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Review 3: "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 3: "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:

Dr. Chandel et al. retrospectively described markers of coagulation and inflammation among 24 patients with severe COVID-19 requiring ECMO at their institution. The authors demonstrated an association between CRP and fibrinogen with thrombotic events in this cohort. D-dimer had a negative correlation with TEG MA while fibrinogen had a positive correlation with MA. The former trend is surprising and counterintuitive. However, TEG parameters themselves did not predict clinical events in this study. We believe this is an interesting and important cohort of patients that could be explored in more depth to develop a stronger manuscript. However, associations between lab values may be less clinically important than with clinical events. There are a few important issues that should be addressed:

1. Table 1 should be expanded to describe important clinical characteristics that may also be independently associated with thrombotic events. For instance, co-morbid illness (ie malignancy, cardiovascular disease), shock, antiplatelet therapies, need for renal replacement therapies, etc. Additional lab values such as the CBC and range of anti-Xa or PTT values should be included as well. It would be interesting to understand risk factors for thrombotic events among patients with severe COVID-19 on ECMO. Please also note if any patients were on VA-ECMO or if all were on VV-ECMO.

2. While the TEG MA is one value that has been previously associated with thrombotic events, the authors should report on the K, alpha-angle, Ly30, and coagulation index which should all be available with the TEG 5000. The coagulation index as well as abnormalities in multiple TEG parameters in prior literature have been associated with thrombotic events. The association between some of these markers and events is more relevant than association between lab values and the MA.

3. Were there TEG parameter cut points that could predict thrombotic events in a sensitivity analysis?

4. Discussion point to abandon D-dimer thresholds in decision making regarding anticoagulation is too strong and does not follow from data in your manuscript. Would eliminate this statement.

5. Would explore in the discussion the negative association between the D-dimer and the MA as this is a major finding in the project. Here, looking at the association between other TEG parameters and D-dimer may be useful. If patients were in hypocoagulable DIC, the D-dimer may be elevated and the MA may be low as one possibility.

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