We documented a pediatric patient with EGPA who experienced deep vein thrombosis (DVT) of the lower limb during induction treatment and massive pulmonary thromboembolism during a relapse to highlight the high risk and significance of thromboembolic events in pediatric EGPA patients and raise awareness among clinicians. In the literature search, we identified 13 pediatric EGPA patients with thromboembolic events. The treatment modalities varied between centers. Therefore, we summarized treatment choices and offered recommendations on the management of thromboembolic events in pediatric EGPA.

A high risk of arterial and venous thromboembolic events (AVTE) in EGPA patients have been shown by various authors [11, 14, 15]. Furthermore, some experts have shown that EGPA causes the highest risk of venous thromboembolism (VTE) and pulmonary embolism (PE) among other subtypes of AAV [15]. Hypothesis explaining the mechanisms of increased risk of thrombosis include endothelial injury due to vasculitis, defective fibrinolytic activity, hypereosinophilia and eosinophil extracellular traps and immunothrombosis, presence of antiphospholipid antibodies, and renal disease leading to the loss of anti-thrombotic factors [16,17,18]. There are numerous molecular pathways that are required to be elucidated to conclude the exact pathophysiological mechanism leading to thrombosis. However, eosinophils play a pivotal role in the pathogenesis of EGPA, differentiating it from other AAV subtypes and vasculitides, and current findings point to hypereosinophilia as a major player in the pathogenesis of AVTE [1, 17,18,19,20]. Treatments targeting interleukin (IL)-5, including mepolizumab, have been utilized in patients with hypereosinophilic syndromes presenting with AVTE [21]. Therefore, EGPA patients with consistent hypereosinophilia presenting with AVTE may benefit from treatments targeting eosinophils, such as monoclonal antibodies against IL-5, IL-13 and IL-4 receptor alpha. Future studies should be more focused on these targeted drugs instead of other immunosuppressive agents.

There were very scarce data on pediatric EGPA patients who presented with AVTE in the literature. Clinical findings of the 14 patients were demonstrated in Table 1, and characteristics of AVTE and treatments utilized are summarized in Table 2 [3, 4, 22,23,24,25,26,27,28,29,30,31]. Notably, detailed data of three patients could not be reached [3, 26, 27]. Furthermore, disease involvements of pediatric cases with AVTE were compared with pediatric EGPA patients documented by Gendelman et al. and their literature review in Table 3 [4]. Although mortality and renal involvement rates were slightly higher in the AVTE group, no significant differences were found between the groups. However, in adult studies, skin, pulmonary, and renal involvement was associated with a higher risk of thromboembolism [10]. Our conflicting results with the literature may be due to the limited number of cases or differences between the characteristics of adulthood and childhood EGPA. High disease activity was observed in 78% of our patients, and AVTE occurred during the presentation in those patients, which is compatible with the literature [10, 32]. Clinicians should be very diligent regarding AVTE for patients with EGPA during presentation and high disease activity. Additionally, the patients are generally immobilized during their presentation or have high disease activity due to being in inpatient clinics, which is a risk factor for venous thrombosis [33]. American Society of Hematology (ASH) recommends utilization of LMWH or fondaparinux for acutely ill patients for VTE prophylaxis in adults [34]. However, ASH does not address pediatric patients [34]. Therefore, future studies should focus on the prophylactic utilization of anticoagulant treatment or compression stockings for pediatric EGPA patients with a high AVTE risk or a history of AVTE during presentation and high disease activity.

Documented cases had thrombosis in various sites of the vascular system. The most common thrombosis sites are cerebral, intracardiac, DVT of the lower limb, and pulmonary arteries. Notably, the hepatic vascular system and limb arteries can also be involved [25, 29]. Therefore, clinicians should be aware of that pediatric AVTE generally presents with stroke and dyspnea, but rare involvements may occur.

Thrombocytosis is a common presentation finding in patients with inflammation, including vasculitides. However, four out of six pediatric EGPA patients exhibited thrombocytopenia during a VTE event [25, 28, 30]. Notably, none of the arterial thrombosis patients had thrombocytopenia. Although the association of thrombocytopenia and VTE in EGPA patients was highlighted in the literature with case reports previously, the significance of thrombocytopenia was proven with the case series in our literature review [35, 36]. Furthermore, this thrombocytopenia during VTE may be due to consumption and may serve as a distinguishing feature compared to disease exacerbations, where thrombocytosis is typically expected [35]. Clinicians should promptly evaluate the patient regarding VTE if thrombocytopenia is detected in a patient with EGPA.

In our literature review, twelve out of thirteen pediatric EGPA patients received CS after being diagnosed with AVTE. Immunosuppressive treatments were utilized in eight (61%) patients. CYC was the most common treatment. Although the cause of thrombosis in EGPA involves various molecular pathways, achieving disease remission should be a top priority [16]. Therefore, initiating prompt immunosuppressive treatment is essential. Regarding immunosuppressive selection, the Five Factor Score (FFS) was designed to predict prognosis and can be used to help clinicians choose the most adequate treatment for EGPA patients [37]. However, AVTE was not in the FFS. Emmi et al. recommended adding rare but severe complications, including retinal artery or vein occlusion, to the FFS [1]. Therefore, clinicians should evaluate each AVTE event on a case-by-case basis, decide on the severity of the event, and initiate immunosuppressive treatment accordingly. DVT may be managed as a non-severe disease presentation, while severe arterial thrombosis, which may lead to loss of limb or sight, requires intensive remission induction treatment for severe disease, including pulse CS along with CYC or RTX [1, 8, 9].

American Society of Hematology established management guidelines regarding pediatric VTE in 2018 [38]. According to these guidelines, patients with cerebral sino/venous thrombosis should receive anticoagulation but not thrombolytics. Furthermore, pediatric patients with symptomatic DVT and PE should receive anticoagulation, while asymptomatic patients may or may not receive treatment since adult data suggest that treatment is not required for most asymptomatic patients [38]. However, the current opinion of most clinicians leans towards treating even asymptomatic pediatric VTE cases. Additionally, ASH recommended the utilization of thrombolysis followed by anticoagulation in pediatric patients with PE and hemodynamic compromise [38]. Our patient did not receive thrombolytics because he was hemodynamically stable, and he recovered promptly with anticoagulation. ASH did not prioritize either LMWH or vitamin K antagonists as first line treatment; both can be utilized [38]. Anticoagulation treatment was initiated in six out of seven patients during VTE. Additionally, one patient received antiplatelet treatment along with LMWH contrary to the recommendations of ASH guidelines. The duration of the anticoagulation was not addressed [1, 8, 9]. ASH recommended that patients with provoked VTE should not receive anticoagulation for longer than 3 months [38]. Although there is no data regarding the duration of anticoagulation in our VTE patients, we recommend that continuing anticoagulation at least until disease remission is achieved due to the increased risk of thrombosis during active disease. However, there is no sufficient evidence regarding the effectiveness and relapse risk reduction of anticoagulation longer than three or six months in pediatric EGPA patients with VTE and inactive disease [8].

EGPA patients with arterial thrombosis and infarctions should be treated as having vasculitic involvement and managed with immunosuppressive agents. There is no available evidence regarding antiplatelet or anticoagulant treatment for AAV patients with arterial thrombosis [39]. However, antiplatelet or anticoagulant treatment may worsen the clinical picture due to hemorrhage risk of already vulnerable inflamed arteries or aneurysms in certain vasculitides, including Behçet’s disease [39,40,41]. Therefore, clinicians should be aware of both the possible risks and the lack of evidence of efficacy before utilizing anticoagulation or antiplatelet treatment for arterial thromboses [39]. Future studies should investigate the efficacy and risks of anticoagulation and antiplatelet treatment for arterial thrombosis in pediatric EGPA patients to establish clinical practice recommendations. In our review, intracardiac thrombus was the most common site, followed by cerebral infarcts. The clinicians utilized anticoagulation for four patients and one of them received antiplatelet along with anticoagulation, and one patient received only antiplatelet treatment. Additionally, two patients required surgical intervention out of seven arterial thrombosis patients.

If immunosuppressive treatment fails, surgical interventions may be performed for patients with thrombosis that may cause severe morbidity or mortality. Notably, surgical intervention should not be performed before immunosuppressive treatment due to the high risk of complications caused by the fragile nature of inflamed vascular structures [40].

The prognosis of AVTE in pediatric EGPA patients may depend on involved vascular system, and timely diagnosis and intervention. Out of nine patients, seven recovered completely, while one with sequela. Additionally, one patient’s condition was deteriorated, and he was lost three days after the event. In our review, the prognosis of AVTE was favorable. However, the patient who recovered with sequela received prompt and intensive immunosuppression including pulse CS and CYC for cerebral infarction, yet minimal hemiparesis persisted. Therefore, establishing conclusions on the prognosis would be ungrounded due to the retrospective nature of this review and limited number of cases.