Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development
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Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. / Subramaniam, Saravanan; Jurk, Kerstin; Hobohm, Lukas; Jäckel, Sven; Saffarzadeh, Mona; Schwierczek, Kathrin; Wenzel, Philip; Langer, Florian; Reinhardt, Christoph; Ruf, Wolfram.
In: BLOOD, Vol. 129, No. 16, 20.04.2017, p. 2291-2302.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development
AU - Subramaniam, Saravanan
AU - Jurk, Kerstin
AU - Hobohm, Lukas
AU - Jäckel, Sven
AU - Saffarzadeh, Mona
AU - Schwierczek, Kathrin
AU - Wenzel, Philip
AU - Langer, Florian
AU - Reinhardt, Christoph
AU - Ruf, Wolfram
N1 - © 2017 by The American Society of Hematology.
PY - 2017/4/20
Y1 - 2017/4/20
N2 - Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3-/-mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5-/-mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.
AB - Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3-/-mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5-/-mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.
KW - Animals
KW - Blood Platelets
KW - Complement Activation
KW - Complement C3
KW - Complement C5
KW - Extracellular Traps
KW - Fibrin
KW - Gene Expression
KW - Hemostasis
KW - Humans
KW - Hydrolases
KW - Immunity, Innate
KW - Leukocytes
KW - Ligation
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Myeloid Cells
KW - Phosphatidylserines
KW - Platelet Activation
KW - Protein Disulfide-Isomerases
KW - Thromboplastin
KW - Thrombosis
KW - Vena Cava, Inferior
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
KW - Research Support, N.I.H., Extramural
U2 - 10.1182/blood-2016-11-749879
DO - 10.1182/blood-2016-11-749879
M3 - SCORING: Journal article
C2 - 28223279
VL - 129
SP - 2291
EP - 2302
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 16
ER -
