The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin–antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.

Sepsis is a complex of life-threating organ dysfunction in critically ill patients, with a primary infectious cause or through secondary infection of damaged tissues. The systemic consequences of sepsis have been intensively examined and evidences of local alterations and repercussions in the intestinal mucosal compartment is gradually defining gut-associated changes during sepsis. In the present review, we focus on sepsis-induced dysfunction of the intestinal barrier, consisting of an increased permeability of the epithelial lining, which may facilitate bacterial translocation. We discuss disturbances in intestinal vascular tonus and perfusion and coagulopathies with respect to their proposed underlying molecular mechanisms. The consequences of enzymatic responses by pancreatic proteases, intestinal alkaline phosphatases, and several matrix metalloproteases are also described. We conclude our insight with a discussion on novel therapeutic interventions derived from crucial aspects of the gut mucosal dynamics during sepsis.

After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study, we hypothesized that multiple trauma results in immediate activation, consumption, and dysfunction of the complement cascade and that the resulting severe “complementopathy” may be associated with morbidity and mortality. Therefore, a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score = 30.3 ± 2.9) was performed. After polytrauma, serum was collected as early as possible at the scene, on admission to the emergency room (ER), and 4, 12, 24, 120, and 240 h post-trauma and analyzed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma, and discriminated between lethal and nonlethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin showed a biphasic response after trauma. Key fluid-phase inhibitors of complement, such as C4b-binding protein and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronical rapid activation and dysfunction of complement, suggesting a trauma-induced complementopathy early after injury. These events may participate in the impairment of the innate immune response observed after severe trauma.

Cells communicate with other cells in their microenvironment by transferring lipids, peptides, RNA, and sugars in extracellular vesicles (EVs), thereby also influencing recipient cell functions. Several studies indicate that these vesicles are involved in a variety of critical cellular processes including immune, metabolic, and coagulatory responses and are thereby associated with several inflammatory diseases. Furthermore, EVs also possess anti-inflammatory properties and contribute to immune regulation, thus encouraging an emerging interest in investigating and clarifying mechanistic links between EVs and innate immunity. Current studies indicate complex interactions of the complement system with EVs, with a dramatic influence on local and systemic inflammation. During inflammatory conditions with highly activated complement, including after severe tissue trauma and during sepsis, elevated numbers of EVs were found in the circulation of patients. There is increasing evidence that these shed vesicles contain key complement factors as well as complement regulators on their surface, affecting inflammation and the course of disease. Taken together, interaction of EVs regulates complement activity and contributes to the pro- and anti-inflammatory immune balance. However, the molecular mechanisms behind this interaction remain elusive and require further investigation. The aim of this review is to summarize the limited current knowledge on the crosstalk between complement and EVs. A further aspect is the clinical relevance of EVs with an emphasis on their capacity as potential therapeutic vehicles in the field of translational medicine.