Point-of-care Diagnosis and Monitoring of Hypofibrinolysis in the Critically Ill: Results from a Feasibility Study. (preprint)

ABSTRACT

Background In critical conditions such as sepsis, severe trauma, COVID-19 and non-COVID acute respiratory failure, hypofibrinolysis is associated with multi-organ dysfunction syndrome and death. The mechanisms underpinning hypofibrinolysis may include reduced tissue plasminogen activator (t-PA) and/or plasmin effect due to elevated inhibitor levels, reduced expression and/or exhaustion. This study in critically ill patients with hypofibrinolysis aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis assessed by bedside viscoelastic testing (VET).Methods Prospective observational and interventional studies were undertaken in 28 critically ill patients identified as hypercoagulant and hypofibrinolytic using standard ClotPro VET. Hypercoagulation was defined as above normal values for clot amplitude on the EX-test (tissue factor (TF) activated coagulation) or FIB-test (TF activated coagulation with platelet inhibition). Hypofibrinolysis was defined as a clot lysis time > 300 seconds on the TPA-test (TF activated coagulation with t-PA accelerated fibrinolysis). In experimental VET, repeat TPA-tests were spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In a hypofibrinolytic patient, alteplase was administered intravenously over a 24-hr period with standard ClotPro VET repeated frequently throughout to monitor the effect on coagulation and fibrinolysis.Results In the ex-vivo studies, distinct response groups emerged with increased fibrinolysis observed following (i) additional t-PA supplementation only, or (ii) combined plasminogen and t-PA supplementation. A baseline TPA-test lysis time of > 1000 sec associated with the latter group. In the interventional study, alteplase administered as a 2-hr bolus (25 mg) followed by a 22-hr infusion (1 mg/hr) resulted in a gradual reduction in serial TPA-test lysis times.Conclusions ClotPro viscoelastic testing, the associated TPA-test and the novel spiked ex-vivo assays may be utilised to (i) investigate the potential mechanisms of hypofibrinolysis, (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 hypofibrinolysis has the potential to increase treatment benefit, whilst minimising adverse events in hypofibrinolytic critically ill patients.Trial Registration VETtiPAT ARF, a clinical trial evaluating the use of ClotPro-guided tissue plasminogen activator (alteplase) administration in hypofibrinolytic patients with acute respiratory failure is ongoing (ClinicalTrials.gov NCT05540834, registered 15 September 2022, retrospectively registered).