Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation

We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs, including liver, lung, spleen, and kidney. Approximately 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy, and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macrovasculature.

Source: Blood - March 1, 2017 Category: Hematology Authors: Ueda, Y., Mohammed, I., Song, D., Gullipalli, D., Zhou, L., Sato, S., Wang, Y., Gupta, S., Cheng, Z., Wang, H., Bao, J., Mao, Y., Brass, L., Zheng, X. L., Miwa, T., Palmer, M., Dunaief, J., Song, W.-C. Tags: Immunobiology, Platelets and Thrombopoiesis, Thrombosis and Hemostasis Source Type: research