Innate immunity and coagulation

Abstract

Infection frequently elicits a coagulation response. Endotoxin triggers the formation of tissue factor initiating coagulation, down regulates anticoagulant mechanisms including the protein C pathway and heparin-like proteoglycans and up regulates plasminogen activator inhibitor. The overall physiological result of this is to promote coagulation through enhancing initiation, suppressing negative regulation and impairing fibrin removal. The response to infection also leads to tissue destruction. Nucleosomes and histones released from the injured cells trigger further inflammation, protection from the pathogen but further tissue injury leading to multi-organ failure. Such a complex response to infection presumably arises due to the role of coagulation in the control and clearance of the infectious agent.

Fig. 1. Histone induced structural changes of the lungs

a-b: Intravascular infused histones disrupt the integrity of the lung capillaries leading to intralveolar haemorrhage (a, histone infused; b, control). c-d: Immunofluorescence staining for neutrophil elastase reveals substantial neutrophil accumulation in the lung of histone treated mice (c) as compared to non-treated controls (d). e-f: Immunofluorescence (e) and phosphotungstic acid (f; PTH) staining for fibrin detects considerable fibrin deposition in the lung of histone treated mice. g-h: Electron micrographs demonstrating the presence of platelet-rich intravascular microthrombi (g) strong alterations of the ultrastructure of the endothelial and epithelial cells, including vacuolisation and intracellular edema (asterisks) in the lungs of histone treated mice. The abbreviations used were av for aveolae and fn for fibrin.

Fig. 2. Blocking histone cytotoxicity improves survival in endotoxemia

Mice were injected with 10 mg/kg LPS in the presence of an anti-H4 monoclonal antibody or control antibody (20 mg/kg). Survival was determined daily and the mice surviving at 7 days are shown above. There were 10 mice in each group as described in reference . The P value for the difference was P=0.004.

Fig. 3. The impact of coagulation on inflammation and the impact of inflammation on coagulation

Coagulation triggers platelet activation and leads to P selectin and CD40 ligand expression platelet surface. Ischaemia leads to cell death and the release of histones and HMGB1, both of which augment inflammation. Inflammation in turn leads to tissue factor induction, leukocyte adhesion, thrombomodulin down regulation, and complement activation, Thus coagulation increases inflammation that in turn increases coagulation.