In case-control studies, elevated levels of interleukins 6 and 8 have been found to be associated with an increased risk of venous thrombosis (VT). Because of the design of these studies, it remained uncertain whether these alterations were a cause or a result of the VT. In order to distinguish between the two, we set out to measure the levels of six inflammatory markers prior to thrombosis in a population-based cohort using a nested case-cohort design.
Methods and Findings
Between August 1995 and June 1997, blood was collected from 66,140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). We identified venous thrombotic events occurring between entry and 1 January 2002. By this date we had registered 506 cases with a first VT; an age- and sex-stratified random sample of 1,464 controls without previous VT was drawn from the original cohort. Levels of interleukins 1β, 6, 8, 10, 12p70, and tumour necrosis factor-α were measured in the baseline sample that was taken 2 d to 75 mo before the event (median 33 mo). Cut-off points for levels were the 80th, 90th, and 95th percentile in the control group. With odds ratios ranging from 0.9 (95% CI: 0.6–1.5) to 1.1 (95% CI: 0.7–1.8), we did not find evidence for a relationship between VT and an altered inflammatory profile.
The results from this population sample show that an altered inflammatory profile is more likely to be a result rather than a cause of VT, although short-term effects of transiently elevated levels cannot be ruled out.
An altered inflammatory profile appears more likely to be a result than a cause of venous thrombosis.
Blood clots (thromboses) are a common medical problem, especially in people who have been immobilized for a variety of reasons, who have other medical or surgical conditions, or who take certain types of drugs such as oral contraceptives. As well as these factors, various genetic changes make it more likely that certain people will develop a thrombosis. The most well known of these genetic changes is in a clotting factor, Factor V. Instead of the normal clotting factor V, some people have a variant known as Factor V Leiden, which makes them more likely to develop a thrombosis. (It is so named as it was discovered by researchers in Leiden, Netherlands.) Researchers are trying to find out if other abnormalities, particularly in levels of substances involved in inflammation, might make the chance of thrombosis more common. Identifying such changes might make it easier to predict who might be at risk of getting a thrombosis—for example, when a patient has to have an operation—and thus give them appropriate preventative measures.
Why Was This Study Done?
Previous studies have shown that the levels of inflammatory substances, known as cytokines, are raised around the time of a thrombosis. However, because of the design of these studies it was not clear whether these alterations were a cause or a result of the thrombosis. These researchers wanted to measure the levels of six cytokines before thrombosis in a large group of people and follow them to see if any particular level of cytokine made it more likely that they would go on to develop a thrombosis.
What Did the Researchers Do and Find?
During a three-year period between August 1995 and June 1997, blood was collected from 66,140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). Anyone who had a thrombosis between the start of the study and the beginning of 2002 was identified—506 people in all. Blood samples, taken from these people (cases) between two days and 75 months before the thrombosis happened, were used to measure levels of a number of different cytokines (abbreviated to IL-1β, IL-6, IL-8, IL-10, IL12p70, and tumour necrosis factor alpha [TNF-α]). These levels were then compared with those in samples also taken earlier from 1,464 people who were similar to the cases but had no thrombosis (controls). The authors found no evidence for a relationship between the chance of getting a thrombosis and a change in any of these markers of inflammation.
What Do These Findings Mean?
It seems unlikely that any long-term changes in levels of cytokines make any difference as to whether or not people develop a thrombosis. Hence, any changes seen in previous studies are most likely to have been the result of the thrombosis. However, the researchers could not rule out that changes occurred in the hours or days immediately before the thrombosis, although that seems unlikely. In any case, the levels of these cytokines do not seem to be useful as a clinical tool to predict who is at risk of thrombosis.
Please access these Web sites via the online version of this summary at http://dx.doi.org/101371/journal.pmed.0030334.
MedlinePlus encyclopedia entries on deep venous thrombosis and pulmonary embolus
Omni, a health information service in the UK run by the Resource Discovery Network, has links to pages of information on venous thrombosis
The HUNT studies are described in this Web site