P3C244: A Novel Case of a Deletion Variant in SERPINC1 Associated with Extensive Neonatal Thromboembolism

Introduction: Antithrombin (AT), a serpin encoded by SERPINC1, is a potent natural anticoagulant that acts mainly by inactivating thrombin and factor Xa. Heterozygous carriers with antithrombin deficiency (ATD) have a higher risk of thrombotic events compared to other inherited thrombophilias. Those afflicted with hereditary ATD often have AT levels reduced to 40-60% of normal levels. An AT activity < 70% strongly indicates ATD and requires further testing. Here, we report a novel deletion mutation in exon 5 of SERPINC1 resulting in Type I AT deficiency, presenting as extensive venous thromboembolism (VTE) in a neonate.

Case Description: A nine-day-old full-term male presented with respiratory distress and a hepatic lesion concerning for a cyst on abdominal ultrasound. Magnetic resonance imaging, angiography and venography of the brain and abdomen revealed bilateral adrenal hemorrhages and thromboses within the superior sagittal sinus, bilateral cortical veins and transverse sinuses, inferior vena cava, left renal vein, possibly right renal vein, left portal vein and ductus venosus. Computed tomography and angiography of the chest showed a pulmonary embolism within the right pulmonary artery. Serum AT activity was low at 29%. Antithrombin concentrate was administered to maintain levels greater than 80% along with enoxaparin to achieve an anti-Xa goal of 0.5-1 U/ml. Other thrombophilia testing was unremarkable though low levels of factor XIII activity (33%) were detected. He was eventually transitioned to warfarin, with a goal international normalized ratio of 2-3, and did not have progression of clotting or bleeding. Next-generation sequencing confirmed the presence of a heterozygous, frameshift deletion variant in exon 5 of SERPINC1, as well as other mutational variants in PROC, MTHFR, FGA and F13A1.

Discussion: There have been limited reports regarding heritable ATD in the neonatal population. The current clinical approach for managing heritable ATD has focused on affected adolescents and adults in transient high-risk clinical settings or with acute VTE events and follows similar guidelines for treating VTE in the general population with the addition of antithrombin concentrate in selected settings. Despite hemorrhages in the bilateral adrenal glands, our patient received moderate intensity anticoagulation with low-molecular weight heparin and AT concentrate prior to transitioning to warfarin given he exhibited severe thrombotic burden resulting in multiple VTE with end-organ dysfunction. To the best of our knowledge, this is the first case of SERPINC1 c.955_965delAAGCCTGAGAA, p.Lys319GlufsTer20 deletion mutation to be reported.

Conclusion: This case suggests AT replacement as an effective therapy for acute VTE in neonates and encourages testing for ATD in children with early, extensive venous thrombosis, unusual clot location, and/or a strong family history. Furthermore, it underscores the significance the molecular findings described herein have on clinical variability and the need for further explorations to achieve a more standardized approach for treating VTE in ATD.