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Letter

Fibrinolysis Shutdown in Severe COVID-19: Highly Prevalent but not Independently Predictive of Thrombosis or Poorer Outcomes

Littlejohn, James MD, PhD; Vasovic, Ljiljana V MD; Cushing, Melissa M MD; Barie, Philip S MD, MBA, MCCM, FSIS, FACS, MAMSE

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Journal of the American College of Surgeons: January 2022 - Volume 234 - Issue 1 - p 97-98
doi: 10.1097/XCS.0000000000000007
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Meizoso and colleagues1 recently analyzed the pathophysiology of fibrinolysis shutdown (FSD) in coronavirus disease 2019 (COVID-19). The underpinnings of severe COVID-19 coagulopathy may differ from that of sepsis,1 including by viscoelastic testing. We urge caution in drawing conclusions about the observation of FSD in COVID-19 and its relevance to patient outcomes and thrombosis.

FSD is a phenomenon evaluated recently by viscoelastic testing in critical illness. Both its existence and importance were originally highlighted by Moore and colleagues2 in trauma patients using thromboelastography (TEG). In 2,540 severely-injured patients, FSD was the most common fibrinolytic phenotype (vs normal- or hyper-fibrinolysis), and associated with increased mortality.2 Gomez-Builes and colleagues3 analyzed admission rotational thromboelastographies (ROTEMs) of 550 severely injured patients, defining FSD as a maximum lysis (ML) of < 3.5%. By contrast, they concluded that FSD was not associated with mortality and suggested that FSD could represent an adaptive physiologic response.3 This incongruency regarding FSD may be explained by the difference between the viscoelastic tests (TEG, ROTEM).

Fibrinolysis parameters cannot be compared directly between ROTEM and TEG. With TEG, the fibrinolysis measurement begins at the maximum amplitude of the curve, whereas ROTEM timing begins at the clotting time. Moreover, ROTEM may have different sensitivity than TEG for detecting fibrinolysis, owing to differences in activation by tissue factor (ROTEM) vs kaolin (TEG).

Meizoso and colleagues1 mentioned eight studies using ROTEM to evaluate coagulopathy in COVID-19 patients. Three evaluated FSD, with discrepant findings. Creel-Bulos and Sniecinski4 evaluated FSD (defined per Gomez-Builes3; EXTEM ML < 3.5%) in 25 COVID-19 ICU patients, noting that 11 (44%) had FSD and 78% of those (8 of 11) had a thrombotic event; they asserted that FSD correlated significantly with thrombosis.4 Kruse and colleagues5 noted a difference in ML values in COVID-19 patients with thrombosis, but the difference was only 2% and the data were not evaluated per Gomez-Builes’ definition of FSD. They concluded that correlation with thrombosis was strongest when ROTEM ML was combined with D-dimer. Pavoni and colleagues6 found that all four COVID-19 ICU patients with FSD persisting to Day 10 died, but they mentioned no correlation with death for patients with FSD by ROTEM performed earlier during admission. Our group found that FSD (using Gomez-Builes’ definition) was prevalent in 44 COVID-19 ICU patients, but there was no association between FSD and thrombosis.7

The ML value evolves over time during viscoelastic testing, reflecting clot degradation. If a test is run longer, ML increases. Thus, it is imperative to compare ML values at similar time points, underscoring the utility of ML at 60 min (or its reciprocal, LI60). Earlier in the assay, there is less clot lysis, calling the findings of Creel-Bulos and Sniecinski into question because their assays were run for different amounts of time and for fewer than 60 min.4

We concur that severely ill COVID-19 patients demonstrate a hypercoagulable ROTEM profile and higher rates of FSD, but not the assertion that FSD is independently associated with thrombotic events.1,4

REFERENCES

1. Meisozo JP, Moore HB, Moore EE. Fibrinolysis shutdown in COVID-19: clinical manifestations, molecular mechanisms, and therapeutic implications. J Am Coll Surg. 2021;232:e995–e1003.
2. Moore HB, Moore EE, Liras IN, et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg. 2016;222:e347–e355.
3. Gomez-Builes JC, Acuna SA, Nascimento B, et al. Harmful or physiologic: diagnosing fibrinolysis shutdown in a trauma cohort with rotational thromboelastometry. Anesth Analg. 2018;127:840–849.
4. Creel-Bulos C, Sniecinski R. Fibrinolysis shutdown and thrombosis in a COVID-19 ICU. Shock. 2021;55:845–846.
5. Kruse JM, Magomedov A, Kurreck A, et al. Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis. Crit Care. 2020;24:676.
6. Pavoni V, Gianesello L, Pazzi M, et al. Derangement of the coagulation process using subclinical markers and viscoelastic measurements in critically ill patients with coronavirus disease 2019 pneumonia and non-coronavirus disease 2019 pneumonia. Blood Coagul Fibrinolysis. 2021;32:80–86.
7. Vasovic LV, Littlejohn J, Alqunaibit D, et al. Rotational thromboelastometry (ROTEM) in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): is there a viscoelastic fingerprint and a role for predicting thrombosis? Surgery. 2021, September 9 [Online ahead of print].
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