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