Classification and Nomenclature of Prothrombin Activators Isolated from Snake Venoms - On behalf of the Registry of Exogenous Hemostatic Factors of the Scientific and Standardization. Committee of the ISTH

Several prothrombin activators from snake venoms have been isolated and characterized (For details, see 1). Initially, they were classified into three major groups based on their structural and functional properties (1, 2). They differ from each other in their cofactor requirements and the products formed. Group I activators are metalloproteinases. They convert prothrombin to meizothrombin and do not require any additional protein cofactors for optimal activity. Recently, Yamada et al. (3, 4) proposed subclassification of group I prothrombin activators based on their dependency on Ca2+ ions; group IA activators are Ca2+independent (former group I activators), whereas group IB are Ca2+-dependent. The group IB activators have two subunits that are held together by non-covalent interaction (3, 4). The larger metalloproteinase subunit activates prothrombin in a Ca2+-independent manner, similar to group IA prothrombin activators. The smaller subunit (structurally related to C-type lectins) enhances the activity of the metalloproteinase subunit by ~100 fold and confers Ca2+-dependency. Group II and III activators are serine proteinases. They cleave both the peptide bonds in prothrombin converting it into thrombin. Group II activators require Ca2+, phospholipids and factor Va for optimal prothrombin activation and they are structurally and functionally similar to mammalian coagulation factor Xa (5-8). Group III activators, on the other hand, require only Ca2+ and phospholipids and they are structurally similar to the complex between factor Xa and Va, the protein components of the prothrombinase complex (9-11). The catalytically active factor Xa component of these venom activators behaves like a group II prothrombinase activator. To accommodate these recent findings, the subcommittee proposes the revised classification (Table 1) of the snake venom prothrombin activators. As proposed earlier by this subcommittee, the names of the prothrombin activators are formed by attaching suffix “-arin” (or “-activase”) to the prefixes derived from the Latin names of the species (12). When Latin names are not unique, prefixes can contain elements from the genus names. In addition, we recommend the inclusion of letter A, B, C or D to indicate the group it belongs to (Table 2). For example, a complex of venom factor Xa and factor Va, belonging to class C from Pseudonaja textilis should be named as pseutarin C. However, there is a possibility that using different purification conditions/methods, one can purify the venom Xa component of this complex alone in a non-complexed form. This protein will behave as a class D activator and the investigators, due to lack of information on its complex formation, will classify it under class D activators. Under these circumstances, it should be named pseutarin D. Thus the new nomenclature will avoid confusion when the complex and the catalytically active component are purified separately. In snake venoms, most protein components exist as several isoenzymes (or isoforms). These isoforms can be either products of different genes or formed by differences in the post-translational modifications. The isoenzymes of prothrombin activators from single snake venom should be identified as A1, A2, A3, etc.