Infections Can Induce Widespread Blood Clotting

MedicalResearch.com Interview with:
Professor Adam Cunningham PhD
Institute of Immunology and Immunotherapy
MRC Centre for Immune Regulation
University of Birmingham

Medical Research: What is the background for this study?

Dr. Cunningham: Our original question was “Why do people die from Salmonella infections that spread beyond the gut”. Some reasons are known but these do not account for all. In particular infants in sub-Saharan Africa seem particularly prone to Salmonella infections that in the West do no more than cause a self-limiting gastroenteritis. A puzzling feature of many of infections in such infants is that they do not have many bacteria in the blood, probably <10 / ml of blood, yet this low density is a strong predictor of death. Therefore, we thought that it may be the host response to the infection that complicates its control and contributes.

Medical Research: What are the main findings?

Dr. Cunningham: We have found that infection induces a really extensive thrombosis (clotting) in the blood. Thrombosis in a controlled manner during infection may be beneficial, but too much is not. We suspect this poorly controlled clotting contributes to the poor outcome seen in blood borne infections caused by Salmonella. There are a number of interesting features associated with what we have found. First, it seems that whilst infection is needed to cause the thrombosis after it starts it is maintained by the inflammatory response to the organism. In a bitter twist to this, the type of inflammatory response and cell that is responsible for the thrombi to develop is actually the same that controls the early stages of infection. Therefore, what protects you can possibly harm you at the same time.

A second key finding is that the way the thrombi develop is also unusual. Instead of using well defined pathways platelets, the cells responsible for the clotting, are activated through an unusual mechanism that is not well investigated but can be associated with inflammation. Critically, this explains why common anti-clotting drugs may not always be beneficial in cases of sepsis but offers the exciting potential to identify drugs that may be beneficial but that work without having side-effects such as increased risk of bleeding. Moreover, it appears that the macrophages that are important for the thrombosis reside in organs and tissues and not in the blood. They can activate the platelets through damaged regions of the blood vessels, similar to reaching across gaps in a wall. This means the clotting in the vessels is initiated by contact with cells in the tissues. In humans this would be incredibly hard to detect as sampling both the blood and the tissues at the same time during sepsis would be incredibly difficult to do.

This leads onto the third significant finding. Although we have examined the response to Salmonella here, our work is high relevant to a wider audience who have to work with sepsis. In about half of sepsis cases no pathogen is identified. By identifying how the inflammatory response propagates thrombosis we now understand better why it may be difficult to detect the invading pathogen. We suspect this is because by the time the patient presents then ironically the infection itself may be under control but that problems such as thrombosis are the “collateral damage” associated with achieving this.

Medical Research: What should clinicians and patients take away from your report?

Dr. Cunningham: Sepsis, in its variable forms, has a fatality rate of around 30%. The major message is that this offers hope for being able to help control thrombosis after infection and thrombosis is known to be a major indicator of poor outcome in sepsis. By opening the door to new pathways of investigation we can find new ways to reduce the risks from this potentially devastating consequence of infection.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Cunningham: Major recommendations include:

1.    To understand whether other infections cause thrombosis using the same mechanisms

2.    To understand how we can control the extent of clotting after infection.

3.    To identify whether drugs that target this novel pathway of platelet activation after infection do so without increasing the risk of bleeding

4.    To see if this pathway is active in non-infectious inflammatory diseases too where thrombosis is a major complication

Citation:

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets
Jessica R. Hitchcock … Steve P. Watson, Adam F. Cunningham
Published November 16, 2015
Citation Information: J Clin Invest. 2015. doi:10.1172/JCI79070.

Professor Adam Cunningham PhD (2015). Infections Can Induce Widespread Blood Clotting MedicalResearch.com