The Landscape of Coagulation Cascade in Pulmonary Arterial Hypertension

Background Both the thrombotic and bleeding events were frequently complicated in pulmonary arterial hypertension (PAH), making recommendations regarding anticoagulation difficult.Methods The 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.Results RNA 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)-Ⅲ in the peripheral circulation. Additionally, clinical evaluation of hemostatic parameters in PAH patients demonstrated hemostatic deficiency and lower AT-Ⅲ 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-Ⅲ anticoagulant pathway.Conclusions The activation of extrinsic pathway and impairment of heparin/AT-Ⅲ 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 Perspective What Is New? What Are the Clinical Implications? ### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis work was supported by the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Disease, Ministry of Education (Grant No. XN202010 to G.X.) and Applied Research Cultivation Program of Jiangxi Province (Grant No. 20212BAG70028 to G.X.), and National Natural Science Foundation of China (Grant No. 82260017 to G.X. and Grant No.82370351 to L.X.)### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The animal studies and procedures were approved by the Laboratory Animal Welfare and Ethics Committee of Fujian Medical University (Approval No. IACUC FJMU 2022-0842).This study protocol was approved by the ethics committee of First Affiliated Hospital of Gannan Medical University and written informed consent was obtained from each participant (Approval Number LLSC-2023No.235).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Yes