Accepted Article

Article type : Original Article

TITLE: SARS-COV-2 ASSOCIATED COAGULOPATHY AND THROMBOEMBOLISM

PROPHYLAXIS IN CHILDREN: A SINGLE CENTRE OBSERVATIONAL STUDY.

Giovanni Del Borrello1, MD, Isaac Giraudo1, MD, Claudia Bondone2, MD, Marco Denina3, MD, Silvia
Garazzino3, MD, PhD, Claudia Linari4, MD, Federica Mignone3, MD, Giulia Pruccoli1, MD, Carlo
Scolfaro3, MD, Manuela Spadea1, MD, Berardino Pollio5, MD, Paola Saracco6, MD

AFFILIATIONS:
1 Sciences of Public Health and Paediatrics - University of Turin
2 Paediatric Emergency Department - University Hospital “Città della Salute e della Scienza di Torino”
3 Paediatric Infectious Disease Unit - Department of Paediatrics - University Hospital “Città della Salute e
della Scienza di Torino”
4 Laboratory Medicine - University Hospital “Città della Salute e della Scienza di Torino”
5 Immune-Haematology and Transfusion Medicine - University Hospital “Città della Salute e della Scienza
di Torino”
6 Paediatric Haematology Unit - Department of Paediatrics - University Hospital “Città della Salute e della
Scienza di Torino”

CORRESPONDING AUTHOR:
Giovanni Del Borrello, MD
E-mail: giovanni.delborrello1989@gmail.com
Address: Haematology Clinic - 1st floor (A), Regina Margherita Children Hospital, Piazza Polonia, 94,
10126, Torino, Italy
Phone: +390113135259

RUNNING HEAD: COAGULATION PARAMETERS IN PAEDIATRIC COVID-19

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/JTH.15216
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Accepted Article
ESSENTIALS
- Data concerning haemostatic complications in children hospitalised for COVID-19/MIS-C are lacking
- D-dimer values may not parallel disease severity in pediatric COVID-19 but increase in MIS-C
- Laboratory assessment at multiple time points revealed no signs of consumptive coagulopathy in both
conditions
- COVID-19/MIS-C pediatric patients with multiple prothrombotic risk factors might benefit from
anticoagulant prophylaxis

SUMMARY
BACKGROUND: Multiple investigators have described an increased incidence of thromboembolic events
in SARS-CoV-2 infected individuals. Data concerning haemostatic complications in children hospitalised
for COVID-19/MIS-C are scant.
OBJECTIVES: To share our experience in managing SARS-CoV-2 associated pro-coagulant state in
hospitalised children.
METHODS: D-dimer values were recorded at diagnosis in children hospitalised for SARS-CoV-2 related
manifestations. In moderately to critically ill patients and MIS-C cases, coagulation and inflammatory
markers were checked at multiple time-points and median results were compared. Pro-thrombotic risk
factors were appraised for each child and thromboprophylaxis was started in selected cases.
RESULTS: 35 patients were prospectively enrolled. D-dimer values did not discriminate COVID-19 of
differing severity, whereas were markedly different between the COVID-19 and the MIS-C cohorts. In both
cohorts, D-dimer and C Reactive Protein levels increased upon clinical worsening but were not
accompanied by decreased fibrinogen or platelet values, with all parameters returning to normal upon
disease resolution. 6 patients had multiple thrombotic risk factors and were started on pharmacological
thromboprophylaxis. No deaths, thrombotic or bleeding complications occurred.
CONCLUSIONS: COVID-19 pediatric patients show mildly altered coagulation and inflammatory
parameters; on the other hand, MIS-C cases show laboratory signs of an inflammatory driven pro-coagulant
status. Universal anticoagulant prophylaxis in hospitalised children with SARS-CoV-2 related

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 manifestations is not warranted, but may be offered to patients with other pro-thrombotic risk factors in the
Accepted Article
context of a multi-modal therapeutic approach.
KEYWORDS: Blood Coagulation Tests, Child, COVID-19, Enoxaparin, Thrombosis
INTRODUCTION
With approximately 50 million people infected, over 1 million deaths (as of mid-October 2020)1
and innumerable economic losses, SARS-CoV-2 related disease (COVID-19) is among the most
severe pandemics to seize the world since the 1918 “Spanish Flu”. As this infection spread across
the globe, the medical literature has been flooded by clinical observations and tentative
pharmacologic trials, all striving to better inform bedside practice. Nonetheless, as this pandemic
reaches its twelfth month, there are still many uncertainties regarding the best therapeutic
approach to this elusive disease.
A pattern of increased thrombotic risk among adult patients (especially those most greatly
affected) has insofar emerged2, resulting from an inflammatory-driven endothelial dysfunction and
hypercoagulable state3,4, and translating into a high rate of multi-organ macro- and micro-vascular
injury, and death5. Thus, international societies and multiple national healthcare institutions have
offered guidance on how to evaluate for coagulopathy and implement an anticoagulation
prophylaxis protocol in patients admitted with a diagnosis of COVID-196-8.
The available evidence concerning COVID-19 paediatric patients draws a reassuring picture in
terms of morbidity and mortality, with a low incidence of thrombotic complications (widely un-
reported in even the most severely-affected patients9,10). Nonetheless, the ISTH-endorsed
Consensus-Based Clinical Recommendations for Anticoagulant Thromboprophylaxis in Children
Hospitalized for COVID-19-Related Illness suggest a low threshold of clinical suspicion (i.e. a
single additional pro-thrombotic risk factor) and an explicit reliance on D-dimer values to guide
the choice of pharmacologic prophylaxis11.
To further complicate the issue, children may develop a SARS-CoV-2 related inflammatory
syndrome (i.e. MIS-C, Mutisystem Inflammatory Syndrome in Children) that usually arises weeks
after an infection. This condition may present with a wide range of cardiovascular complications,
ranging from arrhythmias to coronary arteries aneurysm, from myocarditis to sudden cariogenic
shock, tends to evolve rapidly and may come to the attention of the practicing paediatrician at its
early stages, characterised only by persistent fever, various cutaneous manifestations and mild-to-
moderate gastrointestinal disorders (i.e. mimicking COVID19-related symptoms in children)12.

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 As the haemostatic impact of these two related conditions is still not clearly defined in children,
Accepted Article
we hereby share our preliminary experience in evaluating and managing the SARS-CoV-2—
related pro-coagulant state and thromboembolism risk in hospital-admitted children.

MATERIALS AND METHODS

Patient population
We performed a single-center observational cohort study at a tertiary care children hospital
(Regina Margherita Children Hospital) in Turin, Italy. We prospectively enrolled all paediatric
patients (birth to 21 years old) with SARS-CoV-2-related acute clinical manifestations requiring
hospitalisation. Current or previous SARS-CoV-2 infection was confirmed by either Real Time-
PCR performed on nasal and pharyngeal swabs (SimplexaTM COVID-19 Direct Reaction Mix),
and/or by anti-S specific antibodies (In3diagnostic Eradikit COVID19), as previously described14.
Patients were labeled in terms of severity according to the following pragmatic parameters (largely
in agreement with internationally-recognised indications12): mild disease was defined as acute
upper respiratory or gastrointestinal symptoms, without systemic involvement or abnormal
findings on chest radiographs or lung ultrasounds; moderate disease was defined as imaging-
confirmed pneumonia with mild respiratory distress and no oxygen requirement, or as
gastroenteritis with dehydration requiring intravenous fluids; severe disease was defined as
oxygen-dependent imaging-confirmed pneumonia, severe gastroenteritis or overt sepsis; critical
illness was defined as single- or multi-organ failure requiring Pediatric Intensive Care Unit (PICU)
admission and monitoring and/or mechanical ventilation. MIS-C cases were defined according to
CDC criteria13. Informed consent was obtained from the parents of all minors involved in this
study, as well as from the patients themselves, if older than 14 years of age. The study protocol
was approved by the local Ethics Committee.

Laboratory analysis
A D-dimer assay were performed at diagnosis in all hospitalised patients. In order to uncover the
evolution of coagulation and inflammatory parameters, a complete blood count, Prothrombin Time
(PT), fibrinogen, D-dimer and C Reactive Protein (CRP) quantification were recorded at three
time points (i.e. hospital admission, day of worst clinical manifestations, symptoms resolution)
only in a subset of hospitalised patients (namely, the moderately to critically-ill COVID-19

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 patients and the MIS-C cases). Serial measurements were not performed in patients with
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persistently mild clinical disease, as we did not want to burden these children with repeated blood
draws which would have likely not impacted on their clinical management. We defined the day of
worst clinical manifestation retrospectively, taking into consideration all the usual clinical
parameters and vital signs (e.g. temperature, respiratory rate, work of breathing, number of bowel
movements, etc…), and we used the laboratory values collected within 24h of that day. In case of
mechanically-ventilation or extracorporeal circulation were instituted, we made sure to include
only laboratory values collected before such measures were started, given their impact on
coagulation and inflammatory markers.
D-dimer values were tested with an automated, latex enhanced turbidimetric immunoassay
(HemosIL® D-Dimer HS 500, Instrumentation Laboratory (IL)), upper limit of normal 500 ng/ml
expressed as Fibrinogen Equivalent Units), fibrinogen values were determined with an automated
assays based on the Clauss method (HemosIL® Q.F.A. Thrombin (Bovine), IL) and PT was
quantified by means of a recombinant tissue factor-based reagent (HemosIL® RecombiPlasTin
2G, IL - local average value is 11 s). All coagulation testing was performed on ACL TOP systems
and underwent a two-stage quality control.
Thrombotic risk appraisal and anticoagulation management
Our institutional Risk Assessment Model (RAM) was applied as previously described14 (Table 1).
For the purpose of the RAM, MIS-C patients were attributed a starting score of +2 pts and
COVID-19 patients were attributed a starting score of +1 pt in case of at least “moderate” disease
severity. Our approach was compared with the ISTH-endorsed recommendations. Asymptomatic
venous thromboembolic events (VTE) were not screened for by means of ultrasonography or
computed tomography imaging.

Statistical analysis
Statistical analyses were performed with Microsoft Office Excel 2019 and R version 4.0. Data are
shown as median for continuous variables and as percentage for categorical variables. The
Shapiro-Wilk test was performed to assess if continuous variables were normally distributed. The
Kruskal-Wallis test was performed for comparison of the median values of continuous variables.
Proportions of categorical variables between groups were compared with Fisher's exact test. A
two-sided p-value less than 0.05 was judged statistically significant. Missing values were imputed
by mean substitution.

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Accepted Article
RESULTS
Between March the 1st and October the 15th 2020, 36 children with SARS-CoV-2-related
illnesses were admitted to the Infectious Disease Unit of Regina Margherita Children Hospital,
including 30 COVID-19 cases (median age 3 years, range 10 days to 19 years) and 6 MIS-C cases
(median age 6,8 years, range 4,5 to 12,5 years) (Table 2). Among the COVID-19 cases, 11 (40%)
patients were female, 14 (47%) patients followed a mild course, 10 (33%) presented with a
moderate disease, 3 (10%) showed a severe illness and 3 (10%) required admission to the PICU.
In all, we identified 6 MIS-C cases (17%). Among the MIS-C cases, 3 (50%) were girls and only
one (16,5%) required admission to the PICU. Overall, mild COVID-19 cases were younger
(median 0.8 vs 3.9 y.o., p = .116) and showed a lower rate of co-morbidities (14% vs 56%,
p=0.064) compared to the rest of the COVID-19 cohort. Co-morbidities included hemato-
oncologic diseases (6 patients), congenital heart diseases and obesity (2 patients each), chronic
respiratory diseases, diabetes mellitus and rheumatological diseases (1 patient each). 2 patients
had multiple co-morbidities. A single patient was excluded from further analysis, as her clinical
and laboratory picture was likely confounded by the co-occurence of pneumococcal sepsis and
multi-organ failure in the context of previously undiagnosed sickle cell disease.
Among COVID-19 patients, D-dimer values were not statistically different between disease
categories (mildly affected, medan value 814 ng/ml vs moderately affected, median value 916
ng/mL vs severly/critically affected 823 ng/ml, p = .46). In fact, in at least 5 cases, all moderately
to critically ill, D-dimer values above 500 ng/ml might have been due to a baseline condition,
given the facts that D-Dmer was persistently above the upper level of normal even after complete
disease resolution and that those five patients had all comorbidities known to be associated with
increased baseline D-dimer values (e.g. Acute Lymphoblastic Leukemia, sickle cell disease, cystic
fibrosis). We suspect that also two mildly affected newborn might have baseline increased values,
although we did not collect a sample upon symptoms resolution. Nonetheless, repeating
calculations upon removal of these patients did not change the overall results (data not shown).
Furthermore, coagulation and inflammatory markers did change significantly over time in
moderately-to-critically ill COVID-19 patients (Figure 1): D-dimer levels increased slightly at the
peak of clinical manifestations, returning to normal upon disease resolution (median values of 916
vs 1200 vs 416 ng/ml, respectively, p = 0.159 and < 0.001). Concurrently, fibrinogen values
stayed at the upper level of normal during the course of the disease, returning to normal upon

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 disease resolution (median values 373 vs 348 vs 233, respectively; p = .101 and p= .003),
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consistently with a mild inflammatory acute phase response (CRP levels of 9 vs 26 vs 1 mg/L,
respectively; p = 0.330 and p = .0048). Platelet remained globally unchanged over the whole
course of the disease, with a trend to higher counts upon recovery (223 vs 225 vs 292x109/L, p=
0.938 and p = 0.153); PT values were within normal values at all time points. 8 patients, 7 in the
moderate disease category and 1 the severe disease category, presented the peak of clinical
manifestations upon diagnosis; in these cases, only two values were recorded for each blood
parameter (included in the intermediate and last time points, respectively), and the third one was
imputed as missing value.
Comparing D-dimer values upon admission, MIS-C cases showed significantly higher values than
COVID-19 cases as a whole (1906 vs 817 ng/mL, p < 0,001). In fact, a D-dimer value above 1000
ng/mL (2 times the ULN) showed a good diagnostic accuracy to distinguish between COVID-19
and MIS-C cases (sensitivity 100%, 95%CI 54.07% to 100.00%; specificity 83.33%, 95%CI
62.62% to 95.26%). On the other hand, CRP values were actually more accurate (median values
215,5 vs 5 mg/L, with values > 100 mg/L being 100% sensitive and specific). With respect to the
changing of coagulation and inflammatory parameters over time in MIS-C patients (Figure 1), D-
dimer (1906 vs 3980 ng/mL, p = 0.05466), fibrinogen (580 vs 650 mg/dL, p = 0.10931) and CRP
(215 vs 289 mg/L, p = 0..20018) increased paralleling a worsening of the patient’s clinical
condition, while platelet slightly decreased (144 vs 110x109/L, p = 0.10931) - although this didn’t
reach statistical significance due to the low number of cases. All values normalised upon disease
resolution, with a trend towards higher than normal platelet values (D-dimer 296 ng/mL,
fibrinogen 221 mg/dL, CRP 1 mg/L and PLT 370x109/L, p < 0.001). Again, PT values were
basically within the range of normal at all time points (PT ratio 1,1 vs 1,2 vs 1,1, p = 0,458).
Prophylactic anticoagulation (PA) was started in 6 patients (14%) (Table 3). These patients
received enoxaparin 100 U/kg every 24h, except for two patients, who received unfractionated
heparin (UFH) at 10 U/kg/h given the concurrent high bleeding risk. PA was continued until
discharge or thrombotic RFs resolution/attenuation, whichever came earlier. No patient received
acetylsalicylic acid. No patient died, and no thrombotic or bleeding complications were observed.
If we had applied the ISTH-endorsed recommendations, we should have offered PA to 14 patients
(40%), including all our MIS-C cases; also, we should have suggested our single patient with
persistently elevated D-dimer values to continue enoxaparin at home11.

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 DISCUSSION
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Multiple investigators have reported clinical and anatomo-pathological evidence of an increased
incidence of thromboembolic events in adult COVID-19 patients2,15, with up to 57% of critically
ill individuals developing symptomatic venous or arterial thrombotic complications despite
pharmacological prophylaxis2, 16-19. From what could be gained so far, COVID-19 related
coagulopathy is a multi-pronged process consisting of endothelialitis and inflammatory-driven
endothelial dysfunction20, platelet activation21 and increased interaction with neutrophils and
monocytes22, increased tissue factor expression by monocytes23, increased neurotrophic
extracellular traps (NET) production and delayed removal24, deregulated complement activation25
and fibrinolysis shutdown26, to name a few. Even though the exact sequence of events has not
been clarified, a deregulated immunological process starting at the interface between alveoli and
lung endothelium seemingly determines a local activation of haemostasic processes leading to
platelets, neutrophils and fibrin deposition (i.e. in situ micro- and macro-vascular pulmonary
thrombosis), which likely contributes to the overall respiratory insufficiency and facilitates the
systemic spread of inflammation and coagulopathy.
Many study groups have tried to define laboratory markers who could better describe and predict
disease evolution, in order to guide treatments, among which one of the most studied is D-dimer27.
Unfortunately, D-dimer testing has numerous well known drawbacks, including lack of
specificity28, and its role in term of VTE prediction is still controversial29: it tend to increase in all
inflammatory conditions, which are per se associated with an increase in the thrombotic risk,
without a clear association between the intensity of D-dimer alteration and the magnitude of the
thrombotic risk; in fact, D-dimer is not currently included in the usually applied VTE RAMs in
adult population.
From the earlier reports of adult COVID-19 cases, D-dimer levels upon hospital admission and/or
its increase during hospital stay have been linked to worse clinical outcomes and thrombotic
complications. These observations led many clinicians to use increasing D-dimer values as a
trigger to intensify their anticoagulation prophylaxis protocol, increasing the administered dose of
anticoagulant up to full therapeutic levels30, in the hope of counteracting the pro-coagulant status
so frequently observed. This practice lacks a solid evidence-based foundation and may be
associated with increased bleeding risk31,32, which is well-known to accompany hyper-
inflammatory conditions in general and microvascular complications in particular. Also, the fact
that the thrombotic process is mainly inflammatory-driven (i.e. immunothrombosis) and that

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 inflammatory biomarkers ( e.g. CRP, InterLeukin-6 and soluble triggering receptor expressed on
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myeloid cells, s-TREM) have proven to be even better predictors than D-dimer in terms of clinical
outcome33 point to a multimodal approach, possibly combining agents active at different levels of
the immuno-thrombotic process34,35, as better suited to overcome this difficult challenge. Luckily,
multiple randomised trial are ongoing to provide the practicing community with solid data.
Paediatric COVID-19 patients usually follow a less severe course, with a very low mortality rate
(less than 0.1% according to data released by the Italian National Institute of Health, ISS);.even,
critically ill children have better outcomes of their adult counterparts9,10,36. Thrombotic
complications does not appear to occur more often that what is expected in hospitalised children: a
Italian observational study (unpublished data, curtesy of Dr. Garazzino) recorded a prevalence of 1
VTE in over 350 hospitalised pediatric COVID-19 cases, compared to an estimated incidence of
hospital-acquired VTE in the general pediatric population of approximately 1/20037,38. MIS-C
apparently conveys a risk of thrombosis of approximately 3.5% (which may be overestimated,
given the paucity of reports that details the observed numbers of VTE)39, likely driven by a pro-
coagulant highly inflammatory milieu and increased venous stasis secondary to decreased
myocardial function. In fact, this observed risk is also lower than what would be expected in
pediatric myocarditis (approximately 6%40).
Our single-center cohort appear to be similar in composition to the comprehensive report by
Duarte-Salles T. et al41 (available only an pre-print), with a prevalence of severe respiratory
manifestations of 17% among hospitalised patients with COVID-19. In terms of laboratory
alterations, our COVID-19 cohort displayed only mildly increased D-dimer values across all
severity categories, consistent with previous descriptions9,10,42. Moreover, our dynamic evaluation
of laboratory data confirmed that clinical worsening - albeit mirrored by spiking D-dimer values,
especially in the MIS-C cohort - was not associated with fibrinogen consumption, with all patients
recovering without thrombotic sequelae. On the other hand, our MIS-C cohort showed markedly
increased values of both CRP and D-dimer, as previously reported, which rapidly decreased within
48 to 72h of corticosteroid therapy administration; only a single patient, who never received
steroids as she did not show significant cardiovascular involvement, maintained increased D-
dimer values upon disease resolution (2637 ng/mL). Again, these observations corroborate the
view of D-dimer in children being a mere low-specificity marker of the intensity of the
inflammatory response, without a direct link with increased thrombotic risk. Indeed, contrary to
the adult experience, D-dimer has generally proved to be an unreliable biomarker for diagnosing

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 or predicting thrombotic complications in children: it shows low accuracy in identifying
Accepted Article
pulmonary embolism43 and in predicting venous thrombosis recurrence44. Finally, a recent report
by Al-Ghafry M. et al42 described viscoelastic testing consistent with a pro-thrombotic state
(increased maximum clot firmness, MCF, in both EXTEM and FIBTEM) in 8 COVID-19
pediatric patients, with no correlation between D-dimer values and MCF. Thus, D-dimer may be a
poor choice as a parameter to guide therapeutic decisions in terms of anticoagulant prophylaxis.
We and others have observed that the pro-coagulant state induced by COVID-19 is unlikely to
translate in clinically relevant thrombotic complications in children. Pediatrics’ central dogma is
that children are not just little adults. This tenet holds particularly true in the field of thrombotic
disorders, as it is a widely recognised notion that children develop far less thrombotic
complications compared to adults, even in high-risk scenarios (e.g. severe trauma, complex
orthopaedic surgeries, critically-ill diseases)45. The reasons behind this reduced susceptibility are
still non completely understood and likely lie on both a more robust array of natural anticoagulants
(i.e. increased levels of alpha-2-macrogloulin) and healthier vascular linings (i.e. reduced
cumulative exposure to substances that are toxic to the endothelium - pollution, smoking,
metabolism by-products)46. So, contrary to adult indications, we believe that universal
pharmacologic prophylaxis in the paediatric population is unwarranted and that raised D-dimer
values should not be taken into consideration, given its mere role as a marker of the acute phase
response in children. On the other hand, as hinted by our data and corroborated by recent case-
series36,47 this disease tends to follow a more severe course in the presence of co-morbidities (i.e.
obesity, active malignancy, sickle cell disease) that enhance the baseline thrombotic risk,
especially by priming the vascular surface towards endothelial dysfunction. This baseline risk
would be boosted by COVID-19 and could be counteracted by a targeted PA course with
enoxaparin or UFH, which might also contribute anti-inflammatory activity48. Therefore, we
suggest to evaluate every child hospitalised with COVID-19 for possible concurrent pro-
thrombotic risk factors, and to consider a personalised PA strategy accordingly. Also, given the
concerning report by Duarte-Salles T. et al41 of a bleeding rate of 2-3% in hospitalised children
with COVID-19 (in a cohort where over 30% of patients received some sort of anticoagulation),
we suggest to carefully balance the thrombotic and the haemorragic risks for every child.
Our study has several limitations. First, it comprises a small number of patients, so its result may
not be generalisable and should be interpreted with caution. Secondly, our patient cohort was quite
heterogeneous, including 3 patients with Acute Lymphoblastic Leukaemia at different stages of

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 their treatment protocol, which impacted on the platelet valued recorded (both in terms of being
Accepted Article
surreptitiously low and of being confounded by transfusions). It must be noted, though, that
consistently with the absence of a consumptive process, none of those children showed platelet
transfusion refractoriness in the course of COVID-19. Thirdly, D-dimer assays in paediatrics are
prone to pre-analytic confounders (e.g. quality of the blood draw, age, baseline conditions) which
may limit their reliability. Though acknowledging these possible drawbacks, we tried to minimise
them by performing multiple assessments for each patient: the fact that our data are consistent and
show a time-dependent and pathophysiologically plausible trend corroborates their validity; also,
excluding patients with persistently raised D-dimer values even after disease resolution did not
change the overall results. Also, as the clinical significance of asymptomatic VTE in children is
controversial, we decided not to systematically screen for thromboembolic complications, relying
instead only on clinical judgment: thus, we cannot exclude that an asymptomatic event might have
been missed. Finally, we did not consistently check for abnormalities in other coagulation
parameters (e.g. protein C, protein S, ATIII, viscoelastic tests), thus we may have overlooked
important aspects of COVID-19 associated coagulopathy in children. Given the speculative nature
of this study without an immediate clinical benefit for our participants, however, we opted not to
burden patients with excessive blood draws. Following the results of this preliminary analysis, a
protocol was devised to include these tests in the prospective assessment of moderate to critically
ill cases.
In conclusion, D-dimer values apparently do not distinguish mildly-affected COVID-19 patients
from more severely affected cases. On the other hand, D-dimer and CRP values accurately
distinguish MIS-C cases from COVID-19 cases, as reflected by a heightened
immunological/inflammatory component in the former. We did not found evidence in neither case
that a consumptive coagulopathy was in place, given only slightly alteration in platelet counts and
fibrinogen values. Contrary to adult guidance, universal anticoagulant prophylaxis in hospitalised
children suffering from COVID-19 is not advised, but might be considered in highly selected
cases with multiple concurrent pro-thrombotic risk factors without taking into account D-dimer
values.

ADDENDUM

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 G. Del Borrello designed the study, interpreted the data and drafted the manuscript; I. Giraudo, C.
Accepted Article
Bondone, G. Pruccoli, M. Spadea collected and analysed the data, and contributed to drafting the
manuscript; M. Denina, S. Garazzino, C. Linari, F. Mignone, B. Pollio and P. Saracco helped
interpret the data and critically revised the manuscript. All authors approved the final version of
the manuscript. No author has any real or potential conflict of interest to disclose.

ACKNOWLEDGMENTS
We cordially thank G. Iegiani for her contribution in drafting the graphs for this manuscript.

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 non‐critically ill patients with Covid‐19: The Padua province experience. J Thromb Haemost, 18(10),
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 48 Young E. The anti-inflammatory effects of heparin and related compounds. Thrombosis Research 2008;
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LEGENDS
Table 1 - Institutional Risk Assessment Model
* compared to baseline mobility status; ** based on positive cultures or characteristics of the skin
surrounding the catheter exit site; *** consider therapeutic anticoagulation; § protein S, protein C, or
antithrombin deficiency; homozygosity or compound heterozygosity for factor V Leiden and/or factor
II G20210A; persistent triple-positive antiphospholipid antibodies; ° one 1st and/or multiple 2nd degree
relative with unprovoked/minimally provoked deep venous thrombosis, pulmonary embolism, myocardial

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 infarct or stroke < 50 years or recurrent unexplained late-occurring abortions (> 2); # current spot urinary
Accepted Article
protein to creatinin ratio above 2; ^ oestrogen-containing oral contraceptive pill, systemic steroids (> 1-2
mg/kg/die of prednisone equivalent) for over 2 weeks, L-Asparaginase in the previous 3 weeks.
Abbreviations used: BMI = Body Mass Index; BQM = Braden Q Mobility score; CNS = Central Nervous
System; CVC = Central Venous Catheter; EF = Ejection Fraction; IBD = Inflammatory Bowel Disease;
LIC = Localised Intravascular Coagulation; ntCICC = non-tunnelled Centrally Inserted Central Catheter;
PICC = Peripherally Inserted Central Catheter; PICU = Pediatric Intensive Care Unit; tCICC = tunnelled
Centrally Inserted Central Catheter; TPN = Total Parenteral Nutrition; SLE = Systemic Lupus
Erythematosus

Table 2 - Clinical and demographic characteristics of pediatric hospitalised patients with SARS-
CoV-2 related manifestations. # values recorded upon hospital admission, data displayed as median and
overall range; * the D-dimer value of 1800 ng/mL was recorded in a mildly-affected newborn; **the D-
dimer value of 2750 ng/mL was recorded in a critically-affected sickle cell disease patient.
Abbreviations used: CRP = C Reactive Protein; MIS-C = Multi-Inflammatory Syndrome in Children.

Table 3 - Clinical description of patients who received prophylactic anticoagulation.

Abbreviations used: BQM = Braden Q Mobility score; CVC = Central Venous Catheter; TS = Tanner
Stage.

Table 1

ITEM SCORES

AGE/PUBERTAL
IF over 10 years old or Tanner stage above 2, + 1 pt; otherwise -1 pt
STAGE

MOBILITY* IF BQM 1, +1 pt; IF BQM 2-3, 0 pt; IF BQM 4, -1 pt

IF Port or tCICC, +1 pt; IF PICC, +1,5 pts; IF ntCICC or inserted within the previous 2 weeks, +2 pts;
CVC IF TPN or hyperosmolar drugs infusion, add +0,5 pt; IF catheter infection**, add + 1 pt; IF > 2 catheter
blockages requiring fibrinolytic infusion, add +1 pt

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 IF bacterial sepsis or severe systemic viral infection or severe localised bacterial infection (e.g.
INFECTIONS
Accepted Article osteomyelitis) +1 pt

IF personal history of VTE or known major thrombophilia§, +3 pts; IF known minor thrombophilia, +
THROMBOPHILIA
1pt; IF positive family history° +1 pt

IF PICU admission lasting over 48h within the previous 2 weeks or major surgical operation within the
TRAUMA/SURGERY
previous 2 weeks: +1; IF major orthopaedic operation (upper extremity excluded) within the previous 2
/PICU
weeks, + 2 pts; if major trauma within the previous 2 weeks,+2 pts

IF previous cardiac disease requiring anti-platelet agents, +3 pts; IF chronic pulmonary hypertension, +2
CARDIOVASCULAR
pts; if acute decrease of EF to 35-45%, + 2 pts; if acute decrease of EF to 25-35% or inotropes
COMORBIDITIES
requirement, + 4pts***; if acute decrease of EF to less than 25% or persistent arrhythmia, +6***

Obesity (BMI over 95° centile), +1 pt

Sickle Cell Disease, +1 pt; IF vaso-occlusive crisi or acute chest syndrome, +2 pts
Status-post splenectomy for underlying haematological disease, +1 pt
Underlying inflammatory disease (eg. SLE, IBD), +1 pt; IF acute flare of underlying disease, +2 pts
Nephrotic syndrome#, +2 pts
OTHER Active malignancy: leukemia, +2 pts; localised solid tumor, +1 pt; metastatic solid tumor, +2 pts;
COMORBIDITIES vascular compression/invasion by solid tumor, +3 pts; CNS tumor, 0 pt; vascular tumor or malformation
with LIC, +3 pts
Respiratory exacerbation due to Cystic Fibrosis, +1 pt
Pro-thrombotic drugs^, +1 pt
Mechanical ventilation, + 1 pt
Cigarette smoking, +1 pt

Known bleeding disorder or personal/family history suggestive of a bleeding disorder

Severe uncontrolled hypertension
BLEEDING RISKS Moderate-to-severe head trauma or neurosurgical operation in the previous 72h
Major surgical operation in the previous 24h
Active gastrointestinal lesions

IF SUM OF SCORES 3 PTS OF HIGHER IN THE ABSENCE OF BLEEDING RISKS,

CONSIDER PROPHYLACTIC ANTICOAGULATION AND HAEMATOLOGY CONSULT

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Accepted Article
Table 2

Clinical Gender Comorbidities D-Dimer# CRP*

Age
category (F/M) (Y/N) (ng/mL) (mg/L)

Mild COVID-19 9m 800 4

4/10 2/16
(14) (10 d - 17 y) (200-1800*) (0-20)

Moderate
3,5 y 900 5
COVID-19 2/8 3/7
(2 m - 5,5 y) (200-1700) (0-76)
(10)

Severe-critical
7,5 y 800 25
COVID-19 3/3 6/0
(9 m - 19 y) (100-2750**) (3-42)
(6)

MIS-C 6,8 y 1900 215

3/3 0/6
(6) (4,5 - 12,5 y) (1300-4400) (120-300)

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Accepted Article
Table 3

Totale
Description
score

Patient 1 3 14 years old post-pubertal girl (TS 4) with COVID-19-driven respiratory

exacerbation of underlying cystic fibrosis,who scored 2 on the BQM in
the early course of her hospital admission

Patient 2 8 7 years old boy with MIS-C, severe myocardial involvement requiring
continuous inotropic support and placement of a non-tunnelled right-
jugular CVC, who scored 1 on the BQM over the first 10 days of his
hospital admission

Patient 3 3 15 years old obese post-pubertal boy (TS 5) with moderate COVID-19,
who scored 3 on the BQS over the course of his hospitalisation

Patient 4 6 19 years old boy (TS 5) with critical COVID-19 requiring mechanical
ventilation, who had recently undergone matched unrelated donor
Hematopoietic Stem Cell Transplantation due to relapsed Acute
Lymphoblastic Leukemia and had suffered from multiple transplant-
related complications (including EBV reactivation and fungal
pneumonia). A tunnelled CVC had been inserted approximately 6 weeks
before the current presentation.

Patient 5 3 a 6 years old obese girl with MIS-C and reduced ejection fraction (40%)
but preserved mobility

Patient 6 6 9 month-old with a previously undiagnosed Sickle Cell Disease with

critical COVID-19-induced acute chest syndrome who required
mechanical ventilation and was later escalated to veno-venous extra-
cardiac circulation (switching at that point from PA to full therapeutic
anticoagulation)

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 A B
Accepted Article Clinical classes: COVID-19 MIS-C Clinical classes: COVID-19 MIS-C

7000 400

6000
300
5000
D-Dimer (ng/ml)

CRP (mg/L)
4000
200
3000

2000
100
1000

0 0
Admission Peak Discharge Admission Peak Discharge

C D
Clinical classes: COVID-19 MIS-C Clinical classes: COVID-19 MIS-C

1000 1000

800
750
Fibrinogen (ml/dl)

PLTS (109/L)

600
500
400

250
200

0 0
Admission Peak Discharge Admission Peak Discharge

jth_15216_f1.eps

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