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.