|

Received: 15 May 2020    Accepted: 7 December 2020

DOI: 10.1111/jth.15216

ORIGINAL ARTICLE

SARS-COV-2–associated coagulopathy and thromboembolism

prophylaxis in children: A single-center observational study

Giovanni Del Borrello1 | Isaac Giraudo1 | Claudia Bondone2 | Marco Denina3 |

Silvia Garazzino3 | Claudia Linari4 | Federica Mignone3 | Giulia Pruccoli1 |
Carlo Scolfaro3 | Manuela Spadea1 | Berardino Pollio5 | Paola Saracco6

1
Sciences of Public Health and Paediatrics,
University of Turin, Torino, Italy Abstract
2
Paediatric Emergency Department, Background: Multiple investigators have described an increased incidence of throm-
University Hospital “Città della Salute e della
boembolic events in SARS-CoV-2–infected individuals. Data concerning hemostatic
Scienza di Torino”, Torino, Italy
3
Paediatric Infectious Disease Unit,
complications in children hospitalized for COVID-19/multisystem inflammatory syn-
Department of Paediatrics, University drome in children (MIS-C) are scant.
Hospital “Città della Salute e della Scienza di
Torino”, Torino, Italy
Objectives: To share our experience in managing SARS-CoV-2–associated pro-coag-
4
Laboratory Medicine, University Hospital ulant state in hospitalized children.
“Città della Salute e della Scienza di Torino”, Methods: D-dimer values were recorded at diagnosis in children hospitalized for
Torino, Italy
5 SARS-CoV-2–related manifestations. In moderately to critically ill patients and MIS-C
Immune-Haematology and Transfusion
Medicine, University Hospital “Città della cases, coagulation and inflammatory markers were checked at multiple time points
Salute e della Scienza di Torino”, Torino, Italy
6
and median results were compared. Pro-thrombotic risk factors were appraised for
Paediatric Haematology Unit, Department
of Paediatrics, University Hospital “Città each child and thromboprophylaxis was started in selected cases.
della Salute e della Scienza di Torino”, Torino, Results: Thirty-five patients were prospectively enrolled. D-dimer values did not dis-
Italy
criminate COVID-19 of differing severity, whereas were markedly different between
Correspondence the COVID-19 and the MIS-C cohorts. In both cohorts, D-dimer and C-reactive protein
Giovanni Del Borrello, Haematology Clinic,
1st floor (A), Regina Margherita Children levels increased upon clinical worsening but were not accompanied by decreased fibrin-
Hospital, Piazza Polonia, 94, 10126, Torino, ogen or platelet values, with all parameters returning to normal upon disease resolution.
Italy.
Email: giovanni.delborrello1989@gmail.com Six patients had multiple thrombotic risk factors and were started on pharmacological
thromboprophylaxis. No deaths or thrombotic or bleeding complications occurred.
Conclusions: COVID-19 pediatric patients show mildly altered coagulation and in-
flammatory parameters; on the other hand, MIS-C cases showed laboratory signs of
an inflammatory driven pro-coagulant status. Universal anticoagulant prophylaxis in
hospitalized children with SARS-CoV-2–related manifestations is not warranted, but
may be offered to patients with other pro-thrombotic risk factors in the context of a
multi-modal therapeutic approach.

KEYWORDS

blood coagulation tests, child, COVID-19, enoxaparin, thrombosis

Manuscript handled by: Jill Johnsen

Final decision: Jill Johnsen, 7 December 2020

© 2020 International Society on Thrombosis and Haemostasis

|
522     
wileyonlinelibrary.com/journal/jth J Thromb Haemost. 2021;19:522–530.
DEL BORRELLO et al.
1 |  I NTRO D U C TI O N
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 elu-
sive disease.
A pattern of increased thrombotic risk among adult patients (espe-
cially those most greatly affected) has so far emerged,2 resulting from
an inflammatory-driven endothelial dysfunction and hypercoagulable
state,3,4 and translating into a high rate of multi-organ macro- and mi-
cro-vascular injury, and death.5 Thus, international societies and mul-
tiple national health-care institutions have offered guidance on how to
evaluate for coagulopathy and implement an anticoagulation prophy-
laxis protocol in patients admitted with a diagnosis of COVID-19.6-8
The available evidence concerning COVID-19 pediatric patients
draws a reassuring picture in terms of morbidity and mortality, with a
low incidence of thrombotic complications (widely unreported in even
the most severely affected patients9,10). Nonetheless, the International
Society on Thrombosis and Haemostasis (ISTH)-endorsed
Consensus-Based Clinical Recommendations for Anticoagulant
Thromboprophylaxis in Children Hospitalized for COVID-19--Related
Illness suggest a low threshold of clinical suspicion (ie, a single addi-
tional pro-thrombotic risk factor) and an explicit reliance on D-dimer
11
values to guide the choice of pharmacologic prophylaxis.
To further complicate the issue, children may develop a SARS-
CoV-2–related inflammatory syndrome (ie, MIS-C, multisystem in-
flammatory syndrome in children) that usually arises weeks after an
infection. This condition may present with a wide range of cardio-
vascular complications, ranging from arrhythmias to coronary artery
aneurysm, from myocarditis to sudden cariogenic shock; tends to
evolve rapidly and may come to the attention of the practicing pedia-
trician at its early stages; characterized only by persistent fever, vari-
ous cutaneous manifestations, and mild-to-moderate gastrointestinal
disorders (ie, mimicking COVID-19--related symptoms in children).12
As the hemostatic impact of these two related conditions is still
not clearly defined in children, 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.
2 |  M ATE R I A L S A N D M E TH O DS
2.1 | Patient population
We performed a single-center observational cohort study at a ter-
tiary care children hospital (Regina Margherita Children Hospital)
|
      523
Essentials
• Hemostatic complications in children hospitalized for
COVID-19/MIS-C are not well characterised.
• D-dimer values may not parallel disease severity in pedi-
atric COVID-19 but increase in MIS-C.
• Repeated laboratory assessments revealed no signs of
consumptive coagulopathy in either condition.
• COVID-19/MIS-C pediatric patients might benefit from
a tailored anticoagulant prophylaxis regimen.
in Turin, Italy. We prospectively enrolled all pediatric patients
(birth to 21  years old) with SARS-CoV-2--related acute clini-
cal manifestations requiring hospitalization. Current or previous
SARS-CoV-2 infection was confirmed by either real-time polymeri-
zation chain reaction (rt-PCR) performed on nasal and pharyngeal
swabs (SimplexaTM COVID-19 Direct Reaction Mix), and/or by anti-
S specific antibodies (In3diagnostic Eradikit COVID19), as previ-
ously described.13
Patients were labeled in terms of severity according to the fol-
lowing pragmatic parameters (largely in agreement with interna-
tionally recognized 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 require-
ment, or as gastroenteritis with dehydration requiring intravenous
fluids; severe disease was defined as oxygen-dependent imag-
ing-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
Centers for Disease Control (CDC) criteria.14 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.
2.2 | Laboratory analysis
A D-dimer assay was performed at diagnosis in all hospitalized pa-
tients. In order to uncover the evolution of coagulation and inflam-
matory parameters, a complete blood count, prothrombin time (PT),
fibrinogen, D-dimer, and C-reactive protein (CRP) quantification
were recorded at three time points (ie, hospital admission, day of
worst clinical manifestations, symptoms’ resolution) only in a sub-
set of hospitalized patients (namely, the moderately to critically
ill COVID-19 patients and the MIS-C cases). Serial measurements
were not performed in patients with persistently mild clinical dis-
ease, as we did not want to burden these children with repeated
 |
524       DEL BORRELLO et al.
blood draws that would have likely not impacted their clinical man-
agement. We defined the day of worst clinical manifestation retro-
spectively, taking into consideration all the usual clinical parameters
and vital signs (eg, temperature, respiratory rate, work of breathing,
number of bowel movements, and so on), and we used the labora-
tory values collected within 24 hours of that day. In mechanical ven-
tilation 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-en-
hanced 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 assay based on the Clauss method
(HemosIL® QFA 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.
2.3 | Thrombotic risk appraisal and
anticoagulation management
Our institutional risk assessment model (RAM) was applied as pre-
viously described13 (Table  1). For the purpose of the RAM, MIS-C
patients were attributed a starting score of + 2 points and COVID-
19 patients were attributed a starting score of + 1 point 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.
2.4 | Statistical analysis
Statistical analyses were performed with Microsoft Office Excel
2019 and R version 4.0. Data are shown as median for continu-
ous 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 com-
pared 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.
3 |   R E S U LT S
Between 01 March and 15 October 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 fe-
male, 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
1 (16.5%) required admission to the PICU. Overall, mild COVID-
19 cases were younger (median age 0.8 versus 3.9, P = .116) and
showed a lower rate of comorbidities (14% versus 56%, P = .064)
compared to the rest of the COVID-19 cohort. Comorbidities in-
cluded hemato-oncologic diseases (six patients), congenital heart
diseases and obesity (two patients each), chronic respiratory dis-
eases, diabetes mellitus, and rheumatological diseases (one patient
each). Two patients had multiple comorbidities. A single patient
was excluded from further analysis, as her clinical and laboratory
picture was likely confounded by the co-occurence of pneumococ-
cal sepsis and multi-organ failure in the context of previously undi-
agnosed sickle cell disease.
Among COVID-19 patients, D-dimer values were not statistically
different between disease categories (mildly affected, median value
814  ng/mL versus moderately affected, median value 916  ng/mL
versus severely/critically affected 823 ng/mL, P = .46). In fact, in at
least five 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-dimer was persistently above the upper level of normal
even after complete disease resolution and that those five patients
had comorbidities known to be associated with increased baseline
D-dimer values (eg, acute lymphoblastic leukemia, sickle cell disease,
cystic fibrosis). We suspect also that two mildly affected newborns
might have had baseline increased values, although we did not col-
lect a sample upon symptoms resolution. Nonetheless, repeating
calculations upon removal of these patients did not change the over-
all results (data not shown).
Furthermore, coagulation and inflammatory markers did change
significantly over time in moderately-to-critically ill COVID-19 pa-
tients (Figure  1): D-dimer levels increased slightly at the peak of
clinical manifestations, returning to normal upon disease resolution
(median values of 916 versus 1200 versus 416 ng/mL, respectively,
P = .159 and < 0.001). Concurrently, fibrinogen values stayed at the
upper level of normal during the course of the disease, returning
to normal upon disease resolution (median values 373 versus 348
versus 233, respectively; P = .101 and P= .003), consistently with
a mild inflammatory acute phase response (CRP levels of 9 versus
26 vs 1  mg/L, respectively; P  = .330 and P = .0048). Platelets re-
mained globally unchanged over the whole course of the disease,
with a trend to higher counts upon recovery (223 versus 225 versus
292 x 109/L, P = .938 and P = .153); PT values were within normal
values at all time points. Eight patients, seven in the moderate dis-
ease category and one in 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
DEL BORRELLO et al. |
      525

TA B L E 1   Institutional risk assessment model

Item Scores

Age/pubertal stage IF over 10 years old or Tanner stage above 2, + 1 pt; otherwise −1 pt
Mobilitya  IF BQM 1, +1 pt; IF BQM 2-3, 0 pt; IF BQM 4, −1 pt
CVC IF Port or tCICC, +1 pt; IF PICC, +1,5 pts; IF ntCICC or inserted within the previous 2 weeks, +2 pts; IF TPN or
hyperosmolar drugs infusion, add + 0,5 pt; IF catheter infectionb , add + 1 pt; IF > 2 catheter blockages requiring
fibrinolytic infusion, add + 1 pt
Infections IF bacterial sepsis or severe systemic viral infection or severe localized bacterial infection (eg osteomyelitis) +1 pt
Thrombophilia IF personal history of VTE or known major thrombophiliad , +3 pts; IF known minor thrombophilia, + 1pt; IF positive
family historye  + 1 pt
Trauma/surgery/PICU IF PICU admission lasting over 48 hours within the previous 2 weeks or major surgical operation within the previous
2 weeks: +1; IF major orthopaedic operation (upper extremity excluded) within the previous 2 weeks, + 2 pts; if
major trauma within the previous 2 weeks,+2 pts
Cardiovascular IF previous cardiac disease requiring anti-platelet agents, +3 pts; IF chronic pulmonary hypertension, +2 pts; if acute
comorbidities decrease of EF to 35%-45%, + 2 pts; if acute decrease of EF to 25%--35% or inotropes requirement, + 4ptsc ; if acute
decrease of EF to less than 25% or persistent arrhythmia, +6c 
Other comorbidities Obesity (BMI over 95e  centile), +1 pt
Sickle cell disease, +1 pt; IF vaso-occlusive crisis or acute chest syndrome, +2 pts
Status-post splenectomy for underlying hematological disease, +1 pt
Underlying inflammatory disease (eg, SLE, IBD), +1 pt; IF acute flare of underlying disease, +2 pts
Nephrotic syndromef , +2 pts
Active malignancy: leukemia, +2 pts; localized solid tumor, +1 pt; metastatic solid tumor, +2 pts; 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 drugsg , +1 pt
Mechanical ventilation, + 1 pt
Cigarette smoking, +1 pt
Bleeding risks Known bleeding disorder or personal/family history suggestive of a bleeding disorder
Severe uncontrolled hypertension
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 or higher in the absence of bleeding risks, consider prophylactic anticoagulation and haematology consult

Abbreviations: 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, localized 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.
a
Compared to baseline mobility status.
b
Based on positive cultures or characteristics of the skin surrounding the catheter exit site.
c
Consider therapeutic anticoagulation.
d
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.
e
One first- and/or multiple second-degree relative with unprovoked/minimally provoked deep venous thrombosis, pulmonary embolism, myocardial
infarct, or stroke < 50 years or recurrent unexplained late-occurring abortions (> 2).
f
Current spot urinary protein to creatinin ratio above 2.
g
Estrogen-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.

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 versus 817 ng/mL, P < 0,001). In fact, a D-dimer value above
1000 ng/mL (two times the upper limit of normal) showed a good
diagnostic accuracy to distinguish between COVID-19 and MIS-C
cases (sensitivity 100%, 95% confidence interval [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 versus 5  mg/L, with values  >  100  mg/L being 100% sensi-
tive and specific). With respect to the changing of coagulation and
inflammatory parameters over time in MIS-C patients (Figure  1),
D-dimer (1906 versus 3980  ng/mL, P  =  .05466), fibrinogen (580
versus 650  mg/dL, P  =  .10931), and CRP (215 versus 289  mg/L,
P  =  .0.20018) increased paralleling a worsening of the patient's
clinical condition, while platelets slightly decreased (144 versus
110x109/L, P  =  .10931)---although this did not reach statistical
526       | DEL BORRELLO et al.

TA B L E 2   Clinical and demographic characteristics of pediatric hospitalized patients with SARS-CoV-2–related manifestations

Gender Comorbidities D-dimera  CRPb 

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

Mild COVID-19 9 m 4/10 2/16 800 4

(14) (10 d--17 y) (200--1800 b ) (0--20)
Moderate COVID-19 3.5 y 2/8 3/7 900 5
(10) (2 m--5.5 y) (200--1700) (0--76)
Severe-critical 7.5 y 3/3 6/0 800 25
COVID-19 (9 m--19 y) (100--2750 c ) (3--42)
(6)
MIS-C 6.8 y 3/3 0/6 1900 215
(6) (4.5--12.5 y) (1300--4400) (120--300)

Abbreviations: CRP, C-reactive protein; MIS-C, multi-inflammatory syndrome in children.

a
Values recorded upon hospital admission, data displayed as median and overall range.
b
The D-dimer value of 1800 ng/mL was recorded in a mildly affected newborn.
c
The D-dimer value of 2750 ng/mL was recorded in a critically affected sickle cell disease patient.

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

F I G U R E 1   Trends of laboratory assessments over the hospital stay. Coagulation and inflammatory response parameters (A, D-dimer
levels; B, C-reactive protein; C, fibrinogen; D, platelet counts) as they progressed in COVID-19 patients (moderately to critically ill) and in
multi-inflammatory syndrome in children patients at diagnosis (= ADMISSION), at peak of clinical symptoms (= PEAK), and upon disease
resolution (= DICHARGE) [Colour figure can be viewed at wileyonlinelibrary.com]

significance due to the low number of cases. All values normalized 1 mg/L, and PLT 370x109/L, P < .001). Again, PT values were ba-
upon disease resolution, with a trend toward higher than normal sically within the range of normal at all time points (PT ratio 1.1
platelet values (D-dimer 296  ng/mL, fibrinogen 221  mg/dL, CRP versus 1.2 versus 1,1, P = .458).
DEL BORRELLO et al.
Prophylactic anticoagulation (PA) was started in six patients
(14%; Table 3). These patients received enoxaparin 100 U/kg every
24 hours, 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 risk factor res-
olution/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 home.11
4 |  D I S CU S S I O N
Multiple investigators have reported clinical and anatomopathologi-
cal evidence of an increased incidence of thromboembolic events in
adult COVID-19 patients, 2,15 with up to 57% of critically ill individu-
als developing symptomatic venous or arterial thrombotic complica-
tions despite pharmacological prophylaxis.2,16-19 From what could be
gained so far, COVID-19–related coagulopathy is a multi-pronged pro-
cess consisting of endothelialitis and inflammatory-driven endothelial
dysfunction, 20 platelet activation21 and increased interaction with
TA B L E 3   Clinical description of
patients who received prophylactic
anticoagulation
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Abbreviations: BQM, Braden Q mobility score; CVC, central venous catheter; EBV, Epstein-Barr
virus; PA, prophylactic anticoagulant; TS, Tanner stage.
|
      527
neutrophils and monocytes, 22 increased tissue factor expression by
monocytes, 23 increased neurotrophic extracellular trap (NET) pro-
duction and delayed removal, 24 deregulated complement activa-
tion, 25 and fibrinolysis shutdown, 26 to name a few. Even though the
exact sequence of events has not been clarified, a deregulated immu-
nological process starting at the interface between alveoli and lung
endothelium seemingly determines a local activation of hemostasic
processes leading to platelets, neutrophils, and fibrin deposition (ie,
in situ micro- and macrovascular 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 that
could better describe and predict disease evolution, in order to guide
treatments, among which one of the most studied is D-dimer. 27
Unfortunately, D-dimer testing has numerous well-known draw-
backs, including lack of specificity, 28 and its role in terms of VTE
prediction is still controversial29: it tends to increase in all inflamma-
tory 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 the adult population.
From the earlier reports of adult COVID-19 cases, D-dimer lev-
els upon hospital admission and/or its increase during hospital stay
Totale
score Description
3 14-year-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
8 7-year-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
3 15-year-old obese post-pubertal boy (TS 5) with moderate
COVID-19, who scored 3 on the BQM over the course of his
hospitalization
6 19-year-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
3 6-year-old obese girl with MIS-C and reduced ejection fraction
(40%) but preserved mobility
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)
 |
528       DEL BORRELLO et al.
have been linked to worse clinical outcomes and thrombotic com-
plications. These observations led many clinicians to use increasing
D-dimer values as a trigger to intensify their anticoagulation pro-
phylaxis protocol, increasing the administered dose of anticoagulant
up to full therapeutic levels,30 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
31,32
bleeding risk, which is well known to accompany hyperinflam-
matory conditions in general and microvascular complications in
particular. Also, the fact that the thrombotic process is mainly in-
flammatory-driven (ie, immunothrombosis) and that inflammatory
biomarkers (eg, CRP, interleukin-6, and soluble triggering receptor
expressed on myeloid cells [s-TREM]) have proven to be even bet-
33
ter predictors than D-dimer in terms of clinical outcome point to a
multimodal approach, possibly combining agents active at different
levels of the immuno-thrombotic process,34,35 as better suited to
overcome this difficult challenge. Luckily, multiple randomized trials
are ongoing to provide the practicing community with solid data.
Pediatric COVID-19 patients usually follow a less severe course,
with a very low mortality rate (less than 0.1% according to data re-
leased by the Italian National Institute of Health [ISS]); also, critically
9,10,36
ill children have better outcomes than their adult counterparts.
Thrombotic complications do not appear to occur more often than
what is expected in hospitalized children: a Italian observational
study (unpublished data, courtesy of Dr Garazzino) recorded a prev-
alence of 1 VTE in more than 350 hospitalized pediatric COVID-19
cases, compared to an estimated incidence of hospital-acquired VTE
in the general pediatric population of approximately 1/200.37,38
MIS-C apparently conveys a risk of thrombosis of approximately
3.5% (which may be overestimated, given the paucity of reports that
detail the observed numbers of VTE),39 likely driven by a pro-coag-
ulant highly inflammatory milieu and increased venous stasis sec-
ondary 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 et al41 (available in pre-
print), with a prevalence of severe respiratory manifestations of 17%
among hospitalized 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 pre-
9,10,42
vious descriptions. Moreover, our dynamic evaluation of lab-
oratory 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 72 hours
of corticosteroid therapy administration; only a single patient, who
never received steroids as she did not show significant cardiovascu-
lar 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 expe-
rience, D-dimer has generally proved to be an unreliable biomarker
for diagnosing or predicting thrombotic complications in children:
it shows low accuracy in identifying pulmonary embolism43 and in
predicting venous thrombosis recurrence.44 Finally, a recent report
by Al-Ghafry et al42 described viscoelastic testing consistent with
a pro-thrombotic state (increased maximum clot firmness [MCF] in
both EXTEM and FIBTEM) in eight 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 in-
duced 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 recognized
notion that children develop far fewer thrombotic complications
compared to adults, even in high-risk scenarios (eg, severe trauma,
complex orthopedic surgeries, critical diseases).45 The reasons be-
hind this reduced susceptibility are still not completely understood
and likely lie on both a more robust array of natural anticoagulants
(ie, increased levels of alpha-2-macrogloulin) and healthier vascular
linings (ie, 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 pharmaco-
logic prophylaxis in the pediatric 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 comorbidities (ie, obesity, active malignancy, sickle
cell disease) that enhance the baseline thrombotic risk, especially by
priming the vascular surface toward endothelial dysfunction. This
baseline risk would be boosted by COVID-19 and could be counter-
acted by a targeted PA course with enoxaparin or UFH, which might
also contribute anti-inflammatory activity.48 Therefore, we suggest
to evaluate every child hospitalized with COVID-19 for possible
concurrent pro-thrombotic risk factors, and to consider a person-
alized PA strategy accordingly. Also, given the concerning report by
Duarte-Salles et al41 of a bleeding rate of 2% to 3% in hospitalized
children with COVID-19 (in a cohort in which more than 30% of pa-
tients received some sort of anticoagulation), we suggest to carefully
balance the thrombotic and the hemorrhagic risks for every child.
Our study has several limitations. First, it comprises a small num-
ber of patients, so its results may not be generalizable and should
be interpreted with caution. Second, our patient cohort was quite
heterogeneous, including three patients with acute lymphoblas-
tic leukemia at different stages of their treatment protocol, which
impacted the platelet valued recorded (both in terms of being sur-
reptitiously low and of being confounded by transfusions). It must
be noted, though, that consistent with the absence of a consump-
tive process, none of those children showed platelet transfusion
DEL BORRELLO et al.
refractoriness in the course of COVID-19. Third, D-dimer assays in
pediatrics are prone to pre-analytic confounders (eg, quality of the
blood draw, age, baseline conditions), which may limit their reliabil-
ity. Though acknowledging these possible drawbacks, we tried to
minimize 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 contro-
versial, we decided not to systematically screen for thromboem-
bolic 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 (eg, protein C, protein S, antithrombin,
viscoelastic tests), thus we may have overlooked important aspects
of COVID-19–associated coagulopathy in children. Given the specu-
lative nature of this study without an immediate clinical benefit for
our participants, however, we opted not to burden patients with ex-
cessive blood draws. Following the results of this preliminary analy-
sis, 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 dis-
tinguish MIS-C cases from COVID-19 cases, as reflected by a height-
ened immunological/inflammatory component in the former. We did
not find evidence in either case that a consumptive coagulopathy
was in place, given only slight alteration in platelet counts and fi-
brinogen values. Contrary to adult guidance, universal anticoagulant
prophylaxis in hospitalized children suffering from COVID-19 is not
advised, but might be considered in highly selected cases with mul-
tiple concurrent pro-thrombotic risk factors without taking into ac-
count D-dimer values.
AC K N OW L E D G M E N T S
We cordially thank G. Iegiani for her contribution in drafting the
graphs for this article.
C O N FL I C T O F I N T E R E S T
No author has any real or potential conflict of interest to disclose.
AU T H O R C O N T R I B U T I O N S
G. Del Borrello designed the study, interpreted the datam and drafted
the manuscript; I. Giraudo, C. Bondone, G. Pruccoli, M. Spadea col-
lected and analyzed the data, and contributed to drafting the manu-
script; M. Denina, S. Garazzino, C. Linari, F. Mignone, B. Pollio, and
P. Saracco helped interpret the data and critically revised the manu-
script. All authors approved the final version of the manuscript.
REFERENCES
1. https://www.who.int/emerg​e ncie​s /disea​s es/novel​- coron​a viru​
s-2019 (Accessed on November the 8th 2020)
|
      529
2. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous throm-
boembolism in patients with COVID-19: A systematic review and
meta-analysis. Res Pract Thromb Haemost. 2020;4:1178-1191.
3. Teuwen L-A, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vascu-
lature unleashed [published correction appears in Nat Rev Immunol.
2020; 20(7):448]. Nat Rev Immunol. 2020;20(7):389-391.
4. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C.
Immune mechanisms of pulmonary intravascular coagulopathy in
COVID-19 pneumonia. Lancet Rheumatol. 2020;2:e437-e445.
5. McFadyen JD, Stevens H, Peter K. The Emerging Threat of (Micro)
Thrombosis in COVID-19 and Its Therapeutic Implications. Circ Res.
2020;127:571-587.
6. Flaczyk A, Rosovsky RP, Reed CT, Bankhead-Kendall BK, Bittner
EA, Chang MG. Comparison of published guidelines for manage-
ment of coagulopathy and thrombosis in critically ill patients with
COVID 19: implications for clinical practice and future investiga-
tions. Crit Care. 2020;24:1.
7. Cohoon KP, Mahé G, Tafur AJ, Spyropoulos AC. Emergence of
Institutional Antithrombotic Protocols for Coronavirus 2019. Res
Pract Thromb Haemost. 2020;4:510-517.
8. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a
position paper from Italian Society on Thrombosis and Haemostasis
(SISET). Blood Transfus. 2020;18:167-169.
9. Chao JY, Derespina KR, Herold BC, et al. Clinical Characteristics
and Outcomes of Hospitalized and Critically Ill Children and
Adolescents with Coronavirus Disease 2019 at a Tertiary Care
Medical Center in New York City. J Pediatr. 2020;223:14-19.
10. DeBiasi RL, Song X, Delaney M, et al. Severe Coronavirus
Disease-2019 in Children and Young Adults in the Washington, DC,
Metropolitan Region. J Pediatr. 2020;223:199-203.
11. Goldenberg NA, Sochet A, Albisetti M, et al. Consensus-Based
Clinical Recommendations and Research Priorities for Anticoagulant
Thromboprophylaxis in Children Hospitalized for COVID-19-
Related Illness. J Thromb Haemost. 2020;18(11):3099-3105.
12. Jiang L, Tang K, Levin M, et al. COVID-19 and multisystem inflam-
matory syndrome in children and adolescents. Lancet Infect Dis.
2020;20(11):e276-e288.
13. Del Borrello G, Calvo P, Farinasso D, et al. Systematic evaluation of
thrombotic risk in hospitalized pediatric patients: Preliminary results
from the TRIPP study. Blood Transfus. 2018;16(Supplement 4):s524.
14. https://emerg​ency.cdc.gov/han/2020/han00​432.asp (Accessed on
November the 8th 2020)
15. Schurink B, Roos E, Radonic T, et al. Viral presence and immuno-
pathology in patients with lethal COVID-19: a prospective autopsy
cohort study. Lancet Microbe. 2020;1(7):e290-e299.
16. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thrombo-
embolism in patients with severe novel coronavirus pneumonia. J
Thromb Haemost. 2020;18:1421-1424.
17. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of ve-
nous thromboembolism in hospitalized patients with COVID-19. J
Thromb Haemost. 2020;18:1995-2002.
18. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of throm-
botic complications in critically ill ICU patients with COVID-19.
Thromb Res. 2020;191:145-147.
19. Shah A, Donovan K, McHugh A, et al. Thrombotic and haemorrhagic
complications in critically ill patients with COVID-19: a multicentre
observational study. Crit Care. 2020;24:1.
20. Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the
cornerstone of organ dysfunction in severe SARS-CoV-2 infection.
Crit Care. 2020;24:1.
21. Manne BK, Denorme F, Middleton EA, et al. Platelet gene ex-
pression and function in patients with COVID-19. Blood.
2020;136(11):1317-1329.
22. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, et al. Platelet ac-
tivation and platelet- monocyte aggregate formation trigger
530      |
tissue factor expression in patients with severe COVID-19. Blood.
2020;136(11):1330-1341.
23. Martinez FO, Combes TW, Orsenigo F, Gordon S. Monocyte ac-
tivation in systemic Covid-19 infection: Assay and rationale.
EBioMedicine. 2020;59:102964.
24. Barnes BJ, Adrover JM, Baxter-Stoltzfus A, et al. Targeting poten-
tial drivers of COVID-19: Neutrophil extracellular traps. J Exp Med.
2020;217:6.
25. Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA.
Direct activation of the alternative complement pathway by SARS-
CoV-2 spike proteins is blocked by factor D inhibition. Blood.
2020;136(18):2080-2089.
26. Nougier C, Benoit R, Simon M, et al. Hypofibrinolytic state and high
thrombin generation may play a major role in SARS-COV2 associ-
ated thrombosis. J Thromb Haemost. 2020;18(9):2215-2219.
27. Gungor B, Atici A, Baycan OF, et al. Elevated D-dimer levels on ad-
mission are associated with severity and increased risk of mortality
in COVID-19: A systematic review and meta-analysis. Am J Emerg
Med. 2020;39:173-179.
28. Lippi G, Franchini M, Targher G, Favaloro EJ. Help me, Doctor! My
D-dimer is raised. Ann Med. 2008;40:594-605.
29. Darzi AJ, Karam SG, Spencer FA, et al. Risk models for VTE and
bleeding in medical inpatients: systematic identification and expert
assessment. Blood Adv. 2020;4(12):2557-2566.
3 0. Rosovsky RP, Sanfilippo KM, Wang TF, et al. Anticoagulation
practice patterns in COVID-19: A global survey. Res Pract Thromb
Haemost. 2020;4(6):969-983.
31. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coag-
ulation: bleeding and thrombotic manifestations of SARS-CoV-2
infection. Blood. 2020;136(4):489-500.
32. Pesavento R, Ceccato D, Pasquetto G, et al. The hazard of (sub)
therapeutic doses of anticoagulants in non-critically ill patients
with Covid-19: The Padua province experience. J Thromb Haemost.
2020;18(10):2629-2635.
33. Van Singer M, Brahier T, Ngai M, et al. COVID-19 risk stratification
algorithms based on sTREM-1 and IL-6 in emergency department. J
Allergy Clin Immunol. 2020;20:31401-31409.
3 4. Merrill JT, Erkan D, Winakur J, James JA. Emerging evidence of a
COVID-19 thrombotic syndrome has treatment implications. Nat
Rev Rheumatol. 2020;16(10):581-589.
35. Nicolai L, Leunig A, Brambs S, et al. Immunothrombotic Dysregulation
in COVID-19 Pneumonia Is Associated With Respiratory Failure and
Coagulopathy. Circulation. 2020;142(12):1176-1189.
36. Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics
and Outcomes of Children With Coronavirus Disease 2019 (COVID-
19) Infection Admitted to US and Canadian Pediatric Intensive Care
Units. JAMA Pediatr. 2020;174(9):868-873.
37. Raffini L, Huang Y-S, Witmer C, Feudtner C. Dramatic Increase in
Venous Thromboembolism in Children’s Hospitals in the United
States From 2001 to 2007. Pediatrics. 2009;124(4):1001-1008.
DEL BORRELLO et al.
38. Carpenter SL, Richardson T, Hall M. Increasing rate of pulmonary
embolism diagnosed in hospitalized children in the United States
from 2001 to 2014. Blood Adv. 2018;2(12):1403-1408.
39. Aronoff SC, Hall A, Del Vecchio MT. The Natural History of Severe
Acute Respiratory Syndrome Coronavirus 2–Related Multisystem
Inflammatory Syndrome in Children: A Systematic Review. J Pediatr
Infect Dise Soc. 2020. Online ahead of print.
4 0. Lin KY, Kerur B, Witmer CM, et al. Thrombotic events in critically ill
children with myocarditis. Cardiol Young. 2014;24(5):840-847.
41. Duarte-Salles T, Vizcaya D, Pistillo A, et al. Baseline characteristics,
management, and outcomes of 55,270 children and adolescents di-
agnosed with COVID-19 and 1,952,693 with influenza in France,
Germany, Spain, South Korea and the United States: an interna-
tional network cohort study.
42. Al-Ghafry M, Aygun B, Appiah-Kubi A, et al. Are children with
SARS-CoV-2 infection at high risk for thrombosis? Viscoelastic test-
ing and coagulation profiles in a case series of pediatric patients.
Pediatr Blood Cancer. 2020;67:12.
43. Biss TT, Brandão LR, Kahr WHA, Chan AKC, Williams S. Clinical
probability score and D-dimer estimation lack utility in the di-
agnosis of childhood pulmonary embolism. J Thromb Haemost.
2009;7(10):1633-1638.
4 4. Betensky M, Mueller MG, Amankwah EK, Goldenberg NA. In
Children with Provoked Venous Thromboembolism, Increasing
Plasma Coagulability during the First 3 Months Postdiagnosis is
Prognostic of Recurrence. Thromb Haemost. 2020;120:823-831.
45. Leeper CM, Vissa M, Cooper JD, Malec LM, Gaines BA. Venous
thromboembolism in pediatric trauma patients: Ten-year experi-
ence and long-term follow-up in a tertiary care center. Pediatr Blood
Cancer. 2017;64(8):e26415.
46. Ignjatovic V, Mertyn E, Monagle P. The Coagulation System in
Children: Developmental and Pathophysiological Considerations.
Semin Thromb Hemost. 2011;37:723-729.
47. Telfer P, De la Fuente J, Sohal M, et al. Real-time national survey of
COVID-19 in hemoglobinopathy and rare inherited anemia patients.
Haematologica. 2020;105:2651-2654.
48. Young E. The anti-inflammatory effects of heparin and related com-
pounds. Thromb Res. 2008;122:743-752.
How to cite this article: Del Borrello G, Giraudo I, Bondone C,
et al. SARS-COV-2–associated coagulopathy and
thromboembolism prophylaxis in children: A single-center
observational study. J Thromb Haemost. 2021;19:522–530.
https://doi.org/10.1111/jth.15216