Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development

Abstract

• Myeloid cell TF-dependent venous thrombosis is under control of PDI and the complement cascade.• C5 deficiency reduces fibrin formation and leukocyte PS exposure with normal platelet deposition in flow-restricted vessels.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 2/2 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 2/2 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. (Blood. 2017;129(16):2291-2302

Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking

“…TF expressed by blood monocytes is known to be rendered fully procoagulant dependent on PDI in the context of activation of the complement pathway 3 and complement-dependent monocyte TF activation plays a pivotal role in venous thrombus development in mice 5 . In addition, LPS stimulation of human whole blood causes a PDI-dependent appearance of MV procoagulant activity 5 . In order to confirm that TF release from human cells was also associated with affinity maturation, we isolated MV from LPS-stimulated whole blood.…”

“…Secondary signals can activate TF procoagulant function and thus cause thrombotic complications in disease 1 . Relevant injury and danger signals in this context are degradation of TF pathway inhibitor (TFPI) by neutrophil proteases 2 , complement activation 3–5 , protein disulfide isomerase (PDI) release by injured cells 6, 7 , and triggers of neutrophil extracellular traps incorporating TF 8–11 .…”

Anticoagulant Activity of Low-Molecular Weight Compounds from Heterometrus laoticus Scorpion Venom

“…There is also evidence about multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Thus, complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition as well as diminished platelet activation in vitro [33]. Although there are no data about influence of dipeptides on immune system, one cannot exclude their possible action on blood coagulation through effects on immune system.…”

Complement and clot

“…1 T he complement system is a component of innate immunity that preceded adaptive immunity during evolution, and comprises a cascade of cysteine proteases similar to the organization of the coagulation cascade. The complement system and hemostatic factors interact at several points during the initiation, propagation, and regulation of complement activation and blood coagulation.…”