Can systemic intravascular thrombosis cause brain infarction?

Question

I wonder if the thrombus can pass through the brain-blood barrier because I think small molecules like O₂, CO₂ and ethanol can pass it. Probably, in some diseases where the permeability of the barrier changes.

Can systemic intravascular thrombosis cause brain infarction?

Answer 1

This question seems to stem from a misunderstanding of the nature of the Blood-Brain-Barrier, the circulatory system of the brain and of thrombi. The BBB is describes differences in the structure of the walls of the blood vessels of the brain, it is not a barrier to flow within the vessel, but a specialized barrier to flow out of the vessel. In many tissues the walls of capillaries (the smallest vessels) are not tightly adjoined, small molecules and even some proteins from the blood are able to pass through these minute gaps between the endothelial cells and into the tissue.

However, in the brain, these endothelial cells are tightly linked in a specialized fashion that prevents the non-specific travel of solutes between cells. Instead, molecules that cannot diffuse through the membranes of the cells must be actively transported across them (cannot leak across).

An intravascular thrombus is much larger than these minute gaps, it is often considerably larger than these small vessels and becomes lodged in larger arteries, blocking flow. There is no passage through the BBB, but there is no passage of the thrombus through the walls of other capillaries in the body either. The damage caused by the infarct is due to the blockage of flow in the larger vessels.

The circle of Willis is no magical stopping point either. Many important sites of infarct (such as the MCA middle cerebral artery), micro-infarcts in even smaller vessels can also cause difficulties.

In short, thrombi and the Blood-Barrier-Brain exist on different scales, the presence or absence of the BBB is irrelevant when discussing the capacity of a thrombus to occlude arteries.

Answer 2

No, a thrombus would be much too large to pass through the highly selective blood brain barrier. However, there are some cases where intra-vascular thrombosis can cause stroke.

One example would be non anti-coagulated atrial fibrillation, where the inefficient beating of the heart causes blood to remain stagnant in the left atrium. This can cause a thrombus to form within the atrium which can then throw off emboli, some of which may enter the cerebral circulation. These may then partially or fully occlude one of the arteries in the Circle of Willis (the brain's circulation system), however the blockage is proximal to the blood brain barrier.

See Management of atrial fibrillation (GY Lip,2007) or for those hitting a pay-wall the professional reference section on AF

Answer 3

No, thrombi are far too bulky to cross the blood brain barrier. Now regarding the risk of stroke in case of systemic thrombi Yes, there are 2 situations where this can arise:

• floating thrombus of the great circulation proximal to the aortic arch (i.e. Most of the time, chronic atrial fibrillation)
• venous thrombus with an associated patent foramen ovale, allowing the thrombi to pass through the atrial septum and get to the great circulation.

Answer 4

The question has a vague term cause which is confusing people here. For me, it means that the event increases the risk of the outcome. For some others, it means the event is a definite factor in resulting in the outcome. So I avoid answering to the question Yes or No because of different interpretations of the term.

The systemic intravascular thombosis increases the risk of stroke, for example, through the two situations as described in Raoul's answer here but those are not sufficient for the accurate risk score of the stroke risk. The factors of stroke risk interact with each other so we cannot leave this question just only about intravascular thombosis and stroke risk, but must consider stroke risk more generally.

CHA2VASc Score for General Stroke score

The Role of the Left Atrial Appendage in AF-Related Strokes, 2013.

Chads-Vasc score. CHA2 DS2-VASc. 
                        SCORE
C    CHF or LVEF < 40\%  1
H    Hypertension        1
A    Age > 75            2
D    Diabetes            1
S    Stroke/TIA/ HF
    thromboembolism/     2
V    Vascular disease    1
A    Age 65-74           1
S    Sex Category female 1
                        Max points 9. 

which specificity and sensitivity are not so high which has resulted in many variations of the initial CHAD VASc score, for example in this study:

We studied 94 patients, 66.0% male, mean age 64.4 years (standard deviation 14.2). A cardioembolic source was detected in 20 patients. ROC curve analysis identified as predictors of cardioembolic source CHADS2 score ≥4 (sensitivity of 75.0%, specificity of 66.0%, p=0.014) and CHA2DS2-VASc score ≥5 (sensitivity of 83.3%, specificity of 58.0%, p=0.009).

To improve this score is ongoing research:

• CHADS2 as well as the CHA2DS2VASc risk score can exclude a large proportion of patients from having high risk of stroke or death, here
• Negative predictive value for zero as cut off value for the endpoint Stroke between CHADS2 (solid dots) and CHA2DS2VASc (circles) in Figure 1

Figure 1: CHADS2 (solid dots) and CHA2DS2VASc (circles).

Sources of thrombosis

• Atrial fibrillation and Left atrial appendix is the source where thrombus can spread into the great circulation
• Patent Foramen Ovale and Stroke where risk factors anatomic variation (PFO size, ASA, eustachian valve anatomy), hemodynamic parameters, presence of venous thrombus identified through higher-sensitivity tests such as lower extremity/abdominal/pelvic MRI, and the presence of hypercoagulable genetic variables

BBB's permeability and Stroke risk

The interaction of the permeability of the brain-blood barrier with the stroke risk is much unknown. The following factors interact with the BBB's permeability

• Montelukast (increases)

Cerebral Blood Flow (CBF) and stroke and Stroke Risk

CBF interaction with the risk of stroke is unknown field

• Alcohol effects on CBF in subjects with low and high responses to alcohol, here.
• carbonated water increases CBF
• aging decreases CBF (standard textbook MRI pictures)

Sources

1. Stoll, Guido. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. 2009. Online available.
2. Homma, Shunichi, et al. Foramen Ovale and Stroke. 2005. Online available.
3. Citings in the body of this question.