Bench-to-bedside review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.     

The interactions between inflammation and coagulation

Inflammation initiates clotting, decreases the activity of natural anticoagulant mechanisms and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in coagulation activation. The natural anticoagulants function to dampen elevation of cytokine levels. Furthermore, components of the natural anticoagulant cascades, like thrombomodulin, minimise endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralisation of some inflammatory mediators and decrease loss of endothelial barrier function. Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When the inflammation-coagulation interactions overwhelm the natural defence systems, catastrophic events occur, such as manifested in severe sepsis or inflammatory bowel disease.     

Interactions between the innate immune and blood coagulation systems

Blood coagulation and inflammation are universal responses to infection and there is crosstalk between inflammation and coagulation that can either amplify or dampen the responses. Loss of appropriate interactions between these systems probably contributes to morbidity and mortality in infectious diseases. For instance, inflammatory cytokines and leukocyte elastase can downregulate natural anticoagulant proteins that help to maintain endothelial-cell integrity, control clotting, inhibit vasoactive peptides and dampen leukocyte infiltration into the vessel wall. This Review will summarize our current understanding of the mechanisms involved in the crosstalk between these two important systems.     

Usage of antimicrobial agents in a private primary healthcare setting in South Africa

Objective The aim of this study was to investigate the prescribing of antimicrobials in a private primary healthcare setting in South Africa. Setting A group of private primary healthcare clinics in South Africa. Method A retrospective, drug utilisation study was conducted on nine clinics that were randomly selected from 33 clinics situated in different geographical areas of South Africa, and whose data were electronically available. Data were obtained from the central database of the private primary healthcare provider and extracted for the period January 1, to December 31, 2001. Key findings The study population consisted of the total patient population (n = 83 655) who visited the clinics during this one‐year period. The total number of medicine items prescribed was 515 976 at a total cost of R1 716 319 ($17 163). Of these, antimicrobials represented 18.69% (n = 96 421) of all medicine items prescribed at a cost of R1 045 108 ($10 451) (60.89%). Antimicrobials were prescribed during 72.72% of consultations at the nine clinics during the one‐year period. The antimicrobials most frequently prescribed were penicillins (38.17%) followed by sulphonamides (22.49%), antiprotozoals (9.88%) and tetracyclines (9.34%). The most common diagnoses for which antimicrobials were prescribed were viral influenza, upper respiratory tract infections, hypertension, acute bronchitis, and common cold. Conclusions The high percentage of antimicrobial prescribing obtained in this study could indicate excessive use of antimicrobials in the private primary healthcare setting. The prescribing of antimicrobials in respiratory tract infections could indicate overuse and inappropriate use of these agents. This could have an effect on the health of the patients needing care, and the general budget for healthcare services. It is recommended that further investigations on the prescribing protocols of antimicrobial usage be done.     

A model for thrombin protection against endotoxin

Infusion of dogs with thrombin (0.5 U/kg/min) for 90 minutes significantly increased percent survival following infusion of endotoxin (0.06 mg/kg/min) for 30 minutes. Nine of fourteen dogs infused with thrombin survived seven days (permanent survivors), whereas thirteen of fourteen dogs infused with saline died within 36 hours. Those dogs which survived responded immediately to endotoxin with enhanced anticoagulant and fibrinolytic activity as measured by the Xa one-stage and fibrin degradation product assays, respectively. Those dogs receiving saline instead of thrombin did not respond with anticoagulant or fibrinolytic activity until the end of the study. We concluded that thrombin in the correct amounts protected dogs from endotoxin and that this protection was associated with an early anticoagulant and fibrinolytic response to endotoxin infusion.     

Effects of thrombomodulin and coagulation Factor Va-light chain on protein C activation in vitro.

Protein C activation by thrombin is significantly accelerated by the endothelial cell surface protein thrombomodulin, Factor Va, or its light chain. In this study we have compared the activation of protein C in the presence of either cofactor and examined the possibility that thrombomodulin and Factor Va-light chain act together to regulate protein C activation by thrombin. At all concentrations of protein C used, thrombomodulin was 20 times more efficient than Factor Va-light chain in accelerating protein C activation by thrombin. Protein C treated with chymotrypsin to remove the amino-terminal 41 amino acids that contain the gamma-carboxyglutamyl residues was activated by the thrombin-thrombomodulin complex at an identical rate to native protein C, whereas the modified protein C was activated by Factor Va-light chain and thrombin at only 5% of the rate obtained by using native protein C. Increasing concentrations of Factor Va-light chain, greater than or equal to 30 nM, inhibited thrombin-thrombomodulin catalyzed protein C activation with complete inhibition observed at 90 nM Factor Va-light chain. On the other hand, increasing thrombomodulin concentrations did not inhibit protein C activation by Factor Va-light chain and thrombin. These reactions in solution mimic, in part, those obtained on endothelial cells where protein C lacking the gamma-carboxyglutamyl domain is activated poorly and Factor Va-light chain at concentrations greater than 50 nM inhibited the activation of native protein C. The results of this study suggest that thrombomodulin and Factor Va-light chain may act in concert to regulate protein C activation by thrombin.