Background: Antithrombin deficiency is a major thrombophilia. In animal models, the absence of antithrombin is lethal. However, role of this deficiency in embryonic states in humans has only been suggested by indirect observations.

Aims: To investigate the potential association of antithrombin deficiency and embryonic lethality in humans by means of case-based analysis.

Methods: Characterization of a thrombophilic family with antithrombin deficiency and history of foetal and neonatal deaths. Plasma antithrombin was analyzed by functional anti-FXa and immunological methods (western-blot in different electrophoretic conditions). Sanger’s sequencing of SERPINC1 was performed in peripheral blood mononuclear cells, as well as in donated tissue from an early miscarriage.

Results: Clinical and molecular characterization of the thrombophilic family is shown in Figure 1. The index case is a 32-year old woman (II-3) with venous thromboembolism (VTE) and two miscarriages (G4:P2:A2:L2), who had type-I antithrombin deficiency with plasma disulphide-linked dimers. Antithrombin deficiency was caused by an intronic splicing variant (c.1154-14G>A) of paternal origin (who also had VTE) that led to an in-frame insertion of 4 residues. The second partner of the patient (II-4) was an asymptomatic carrier of a Budapest 3 variant (p.Leu131Phe). Whilst heterozygous carriers of this type-II/HBS deficiency had no history of VTE (N=7), a homozygous subject (III-7) died from perinatal aortic thrombosis. Genotypic characterization of one of the early foetal losses (III-4) revealed a double heterozygosity for c.1154-14G>A and Budapest 3 pathogenic variants.

Conclusions: We have characterized an exceptional thrombophilic family with an excellent genotype-phenotype association concerning antithrombin defects: from mild heterozygous type-II/HBS deficiency (asymptomatic), to severe type-I and very severe homozygous type-II/HBS deficiencies (with early and neonatal thrombosis, respectively), to the extraordinary severe double heterozygosity of these two variants, that cause embryonic lethality. Thus, this is the first direct evidence in humans that very severe antithrombin deficiency causes embryonic lethality.
ISCIII&FEDER-PI18/00598;FundaciónSéneca-19873/GERM/15

[Clinical and molecular characterization of a thrombophilic family with antithrombin deficiency and foetal losses]

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/first-direct-evidence-in-humans-of-a-severe-antithrombin-defect-causing-embryonic-lethality/