Virchow’s triad and lessons on the causes of ischemic stroke

I wrote a blog post for BMC, the publisher of Thrombosis Journal in order to celebrate blood clot awareness month. I took my two favorite subjects, i.e. stroke and coagulation, and I added some history and voila!  The BMC version can be found here.

When I look out of my window from my office at the Charité hospital in the middle of Berlin, I see the old pathology building in which Rudolph Virchow used to work. The building is just as monumental as the legacy of this famous pathologist who gave us what is now known as Virchow’s triad for thrombotic diseases.

In ‘Thrombose und Embolie’, published in 1865, he postulated that the consequences of thrombotic disease can be attributed one of three categories: phenomena of interrupted blood flow, phenomena associated with irritation of the vessel wall and its vicinity and phenomena of blood coagulation. This concept has now been modified to describe the causes of thrombosis and has since been a guiding principle for many thrombosis researchers.

The traditional split in interest between arterial thrombosis researchers, who focus primarily on the vessel wall, and venous thrombosis researchers, who focus more on hypercoagulation, might not be justified. Take ischemic stroke for example. Lesions of the vascular wall are definitely a cause of stroke, but perhaps only in the subset of patient who experience a so called large vessel ischemic stroke. It is also well established that a disturbance of blood flow in atrial fibrillation can cause cardioembolic stroke.

Less well studied, but perhaps not less relevant, is the role of hypercoagulation as a cause of ischemic stroke. It seems that an increased clotting propensity is associated with an increased risk of ischemic stroke, especially in the young in which a third of main causes of the stroke goes undetermined. Perhaps hypercoagulability plays a much more prominent role then we traditionally assume?

But this ‘one case, one cause’ approach takes Virchow’s efforts to classify thrombosis a bit too strictly. Many diseases can be called multi-causal, which means that no single risk factor in itself is sufficient and only a combination of risk factors working in concert cause the disease. This is certainly true for stroke, and translates to the idea that each different stroke subtype might be the result of a different combination of risk factors.

If we combine Virchow’s work with the idea of multi-causality, and the heterogeneity of stroke subtypes, we can reimagine a new version of Virchow’s Triad (figure 1). In this version, the patient groups or even individuals are scored according to the relative contribution of the three classical categories.

From this figure, one can see that some subtypes of ischemic stroke might be more like some forms of venous thrombosis than other forms of stroke, a concept that could bring new ideas for research and perhaps has consequences for stroke treatment and care.

Figure 1. An example of a gradual classification of ischemic stroke and venous thrombosis according to the three elements of Virchow’s triad.

However, recent developments in the field of stroke treatment and care have been focused on the acute treatment of ischemic stroke. Stroke ambulances that can discriminate between hemorrhagic and ischemic stroke -information needed to start thrombolysis in the ambulance-drive the streets of Cleveland, Gothenburg, Edmonton and Berlin. Other major developments are in the field of mechanical thrombectomy, with wonderful results from many studies such as the Dutch MR CLEAN study. Even though these two new approaches save lives and prevent disability in many, they are ‘too late’ in the sense that they are reactive and do not prevent clot formation.

Therefore, in this blood clot awareness month, I hope that stroke and thrombosis researchers join forces and further develop our understanding of the causes of ischemic stroke so that we can Stop The Clot!

ECTH 2016

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ecth2016.org

Last week was the first edition of the European Congress on Thrombosis and Hemostasis in the Hague (NL). The idea of this conference is to provide a platform for european thrombosis researchers and doctors to meet in the dull years between ISTH meetings. There is a strong emphasis on enabling and training the young researchers, as can be from the different activities and organisational aspects. One os these things was the Junior advisory board, of which I was part. We had the task to give advice both solicited and unsolicited, and help organise and shape some of the innovative aspects. For example: we had the so-called fast and furious sessions, where authors of the best abstract were asked to let go of the standard presentation format and share their research TED talk style.

I learned a lot during these sessions, and even got in contact with some groups that have interesting methods and approaches that we might apply in our studies and patient populations. My thoughts: targeting FXII and FXI as well as DNAse treatment are the next big thing. We also had a great selection of speakers for meet-the-experts and how-to sessions. These sessions demanded active participation of all participants which is really a great way to build new collaborations and friendships.

The 5K fun run with 35+ participants was also a great succes.

The wednesday plenary sessions, including the talks on novel and innovative methods of scholarly communications as well as the very well received sessions from Malcolm Macloud on reducing research waste where inspiring to all. Missed it? do not worry, they have shared their slides online!

All in all, the conference was a great success in both numbers (750+ participants) as well as scientific quality. I am looking forward to the next edition, which will be held in Marseille in two years time. Hope to see you all there!

The ECTH 2016 in The Hague

My first conference experience (ISTH 2008, Boston) got me hooked on science. All these people doing the same thing, speaking the same language, and looking to show and share their knowledge. This is true when you are involved in the organisation. Organising the international soccer match at the Olympic stadium in Amsterdam linked to the ISTH 2013 to celebrate the 25th anniversary of the NVTH was fun. But lets not forget the exciting challenge of organising the WEON 2014.

And now, the birth of a new conference, the European Congress of Thrombosis and Hemostasis, which will be held in The Hague in Netherlands (28-30 sept 2016). I am very excited for several reasons: First of all, this conference will fill in the gap of the bi-annual ISTH conferences. Second, I have the honor to help out as the chair of the junior advisory board. Third, the Hague! My old home town!

So, we have 10 months to organise some interesting meetings and activities, primary focussed on the young researchers. Time to get started!

New article published: the relationship between ADAMTS13 and MI

2015-06-16 14_26_12-Plasma ADAMTS13 levels and the risk of myocardial infarction_ an individual pati

this article is a collaboration with a lot of guys. initiated from the Milan group, we ended up with a quite diverse group of researchers to answers this question because of the methods that we used: the individual patient data meta-analysis. The best thing about this approach: you can pool the data from different studies, even while you can adjusted for potential sources of confounding in a similar manner (given that the data are available, that is). On themselves, these studies showed some mixed results. But in the end, we were able to use the combined data to show that there was an increase MI risk but only for those with very low levels of ADAMTS13. So, here you see the power of IPD meta-analysis!

The credits for this work go primarily to AM who did a great job of getting all PI’s on board, analysing the data and writing a god manuscript. The final version is not online, but you find the pre-publication on pubmed

 

 

New article: the intrinsic coagulation proteins and the risk of arterial thrombosis

I got good news today! A manuscript on the role of the intrinsic coagulation factors in the causal mechanisms leading to myocardial infarction and ischaemic stroke has been accepted for publication by the JTH. It took sometime, but in the end I’m very glad that this paper was published in the JTH because its readership is both clinical as well as biomedical: just the place where I feel most at home.

The basic message? These factors do contribute to ischaemic risk, but not to the risk of myocardial infarction. This is mostly the case for coagulation factor XI, which is a nice finding, because it could be a new target for anti-thrombotic therapies.

The article is now in print and will be made available soon. In the mean time, you can refer to my thesis, in which this research was also described.

New article published: review on obesity and venous thrombosis

Together with colleagues I worked on a review on the role of obesity as a risk factor for venous thrombosis. I’m second author on the article, which come online last week, and most work has been done by SKB from Norway, who is visiting our department for a full year.

The article is written from an epidemiological point of view and discusses several points that are worth mentioning here. First of all, obesity is an ill-defined concept: are we only talking BMI, or do also other measures of obesity need to be taken into account? Second, even when defined, the results are not always easy to interpret. In causal research there are a couple of things that need to be fulfilled before one can answer the question whether something is risk factor of disease. For example, BMI can be reduced by means of exercise   diet or disease, which all three have completely different effects on thrombosis risk. We discuss all these epidemiological problems, together with the existing body of evidence in the new article in seminars of thrombosis and hemostasis. These question are not only important for our understanding of thrombotic disease, but also to grasp the causal role of obesity in (cardiovascular) disease. This research question has in ast couple of years been put on the research agenda of the NEO study, on which perhaps more in the future.

The article, with the full title “Role of Obesity in the Etiology of Deep Vein Thrombosis and Pulmonary Embolism: Current Epidemiological Insights” can be found via PubMed, or via my personal Mendeley page.