Evolution of vertebrate coagulation proteins. (A) Cladogram of vertebrate evolution. Vertebrates (animals with backbones) include fish and tetrapods (land vertebrates). The earliest tetrapods were amphibians, which arose from lobe-finned fish (sarcoptyrigii) ∼390 million years ago. Amphibians are ancestral to reptiles. Mammals descended from proto-mammalian synapsid reptiles, which diverged from sauropsid reptiles (ancestors of extant reptiles and birds) ∼250 to 300 million years ago. The most primitive mammals are egg-laying monotremes, which are represented today by the duck-billed platypus and a few species of spiny anteater (echidnas). Monotremes are the ancestors of pouched (marsupial) and placental (eutherian) mammals. Cetaceans are a group of aquatic placental mammals that include whales, dolphins, and porpoises. A more detailed presentation of the estimated times of divergence for certain vertebrates is presented in supplemental Figure 4. Green lettering indicates estimated points of origin of protein components of the vitamin K-dependent thrombin generation mechanism (factors II, III [tissue factor], V, VII, VIII, IX, and X). Points of origin of the kallikrein-kinin system (FXII, PK, and HK) and FXI are indicated in blue. Red lettering and a “–” sign indicate loss of the FXII or PK genes (–FXII, –PK). Plasma factors indicated in nonitalicized lettering are plasma proteases, whereas factors indicated in italics are nonenzymatic cofactors. (B) Representative vertebrate species. The animals listed in this table are used as representatives of their respective classes in the manuscript. The abbreviations for the 5 right-hand columns are PK, FXI, FXII, HGFA (pro-HGFA), and HK. The symbols in the columns indicate if a gene for the respective proteins was identified (+) or not identified (–) in genomic analyses. There is uncertainty on whether or not a gene for Pro-HGFA is present in jawless fish (?).