Two homologous complexes drive blood coagulation, the tenase complex and the prothrombinase complex. Both are composed of a large protein cofactor and a smaller serine protease assembled on a negatively charged phospholipid membrane surface. The tenase complex converts the zymogen factor X (fX) to the active protease fXa, and the prothrombinase complex converts prothrombin into thrombin. In the absence of the cofactor the rates of conversion are exceedingly slow, with acceleration on the order of 100,000-fold conferred by complex assembly. Last year we published the structure of a prothrombinase complex from the venom of the Australian Eastern Brown snake, Pseudonaja textilis. It revealed the details of the cofactor-protease interaction and gave clues as to how the substrate prothrombin binds. Here we investigate the hypothesis that the cofactor-protease contact is conserved in snake and human prothrombinase, and perhaps even the homologous tenase structure, by creating and analysing molecular models. We find the interfaces are similarly complementary in charge and shape, and are consistent with the majority of biochemical data. However, differences in the structures of fX and prothrombin result in radically altered substrate binding modes.