Prevalence and Factors Associated with Coagulopathy in Children with Sickle Cell Disease

Introduction: Sickle Cell Disease (SCD) is the most common inherited blood disorder globally and remains a major cause of morbidity and mortality in those affected. Factors such as chronic endothelial injury and activation in addition to chronic inflammation promote a prothrombotic state that is classically associated with SCD. A higher prevalence of venous thromboembolic events and ischemic strokes is acknowledged in SCD, but SCD is also associated with bleeding complications. Adults with SCD have an increased cumulative incidence of bleeding complications. While the bleeding risk in children with SCD remains to be defined, an increased frequency of prolonged prothrombin time (PT) and/or prolonged activated partial thromboplastin times (aPTT) on perioperative screening labs has been reported. Yet, available data are insufficient to establish the true prevalence of coagulopathies in SCD, nor are they able to establish etiology. The purpose of this study is to determine the prevalence of coagulopathies in children with SCD and laboratory and disease-related factors associated with coagulopathy.

Methods: We conducted a single-institution, multi-site retrospective review of patients with any SCD genotype aged 12 months to 21 years old with a minimum of one PT and/or aPTT lab drawn in any hospital-affiliated facility between January 1, 2010, to December 31, 2020. Patients with multiple PT/aPTT tests less than 2-weeks apart had only their “baseline” or initial values recorded for this analysis. Tests greater than 2-weeks apart were included. Children <12 months and acute COVID-19 infections were excluded. Descriptive statistics were calculated, and general linear regression was used to examine factors associated with coagulopathy. Statistical significance was determined by p<0.05.

Results: Over the 10-year period, 847 patients with SCD had 1,497 PT and/or aPTT tests performed. The cohort had a median age of 11.8 years [range: 1, 21.9] at first PT/aPTT test. Individuals with HbSS representing 77% of the cohort. There was a slight male predominance (51%) and 42% were on hydroxyurea at any time. Twenty-nine percent of PT tests were prolonged a median of 1.5 [0.6, 3.7] seconds above the laboratory reference range, while 17% of aPTT tests were prolonged a median of 4 [1, 13] seconds. The majority of tests were obtained in the inpatient setting (65%) followed by the outpatient clinic (29%) and emergency department (5%). We observed a higher frequency of prolonged aPTT tests in the inpatient/emergency setting compared to outpatient tests (19% vs 12%, p<0.001), but PT tests did not differ significantly by setting. Indications for testing included pre-operative evaluation, bleeding evaluation, suspected stroke, gastrointestinal or hepatologic workup, intensive care admission, and acute infection. Prolonged PT was associated with significantly higher white blood cell (WBC) counts, lower hemoglobin, lower platelet counts, higher HbS percentage on hemoglobin electrophoresis, higher aspartate aminotransferase (AST), higher total bilirubin values, and lower albumin. For those patients in whom specific factor testing was performed, lower factor VII activity levels were observed with prolonged PT. Prolonged aPTT were associated with the same laboratory abnormalities observed with prolonged PT except there was no observed association between aPTT and total bilirubin levels or factor VII activity. PT prolongations were more likely in adolescent/young adult patients, with this effect being more pronounced in the outpatient setting, but aPTT prolongations were not associated with differences in age in our cohort. Finally, we found various disease-related factors were associated with coagulopathy. The prevalence of PT and aPTT prolongation were significantly higher during acute vaso-occlusive events, acute chest syndrome, splenic sequestration and acute infection (p<0.001). Hydroxyurea use was associated with normal aPTT tests, but no differences were found for PT test based on hydroxyurea use.

Conclusion: This study represents a large pediatric SCD cohort with coagulation testing sampled across all treatment settings demonstrating a high prevalence of prolonged PT and/or aPTT, primarily during acute SCD-related complication. Additional analyses are planned to correlate these findings with clinical manifestations of bleeding.

Batsuli:Octapharma: Honoraria; Genentech: Honoraria; Sanofi: Honoraria.