A novel prothrombin mutation in two families with prominent thrombophilia – the first cases of antithrombin resistance in a Caucasian population

Abstract

To cite this article: Djordjevic V, Kovac M, Miljic P, Murata M, Takagi A, Pruner I, Francuski D, Kojima T, Radojkovic D. A novel prothrombin mutation in two families with prominent thrombophilia -the first cases of antithrombin resistance in a Caucasian population. J Thromb Haemost 2013; 11: 1936-9.

The c.1787G>T and c.1787G>A Mutations are not Found in the Prothrombin Gene in a Spanish Population

“…A similar result has been obtained in studies developed in Japanese, Serbian and Italian populations [4,5,8].…”

“…This mutation is located in the last exon of the prothrombin gene resulting in Arg596Leu replacement. Djordjevic et al [5] also have described another mutation at the same prothrombin gene position (c. 1787G>A prothrombin Belgrade) that results in aminoacid change (Arg596Gln). The mutant prothrombins were shown to have reduced activity in clotting assays and the produced thrombin was markedly resistant to inhibition by antithrombin.…”

Thrombotic and Hemorrhagic Conditions Due to a Gain of Function of Coagulation Proteins: A Special Type of Clotting Disorders

“…7 Recently, a few cases of prothrombin abnormalities have been associated with a thrombotic tendency. [8][9][10][11][12] These abnormal prothrombins show a gain of function toward antithrombin (AT). Antithrombin is a small glycoprotein with a molecular weight of 58 000 dalton produced by the liver and circulating at a concentration of about 0.12 mg/mL.…”

Identification of a new potential mechanism responsible for severe bleeding in myeloma: immunoglobulins bind the heparin binding domain of antithrombin activating this endogenous anticoagulant

“…The variant prothrombins are highly resistant to antithrombin inhibition, ensuing a prolonged procoagulant activity and susceptibility to thrombosis. 9 On the other hand, a point mutation (p.Met358Arg) in SERPINA1, the gene encoding other serpin with no anticoagulant role, α1-antitrypsin, generates a variant (α1-antitrypsin Pittsburgh) with a greatly impaired anti-elastase activity but significantly increased antithrombin activity, which provoked bleeding disorders. 10 Finally, activation of antithrombin by different compounds acting as co-factors (including sulfated small organic ligands such as lignins and flavonoids, heparin and heparin-like molecules) significantly increase the risk of bleeding.…”

“…However, not all interactions cause activation of antithrombin. 9,12 This study identifies a new molecule able to bind the heparin binding domain of antithrombin with functional consequences acting as a heparin-like factor. The IgG from a patient with multiple myeloma, who suffered from a severe bleeding event, had a heparin-like activity.…”