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 31st, 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 years1, 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.16, 17
 
Contrary to expectations, sickle cell disease was not associated with an increased risk of thrombosis: none of 5 patients developed VTE (Supplemental 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 > 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 group18.
 
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.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 use15, 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 >5 ug/mL. An increased rate of breakthrough thrombosis despite prophylactic anticoagulation has been reported in severely ill adult patients14, 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.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 > 5 u/mL and the desire to limit use of higher doses of anticoagulation. Doses and monitoring were different for patients with obesity13 or acute kidney injury22. 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 < 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 > 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-1923, 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 >5 ug/mL, rather than preemptively escalating to therapeutic anticoagulation (Supplemental 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.