Venous thrombosis affects approximately 1/1,000 individuals per year. Most cases involve 1 or more complex genetic factors together with a range of environmental triggers. The majority of monogenic cases of familial thrombosis are associated with defects in the protein C (PC) pathway. It would be of tremendous clinical significance to find genes that modulate the penetrance of mutations in the PC pathway. PC knockout zebrafish will be generated from frozen sperm corresponding to 2 previously identified null alleles of PC, identified in a library of DNA from ENU mutagenized zebrafish. These fish will be used in a sensitized genome-wide ENU mutagenesis screen to identify suppressors of the lethal thrombosis. Heritable mutations will be identified by positional cloning. In addition, the PC knockout zebrafish will be used in a second high-throughput screen to identify novel anticoagulants. The strengths of the zebrafish model organism will again be exploited to assay a diverse set of 35,000 small molecule compounds for in vivo rescue of the lethal phenotype. Successfully rescuing compounds can be quickly tested in human plasma coagulation assays and in vivo mouse models to determine their target and evaluate their therapeutic potential.