The landscape of coagulation cascade in pulmonary arterial hypertension

BackgroundBoth the thrombotic and bleeding events were frequently complicated in pulmonary arterial hypertension (PAH), making recommendations regarding anticoagulation difficult. MethodsThe histopathological examination was performed on the lungs of two PAH models and global coagulation cascade alteration in lung tissue and peripheral venous blood was assessed by RNA sequencing and immunoassay, respectively. The clinical data and plasma samples were collected from PAH patients and controls and plasma coagulation cascade in subject was quantified by both immunoassay and proteomic approach. ResultsRNA sequencing analysis of lung tissues in two PAH models showed the reduced anticoagulants and intrinsic clotting factors and increased tissue factor (TF) expression. The immunoassay assessment of coagulation cascade in PAH models revealed increased TF expression, reduced intrinsic and common clotting factors and decreased anticoagulants antithrombin (AT)- in the peripheral circulation. Additionally, clinical evaluation of hemostatic parameters in PAH patients demonstrated hemostatic deficiency and lower AT- activity. Consistently, proteomic and immunoassay analysis of coagulation cascade in PAH patients revealed the increased extrinsic clotting factors, impairment of intrinsic and common pathways and impairment of AT- anticoagulant pathway. ConclusionsThe activation of extrinsic pathway and impairment of heparin/AT- anticoagulant system are conserved mechanisms for thrombosis across rat and human PAH, restoring its function with heparin supplementation may be a better option for future anticoagulant therapy. Clinical PerspectiveWhat Is New? O_LIThe activation of extrinsic pathway and impairment of heparin/AT- system were responsible for thrombosis in pulmonary arterial hypertension. C_LIO_LIImpairment of intrinsic and common pathways, due to reduced plasma levels of clotting factors F10, F11, F2 and vWF, contributed to hemorrhagic complications, such as hemoptysis in PAH patients. C_LI What Are the Clinical Implications? O_LIIncreased risk of bleeding for anticoagulation with warfarin and novel oral anticoagulants may be attributed to further impairment of intrinsic and common pathways in PAH. C_LIO_LIRestoring function of heparin/ AT- anticoagulant system with heparin supplementation may be a better option for future anticoagulant therapy. C_LI