Discussion
This study describes viscoelastic testing profiles in children with
MIS-C and demonstrates the presence of a pro-thrombotic state
characterized by increased clot formation rate and strength, and slower
fibrinolysis. Increased ESR and platelet count were both associated with
higher clot strength. The majority of patients received treatment with
ASA or anticoagulation, which was well tolerated with 20% incidence of
minor or clinically relevant non-major bleeding events and with no
subsequent development of thrombosis.
Our findings build on prior reports in patients with MIS-C that
demonstrated laboratory evidence of significant inflammation and
coagulopathy.6–10 As in our series, children with
MIS-C have been reported to have elevations in multiple biomarkers of
inflammation, including ESR, CRP, and ferritin.6–8Prior work has demonstrated that baseline platelet count is
significantly lower in patients with MIS-C compared to Kawasaki
disease.8 Although the MIS-C patients in our cohort
had thrombocytopenia early in illness, peak platelet counts later in
illness were just above the normal range, consistent with prior
literature showing a trend towards higher platelet counts upon recovery
from MIS-C.9 Mild prolongation of PT and aPTT are
rarely reported in the MIS-C literature,7 but are much
more prevalent in adult patients with COVID-19
infection12,27 While prolonged PT and aPTT standardly
denote increased bleeding risk, in critically ill adults with COVID-19
pneumonia, they have been shown to be associated with increased
incidence of thrombotic complications.16 In the MIS-C
population, elevations in fibrinogen and D-dimer have been extensively
described;6–10 however, it is unclear whether these
laboratory changes reflect an underlying inflammatory state or are
indicative of increased risk for thrombosis.10,28
Our finding that patients with MIS-C have TEG profiles consistent with
faster clot formation, increased clot strength and slower fibrinolysis
is novel and provides a potential unique biomarker to distinguish risk
for thrombosis in pediatric patients. The MIS-C TEG profiles described
in our study are consistent with multiple prior TEG studies in adult
COVID-19 patients, which also demonstrate varying degrees of decreased K
time, higher alpha angle, higher maximum amplitude, and low
Ly30.12–14 One study in pediatric patients with acute
SARS-CoV-2 infection (not meeting criteria for MIS-C) found evidence of
increased maximal clot firmness on rotational thromboelastometry,
another form of viscoelastic testing.29 In adults,
abnormal TEG profiles predict risk for thrombosis in COVID-19. Indeed,
Wright et al showed that patients with a complete lack of clot lysis at
30 minutes and elevated D dimer had a venous thromboembolism rate of
50% compared to patients with neither risk factor.13In adult patients with COVID-19 infection, TEG with platelet mapping,
used according to an algorithm to guide anti-thrombotic therapy, can
reduce mortality risk.30 Our study was not
sufficiently powered to detect thromboembolism, particularly as rates of
thromboembolism in the pediatric MIS-C population have been reported at
3-6.5%,6,10,11 far lower than in adults with severe
COVID-19.15–17 Future studies should explore the role
of abnormal TEG profiles in patients with MIS-C as a surrogate for
potential thrombosis risk to help guide thromboprophylaxis management.
Proposed mechanisms of thrombosis in adult patients with acute COVID-19
infection include all three components of Virchow’s
triad.12,31,32 Rates of thromboembolism may be lower
in pediatric patients with MIS-C due to more robust anti-coagulant
pathways associated with developmental hemostasis and baseline healthier
endothelial linings.33 Our finding that increased
platelet counts (both initial and peak) are associated with increased
maximal amplitude is consistent with the fact that clot strength is
primarily derived from interactions between fibrin and
platelets.34 Adult COVID-19 literature supports a
potential role for increased platelet count and activation in mediating
thrombosis risk, although further research is needed in
children.35–37 The association between degree of ESR
elevation and increased clot strength in patients with MIS-C supports a
role for inflammation as a potential driver of thromboembolism risk. In
adult patients with COVID-19; increased ESR, increased CRP, and
increased D-dimer were all predictive of thromboembolic
complications.38
Although guidelines for management of thromboprophylaxis in patients
with MIS-C have emerged, the recommendations are primarily based on
evidence in analogous conditions such as Kawasaki disease and adult
COVID-19 infection.39–41 Low-dose ASA, which was
administered to the majority of patients with MIS-C in our study, could
be considered in all patients with MIS-C requiring hospitalization,
particularly those with features of Kawasaki disease, coronary artery
aneurysm, and thrombocytosis.39,40 More than half of
the patients with MIS-C in our study were on anticoagulation prophylaxis
or treatment, with 57% on dual platelet and anticoagulation therapy.
Current guidelines suggest that prophylactic anticoagulation (as well as
mechanical thromboprophylaxis) be considered in patients with higher
baseline risk for venous thromboembolism (such as patients> 12 years old, with altered mobility, obesity,
known thrombophilia or history of thrombus, or critical
presentation).40,41 Some guidelines suggest using
D-dimer to risk stratify pediatric patients hospitalized for COVID-19 in
order to guide initiation of prophylactic
anticoagulation,41 although this is controversial due
to the non-specific nature of an elevated
D-dimer.28,40 Our institution’s algorithm utilizes
D-dimer and additionally incorporates TEG clot strength to guide
thromboprophylaxis, as described in Supplemental Figure S1. Per current
guidelines recommended by the American College of Rheumatology and
International Kawasaki Disease Registry, therapeutic anticoagulation
should be initiated in patients with MIS-C with giant coronary artery
aneurysm (Z-score >10), moderate or severe ventricular
dysfunction, or concern for thrombosis.39,40 The lack
of major bleeding complications in our cohort suggests that antiplatelet
and anticoagulation therapies in the MIS-C patient population are
relatively safe.
Limitations of our study include the single center retrospective design,
which limits potential generalizability. The small sample size of
patients with MIS-C was underpowered to detect the outcome of
thrombosis. Due to variations in clinical practice and management of
these patients, there were incomplete data particularly with regard to
TEG profiles, and there may have been selection bias regarding which
patients had TEG profiles obtained. Moreover, we were unable to draw
conclusions about the causal relationship between
anticoagulation/antiplatelet regimens and outcomes in our cohort due to
our retrospective design, small sample size and variable clinical
practice. There was no formal control group for our study. TEG data are
not routinely obtained in other hospitalized patient cohorts with
similar degrees of inflammation; however, they are often obtained prior
to cardiac surgery, the patient group from which we derived matched
controls.
In conclusion, patients with MIS-C have evidence of hypercoagulability
on TEG, particularly in patients with elevated ESR and platelet counts.
This study supports the safety and utility of antiplatelet and
anticoagulation medication in the management of patients with MIS-C.
Further longitudinal multi-center study is required to determine the
impact of these therapies on the rate of thrombosis and outcomes in
patients with MIS-C.
Conflict of Interest Disclosure: The authors have no conflicts
of interest relevant to this article to disclose.
Funding/Support : Dr. VanderPluym received funding from the
Georgia Claire Bowen (GCB) Foundation IMPACT (Imagine More Possibilities
for Advanced Cardiac Therapies) innovation lab.
Role of Funder/Sponsor: The funder/sponsor did not participate
in the work.