Intrinsic Coagulation Pathway, History of Headache, and Risk of Ischemic Stroke: a story about interacting risk factors

Yup, another paper from the long-standing collaboration with Leiden. this time, it was PhD candidate HvO who came up with the idea to take a look at the risk of stroke in relation to two risk factors that independently increase the risk. So what then is the new part of this paper? It is about the interaction between the two.

Migraine is a known risk factor for ischemic for stroke in young women. Previous work also indicated that increased levels of the intrinsic coagulation proteins are associated with an increase in ischemic stroke risk. Both roughly double the risk. so what does the combination do?

Let us take a look at the results of analyses in the RATIO study. High levels if antigen levels of coagulation factor FXI are associated with a relative risk of 1.7. A history of severe headache doubles the risk of ischemic stroke. so what can we then expect is both risks just added up? Well, we need to take the standard risk that everybody has into account, which is RR of 1. Then we add the added risk in terms of RR based on the two risk factors. For FXI this is (1.7-1=) 0.7. For headache that is 2.0-1=) 1.0. So we would expect a RR of (1+0.7+1.0=) 2.7. However, we found that the women who had both risk factors had a 5-fold increase in risk, more than what can b expected.

For those who are keeping track, I am of course talking about additive interaction or sometimes referred to biological interaction. this concept is quite different from statistical interaction which – for me – is a useless thing to look at when your underlying research is of a causal nature.

What does this mean? you could interpret this that some women only develop the disease because they are exposed to both risk factors. IN some way, that combination becomes a third ‘risk entity’ that increases the risk in the population. How that works on a biochemical level cannot be answered with this epidemiological study, but some hints from the literature do exist as we discuss in our paper

Of course, some notes have to be taken into account. In addition to the standard limitations of case-control studies, two things stand out: because we study the combination of two risk factors, the precision of our study is relatively low. But then again, what other study is going to answer this question? The absolute risk of ischemic stroke is too low in the general population to perform prospective studies, even when enriched with loads of migraineurs. Another thing that is suboptimal is that the questionnaires used do not allow to conclude that the women who report severe headache actually have a migraine. Our assumption is that many -if not most- do. even though mixing ‘normal’ headaches with migraines in one group would only lead to an underestimation of the true effect of migraine on stroke risk, but still, we have to be careful and therefore stick to the term ‘headache’.

HvO took the lead in this project, which included two short visits to Berlin supported by our Virchow scholarship. The paper has been published in Stroke and can be seen ahead of print on their website.