Leukocytes—Innate Immune Cells as Actors in Thrombosis
The recruitment of leukocytes to a thrombus not only aids the immune response but also serves to facilitate platelet activation and coagulation.92 Activated platelets facilitate neutrophils to release NETs, which are a matrix of DNA decorated with neutrophils granule proteins, such as MPO (myeloperoxidase), cathepsin G, and neutrophil elastase.93,94 NETs appear to be a primary defence mechanism to invading pathogens and as such have been demonstrated to trap and kill bacteria and fungi in addition to sequestering viruses.94,95 However, NETs have also been implicated in the pathogenesis of arterial and venous thrombosis in addition to a range of pathologies, including disseminated intravascular coagulation, sepsis, preeclampsia, vasculitis, and systemic lupus erythematosus.96,97 In the context of thrombosis, the release of the highly negatively charged NETs can trap erythrocytes and activate platelets.98 Moreover, NETs serve as a scaffold and potent activator of coagulation via multiple mechanisms. Indeed, neutrophil elastase associated with NETs degrades the anticoagulant protein, TFPI, thereby enhancing TF activity and thrombin generation.96 Histones activate platelets via TLR-2 and TLR-4 and enhance fibrin formation, while the contact activation system, via FXII activation, is initiated by negatively charged DNA.96,99 The activation of FXII not only initiates coagulation but also has important proinflammatory properties by way of its ability to liberate the generation of bradykinin, upregulate neutrophil function, and the generation of monocyte-derived proinflammatory cytokines.100
Activated leukocytes, principally monocytes, and neutrophils, upregulate TF in response to proinflammatory cytokines, predominantly IL-6, and subsequently act to enhance coagulation.101,102 Additionally, monocytes provide a major source of intravascular TF by way of monocyte-derived, TF-bearing microvesicles.103,104 The major danger-associated molecular pattern, HMGB (high mobility group box protein)-1 released by platelets during inflammation has also been shown to be modified by leukocytes, thus facilitating its ability to co-ordinate thrombosis.105 Indeed, platelet-derived HMGB-1 is oxidized by activated monocyte-derived reactive oxygen species, thereby imparting HMGB-1s prothrombotic potential acting in a paracrine fashion to enhance platelet activation, monocyte TF expression and NET formation, and ultimately thrombin generation.105 Interestingly, it has been highlighted that type 1 interferons, a key family of widely expressed cytokines required for the co-ordinated innate immune response to bacterial and viral pathogens, enhance the release of HMBG1 thus enhancing the procoagulant activity of TF.106