The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.

Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19 of 264 (∼7%) patients developed arterial thrombosis, including 4 of 41 (∼10%) patients with hypofibrinogenemia. However, 0 of 8 patients with fibrinogen αC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen αC region on arterial thrombosis, 2 mouse models were employed: (1) wild-type mice treated with lipid nanoparticles encapsulating small interfering RNA against fibrinogen (siFga) and (2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated αC region. Although siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the αC region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of αC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wild-type mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ1 administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen αC region promotes arterial thrombosis in hypofibrinogenemic conditions.