Abstract
INTRODUCTION: Maintaining the balance between procoagulant and anticoagulant factors is essential for effective haemostasis. Emerging evidence suggests a modulation of bleeding tendency by factors in the anticoagulant and fibrinolytic systems. AIM: This study investigates the clinical and laboratory characteristics of a family with combined von Willebrand disease (VWD) and antithrombin (AT) deficiency. METHODS: The study focused on a 38-year-old female index patient (IP) with severe type 3 VWD and a history of bleeding disorders. Coagulation assays included VWF antigen, platelet-dependent VWF activity, factor VIII activity, thrombin generation assay (TGA) and AT activity. Molecular genetic analyses were conducted by a targeted DNA custom next generation sequencing (NGS) panel. RESULTS: The IP and one of her sisters suffered type 3 VWD. While the IP presents with a classical severe bleeding phenotype, the sister (II-2) exhibited less severe bleeding symptoms. Extended family members showed type 1 VWD with mild presentations. NGS revealed a homozygous deletion of exon 6 in the VWF gene in the IP and her sister (II-2). All other family members carry this genetic variant in a heterozygous state. Additionally, II-2 has a heterozygous variant in the SERPINC1 gene (c.133C>T, p.Arg45Trp). Both IP and II-2 carry a homozygous prothrombin G20210A variant. TGA results indicated reduced thrombin generation in severe VWD patients, with a pronounced thrombin burst in those with the AT and prothrombin G20210A variant. CONCLUSIONS: AT deficiency appears to modulate bleeding symptoms in severe VWD. This study emphasizes the importance of comprehensive genetic and phenotypic evaluation in managing complex coagulation disorders.