Modulation of Haemostatic Balance in Combined von Willebrand Disease and Antithrombin Deficiency: A Comprehensive Family Study.

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.