Altered platelet proteome in lupus anticoagulant (LA)-positive patients—protein disulfide isomerase and NETosis as new players in LA-related thrombosis

摘要

Patients with antiphospholipid syndrome (APS) are at high risk of developing venous and arterial thromboembolism (TE). The role of platelets in the pathogenesis of these prothrombotic conditions is not yet fully understood. The aim of this study was to gain mechanistic insights into the role of platelets in APS by comparing the platelet proteome between lupus anticoagulant (LA)-positive patients with (LA+?TE+) and without a history of TE (LA+?TE?) and healthy controls. The platelet proteome of 47 patients with LA, 31 with a history of TE and 16 without thrombotic history, and 47 healthy controls was analyzed by two-dimensional differential in-gel electrophoresis and mass spectrometry to identify disease-related proteins. Afterward, selected LA-related platelet proteins were validated by western blot and ELISA. Alterations of 25 proteins were observed between the study groups. STRING pathway analysis showed that LA-related protein profiles were involved in platelet activation, aggregation, and degranulation. For example, protein disulfide isomerase family members, enzymes that promote thrombosis, were upregulated in platelets and plasma of LA+?TE+?patients. Leukocyte elastase inhibitor (SERPINB1), an antagonist of neutrophil extracellular trap (NET) formation, was decreased in platelets of LA+?TE+?patients compared to healthy controls. Additionally, citrullinated histone H3, a NET-specific marker, was increased in plasma of LA+?TE+?patients. These findings suggest that decreased platelet SERPINB1 levels favor prothrombotic NETosis, especially in LA+?TE+?patients. Our findings reveal protein abundance changes connected to altered platelet function in LA-positive patients, thus suggesting a pathogenic role of platelets in thrombotic complications in APS. Blood coagulation: Protein changes in platelets linked to thrombosis People at high risk for thrombosis (formation of a blood clot inside a blood vessel) show alterations in their platelet protein content. Lena Hell, Maria Zellner, Ingrid Pabinger and colleagues at the Medical University of Vienna, Austria, analyzed proteins found in blood platelets from people who were tested positive for lupus anticoagulants (LAs), antibodies known to increase the risk of thrombosis. Many proteins involved in platelet activation and blood coagulation were found at significantly different levels in people with both LAs and a history of thrombosis compared to control groups. Among these proteins were enzymes that promote clot formation, and regulators of neutrophils, white blood cells involved in the coagulation process. The findings could aid in the search for alternatives to existing anticoagulant therapies.