Von Willebrand Factor and ADAMTS-13 Are Associated with the Severity of COVID-19 Disease

Round 1

Reviewer 1 Report

1 )A table with characteristic of patients is missing 2) Definition for mild , moderate and severe Cobìvid should be included 3) Table 3 is not clear as concern significant differences 4) Method for detection of ab anti ADAMTS is not described Adamts antigen and activity should be specified 6) How can authors explain ab anti ADAMTS appearance in moderate Covid infection ?

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript by Dolgushina et al describes an observational prospective study of 141 patients allocated to 3 groups: mild, moderate and severe COVID19. The authors report a correlation between the level and activity of ADAMTS13 and VWF antigen levels and identify a threshold ratio for VWF/ADAMTS13 blood levels that allows for the stratification of patients with moderate and severe COVID-19. Overall the study design is sound and supports a case for further investigation of ADAMTS13 levels and coagulopathy associated with COVID19 infection.

 

Comments:

1.       The authors highlight two potential mechanisms leading to VWF/ADAMTS13 imbalance namely decreased cleavage of High MW VWF multimers and or increased endothelial release of VWF. It is unclear based on the data presented which of these two predominates?

2.       Further insight into the mechanistic underpinnings of this study could be achieved by assessing overall VWF multimer distribution in patient samples. Do the authors have any evidence that patients with varying severity of disease have correlated levels of high Mw multimers?

3.       Is there any correlation between platelet thrombosis, disease severity and VWF/ADAMSTS13 ratio in the patient groups studied?

Author Response

We thank the Reviewer for the efforts in reviewing the article.

 

Point 1: The authors highlight two potential mechanisms leading to VWF/ADAMTS13 imbalance namely decreased cleavage of High MW VWF multimers and or increased endothelial release of VWF. It is unclear based on the data presented which of these two predominates?

 

Response 1: Research design and methods have been supplemented with more information.

These two potential mechanisms are parts of a system with complex regulatory mechanisms, a more detailed study of which may be the goal of further research (added to the discussion).

 

Point 2: Further insight into the mechanistic underpinnings of this study could be achieved by assessing overall VWF multimer distribution in patient samples. Do the authors have any evidence that patients with varying severity of disease have correlated levels of high Mw multimers?

 

Response 2: Indeed, ADAMTS-13 deficiency results in the accumulation of extra-large vWF multimers. We have not studied the ratio of multimers of different molecular weights; this method is quite laborious and is not often used in clinical practice. In our opinion, the change in von Willebrand factor caused by endothelial dysfunction is more significant (the role of endothelial dysfunction in covid-19 has already been studied in a large number of studies).

 

Point 3: Is there any correlation between platelet thrombosis, disease severity and VWF/ADAMSTS13 ratio in the patient groups studied?

 

Response 3: We did not find an association of platelet consumption or platelet aggregation with the severity of COVID-19 or VWF/ADAMSTS-13 ratio.

Reviewer 3 Report

The authors report on Willebrand factor and ADAMTS-13 are associated with the severity of COVID-19 disease.

Comments:

1--You describe mild, moderate, and severe, but never state how you determined this? Without more specific data and criteria, this report is difficult to interpret.

2- Other factors are also important for prediction, but what are the outcomes? 

3-- What are other data and lab values?

4-  In summary, far more clinical information is needed to define clinical outcomes in this report.   

Author Response

We thank the Reviewer for the efforts in reviewing the article.

 

Point 1: You describe mild, moderate, and severe, but never state how you determined this? Without more specific data and criteria, this report is difficult to interpret.

 

Response 1: We have included the definition for mild, moderate and severe COVID-19.

The severity of COVID-19 was established on the basis of the interim guidelines of the Ministry of Health of Russian Federation “Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19)”:

- mild COVID-19:

• body temperature <38 °C, cough, weakness, sore throat;
• absence of criteria for moderate and severe COVID-19;

- moderate COVID-19:

• body temperature >38 °C;
• respiratory rate >22 per minute;
• shortness of breath during physical exertion;
• changes in CT (radiography), typical of a viral lesion;
• SpO2 <95%;
• serum CRP >10 mg/L.

- severe COVID-19:

• respiratory rate >30 per minute;
• SpO2 ≤93%;
• PaO2/FiO2 ≤300 mmHg;
• decreased level of consciousness, agitation;
• unstable hemodynamics (systolic blood pressure less than 90 mm Hg or diastolic blood pressure less than 60 mm Hg, diuresis less than 20 ml/hour)
• arterial blood lactate >2 mmol/l;
• qSOFA >2 points.

 

Point 2: Other factors are also important for prediction, but what are the outcomes?

 

Response 2: No acute thrombosis was recorded during the study. There were no deaths, all patients were discharged from the hospital in a satisfactory condition (added to Materials and Methods).

 

Point 3: What are other data and lab values?

 

Response 3: We have added a table with characteristics of patients (table 1).

Evaluation of other indicators, such as parameters of the general blood test and parameters of the general hemostasis system, are very important. However, they are mostly known already and their assessment was not the aim of this study.

 

Point 4: In summary, far more clinical information is needed to define clinical outcomes in this report.   

 

Response 4: We tried to expand the clinical part of the article as much as possible without compromising the main content. Clinical risk factors for the development of a more severe course of COVID-19 in our study were: (1) male gender; (2) older age (56 years and older); (3) higher BMI (≥25 kg/m2); (4) A(II) blood group; (5) cardiovascular disease; (6) arterial hypertension; (7) diabetes mellitus. This was consistent with literature data.

Round 2

Reviewer 3 Report

I have no further comments.