Our report explores the complex role that nuclear factor-kappa B (NF-κB) plays in thrombosis formation, inflammation, and immunity; while additionally demonstrating that patients with NF-κB pathway pathogenic variants appear to carry a substantial thrombotic risk, particularly when secondary thrombotic risk factors are present. We propose that prophylactic anticoagulation should be strongly considered in such patients during high-risk situations and provide additional hematologic management strategies for those with NF-κB pathway alterations. We hope our work also calls to attention the potential need for a broader assessment of venous thromboembolism risk in patients with immune dysregulation to better delineate which patient populations may benefit from anticoagulation prophylaxis.