How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant.

Abstract

Background: Antithrombin deficiency represents one of the most severe inherited thrombophilias. Albeit a rare disorder, available knowledge suggests that antithrombin deficiency is underestimated due to limitations of current diagnostic algorithms. The high clinical variability of this patient population may be another cause of underdiagnosis. Heterozygous type I (quantitative) variants are normally associated with a severe thrombophilic phenotype, whilst heterozygous type II (qualitative) variants are heterogeneous, including heparin binding site (HBS) defects, which are mild/moderate and the most prevalent. Antithrombin Budapest 3 (p.Leu131Phe) is the most frequent type II/HBS deficiency in Europe, particularly in Roma population, with a remarkable existence of homozygous subjects.

Objectives: Clinical features, diagnostic procedures, and management of patients with severe antithrombin deficiency, leveraging the study of cases homozygous for the antithrombin Budapest 3 variant.

Patients/methods: Patients were selected from 699 subjects with antithrombin deficiency, recruited over 25 years in reference centers from Spain, Belgium, and Hungary.

Results and conclusions: Guided by two illustrative cases with homozygous antithrombin Budapest 3, we report the spectrum and clinical management of patients suffering from this disorder. These cases, with very low antithrombin activity (<20%), and juvenile and recurrent venous thromboembolism, recapitulate numerous issues that one might encounter when treating patients with antithrombin deficiency. In addition, special clinical scenarios for which no formal evidence-based guidelines exist might be found more frequently in these patients, including heparin resistance, vena cava anomalies and obstetric complications. Expert proposals on the optimal management of these controversial areas, as well as future perspectives are also formulated.