Clostridium difficile Induced Inflammasome Activation and Coagulation Derangements

Abstract

C. difficile enterocolitis (CDAC) is the most common hospital infection, burdened by an increased incidence of coagulation-related complications such as deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) as well as a significant sepsis-related mortality. In this review, we analyzed the available data concerning the correlation between coagulation complications related to C. difficile infection (CDI) and inflammasome activation, in particular the pyrin-dependent one. The little but solid available preclinical and clinical evidence shows that inflammasome activation increases the risk of venous thromboembolism (VTE). As proof of this, it has been observed that in vitro inhibition of the molecules (e.g., tissue factor) mainly involved in coagulation activation could block the process. In vivo studies show that it could be possible to reduce the incidence of complications associated with C. difficile infection (CDI) and mortality due to a state of hypercoagulability. A personalized therapeutic approach to reduce the inflammatory activity and prevent thromboembolic complications could be preliminarily defined to reduce mortality.

Melatonin as an Antimicrobial Adjuvant and Anti-Inflammatory for the Management of Recurrent Clostridioides difficile Infection

“…Targeting the cascade of CDI inflammatory processes could serve as a pharmacotherapy option for the management of recurrent CDI. Specific inflammatory mechanisms and pathways associated with C. difficile include NLRP3, TLR4, and host heme hijacking for incorporation into an oxidative stress defense system [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Interestingly, melatonin has been shown to have strong anti-inflammatory and antioxidant properties via several of the same inflammatory pathways associated with C. difficile , which led our research team to hypothesize that exposure to melatonin could be utilized as an antimicrobial adjuvant to decrease recurrent CDI.…”

Clustering Disease of Clostridioides Difficile Infection: Implication for the Management in Internal Medicine

“…Contrary to the various studies cited so far, severe forms of CDI are burdened by an increased incidence of complications related to coagulation such as deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) [70]. Coagulation complications related to CDI depend on inflammasome activation [70]. Inflammasomes are complexes of multiple related proteins present within the cytosol of cells of the innate immune system primarily involved in the first-line activation of inflammatory responses, against pathogens and associated signals that configure tissue damage as occurs in CDI [71].…”

“…In the fragile immunocompromised patient with high assistance complexity, it has been observed that in the case of CDI, the risk of mortality from all causes increases in the short term [69]. Contrary to the various studies cited so far, severe forms of CDI are burdened by an increased incidence of complications related to coagulation such as deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) [70]. Coagulation complications related to CDI depend on inflammasome activation [70].…”

“…Fulminant colitis occurs in those patients where CDI presents as severe hemorrhagic colitis with bloody diarrhea and can cause systemic manifestations such as severe hypotension, multiple organ failure, and renal insufficiency. Shock, ileus, or megacolon can be complications of fulminant colitis, up to disseminated intravascular coagulation [70]. The reason why the course is indolent in some patients while others are more severe is unclear, but in general, it is possible to state that it depends on the bacterial load, the virulence of CD aggression, and the severity of the inflammatory picture in response to the cytopathic damage.…”

“…S-layer binding to dendritic cells stimulates nuclear transcription factor kappa β (NF-kB) and interferon regulatory factor 3, resulting in the production of inflammatory cytokines and activation of immune cells including neutrophils [164]. This demonstrates that the activation of the immune system is essential to inhibit the permeability of the intestinal barrier through the damaged mucosa [70]. Additionally, at the level of the CD flagella, there are proteins that act as activators of the immune response (flagellins of b-proteobacteria and g-proteobacteria) which are recognized by TLR5, which is expressed by enterocytes and dendritic cells.…”