Abstract Number: OC 44.1
Meeting: ISTH 2022 Congress
Theme: Coagulation and Natural Anticoagulants » Contact Pathway
Background: Fat embolism syndrome (FES) is a rare but severe thrombo-inflammatory complication associated with neurologic changes, petechial rash, and thrombosis including pulmonary embolism. It occurs after major trauma with fractures of long tubular bones and involves the release of bone marrow (BM) components into the circulation. The mechanism underlying FES is poorly understood, and targeted therapy remains to be developed.
Aims: We studied the mechanism of FES and focused on the role of the procoagulant and proinflammatory factor XII (FXII)-driven plasma contact system.
Methods: We analyzed post mortem lung tissue of FES patients by immunohistochemistry. We used chromogenic assays, real time thrombin generation analysis and clotting assays in patient and mouse plasma to assess FXII activities and tested for FXII-driven signaling in primary and cultured endothelial cells. A murine lethal pulmonary embolism model was used to study the prothrombogenic potential of BM-derived lipids in vivo.
Results: Synthetic, bovine and human BM-derived lipids activated FXII and initiated coagulation time- and dose-dependently. Contact system inhibitors and inherited contact factor deficiencies abrogated lipid-induced thrombin formation. BM-derived lipids induced plasma kallikrein activity and triggered plasma clotting in a FXII-dependent manner. Further, BM-derived lipids induced the generation of the proinflammatory mediator bradykinin that increased intracellular calcium levels and nitric oxide production in endothelial cells. Immunostaining of FES patient lungs revealed lipid depositions in close proximity to activated FXII and fibrin. Wild-type mice challenged by intravenously injected BM-derived lipids developed lethal pulmonary emboli, whereas FXII-deficient animals were protected and survived BM-derived lipid challenge.
Conclusion(s): We show that the procoagulant and proinflammatory FXII-driven plasma contact system mediates FES in vitro and in vivo. Targeting the contact system presents a novel therapeutic option for FES patients.
To cite this abstract in AMA style:
Konrath S, Hemkemeyer S, Mailer R, Püschel K, Ondruschka B, Renné T. Activation of the Plasma Contact System Triggers the Fat Embolism Syndrome [abstract]. https://abstracts.isth.org/abstract/activation-of-the-plasma-contact-system-triggers-the-fat-embolism-syndrome/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/activation-of-the-plasma-contact-system-triggers-the-fat-embolism-syndrome/