A new study has identified a potential mechanism to explain the development of cerebral venous thrombosis, which could lead to new treatments for this rare but severe condition.
Cerebral venous thrombosis has achieved recent prominence as a rare complication of COVID-19 vaccinations, although it has since been shown it is more common as a side-effect of COVID itself.
To date, the molecular mechanisms underlying cerebral venous thrombosis, potentially involving pathological platelet activation, have been unknown.
The research was led jointly by Professor David Stegner and Vanessa Göb of the University of Würzburg, Germany. Writing in Nature Cardiovascular Research, the team describe experiments involving mice which show that the activity of certain receptors on platelet cells is affected by exposure to antibodies.
They tested the antibody INU1, which binds to a receptor called CLEC-2 found on platelets. Administering INU1 “triggers within minutes a cerebral venous thrombosis-like thrombotic syndrome in mice, characterised by tonic-myoclonic seizures, platelet consumption and death”.
Professor Stegner said: “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 - symptoms that closely resembled those of patients with acute cerebral venous thrombosis.
Autopsies of the animals’ brains showed thrombi, or clots, in the cortical blood vessels, but no sign of haemorrhages or swelling from excess fluid. Thrombosis developed in the same part of the animals' brains as in human patients, but nowhere else in the body.
The team found that as well as CLEC-2, a second platelet receptor, GPIIb/IIIa, is involved in the development of cerebral venous thrombosis. Only the interaction of both receptors leads to thrombus formation in the brain.
Blocking GPIIb/IIIa after symptoms began “protected mice from platelet consumption, cerebral venous thrombosis and death,” they report, “which was not seen after treatment with heparin”.
The authors conclude that: “These results point to aberrant platelet activation as a major trigger of cerebral venous thrombosis and potential target for treatment.”
Professor Stegner said: “We hypothesise 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.”
Source: Stegner D, Göb V, Krenzlin V, Beck S, Hemmen K, Schuhmann MK, Schörg BF, Hackenbroch C, May F, Burkard P, Pinnecker J, Zernecke A, Rosenberger P, Greinacher A, Pichler BJ, Heinze KG, Stoll G, Nieswandt B (2022) “Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation.” Nature Cardiovascular Research, doi: 10.1038/s44161-021-00017-1
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