94 [14-100] %, p ¼ 0.02), as was FS (0.41 [0.0-1.4] vs. 1.6 [0.1-2.7] mm/min, p ¼ 0.01). t-AUCi was higher in sepsis patients than nonsepsis patients, although the difference was not statistically significant (17 [12][13][14][15][16][17][18][19][20][21][22][23][24][25] vs. 15 [11][12][13][14][15][16][17][18][19][20][21] minutes, p ¼ 0.21). Furthermore, the sepsis population showed prolonged LOT as well as higher LI45, all indicative of hypofibrinolysis.…”

“…4 In recent years, viscoelastic assays modified with tissue plasminogen activator (tPA) or other plasminogen activators have been developed. [17][18][19][20] Exogenous tPA is added to stimulate fibrinolysis, which means that in contrast to standard viscoelastic tests, full lysis is obtained within the clinically relevant runtime of an hour. This allows the detection of hypofibrinolysis in the patient sample.…”