key: cord-0836700-7ad5bolu
authors: Panigada, Mauro; Meli, Andrea; Properzi, Paolo; Grasselli, Giacomo; Iapichino, Giacomo Emilio
title: Normal Response to Fibrinolytic Challenge in COVID-19 Patients: Viscoelastic Evaluation Using Urokinase-Modified Thromboelastography
date: 2021-03-13
journal: J Am Coll Surg
DOI: 10.1016/j.jamcollsurg.2021.02.004
sha: 2f5296d89d161657600462862f824ad16581f0fa
doc_id: 836700
cord_uid: 7ad5bolu

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Patients hospitalized with COVID-19 frequently show coagulation derangements, such as prothrombin time and D-dimer elevation, resulting in a tendency toward thrombosis. 1 Administration of increased doses of antithrombotic prophylaxis has been proposed for critically ill patients. 2 We have recently shown that thromboelastography (TEG) parameters are consistent with hypercoagulability in patients with COVID-19, as shown by short reaction times, K values, and increased maximum amplitude of the TEG tracings. 3 Another feature of COVID-19 coagulopathy might reside in fibrinolysis alteration, even though high D-dimer might indicate hyperactive fibrinolysis. In the recent article by Wright and colleagues, 4 increased persistence of clot firmness at TEG was observed in the majority of patients with severe COVID-19, and this pattern predicted venous thromboembolic episodes, as well as need for hemodialysis. Lastly, Nougier and colleagues 5 reported hypofibrinolysis associated with raised plasminogen activator inhibitor 1 in patients with COVID-19, and high thrombin generation capacity was maintained. This combination leads to simultaneous hypercoagulability and hypofibrinolysis, eventually increasing risk for thrombosis.

We reported previously that a modified TEG assay named urokinase-modified TEG (UK-TEG) is a feasible bedside tool to detect sepsis-induced defective fibrinolysis was added to the cup containing citrated blood (340 mL) recalcified with 0.2 M calcium chloride (20 mL), allowing for a final urokinase concentration of 80 U/mL of blood. 6 UK-TEG was validated in healthy subjects who responded to ex vivo addition of urokinase with a lysis at 30 minutes value > 64.9%. Values < 64.9% were considered indicative of "impaired fibrinolysis." This pattern, associated with higher markers of cellular damage, higher severity score, and worse outcomes, was observed in half of the septic patients. During the COVID-19 pandemic, we performed TEG daily for the evaluation of our critically ill patients' hemostatic profile. As soon as it was technically feasible and after ethics committee approval (674/2020), we also performed UK-TEG in a series of 22 patients with COVID-19 to assess the prevalence of "impaired fibrinolysis." Heparinase cups were used to quench the effect of heparin, as all patients were on heparin prophylaxis. Fibrinolysis shutdown at TEG (defined as lysis at 30 minutes < 0.8%) was present in 14 of 22 patients (63.6%), confirming previous results. 4 Yet, once stimulated with urokinase, 13 of 14 patients (93%) showed normal response to the fibrinolytic stimulus at a simultaneous UK-TEG. Results are reported in Table 1 and typical TEG and UK-TEG tracings are displayed in Figure 1 . These data suggest that the potential for fibrinolysis, once stimulated, remains normal in patients with COVID-19, and stands in substantial contrast with previous data. 5 This might be explained by the high level of measured tissue plasminogen activator in ICU patients, coupled to at least preserved levels of circulating plasminogen (not measured), despite high levels of plasminogen activator inhibitor 1 and thrombin-activatable fibrinolysis inhibitor observed in the cited report. Although differences among patients with COVID-19 and septic patients have to be taken into account, our findings suggest that patients with COVID-19 are able to dissolve stable clots when fibrinolysis is stimulated pharmacologically.

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis

Bold lines indicate urokinase kaolin-activated TEG (UK-TEG), fine lines indicate regular TEG. Patient 1 had a low response to urokinase (ie UK-TEG lysis at 30 minutes

Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection

Hypofibrinolytic state and high thrombin generation may play a major role in SARS-CoV2 associated thrombosis

Assessment of fibrinolysis in sepsis patients with urokinase modified thromboelastography