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.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.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.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.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.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.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.27 While COVID-19 is a highly
thrombogenic condition as well,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.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.24 Based
on these findings, the American Society of Hematology now recommends
indefinite anticoagulation for adults with SCD after their first
unprovoked VTE.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.
Conflict of interest disclosure (including financial
disclosures): Authors have no conflicts of interest to disclose.
Funding/Support: None
Role of funder/sponsor : Not applicable
Clinical trial registration: Not applicable