INACTIVATION OF THE GENE FOR ANTICOAGULANT PROTEIN-C CAUSES LETHAL PERINATAL CONSUMPTIVE COAGULOPATHY IN MICE

Matings of mice heterozygous for a protein C (PC) deficient allele, pr oduced by targeted PC gene inactivation, yielded the expected Mendelia n distribution of PC genotypes. Pups with a total deficiency of PC (PC -/-), obtained at embryonic day (E) 17.5 and at birth, appeared to dev elop normally macroscopically, but possessed obvious signs of bleeding and thrombosis and did not survive beyond 24 h after delivery. Micros copic examination of tissues and blood vessels of E17.5 PC-/- mice rev ealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed. In addition, bleeding was noted in the brain near sites of fibrin depo sition. The severity of these pathologies was exaggerated in PC-/- neo nates. Plasma clottable fibrinogen was not detectable in coagulation a ssays in PC-/- neonatal mice, suggestive of fibrinogen depletion and s econdary consumptive coagulopathy. Thus, while total PC deficiency did not affect the anatomic development of the embryo, severe perinatal c onsumptive coagulopathy occurred in the brain and liver of PC-/- mice, suggesting that a total PC deficiency is inconsistent with short-term survival.