Antithrombin Registry - Investigation of Phenotype-genotype Correlations in Patients With Inherited Antithrombin Deficiency

Background:

Antithrombin (AT) is the most important physiological inhibitor of blood coagulation, targeting predominantly factor X and thrombin (Factor II). It is a serine protease inhibitor encoded by the SERPINC1 gene and is synthesized in the liver. Inherited antithrombin deficiency is a rare autosomal dominant disorder that predisposes to the development of venous thromboembolism (VTE), even at young age. We can distinguish two types of AT deficiency: quantitative (type I) and qualitative (type II) deficiencies. According to which function of the protein is affected, type II deficiencies are subdivided into Heparin Binding Site (HBS), Reactive Site (RS) or Pleiotropic Effect (multiple functions or conformational consequences) deficiencies.

Inherited AT deficiency is considered the most severe form of inherited thrombophilia, increasing up to 40 times the risk of venous thrombosis. Antithrombin deficiency is a rare monogenic autosomal dominant disorder although the exact prevalence of AT deficiency remains largely unknown, probably because of the wide clinical heterogeneity. More than 400 different genetic variants in SERPINC1 have been identified. Diagnosis of AT deficiency is done by functional assays that are based on the inhibition of target proteases (Factor Xa or Factor IIa) in the presence of heparin. While biochemical, structural, and molecular information about AT is ample, there is a limited knowledge about the natural history of this disorder. The risk of venous thrombosis in carriers of AT deficiency is well documented but there are many important issues concerning the natural history of AT deficiency that must be unraveled: First, there is a remarkable heterogeneous presentation of AT deficiency. Type I deficiency has been associated with poorer prognosis than type II, but no systematic genotype-phenotype correlations have been done. Moreover, as for any other thrombotic disorder, we could expect that additional factors may modulate the risk of thrombosis in AT deficiency, even for carriers of the same genetic defect.

Objective In this study, the investigators will retrospectively and prospectively collect data on all AT deficient patients diagnosed in or referred to our center for diagnostic work up. The data will be used to create a national registry of antithrombin deficient patients.

The data collected in this registry will allow to gain more insight into what drives the development of a thrombotic event in patients with AT deficiency, both at the environmental level (lifestyle, management of risk situations, presence of additional thrombotic risk factors...) and at the genetic level. Data on obstetric complications and use of anticoagulant drugs will also be collected.