Consensusbased clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID19related illness

Background:Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in

## | introduc ti on
 [bib_ref] Autopsy findings and venous thromboemobolism in COVID-19, Wichmann [/bib_ref] Other studies have revealed an increased incidence of venous thromboembolism (VTE) in patients hospitalized with COVID-19 compared to those with other underlying illnesses, [bib_ref] Incidence of venous thromboembolism in hospitalized patients with COVID-19, Middeldorp [/bib_ref] [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] and one large retrospective analysis indicated a significantly reduced mortality among hospitalized patients with COVID-19 who received anticoagulant thromboprophylaxis, predominantly with low molecular weight heparin (LMWH). [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] All of these studies were principally, if not exclusively, comprised of adult patients. Twenty surveys were sent, and there were 18 respondents (response rate, 90%), consisting of 11 pediatric hematologists (North America, n = 6; South America n = 1; Europe, n = 1; Asia/ Middle East, n = 2; Australia/New Zealand, n = 1) and seven pediatric intensivists (North America, n = 2; South America, n = 1;

## | me thods
Europe, n = 3; Asia and Australia/New Zealand, n = 1). Specific management approaches serving as the basis for consensus recommendations reported here (see Results) had received affirmative votes by 61% to 89% of respondents; agreement of >80% was designated as "strong consensus" while agreement of 60 to <80% was designated as "weak consensus," Priorities for future research were evaluated for themes, which were then ranked in order of frequency of mention across the respondents. The four most frequently cited themes (ranging from 39% to 78% of respondents) were used to inform consensus-based recommendations reported here on priorities for future research. In addition, to inform the background for this work and the discussion of our survey findings and recommendations, the first author performed a comprehensive review of the English-and French-language literature on pediatric COVID-19 on 08 August 2020, using the search term strategy ["pediatric" OR "children"] AND ["COVID-19" OR "SARS-CoV-2"].

## | re sults

## | clinical recommendations
Based on a consensus of expert opinions (see survey Methods, above), we suggest that (see also 3. Marked thrombocytopenia (eg, platelet count <20 000-50 000/ L), hypofibrinogenemia (eg, fibrinogen activity <100 mg/dL by Clauss method), recent ISTH-defined major bleeding, 20 and concomitant aspirin administration at doses >5 mg/kg/d likely con-

## | research priorities
Based on a consensus of expert opinions (see survey Methods, above), we identify the following priorities for future research: [fig_ref] Table 2: Previous history of VTE 19  First-degree family history of VTE before... [/fig_ref] 

## | d iscuss i on
In this scientific statement, we provide consensus-based recommen- itations of the present work, is that our consensus-based recommendation (and indeed, the survey responses from experts themselves) are informed by a paucity of evidence from published pediatric experience and research; therefore, it will be critical that these consensus-based recommendations are updated as more evidence emerges on anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness.
Notwithstanding the aforementioned limitations, we hope that these consensus-based recommendations will help to guide future research and aid in clinical decision making on anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illness.
Although not mentioned among these recommendations, the treatment of underlying disease also deserves emphasis in any discussion of optimal thromboprophylaxis. Because the systemic proinflammatory response elicited by SARS-CoV-2 mediates marked hypercoagulability, and because SARS-CoV-2 angio-invasion appears to induce endothelial damage, evidence-based immunomodulatory and antiviral strategies-particularly in MIS-C-may provide important adjunctive therapies to reduce the risk and extent of thromboembolic complications in children hospitalized for COVID-19-related illnesses.

## Co n fli c t s o f i nte r e s t
None of the authors has relevant conflicts of interest to declare.

## Auth o r co ntr i b uti o n s
N Goldenberg: designed the survey study, collected the data, analyzed the data, interpreted the findings, drafted the manuscript, revised the manuscript, approved submission of the final draft of the manuscript. All other authors: gave input to the survey design, interpreted the data, gave critical input to the manuscript, approved submission of the final draft of the manuscript.

## O rci d

## Graeme maclaren
https://orcid.org/0000-0002-1307-4274
Sarah O'Brien https://orcid.org/0000-0001-8855-9746
Ayesha Zia https://orcid.org/0000-0003-3283-0415
[fig] 1: Characterization of VTE risk and identification of VTE risk factors in children (particularly those hospitalized) with COVID-19-related illness (including MIS-C), via multi-institutional cohort studies, registries, and retrospective studies; 2. Determination of the safety and efficacy of anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness (including MIS-C), via cooperative multicenter clini-dimer >5 times upper limit of normal values Non-COVID-19 clinical risk factors for HA-VTE (see [/fig]
[table] Table 2: Previous history of VTE 19  First-degree family history of VTE before age 40 years or unprovoked VTE 19  Known thrombophilia (eg: protein S, protein C, or antithrombin deficiency; factor V Leiden; factor II G20210A; persistent antiphospholipid antibodies) 19  Pubertal, post-pubertal, or age >12 years 15  Receiving estrogen-containing oral contraceptive pill  Status-post splenectomy for underlying hemoglobinopathy a [/table]