BNP Promotes Platelet Activation and Thrombosis via its Receptor NPRA: A Paradigm Shift from Biomarker to Effector

B-type natriuretic peptide (BNP) is a cardiac-derived vasodilator and a well-established biomarker for heart failure. Elevated BNP and its cleavage product N-terminal proBNP (NT-proBNP) also predict adverse outcomes in acute coronary syndromes and other cardiovascular diseases. However, it remains unclear whether BNP directly contributes to cardiovascular disease pathogenesis, such as by promoting thrombosis, or merely serves as a biomarker. We investigated the effect of BNP on platelets in vitro and thrombosis in vivo. Incubation of platelets with BNP significantly increased intracellular cGMP levels and enhanced platelet aggregation, granule secretion, spreading, and clot retraction in vitro. We further identified that platelets express the receptor for BNP, natriuretic peptide receptor-A (NPRA). The effects of BNP on cGMP production and platelet activation were abolished in NPRA-deficient platelets. Using FeCl₃ carotid injury-induced arterial thrombosis model and a thromboplastin-induced pulmonary embolism model, we found that BNP administration accelerated thrombus formation in wild-type mice. Moreover, NPRA-deficient mice exhibited prolonged tail bleeding times and delayed arterial occlusion following vascular injury. BNP injection failed to promote thrombosis in NPRA-deficient mice. Our study demonstrates that BNP promotes platelet activation and enhances arterial thrombosis and thromboembolism via NPRA signaling. These findings suggest that BNP may not only serve as a biomarker of cardiovascular disease, but may also contribute directly to thrombotic risk, providing a potential mechanistic link between elevated cGMP levels and thrombosis.