Molecular mechanism of cerebral venous thrombosis discovered

Date:
February 11, 2022
Source:
University of Wu"rzburg
Summary:
Cerebral venous thrombosis is a rare, often severe disease that
has been brought to public attention by the COVID-19 pandemic. A
research group has now succeeded for the first time in deciphering
a molecular cause of this disease. This opens the way to new
therapeutic approaches.



FULL STORY ========================================================================== Cerebral venous thrombosis is a rare form of cerebral circulatory disorder that, unlike classic stroke, more often affects younger people. For
unknown reasons, blood clots (thrombi) form in cerebral veins, obstructing blood flow and causing damage to brain tissue. In the spring of 2021,
cerebral vein thrombosis came to public attention as a very rare side
effect of Corona vaccination with vector-based vaccines. In the meantime, however, epidemiological studies have shown that patients with Covid-19
are at a much higher risk for this serious complication.


========================================================================== Scientists from the Rudolf Virchow Center for Integrative and
Translational Bioimaging at the University of Wu"rzburg (RVZ) and the University Hospital Wu"rzburg, who are collaborating with colleagues from Tu"bingen and Greifswald in the Collaborative Research Center Transregio
(SFB TR) 240, have now been able to show for the first time that the
activation of two specific receptors on the surface of blood platelets
leads to cerebral venous thrombosis. "This surprising finding could be
the basis for a new, highly effective therapy for this rare but serious disease," explains the head of the study, Prof. Dr.

Bernhard Nieswandt (Chair of Experimental Biomedicine I), who is also
the spokesperson of the SFB TR 240.

Interaction of two platelet receptors leads to cerebral venous thrombosis
Until now, the molecular processes involved in the development of
cerebral venous thrombosis were poorly understood, and there were
no suitable research models to study them. Known risk factors are
puerperium, oral contraception, and infections. "Actually, we wanted
to investigate whether an antibody against the receptor CLEC-2 on
platelets increases the bleeding tendency when administered into the bloodstream. Quite unexpectedly, the antibody triggered seizures and
other neurological deficits in the treated animals in addition to a drop
in platelet count. Symptoms that closely resembled those of patients
with acute cerebral venous thrombosis. In fact, further investigation
showed that the animals had developed severe cerebral venous thrombosis
within minutes, without clot formation in other organs," explained
Prof. David Stegner, head of the Vascular Imaging group at RVZ and one
of the two first authors of the study. "We hypothesize that the binding
of the antibody alters the properties of the CLEC-2 receptor so that it transmits signals into the cell. This activates platelets and they clump together in the cerebral venous circulation, triggering cerebral venous thrombosis. One mystery is why only the cerebral veins are affected,"
Stegner adds. The research group found that in addition to CLEC-2, a
second platelet receptor, GPIIb/IIIa, is involved in the development
of cerebral venous thrombosis and that only the interaction of both
receptors leads to thrombus formation in the brain.

Platelet blockade as a new therapeutic approach With these findings,
the researchers now specifically sought active substances to block such cerebral vein thromboses. A blood clot is formed by the combination of
two processes: plasmatic coagulation and platelet activation.

Treatment of venous thrombosis generally relies on heparin, as an
inhibitor of plasmatic coagulation. However, in the cerebral venous
thromboses studied here in animal experiments, heparin had only a
comparatively small protective effect. Notably, heparin is the standard medication in the acute treatment of patients with cerebral venous
thrombosis, except when it occurs as a complication associated with
corona vaccination.

The scientists therefore focused on platelet receptors. When these were
blocked in advance, cerebral venous thrombosis did not develop. "The
most interesting finding, however, was that inhibition of platelets by
blocking the GPIIb/IIIa receptor, was extremely effective even after the
onset of neurological symptoms, i.e. in the acute course of the disease,"
says Vanessa Go"b, also first author of the study. The group showed that
the receptor blockade immediately stopped the formation of blood clots
in the cerebral veins, the treated animals recovered completely and no
bleeding complications occurred.

This is of considerable importance for a possible transfer of this
therapeutic approach to patients. Prof. Guido Stoll of the Department
of Neurology adds, "These results were surprising and may pave the way
for the use of GPIIb/IIIa blockers in those patients in whom cerebral
venous thrombosis progresses despite heparin treatment, often leading to
death. GPIIb/IIIa blockers are already approved for other cardiovascular diseases." A key to the success of this project was the interdisciplinary collaboration of different research groups within the Collaborative
Research Center Transregio 240 "Platelets -- Molecular, cellular and
systemic functions in health and disease" (Wu"rzburg -- Tu"bingen),
which has been funded by the German Research Foundation since 2018.

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dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by University_of_Wu"rzburg. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. David Stegner, Vanessa Go"b, Viola Krenzlin, Sarah Beck, Katherina
Hemmen, Michael K. Schuhmann, Barbara F. Scho"rg, Christian
Hackenbroch, Frauke May, Philipp Burkard, Ju"rgen Pinnecker, Alma
Zernecke, Peter Rosenberger, Andreas Greinacher, Bernd J. Pichler,
Katrin G. Heinze, Guido Stoll, Bernhard Nieswandt. Foudroyant
cerebral venous (sinus) thrombosis triggered through CLEC-2 and
GPIIb/IIIa dependent platelet activation. Nature Cardiovascular
Research, 2022; DOI: 10.1038/s44161- 021-00017-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220211102615.htm

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