Clinical & Molecular Analysis of Patients with Type 2 (Qualitative) Hereditary Antithrombin (AT) Deficiency

Hereditary AT deficiency is classified as type 1 (quantitative) or type 2 (qualitative). Type 2 deficiency can be further subdivided into type 2a (reactive center loop [RCL]), type 2b (heparin binding domain), and type 2c (pleiotropic) based on functional and molecular AT analysis. Patients with heterozygous type 2b AT deficiency are thought to be at a lower risk for venous thromboembolism (VTE).

1) To estimate the frequency of type 2 hereditary AT deficiency. 2) To utilize molecular analysis to accurately sub type patients with type 2 defects. 3) To correlate thrombotic and obstetric complications with AT deficiency sub types.

Apparently unrelated Mayo Clinic AT-deficient patients (n=20) were categorized as type 1 or 2 based on plasma AT activity and antigen, or by molecular analysis for previously reported type 2a-c mutations. Demographic and clinical characteristics were abstracted from patient medical records. The SERPINC1 putative promoter region, all exons (n=7) and splice junctions, and the 3′UTR were PCR amplified from leukocyte genomic DNA, and sequenced with nested forward and reverse primers. For patients without identifiable mutations, multiplex ligand-dependent probe amplification (MLPA) was performed.

Out of 20 probands tested 7 (35%) had type 2 AT deficiency. The mean patient age at diagnosis was 36 years (range 18–65) and 5 (69%) were women. There were 2 patients with type 2a, 4 with type 2b (including 1 with a homozygous defect), and 1 with type 2c AT deficiency. The mean plasma AT (range) activity/antigen for these patients were 50% (37-67%)/93% (78-103%) [AT activity & antigen normal range=80-130%]. 6 patients had a previously described mutation, whereas 1 had a novel mutation [S380R] affecting the RCL (Table1). All patients with type 2a and type 2c AT deficiency had unprovoked VTE occurring at a young age. All 3 patients with heterozygous type 2b AT deficiency had no VTE or obstetric complications. One patient with a homozygous type 2b defect (AT Vienna) presented with an unprovoked DVT at age 15. One family with AT Toyama (type 2b AT deficiency) had 5 asymptomatic adult family members with the mutation.

Molecular testing is important for an accurate subtyping of patients with type 2 AT deficiency. Type 2 defects have a diverse clinical spectrum. Patients with heterozygous type 2b AT deficiency have a low rate of VTE and obstetric complications. Homozygous type 2b AT deficiency can be compatible with adult life.

No relevant conflicts of interest to declare.