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