Thrombotic manifestations in GATA2 deficiency: A systematic review of frequency and clinical spectrum Free

Introduction: GATA2 deficiency is a rare autosomal dominant genetic disorder characterized by immunodeficiency, bone marrow failure, and a predisposition to myeloid malignancies. An increasingly recognized feature of this syndrome is the significant early age risk for both arterial and venous thrombosis. The underlying pathophysiology appears multifactorial, involving intrinsic endothelial dysfunction, immune-mediated prothrombotic state, and chronic inflammation (Bierman-Chow et al, 2023; PMID: 36357187). We conducted a systematic review to evaluate the reported frequency and clinical spectrum of thrombotic manifestations associated with GATA2 deficiency.

Methods: A systematic literature review was performed using PubMed to identify cohort studies and case series reporting on thrombosis in genetically confirmed cases of GATA2 deficiency. The search strategy included the terms “GATA2 deficiency,” “thrombosis,” and “stroke.” Studies were included if they provided clinical data on venous and/or arterial thrombotic events in affected individuals.

Results: Data were synthesized from five studies meeting our inclusion criteria. In these small studies, the reported frequency of thrombosis in patients with GATA2 deficiency varied significantly.

Spinner et al. (2014; 24227816): Among 57 US patients (median age 20 years old (y); 54% females), venous thrombo-embolism (VTE) occurred in 25% (n=14), with multiple events in 50% of patients. Arterial events were observed in 3 patients (5%).

Donadieu et al. (2018; 29724903): In a French/Belgium cohort of 79 patients (median age 24.5y; 49% females), thrombosis occurred in 9% (n=7), 3 VTE and 4 arterial/vascular events (2 TIA, 1 MI, and 1 aortic dissection).

Hofman et al. (2020; 32088370): In a pediatric transplant cohort of 15 US patients (median age 15.7y; 33% females), thrombosis occurred in 53% (n=8), with a total of 9 events (2 pre-transplant, 7 post-transplant). Pre-transplant events included 2 VTE whereas post-transplant events included VTE (n=6), and embolic stroke (n=1).

Roncareggi et al. (2023; 37837580): In an Italian cohort of 31 patients (median age 12.5y; 58% females), thrombosis occurred in 10% (n=3); the type of thrombosis was not specified.

Bierman-Chow et al. (2023; 36357187): In a study of stroke in a GATA2 cohort of 127 patients from NIH, early-onset ischemic stroke (<40 years) was reported in 7.9% of cases (n=10, age range 15-38, 60% females), with 6 patients having recurrent strokes. VTE was not reported in this study.

Conclusion: GATA2 deficiency confers a significant risk for both arterial and venous thrombi at a young age. VTE are more frequent than arterial events. Atypical sites of thrombosis including splenic vein, dural venous sinuses, and portal vein are frequent. Arterial events such as early-onset ischemic stroke, embolic stroke, and myocardial infarction, though less common, may also present at a young age and recur. These findings underscore the need to consider GATA2 deficiency in young patients with unexplained thrombosis and cytopenias and highlights the importance of prospective studies to better define thrombotic risk and guide preventive strategies. Early recognition of GATA2 deficiency in such patients may also identify affected family members at risk of thrombosis, immunodeficiency and bone marrow failure syndromes and hence influence their clinical trajectory.