Prevalence and Characteristics of Intracranial Hemorrhage and Acute Ischemic Stroke in Pediatric Patients with Immune Thrombocytopenia and Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis
Authors: Ly Andrew , Ahmad Syed Ameen , Liu Olivia , Feng Amy , Kalra Andrew , Dev Apurva , Spann Marcus , Chaturvedi Shruti , Cho Sung-Min 
Published: December 2024

Background: Immune thrombocytopenia (ITP) and immune-mediated thrombotic thrombocytopenic purpura (iTTP) are associated with significant bleeding risks in pediatric patients, including the risk of intracranial hemorrhage (ICH). Recent data indicate higher rates of bleeding in children with ITP compared to adults [Despostovic & Grimes, Hem ASH Educ Prog, 2018]. However, comprehensive data on stroke prevalence in children with ITP and iTTP are limited. This study aims to determine the prevalence and characteristics of ICH and acute ischemic stroke (AIS) in pediatric patients with ITP and iTTP through a systematic review and meta-analysis.
Methods: We conducted a comprehensive search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies on ITP, iTTP, stroke, ICH, and AIS from inception to November 3, 2023 including pediatric patients. In studies with clearly defined age categories, we included patients under 18 years old. For studies with ambiguous age data, we adhered to the study's definition of pediatric patients. Eligible studies reported the frequency of ICH and/or AIS events in ITP or iTTP patients and used a cohort, cross-sectional, case-control, or case series design with at least five cases. We excluded studies where prevalence could not be calculated, and cohorts focusing on secondary ITP or iTTP. Studies that reported the number of hospitalizations or discharges where a stroke occurred, rather than the number of individual patients, were excluded due to the potential for a single pt to have multiple hospitalizations. ITP staging was defined by each individual study.
Results: We included 22 studies with a total of 17,182 patients. Among all patients, 33.4% were male, 38.1% were female, and sex was not reported for 28.5%. The median age of patients with ITP was 6.0 ± 3.0 years, and the median platelet count was 14.1 ± 7.1 × 109/L. All studies reported patients with ICH and ITP; no studies involving AIS or iTTP met our inclusion criteria, though there were several case reports on congenital TTP and AIS. Regarding ITP staging, 35.6% had acute ITP, 2.1% had persistent/recurrent ITP, 17.7% had chronic ITP, and 21.4% did not have staging described.
The overall prevalence of ICH in pediatric patients with ITP was 1.0% (146 patients out of 17,182, 95% CI 0.4-1.9%). The prevalence was 0.9% (95% CI 0.4-1.5%) in studies with a median or mean age of less than 10 years (n = 12,774) and 1.8% (95% CI 0.0-7.3%) in studies with a median or mean age of 10 years or older (n = 442) (P = 0.03). In a meta-regression of male sex and age, age was associated with ICH (OR 1.75, 95% CI 1.20-2.55). Meta-regression did not identify ITP staging and platelet count as significant risk factors, although there were high levels of data missingness.
Among ICH cases, 32.2% occurred during the initial ITP episode requiring hospitalization, 54.1% during stable ITP, and 13.7% in unspecified contexts. Platelet counts at the time of ICH were &lt;10 × 109/L in 34.9% of episodes, 10-20 × 109/L in 17.7%, &gt;20 × 109/L in 13.6%, and unreported in 34.7%. Traumatic ICH accounted for 20.2% of cases. The youngest ICH onset was at 1 month, with onset ranging from 0 days to 10 years after ITP diagnosis. ICH types included intraparenchymal (60.5%), subarachnoid (14.5%), subdural (13.2%), and epidural (6.6%).
Neurological presenting symptoms included headache (n = 21), vomiting (n = 10), hemiplegia/hemiparesis (n = 9), altered mental status (n = 7), seizures/convulsions (n = 4), facial paralysis (n = 3), and blindness (n = 1). The mortality rate of ICH was 20.5%. Among ICH survivors, 18.1% had neurological sequelae, 44.8% fully recovered, and 37.1% had unspecified neurological recovery.
In studies with available treatment data (n = 89 patients), ICH was managed with steroids (74.2%), IVIG (65.2%), platelet transfusions (49.4%), splenectomy (14.6%), neurosurgery (9.0%), anti-D immunoglobulin (5.6%), and romiplostim (2.2%).
Conclusions: ICH is the predominant form of stroke in children with ITP, with a prevalence of approximately 1.0%. Older age was associated with ICH. No studies in our study reported AIS. While no studies on iTTP met the inclusion criteria, anecdotal evidence from case reports suggests that iTTP may also be associated with stroke, indicating the rarity of iTTP-associated strokes in pediatric patients.