Molecular pathology of novel two variants of antithrombin III

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To know the molecular mechanism by which antitrhombin III (AT III) regulates the coagulation cascade, we analyzed the fnction and structure of two novel variant antithrombin III molecules found in patients with thrombosis. A variant AT III found in the first case bound heaprin normally, but it did not inhibit thrombin as the normal AT III.Analysis of the whole base sequence of the propositus' AT III gene revealed a Arg393-His conversion and that the propsitus was a heterozygote for the abnormality. Purified abnormal AT III did not inhibit thrombin and the affinity for heparin was increased, suggesting that Arg393-His conversion might affect the affnity for heparin. A variant AT III found in the second case did not bind heaprin, but it inhibited thrombin normally. Whole base sequence analysis of the AT III gene disclosed a Ser116-Pro conversion. Alle-specific oligonucleotide hybridization demonstrated that the propositus was a heterozygote and the same mutation was found in his father's AT III gene. Such a substitution was first demonstrated among variants AT III so far reported. Although thrombosis was not associated with a heterozygous state for heparin binding defect in most cases, the propositus suffered from recurrent arterial thrombosis probably due to his heavy smoking habit. Thus, a heterozygous state for heparin binding defect would lead to a predisposition to thrombosis when associated with risk factors for thrombosis.