Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis

Red blood cells (RBCs) influence rheology, and release ADP, ATP, and nitric oxide, suggesting a role for RBCs in hemostasis and thrombosis. Here, we provide evidence for a significant contribution of RBCs to thrombus formation. Anemic mice showed enhanced occlusion times upon injury of the carotid a...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-09, Vol.128 (9), p.3906-3925
Main Authors: Klatt, Christoph, Krüger, Irena, Zey, Saskia, Krott, Kim-Jürgen, Spelleken, Martina, Gowert, Nina Sarah, Oberhuber, Alexander, Pfaff, Lena, Lückstädt, Wiebke, Jurk, Kerstin, Schaller, Martin, Al-Hasani, Hadi, Schrader, Jürgen, Massberg, Steffen, Stark, Konstantin, Schelzig, Hubert, Kelm, Malte, Elvers, Margitta
Format: Article
Language:English
Subjects:
Anemia
Apoptosis
Biomedical research
Blood clots
Blood platelets
Cancer
Carotid artery
CD95 antigen
Cell activation
Clonal deletion
Development and progression
Erythrocytes
FasL protein
Health aspects
Heart attacks
Hemostasis
Immune system
Ligands
Nitric oxide
Occlusion
Phosphatidylserine
Physiological aspects
Platelets
Red blood cells
Rheology
Thrombin
Thrombosis
Tumor necrosis factor
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Summary:Red blood cells (RBCs) influence rheology, and release ADP, ATP, and nitric oxide, suggesting a role for RBCs in hemostasis and thrombosis. Here, we provide evidence for a significant contribution of RBCs to thrombus formation. Anemic mice showed enhanced occlusion times upon injury of the carotid artery. A small population of RBCs was located to platelet thrombi and enhanced platelet activation by a direct cell contact via the FasL/FasR (CD95) pathway known to induce apoptosis. Activation of platelets in the presence of RBCs led to platelet FasL exposure that activated FasR on RBCs responsible for externalization of phosphatidylserine (PS) on the RBC membrane. Inhibition or genetic deletion of either FasL or FasR resulted in reduced PS exposure of RBCs and platelets, decreased thrombin generation, and reduced thrombus formation in vitro and protection against arterial thrombosis in vivo. Direct cell contacts between platelets and RBCs via FasL/FasR were shown after ligation of the inferior vena cava (IVC) and in surgical specimens of patients after thrombectomy. In a flow restriction model of the IVC, reduced thrombus formation was observed in FasL-/- mice. Taken together, our data reveal a significant contribution of RBCs to thrombosis by the FasL/FasR pathway.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci92077