How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant
Carlos Bravo-Pérez 1); Javier Corral 1); Christelle Orlando 2); Vera Ignjatovic 3), 4); Péter Ilonczai 5); Zsuzsanna Bereczky 6)
1 – Department of Hematology, Hospital Universitario Morales Meseguer, University of Murcia, Instituto Murciano de Investigacion Biosanitaria (IMIB)-Pascual Parrilla, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)-Instituto de Salud Carlos III, Murcia, Spain
2 – Department of Hematology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium
3 – Johns Hopkins All Children’s Institute for Clinical & Translational Research, St Petersburg, Florida, USA
4 – Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
5 – Jósa András Teaching Hospital, University of Debrecen, Nyíregyháza, Hungary
6 – Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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 the 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, while heterozygous type II (qualitative) variants are heterogeneous, including heparin-binding site defects, which are mild/moderate and the most prevalent. Antithrombin Budapest 3 (p.Leu131Phe) is the most frequent type II/heparin-binding site deficiency in Europe, particularly in the Roma population, with a remarkable existence of homozygous subjects.
Objectives
To determine the clinical features, diagnostic procedures, and management of patients with severe antithrombin deficiency, leveraging the study of cases homozygous for the antithrombin Budapest 3 variant.
Methods
Patients were selected from 699 subjects with antithrombin deficiency and recruited over 25 years from reference centers in Spain, Belgium, and Hungary.
Results
Guided by 2 illustrative cases with homozygous antithrombin Budapest 3, we report the spectrum and clinical management of patients with 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.
Conclusion
Expert proposals on the optimal management of these controversial areas, as well as future perspectives, are also formulated.