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\begin{document}

\title{Hospital-Acquired Venous Thromboembolism in Children with Sickle Cell
Disease}



\author[1]{Shreya Agarwal}%
\author[2]{Kayla L. Foster}%
\author[2]{Shaniqua Johnson}%
\author[2]{Mary Shapiro}%
\author[2]{Hyojeong Han}%
\author[3]{Michael Scheurer}%
\author[2]{Gladstone Airewele}%
\author[2]{Sarah E. Sartain}%
\affil[1]{Nationwide Children's Hospital Hematology Oncology \& Blood and Marrow Transplant}%
\affil[2]{Baylor College of Medicine Department of Pediatrics}%
\affil[3]{Texas Children's Cancer Center and Hematology Centers}%


\vspace{-1em}



  
  \date{June 03, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Objectives}: Sickle cell disease (SCD) is well recognized as a
hypercoagulable state, however venous thromboembolism (VTE) risk factors
in children remain largely unknown. In this study, we aim to describe
the clinical characteristics, outcomes and recurrence of hospital
acquired VTE in patients younger than 21 years of age. \textbf{Study
Design/Methods}: Data were extracted from electronic medical records
over a 10-year period (2011-2021). Data regarding sickle cell genotype,
demographics, reason for admission, location of thrombus, presence of
central venous catheter (CVC), intensive care unit (ICU) admission,
presence of thrombophilia risk factors, resolution of VTE, mortality,
and bleeding outcomes on anticoagulation were collected. Recurrence of
VTE at 1 and 5 years was assessed. Descriptive statistics were used as
indicated. \textbf{Results}: We identified a total of 21 VTE events over
the ten-year study period. Six of these events occurred in those younger
than 12 years of age. Fifteen (71\%) VTE events occurred in the HbSS or
HbS\selectlanguage{greek}β\selectlanguage{english}Thal \textsuperscript{0} genotypes compared to 8 (29\%) in HbSC.
Eleven (52\%) patients were admitted with acute chest syndrome (ACS).
Most VTE events were associated with ICU admissions (n=13, 62\%) and
presence of central venous catheter (n=12, 57\%). Major bleeding on
anticoagulation occurred in 10\%.All patients had resolution of index
VTE at 12 weeks. Recurrence rate for VTE at 5 years was 13\%. One
patient died from the VTE event. \textbf{Conclusions}: Our study
highlights that VTE can complicate SCD in children and young adults.
Hospital acquired VTE were most associated with ICU admission, CVC, and
ACS, but larger studies are indicated to validate our findings.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy
with an annual incidence of 300,000 to 400,000 live births
worldwide.\textsuperscript{1} SCD is considered a prothrombotic state
due to enhanced platelet function,\textsuperscript{2,3} impaired
fibrinolysis\textsuperscript{4} and chronic activation of coagulation
cascade with decreased levels of natural anticoagulants and increased
pro-coagulant factor activation.\textsuperscript{5} All elements of
Virchow's triad- endothelial injury, vascular stasis, and
hypercoagulability- are present in SCD, creating a highly thrombogenic
state.\textsuperscript{6} Individuals with SCD are at increased risk for
thromboembolism with estimates in adults ranging from 4-fold to 100-fold
increase in risk.\textsuperscript{7} Most of the data regarding the risk
of thrombosis in SCD pertains to adults\textsuperscript{8--10} and
similar data regarding prevalence and risk factors for thrombosis in
children with SCD is limited.

Over the past two decades, children's hospitals in the United States
have seen an alarming 200\% increase in the rate of hospital-acquired
thrombosis.\textsuperscript{11} In response, pediatric-specific venous
thromboembolism (VTE) prophylaxis guidelines have been developed to
prevent hospital-acquired venous thrombosis. However, these guidelines
do not consider unique, disease-specific mechanisms that further
increase the risks of VTE in SCD. This has resulted in wide variability
of thromboprophylaxis practices across different institutions for
hospitalized children with SCD.\textsuperscript{12}

At Texas Children's Hospital (TCH), our practice has been to prescribe
thromboprophylaxis for patients with SCD who are 18 years of age and
older admitted to the hospital or 16 years of age and older admitted to
the intensive care unit (ICU). Over the past few years, we anecdotally
observed an increase in the incidence of VTE events in younger children
with SCD, prompting us to conduct this study. We hypothesized that the
risk of VTE in SCD is higher in adolescents and in the setting of
additional prothrombotic risk factors like intensive care unit (ICU)
admission and presence of central venous catheter (CVC). Our objectives
were to review our institutional cohort of subjects with SCD who had a
hospital acquired VTE, describe their prothrombotic risk factors, and
analyze treatment outcomes. Furthermore, we aimed to revise our
institutional thromboprophylaxis guidelines, with the ultimate goals of
reducing the rate of hospital-acquired thrombotic events and improving
outcomes for this population.

\textbf{Methods:}

\emph{Study design:}

This was a single institution (TCH) retrospective chart review study.
Data were extracted for all hospitalized individuals with SCD and
documented VTE during the hospitalization beginning January 2011, when
our current electronic medical records went into effect, through January
2021. This study was approved by the Baylor College of Medicine
Institutional Review Board.

\emph{Study population}

We included patients less than 21 years of age with any sickle cell
genotype (HbSS, HbSC, and HbS\selectlanguage{greek}β\selectlanguage{english}Thal\textsuperscript{0/+}) and a VTE event
during hospitalization (deep vein thrombosis {[}DVT{]}, cerebral sinus
venous thrombosis {[}CSVT{]}, and pulmonary embolism {[}PE{]}). We
excluded patients with sickle cell trait, arterial thrombosis, and/or
acute stroke. These patients were identified using ICD9 and ICD10 codes
for SCD, DVT, CSVT, and PE. Patient charts were then manually reviewed
for confirmation of SCD diagnosis and presence of hospital-acquired VTE
on imaging. We defined hospital-acquired VTE as any VTE occurring at
least 48 hours after admission, or within 1 week after discharge,
consistent with the guidelines from the Solutions for Patient
Safety.\textsuperscript{13}

\emph{Variables collected:}

Data were collected regarding demographics (age, sex, and sickle cell
genotype), reason for hospitalization (vaso-occlusive pain crisis, acute
chest syndrome {[}ACS{]}, fever, COVID-19, and others), ICU admission
andlength of hospitalization..

With respect to VTE, the index VTE date was defined as the date when the
imaging study identified the VTE. Data were collected on the type (DVT,
CSVT, and PE) and location of the thrombotic event (e.g., cerebral
veins, upper or lower extremity), any thromboembolic complication,
choice of anticoagulant, mechanical thrombectomy or thrombolysis.
Additionally, charts were reviewed for presence of traditional risk
factors for thrombosis including central venous catheter (CVC), family
or personal history of thrombosis, cardiac comorbidity, obesity, use of
estrogen-containing oral contraceptive pills, recent surgery within the
past 30 days\textsuperscript{14--16}, Factor V Leiden gene mutation,
prothrombin gene mutation, deficiency of protein C, S and/or
antithrombin, and presence of antiphospholipid antibodies.

\emph{Outcomes assessed:}

Primary outcomes of interest were VTE resolution on imaging and bleeding
complications with anticoagulation. Major bleeding was defined as per
International Society on Thrombosis and Hemostasis
criteria.\textsuperscript{17} Secondary outcomes included recurrent VTE
and mortality. Recurrent VTE was defined as an acute VTE that occurred
90 days or more after the index VTE (with radiologic evidence of
resolution of the index VTE).

\emph{Statistical analysis:}

Descriptive statistics were used to compare demographic and clinical
characteristics between individuals with SCD younger than 12 years and
those 12 to 21 years of age with VTE. The age at the time of index VTE
was used as a binary variable to compare the clinical characteristics
between the two groups based on the known change in VTE rate after
puberty.\textsuperscript{8} Fisher's exact test was used to compare
categorical variables because of the small sample size in any given cell
of the contingency table. A two-sided p-value of 0.05 was used for
statistical significance.

\textbf{Results:}

\emph{Clinical characteristics of the cohort:}

During the 10-year period, a total of 21 hospital acquired VTE events
were identified. No patient had documentation of a prior VTE. Table 1
summarizes the clinical characteristics of the cohort. Most common VTE
location was isolated PE (n=9, 43\%), closely followed by isolated DVT
(n=8, 38\%). There were 6 total lower extremity DVTs and 6 total upper
extremity DVTs, with some patients having DVTs in both locations.
Majority of subjects had HbSS or HbS\selectlanguage{greek}β\selectlanguage{english}Thal\textsuperscript{0} genotype
(n=15, 71\%). Age ranged from 1.5 years to 19.5 years, with a median age
of 14 years. Fifty-two percent of the cohort were on hydroxyurea at the
time of VTE (n=11). More than seventy percent of the VTE occurred in
children with SCD who were 12 years and older (n=15).

Overall, more than half of the patients with VTE had ACS on admission or
during hospitalization (n=11, 52\%). Thirteen thrombotic events (62\%)
were associated with ICU admission. CVC-associated thrombosis was seen
in 43\% (n=9) of the cohort. CVC type was either tunneled catheters
(n=8, 89\%) or peripherally inserted central catheter line (n=1, 11\%).
Table 2 summarizes the risk factors sub-stratified into the two age
groups for VTE. None of these clinical variables reached statistical
significance, likely owing to small sample size. No patients reported
the use of oral contraceptive pills or personal or family history of
thrombosis.

Not all patients were tested for inherited thrombophilia, but among the
ones who were tested, 3 (14\%) patients had protein C deficiency, 1
(5\%) patient had protein S deficiency, and 2 (9\%) patients had
antiphospholipid antibodies. Two patients with protein C deficiency were
siblings with genetically proven diagnosis of heterozygous protein C
deficiency. Sibling one had baseline protein C antigen and activity
levels of 63\% and 34\% respectively, while sibling two's baseline
levels were never obtained once genetic diagnosis of protein C
deficiency was made. The third patient with protein C deficiency had
baseline protein C antigen and activity levels of 66\% and 56\%
respectively; genetic testing was not performed. The patient with
protein S deficiency had baseline protein S activity of 26\% and did not
undergo genetic testing. In the two latter patients, while the protein C
and protein S levels were obtained in the acute thrombosis setting,
repeat values months later were still below normal, which could be due
to the baseline lower levels of protein C and protein S observed in
patients with SCD.\textsuperscript{18} Regarding the 2 patients with
antiphospholipid antibodies, 1 patient had systemic lupus erythematosus
(SLE) along with positive anticardiolipin IgM and IgG antibodies and a
lupus anticoagulant (positive by DRVVT and staclot) at the time of
thrombotic event. While the anticardiolipin antibodies normalized 6
months later, this patient continued to have intermittent positive
staclot, likely due to the underlying systemic lupus erythematosus
(SLE). Anti beta2 glycoproteins IgG and IgM were normal. The other
patient with antiphospholipid antibodies had positive lupus
anticoagulant assays (DRVVT and staclot) with normal anticardiolipin
IgG/IgM and anti beta2 glycoproteins IgG/IgM at the time of the
thrombotic event. Repeat testing 3 months later showed normal levels of
all 3 antibodies.

\emph{VTE outcomes:}

All patients with documented thrombosis received therapeutic
anticoagulation with at least 1 of the following: unfractionated heparin
(n=7, 33\%), low molecular weight heparin ({[}LMWH{]}, n=21, 100\%),
warfarin (n=2, 9\%), rivaroxaban (n=2, 9\%), or apixaban (n=1, 5\%).
Only 1 patient (with PE and lower extremity DVT) additionally underwent
catheter-directed thrombolysis and mechanical thrombectomy. All patients
(n=21, 100\%) had resolution of the primary VTE on imaging after 12
weeks of therapeutic anticoagulation. The rate of major bleeding was
10\%. There was 1 death (5\%), and it is thought that this patient
likely died from showered emboli causing a PE and cardiorespiratory
arrest that occurred shortly after the central line was pulled.

\emph{Recurrent VTE}

Of the 21 patients, 16 (76\%) were followed for 5 years or more since
the time of index VTE. Of the 5 patients who were not followed for at
least 5 years, 3 were transitioned to adult care and 2 were lost to
follow-up. Among the 16 patients with long-term follow-up data, there
were no documented recurrences at 1-year follow-up after the index VTE,
but 2 patients (13\%) had recurrent thrombosis by 5-year follow-up after
the index VTE, neither CVC-related. One of these 2 patients with
recurrent VTE had PE on initial presentation and recurrent PE 13 months
later while on prophylactic LMWH. Additional thrombotic risk factors in
this patient were systemic lupus erythematosus (SLE) and
antiphospholipid antibody syndrome (APLAS). This patient had a previous
history of pulmonary hemorrhage secondary to capillaritis in the setting
of SLE, and she was kept on prophylactic dose of LMWH rather than the
recommended therapeutic dosage for APLAS to prevent recurrent pulmonary
hemorrhage. The other patient with recurrent VTE had CSVT on initial
presentation and presented with PE in the setting of brachial vein
thrombosis 4 years and 3 months after the index VTE. Additional
thrombotic risk factor in this patient was protein C deficiency
confirmed by genetic testing and managed on warfarin (goal INR of
2.0-3.0) prior to the recurrent VTE. At the time of recurrent VTE, he
was admitted to the hospital for a hip surgery. Prior to the procedure,
he was bridged from warfarin to LMWH, which was held for 24 hours before
and after the surgery. He was on a therapeutic dose, confirmed by
anti-Xa levels, at the time of PE.

\textbf{Discussion:}

In this study, we describe a cohort of 21 patients with SCD at a
quaternary care pediatric hospital who developed a hospital-acquired VTE
over a 10-year period. Majority of the events occurred in adolescents.
Recurrence rate at 5-year follow-up was 13\% (n=2), and both subjects
had additional underlying thrombophilic risk factors (protein C
deficiency and APLAS, respectively). Our data support the growing
recognition of the risk of VTE in SCD, even at a younger age, and the
risk of recurrent VTE in a subgroup of patients with SCD.

Although no clinical characteristic reached statistical significance,
likely owing to small sample size, the overall trend showed that
hospital-acquired VTE in our cohort was most frequently associated with
CVC, ICU admission, and ACS. Based on these data, we have revised our
own institutional practice for thromboprophylaxis in SCD to reduce the
incidence of hospital-acquired thrombosis and improve patient outcomes
(Table 3). While the majority of questions regarding thromboprophylaxis
in children with SCD can be answered by prospective clinical trials, in
the absence of data, we have attempted to risk-stratify in our
institutional practice based on findings from this study. For instance,
patients aged 12 years and older are considered to be at higher risk for
VTE if they are admitted to the ICU or diagnosed ACS or COVID-19; while
patients younger than 12 years are considered to be at higher risk for
VTE if they are admitted to the ICU and have an additional risk factor
(e.g., presence of CVC). Anticoagulation comes with a risk of bleeding,
as seen in our study with 10\% incidence of major bleeding; hence the
assessment of risks and benefits of prophylactic anticoagulation is
necessary in each patient with SCD.

The proportion of patients with PE observed in our cohort is
significantly higher than the previous estimates in pediatric patients
with SCD and overall in pediatrics.\textsuperscript{19,20} A relatively
high prevalence of PE in patients with SCD has also been observed in
previous adult studies and is presumed to be from in situ pulmonary
artery thrombosis.\textsuperscript{21--23} ACS was identified as a risk
factor for VTE in our cohort. There is some evidence that these
pulmonary arterial thrombi are found more frequently in patients with
ACS.\textsuperscript{24} In a large study of ACS in both adult and
pediatric patients, PE was the most common cause of death in ACS,
although VTE and fat embolism could not be
differentiated.\textsuperscript{25} The uncertainty regarding the
etiology of pulmonary arterial thrombi also results in wide variation in
anticoagulation practices. In pediatrics, anticoagulation is not
recommended as an adjunct to ACS treatment, while in adults with SCD,
therapeutic anticoagulation for patients with a positive radiograph is
sometimes considered.\textsuperscript{23} At our institution, we have
revised our anticoagulation guidelines to recommend prophylactic
anticoagulation for patients 12 years of age and older admitted with
ACS. However, given our relatively small sample size, the incidence of
PE may not be reflective of population estimates. For this reason, there
is an urgent need to conduct large, multicenter pediatric studies to
validate our findings and evaluate the utility of anticoagulation in
children and young adults with SCD admitted for ACS to prevent
life-threatening PE.

Other risk factors identified in our cohort are recognized risk factors
for thrombosis in general population, such as presence of CVC and ICU
admission.\textsuperscript{26} The usual reasons for a CVC in children
with SCD are venous access, chronic transfusion therapy, need for
long-term antibiotics, and emergent
erythrocytapheresis.\textsuperscript{27} While COVID-19 is a highly
thrombogenic condition as well,\textsuperscript{28} less than 10\% of
our patients with SCD and VTE were diagnosed with COVID-19 at the time
of VTE. The likely reasons could be this acute illness was prevalent
only in the last 2 years of the 10-year study period. Additionally,
patients with SCD were recognized as high-risk for thrombosis based on
our institutional guidelines for thromboprophylaxis in COVID-19 and were
placed on thromboprophylaxis when admitted to the hospital. This may
have resulted in the overall lower incidence of VTE in this subgroup.

Recurrence of VTE is largely unknown in children and young adults with
SCD. A single center retrospective study in adults with SCD showed a
recurrence rate 33\% while on anticoagulation, however, there was
missing data in 43\% patients.\textsuperscript{8} Furthermore, a large
population-based study of adult patients with SCD treated at various
institutions in California showed a 5-year recurrence rate of 28\% for
those with severe disease (defined as [?]3 hospitalizations in one year)
and 12\% for those with less severe disease.\textsuperscript{24} Based
on these findings, the American Society of Hematology now recommends
indefinite anticoagulation for adults with SCD after their first
unprovoked VTE.\textsuperscript{29} However, there is dearth of data to
guide anticoagulation recommendations in pediatrics. One of the
objectives of our study was to close this knowledge gap. We found a 13\%
recurrence rate at 5 years, however, there were missing long-term
follow-up data on 5 patients (24\%) of our cohort, thereby limiting our
conclusions. Larger prospective studies are indicated to assess the
recurrence rate to help physicians make more informed decisions
regarding the duration of anticoagulation.

We do want to acknowledge some limitations of our study. This is a
single institution study which may limit the generalizability of the
findings. Additionally, given the retrospective nature, it is not
possible to determine causation, and we can only report association with
several high-risk factors. Although the majority of patients were
followed long-term at our center, there were some that were lost to
follow-up or transitioned to adult care, and this fragmentation of care
may have resulted in incomplete data collection. Future studies should
also compare the risk factors for VTE in a SCD cohort to a cohort
without SCD.

In conclusion, this study identifies a subgroup of children and young
adults with SCD who are at a higher risk of VTE and may benefit from
thromboprophylaxis on admission to the hospital. Given the wide
variability in anticoagulation practices across different pediatric
institutions, our proposed guidelines may serve as a framework for other
institutions to adopt. Moreover, our data highlight the need for large,
multicenter collaboration to create a consensus anticoagulation
guideline for children and young adults with SCD to optimize care and
improve outcomes.

\textbf{Conflict of interest disclosure (including financial
disclosures):} Authors have no conflicts of interest to disclose.

\textbf{Funding/Support:} None

\textbf{Role of funder/sponsor} : Not applicable

\textbf{Clinical trial registration:} Not applicable

\textbf{Contributors statement page:}

Drs Shreya Agarwal, Kayla L Foster, Shaniqua J Anum, HyoJeong Han, Mary
C. Shapiro and Sarah E. Sartain conceptualized and designed the study,
collected data, drafted the initial manuscript and critically reviewed
and revised the manuscript.

Dr Gladstone Airewele conceptualized the study, critically reviewed and
revised the manuscript.

Dr Michael Scheurer performed data analysis, critically reviewed and
revised the manuscript.

All authors approved the final manuscript and agreed to be accountable
for all aspects of the work.

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