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).
Background: Thrombocytopenia occurs reasonably frequently with the underlying causes being numerous and requiring time to delineate. Patients may present with active bleeding or low platelet counts may be detected incidentally. Treatments are varied, refractory cases are not uncommon, and in those who do respond, relapses occur. The clinician's principal concern is to limit the risk of a life-threatening hemorrhage, however, the platelet count is an unreliable predictor of bleeding risk. Adult patients presenting with platelet counts < 20 x 109/L present the greatest safety dilemma for clinicians. Previous studies using ROTEM in adult ITP patients with platelet counts < 60 x 109/L and paediatric cases with platelet counts < 30 x 109/L demonstrated that clot firmness parameters correlated with bleeding score1. Our aim, therefore, was to perform ROTEM analysis on patients with a platelet count <20 x 109/L and correlate with bleeding status. Methods: Patients referred to the Haematology Department of The Canberra Hospital with thrombocytopenia were consented to the study. Blood was collected into Na-citrate tubes and analysed within 4 hr of collection. Each patient had an EXTEM and FibTEM assay performed on a ROTEM Delta machine. The measurement of fibrinogen levels was commenced part-way through the study. Data was analysed using PRISM software. Results: Twenty-five blood samples were analysed from 21 patients (17 primary ITP, 2 secondary ITP, 1 AML, 1 sepsis), 7 samples were treatment naive. Platelet count ranged from 0-17 x 109/L (mean 7.1 +/- 5.7) Even in this severely thrombocytopenic cohort, platelet count was a poor predictor of bleeding risk, as was the fibrin clot amplitude measured with FibTEM. In comparison, the calculated value for platelet contribution to clot formation (EXTEM A10 minus FibTEM A10) plotted against the platelet count demonstrated that subjects with a bleeding phenotype had a reduced platelet contribution to clot formation in comparison to their non-bleeding counterparts (Figure). Conclusions: ROTEM has the capacity to detect platelet dysfunction associated with bleeding in severely thrombocytopenic patients. Further studies are underway to elucidate determinants of platelet dysfunction such as specific anti-glycoprotein antibodies that may inhibit platelet function. Reference #1: Lindsey A. Greene et al., British Journal of Haematology 166: 592-600 (2014) Figure Disclosures D'Rozario: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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).
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