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\begin{document}

\title{Children and young adults hospitalized for~ severe COVID-19 exhibit
thrombotic coagulopathy~~~~~~~~}



\author[1]{William Mitchell}%
\author[1]{Jennifer Davila}%
\author[1]{Janine Keenan}%
\author[2]{Jenai Jackson}%
\author[1]{Adit Tal}%
\author[1]{Kerry Morrone}%
\author[2]{Ellen Silver}%
\author[3]{Sarah O'Brien}%
\author[1]{Deepa Manwani}%
\affil[1]{Children's Hospital at Montefiore}%
\affil[2]{Yeshiva University Albert Einstein College of Medicine}%
\affil[3]{Research Institute at Nationwide Children's Hospital}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We report the clinical and laboratory coagulation characteristics of 27
pediatric and young adult patients (2 months to 21 years) treated for
symptomatic COVID-19 at a children's hospital in the Bronx, New York
between March 1 and May 31, 2020. D-Dimer was \textgreater{} 0.5 ug/mL
(upper limit of normal) in 25 (93\%) patients at admission; 11 (41\%)
developed peak D-Dimer \textgreater{} 5 ug/mL during admission. Seven
(26\%) patients developed venous thromboembolism: three with deep vein
thrombosis and four with pulmonary embolism. Requirement of increased
ventilatory support was a risk factor for thrombosis (p=0.006). Three of
eight (38\%) patients on prophylactic anticoagulation developed
thrombosis, however no patients developed VTE on low molecular weight
heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19
disease was severe or critical in 16 (59\%) patients. Four (15\%)
patients died of COVID-19 complications: all had \textbf{}
comorbidities. Elevated D-dimer and increased VTE rate were observed in
this young cohort, particularly in those with severe respiratory
complications suggesting thrombotic coagulopathy. More data is needed to
guide thromboprophylaxis in this age group.%
\end{abstract}%



\sloppy




\textbf{Introduction}

Adult patients with severe COVID-19 develop a thrombotic coagulopathy,
and numerous series have reported high rates of venous thromboembolism
(VTE), including deep vein thrombosis (DVT) and pulmonary embolism
(PE),\textsuperscript{1-4} however, these adult cohorts have median ages
of 63-64 years. Data have been presented on pediatric cohorts with
COVID-19, however, the associated coagulopathy has not been well
described.\textsuperscript{5-10} In particular, whether an aggressive
anticoagulation strategy, as has been implemented in some medical
centers, is necessary, effective or safe for children and young adults
is not clear. Defining the clinical characteristics and severity of the
coagulopathy of COVID-19 in hospitalized pediatric patients is an urgent
need. In this context, we performed a single-site retrospective review
of 27 patients ages 2 months to 21 years, with confirmed, symptomatic
COVID-19, admitted to a single Children's Hospital in the Bronx, New
York. We describe the coagulopathy associated with COVID-19 in these
hospitalized patients and how these data informed the iterative process
that led to the development of institutional anticoagulation guidelines.

\textbf{Methods}

Institutional Review Board (IRB) of Montefiore Medical Center approval
was obtained for this study. In this retrospective analysis, we present
data on 27 patients admitted to the hospital for symptomatic COVID-19
between March 1 and May 31, 2020. Due to the emerging data on
coagulopathy, all COVID-19 patients were followed by the Pediatric
Hematology consult service during this time. ~Primary provider teams
consulted the hematology service for all confirmed COVID-19 cases, which
minimized selection bias. Only patients hospitalized for symptomatic
COVID-19 were included: those admitted for another reason and found to
have incidental COVID-19 infection were excluded. Diagnosis of COVID-19
was confirmed in all cases by nasopharyngeal swab PCR. D-dimer was
measured using the Stago Liquid Xa assay in our clinical hematology
laboratory.

Hospital records were reviewed for laboratory, clinical, radiographic
and demographic data. This included comorbid conditions and concurrent
medications. Descriptive statistics, including proportions, means, and
standard deviations, were calculated for study variables.~ Associations
of risk factors with thrombosis were analyzed using Chi-square or Fisher
Exact tests and odds ratios (ORs) also were calculated for these
comparisons.~ Additionally, a logistic regression analysis including the
variables found to be significant in bivariate analyses was run to
control for confounding and determine which factors independently
predicted thrombosis. For each analysis any cases with missing data were
excluded.

\textbf{Results}

This cohort of 27 children and young adults hospitalized with
symptomatic COVID-19 (\textbf{Table 1}) was roughly equal by gender,
with 14 (52\%) males and 13 (48\%) females. The numbers of patients in
different age ranges were 3 (11\%) less than 1 year, 4 (15\%) 1 through
6 years, 8 (30\%) 7 through 12 years, and 12 (44\%) 13 through 21 years
(\textbf{Table 1}). The background racial and ethnic makeup of the
Bronx, New York based on the 2019 census report is approximately 44\%
Black and 45\% White, with 56\% of all races identifying as Hispanic or
Latino ethnicity. In this cohort 3 (11\%) patients self-identified as
Black, 1 (4\%) White, 11 (41\%) other, and 16 (59\%) patients
self-identified as Spanish/Hispanic/Latino.~ Obesity and sickle cell
disease were the most prevalent comorbid conditions, with 5 (19\%)
patients having BMI \textgreater{} 95\textsuperscript{th} percentile,
and 5 (19\%) having sickle cell anemia.

~

~Clinically, 16 (59\%) patients in this cohort had severe or critical
illness due to COVID-19, based on established criteria (grades
asymptomatic, mild, moderate, severe, critical) \textsuperscript{6,}
~and corresponding to grades 5 and higher by the WHO progression scale
(grades 1-10),\textsuperscript{11} and 14 (52\%) patients required
increased ventilatory support. This was defined by the need for
\textgreater{} 5L oxygen via nasal cannula, high-flow nasal cannula,
non-rebreather mask, or intubation. These patients were labelled as the
``High Ventilatory Support'' sub-group. Patients not requiring any
ventilatory support or only oxygen supplementation of \textless{} 5L
oxygen via nasal cannula were labeled as the ``Low Ventilatory Support''
sub-group. 9 (33\%) patients required intubation. Four (15\%) patients
died of COVID-19 complications.

~

Coagulation parameters were abnormal in much of the cohort
(\textbf{Table 1}). Only one (5\%) of the 22 patients whose D-dimer was
measured had a D-Dimer \textless{} 0.5 ug/mL (institutional normal range
0.27-0.50 ug/mL) and the mean peak D-dimer value was 6.41 ug/mL (range
0.27 -- 16.9 ug/mL). PT and PTT were prolonged with mean peak values of
17.8 seconds (range 13.8-43.3 seconds) and 65.6 seconds (range 29.3 --
200 seconds), respectively (ULN 14.8 seconds and 44.8 seconds,
respectively). Platelet counts were primarily in the normal or high
range, with mean peak count of 416 k/uL (range 183 -- 789 k/uL). There
were 11 (41\%) patients with platelets \textless{} 150 k/uL
(institutional lower limit of normal), and the mean platelet nadir of
the cohort was 175 k/uL (range 5 -- 683 k/uL). Seven (26\%) patients
were significantly thrombocytopenic (\textless{} 50 k/uL). Fibrinogen
was elevated with mean peak value of 642 mg/dL (range 227 -- 1800 mg/dL,
ULN 283 mg/dL). All lab testing was performed in the hospital laboratory
with the usual quality assurance measures in place.

~

Venous thromboembolism (VTE) was identified in 7 (26\%) patients
(\textbf{Table 2}). Three (11\%) patients developed DVT and 4(15\%)
developed PE. One of these patients had bilateral PE.~ A requirement for
increased ventilatory support was a risk factor for VTE, with 7 of 14
(50\%) patients in the High Ventilatory Support group developing VTE as
compared to none of 13 patients in the Low Ventilatory Support group
(p=0.006) (\textbf{Table 3}). Elevated D-dimer was not a statistically
significant risk factor for VTE in the cohort, potentially due to small
sample size. However, there was a trend of D-dimer \textgreater{} 5
ng/uL in patients with VTE, with 2 of 11 (18\%) and 5 of 11 (45\%)
patients developing VTE with D-dimer \textless{} 5 and \textgreater{} 5
ug/mL, respectively. Obesity was not associated with VTE in our cohort,
potentially due to inadequate statistical power from a small sample
size. All three patients with DVT and 2 of 4 (50\%) patients with PE
(total 5 of 7, 71\%) had central venous lines, and 11 of 20 (59\%)
without VTE had central venous lines. This difference too did not reach
statistical significance (p = .446), perhaps due to small sample size.
Given our relatively small sample size and the correlated nature of
these variables, the independent contribution of each risk factor to VTE
could not be statistically analyzed by regression modeling. ~

~

Children and young adults with symptomatic COVID-19 were at risk for VTE
despite prophylactic anticoagulation, as 4 (57\%) of the 7 patients with
confirmed VTE were on prophylaxis. Eleven (41\%) patients received
prophylactic anticoagulation, with 10 (91\%) of those patients receiving
low molecular weight heparin (LMWH, enoxaparin) and 1 (9\%) 20 year old
patient receiving apixaban. The LMWH was dosed at 0.75 mg/kg BID for
neonates up to 2 months, and 0.5 mg/kg BID for over 2 months, with
titration of anti-Xa level to 0.2 -- 0.4 ng/mL (Based on CHEST
guidelines\textsuperscript{12} and institutional anticoagulation
guidelines).

~

Six (60\%) of the 10 patients receiving LMWH had their dose titrated to
ant-Xa level, and none of these patients developed VTE. Four patients
received fixed dose LMWH, which was either 40 mg per day (standard adult
prophylactic dose) or fixed dosing based on weight (generally for obese
patients\textsuperscript{13}). Three (75\%) of the 4 patients receiving
fixed-dose prophylactic LMWH developed VTE, of these individuals one was
obese. The remaining patient on prophylaxis was on apixaban, 2.5 mg
twice daily, and developed a PE. Although the numbers are small, we did
not see breakthrough VTE on anti-Xa-monitored prophylactic dosing of
LMWH. No clear pattern was identified in the subset that developed VTEs
on prophylactic anticoagulation, except the for the anticoagulation
choice/regimen. The remaining 3 confirmed VTEs occurred in patients on
therapeutic dosing of anticoagulation. Since therapeutic anticoagulation
was often initiated in the most ill patients, comparison of VTE rates to
the patients on prophylaxis is not feasible. It should be noted that all
patients in this cohort were started on guideline based anticoagulation
upon admission. Thus, unless their VTE developed before admission, these
patients all received anticoagulation before VTE diagnosis and delayed
start of anticoagulation was not identified as the cause for
breakthrough VTE. Overall, the anticoagulation was well tolerated and no
cases of grade 4 or higher bleeding were observed. Two patients had
oozing from indwelling central venous line insertion sites and one of
those had hematuria but neither had life-threatening hemorrhage.

\textbf{Discussion}

During the 2020 COVID-19 surge in New York City, there were over 200,000
confirmed cases in New York City, with almost 17,000 confirmed deaths by
May 31\textsuperscript{st}, 2020. (https://www1.nyc.gov/). Almost all
data emerging from this time is restricted to the older adult population
with average of age of cohorts ranging between 63 -- 65
years\textsuperscript{1, 14, 15}. There has been limited information on
the impact of COVID-19 on the coagulation of pediatric and young adult
patients. Herein we present data revealing that children and young
adults with symptomatic COVID-19 do in fact suffer from the severe
coagulopathy that has been reported in adult patients and can become
severely or critically ill. Those patients who died were 2 months, 11,
14 and 18 years old, and all had comorbidities, which were cardiac
defect, cancer, genetic syndrome and trisomy 21, respectively. One of
these patients also developed a DVT. Comorbidities may also have
contributed to risk for COVID-19 related VTE in this cohort. Although
obesity, central venous line and sickle cell were not risk factors for
VTE in this cohort, there was a predominance of Black and Hispanic
patients. In the US, there are known higher rates of infection,
morbidity, and mortality in these populations.\textsuperscript{16, 17}

~

Contrary to expectations, sickle cell disease was not associated with an
increased risk of thrombosis: none of 5 patients developed VTE
(Supplemental \textbf{Table S1}). SCD and non-SCD patients did not
differ in baseline demographic and clinical characteristics, except for
the expected preponderance of patients who self-identified as Black in
the SCD group (data not shown). Although all 5 patients with SCD were
admitted with acute chest syndrome, none developed severe or critical
illness or required high ventilatory support, and none had D-dimer
\textgreater{} 5 mcg/mL. Two of the SCD patients were on chronic
transfusions and none were on hydroxyurea. The clinical course of these
patients is described in greater detail in a prior publication from our
group\textsuperscript{18}.

~

A limitation of this study is that it included a relatively small number
of patients from one medical center, which may have introduced treatment
bias. Importantly, this study included only those patients admitted for
symptomatic COVID-19. Patients found to have incidental, asymptomatic
COVID-19 were excluded. Laboratory evaluation of this novel disease
evolved over time as the pandemic continued. In particular, D-dimer was
not reported for about 25\% of the earliest patients in the cohort,
which may have affected the statistical association of this test with
VTE. While the odds ratios of D-dimer and central venous line as risk
factors were fairly high, they failed to reach significance due to small
numbers. An association of D-dimer elevation with mortality and
thrombosis has been observed in adult cohorts and deserves further study
in future pediatric cohorts with larger sample size.\textsuperscript{20,
21} Peak values of the activated partial thromboplastin time (aPTT) were
noted to be significantly elevated in this cohort which is different
from what has been reported in adult cohorts. However, the aPTT standard
deviation was large due to 4 outlier values for which heparin
contamination could not be ruled out. ~Additionally, the presence of a
lupus anticoagulant was not tested for in this population. Even with
these 4 values removed the mean peak aPTT remained prolonged (mean
48.59s, SD 6.19s, ULN 43.8s) while the mean PTT at admission was in the
normal range (mean 35.5s, SD 6.2s). These hemostasis variables will need
to be explored in a larger sample size to determine their exact impact
on VTE in pediatric and young adult patients with COVID-19.

~

In the course of the pandemic it was difficult logistically to obtain
imaging with either sonography or CT scan for patients with COVID-19 due
to isolation precautions. This limited our ability to determine the
absolute incidence of VTE. As our guidelines evolved, imaging was
recommended for all patients but was still not uniformly available. This
potentially limited our ability to diagnose VTE on this cohort. Of those
16 who did have imaging, 7 (43\%) had VTE.~ Nine patients had extremity
dopplers, 2 (22\%) of whom had VTE and both were symptomatic. No
asymptomatic line related clots were diagnosed, although the entire
cohort was not screened. One patient with incidental portal vein
thrombosis was asymptomatic for VTE but had an abdominal sonogram for
abnormal LFTs. Four (57\%) of the 7 patients imaged for PE were positive
-- all were symptomatic. However, imaging was limited due to logistics
of COVID-19-related restrictions and not all patients symptomatic for
possible PE had imaging in real time. We did not observe any stroke in
this cohort and did not perform any head imaging to assess for stroke.

~

Anticoagulation guidelines were put in place initially based on the data
from Wuhan reporting decreased mortality with heparin
use\textsuperscript{15}, as well as our early findings of VTE in
untreated children and young adults. The youngest patient in our cohort
to have a VTE was two months old, leading us to recommend prophylactic
anticoagulation for pediatric patients of all ages hospitalized with
symptomatic COVID-19. ~One patient presented with PE ten days post
discharge, leading us to recommend prophylactic anticoagulation for two
weeks post discharge. This patient presented with pneumonia and required
high flow nasal cannula on both admissions. ~We used the evolving data
from our patients to inform an iterative weekly analysis by which to
base our institutional anticoagulation guidelines. In the absence of
bleeding risk, we recommended anti-Xa-monitored LMWH prophylaxis, with
pre-emptive escalation to therapeutic dosing in patients requiring high
ventilatory support or with D-dimer levels \textgreater{}5 ug/mL. An
increased rate of breakthrough thrombosis despite prophylactic
anticoagulation has been reported in severely ill adult
patients\textsuperscript{14, 19}, highlighting the need for further
evaluation of effective regimens in clinical trials. The use of D-dimer
as a risk factor for thrombosis in COVID-19 was based on adult
literature, as no pediatric data existed at that
time.\textsuperscript{20, 21} The D-dimer cutoff of 10x our
institutional ULN was based both on the observation that patients
developing VTE generally had D-dimer \textgreater{} 5 u/mL and the
desire to limit use of higher doses of anticoagulation. Doses and
monitoring were different for patients with obesity\textsuperscript{13}
or acute kidney injury\textsuperscript{22}. In patients with renal
dysfunction LMWH was used once per day with monitoring of anti-Xa peak
and trough levels to prevent accumulation.

~

In repeated data analysis there was evidence of a clear demarcation
between those patients who needed ventilatory support of \textless{} 5
liters nasal cannula, and those requiring more aggressive ventilatory
management with high-flow nasal cannula, non-rebreather mask or
intubation. Of note, this level of ventilatory support is typically
criteria for admission to our intensive care unit (ICU). However,
because of high ICU volume, primarily only intubated patients were
admitted to the ICU during this period. The rates for confirmed VTE were
0 and 50\% in the low and high ventilatory support cohorts,
respectively. Based on this data and the limited availability of
imaging, we opted to treat patients requiring \textgreater{} 5L NC
ventilatory support with full dose anticoagulation with LMWH, titrated
to an anti-Xa level of 0.6 -- 1.1 ng/mL, which was well tolerated in
this age group. Subsequent to the data collection and reporting period,
both the American Society of Hematology and the International Society of
Thrombosis and Haemostasis published guidance on anticoagulation in
adults with COVID-19\textsuperscript{23, 24}. ~Based on these
publications and our own findings, we further revised our guidelines to
uniformly image patients requiring high ventilatory support or with
D-dimer levels \textgreater{}5 ug/mL, rather than preemptively
escalating to therapeutic anticoagulation (Supplemental \textbf{Figure
S1}). It must be pointed out that these institutional guidelines for
thromboprophylaxis management evolved as the cohort accrued and as more
adult data became available. Their use is subject to change based on the
evolving body of literature. Ongoing and future studies will determine
if intensified thromboprophylaxis, therapeutic dosing anticoagulation,
addition of antiplatelet or anti-inflammatory agents are the correct
approach to address the severe COVID-19 coagulopathy in both children
and adults. Ongoing clinical trials may soon answer these questions in
adults (the ACTIV-4 studies, NCT04505774 and NCT04498273).

~

In conclusion, while many children and young adults may not require
admission to the hospital for COVID-19, the laboratory picture and
clinical course of more severely ill children and young adults is
similar to that of older adult patients. Coagulopathy, elevated D-dimer
and increased VTE rate were observed in this young cohort, particularly
in those with severe respiratory complications. More data is needed to
guide thromboprophylaxis in this age group. However, until more data
from larger studies is available, care will continue to be guided by the
adult experience. In this time of limited experience with this novel
infection, we have closely observed our patients to guide us in how best
to care for them. We hope our findings will inform future management of
children and young adults hospitalized with symptomatic COVID-19.

\par\null

Authorship: WBM collected and analyzed data and wrote the manuscript, JJ
collected data, JD collected data and revised the manuscript, AT
collected data and revised the manuscript, KAM revised the manuscript,
EJS performed statistical analyses, SOB analyzed data and revised the
manuscript, DM oversaw data collection, analyzed data and revised the
manuscript

Conflict of interest statement: The authors declare no competing
financial conflicts.

\par\null

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doi:10.1111/jth.15073



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\verb`Table 3.docx`  available at \url{https://authorea.com/users/363074/articles/483985-children-and-young-adults-hospitalized-for-severe-covid-19-exhibit-thrombotic-coagulopathy}



\textbf{Hosted file}

\verb`SupTable S1 R2.docx`  available at \url{https://authorea.com/users/363074/articles/483985-children-and-young-adults-hospitalized-for-severe-covid-19-exhibit-thrombotic-coagulopathy}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/supplemental-figure-S1/supplemental-figure-S1}
\caption{{This is a caption
{\label{614592}}%
}}
\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

