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Review 2: "Association of D-dimer and fibrinogen magnitude with hypercoagulability by thromboelastography in severe COVID-19"

Fibrinogen & G-reactive protein levels correlate with macrothrombosis in critically ill COVID-19 patients, providing a more practical way of identifying at-risk patients. Reviewer consensus is that the paper is potentially informative but has serious methodological limitations.

Published onSep 10, 2020
Review 2: "Association of D-dimer and fibrinogen magnitude with hypercoagulability by thromboelastography in severe COVID-19"
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Association of D-dimer and fibrinogen magnitude with hypercoagulability by thromboelastography in severe COVID-19
Description

Thermoinhibition, or failure of seeds to germinate at warm temperatures, is common in lettuce (Lactuca sativa) cultivars. Using a recombinant inbred line population developed from a lettuce cultivar (Salinas) and thermotolerant Lactucaserriola accession UC96US23 (UC), we previously mapped a quantitative trait locus associated with thermoinhibition of germination to a genomic region containing a gene encoding a key regulated enzyme in abscisic acid (ABA) biosynthesis, 9-cis-EPOXYCAROTENOID DIOXYGENASE4 (NCED4). NCED4 from either Salinas or UC complements seeds of the Arabidopsis thaliana nced6-1 nced9-1 double mutant by restoring germination thermosensitivity, indicating that both NCED4 genes encode functional proteins. Transgenic expression of Salinas NCED4 in UC seeds resulted in thermoinhibition, whereas silencing of NCED4 in Salinas seeds led to loss of thermoinhibition. Mutations in NCED4 also alleviated thermoinhibition. NCED4 expression was elevated during late seed development but was not required for seed maturation. Heat but not water stress elevated NCED4 expression in leaves, while NCED2 and NCED3 exhibited the opposite responses. Silencing of NCED4 altered the expression of genes involved in ABA, gibberellin, and ethylene biosynthesis and signaling pathways. Together, these data demonstrate that NCED4 expression is required for thermoinhibition of lettuce seeds and that it may play additional roles in plant responses to elevated temperature.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

In their submitted manuscript, “Association of D-dimer and fibrinogen magnitude with hypercoagulability by thromboelastography (TEG) in severe COVID-19,” Chandel et al demonstrate D-dimer appears to have an inverse relationship with degree of hypercoagulability as measured by TEG MA, and fibrinogen is a much better predictor of magnitude of MA than D-dimer. Based upon this study, the authors conclude that fibrinogen may represent a more practical method for the identification of patients at risk for COVID-19 related hypercoagulability and D-dimer elevation may reflect severity of COVID-19 related sepsis rather than designate patients likely to benefit from anticoagulation.

This study is potentially informative, while it would be more profound if the authors could provide data on platelet function, which are known to contribute up to 80% of TEG MA. Also, this study has substantial limitations due to selected population, sample size, lack of control group and distinct features of anticoagulants and associated impacts on TEG MA measurement.

I have the following comments for your consideration:

1. This study provides no novel insights and already many studies have been published. D-dimer as a specific maker for fibrin degradation in secondary fibrinolysis such as DIC and sepsis, may reflect severity of COVID-19. Fibrinogen accounts for clot strength (TEG MA), approximately 20% among normal population. It is expected that hyperfibrinogenemia correlates with increased TEG MA. Since hyperfibrinogenemia due to acute phase is commonly seen, it is not a finding specific to COVID-19, especially during ECMO treatment. Table 1 shows fibrinogen in “no thrombosis” group at a level of 501.5 (447.5, 575.9) mg/dl median (25th percentile, 75th percentile), indicating a conflicting picture of clinical outcome (no thrombosis) and the conclusion that fibrinogen at cut-off of 441 mg/dL predicts TEG MA ≥ 68 mm (hypercoagulability). Also, as mentioned in manuscript, “The interplay between COVID-19 disease and the effects of ECMO may also increase the risk of thromboembolism in these patients.” Therefore, it would be important to include a non-COVID ECMO cohort as control group. As a result, it is too optimistic to conclude that fibrinogen may represent as a risk predictor for COVID-19 related hypercoagulability.

2. Platelet function is known to contribute up to 80% of TEG MA among normal population. In ECMO population, thrombus formation in the ECMO circuit may occur due to direct platelet activation from shear-stress over time and the contact with foreign circuit surface. This hyper-platelet function can significantly contribute to hypercoagulable status and the degree correlates well with TEG MA and clot stability (G) by design. Therefore, it is hard to bypass the contribution of platelets function when using TEG MA as the only indicator of hypercoagulability in this study.

3. Heparin and bivalirudin have distinct features in thrombin generation, coagulation, and fibrinolysis. In this study, 46 TEGs were obtained on heparin while 122 TEGs were obtained on bivalirudin. We know that heparin and bivalirudin in sample can cause decreased TEG MA and the extent is dosage dependent. Heparin effect can be reversed since Heparinase is employed in the TEG, while there is no reversal for bivalirudin leaving TEG MA unreliable. This explains the bad correlations of TEG MA with D-dimer and fibrinogen for patients on bivalirudin (figure 1). Hence the accuracy of TEG MA on bivalirudin sample is questionable in this study.

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