06 May 2022

A newly identified signalling pathway could pave the way to treat blood clots in arteries, German scientists have reported.

Scientists from the Ludwig-Maximilians-Universitaet Muenchen (LMU) say their animal model suggests CXCL12 – a protein messenger – could be suitable as a target for the treatment.

Dr Philipp von Hundelshausen, of LMU’s Institute for Cardiovascular Prevention and the German Centre for Cardiovascular Research (DZHK), said while existing therapies are efficient, they can cause haemorrhaging, and sometimes thromboses can develop anyway.

Reporting in the journal Blood, Dr von Hundelshausen and his team describe a new signalling pathway of blood clotting, which until now has not been possible to influence with drugs. They then demonstrated how this pathway can be experimentally inhibited to reduce the risk of thrombosis.

It was already known that CXCL12 can activate platelets in vitro, and that this happens with CXCR4 as the binding site. CXCR4 is found on all platelets, and platelets are also known to produce CXCL12, the scientists say.

In earlier experiments, the research team discovered a molecule that binds to CXCL12 and inhibits this messenger. Even after manufacturing a synthetic version of the inhibitor, it was still unclear if CXCL12 was involved in arterial thromboses.

Using an animal model, the LMU team has now demonstrated that CXCL12 plays a role in the start of thromboses.

They used gene technology to create a mouse model in which CXCL12 is produced everywhere it is normally produced, but not by blood platelets. The team found thromboses formed later than in wild-type mice and dissolved again faster. In genetically modified mice, blood vessels occluded less often.

The team went on to inhibit CXCL12 with the synthetic molecule they had developed. When mice were injected with the inhibitor before thrombosis was induced, far fewer thromboses occurred and the clots dissolved faster than in untreated animals.

When the team analysed what happens in the inhibition of CXCL12, they found Bruton’s tyrosine kinase – a leukaemia treatment candidate that is also involved in blood clotting – plays a key role. If Bruton’s tyrosine kinase is inhibited with existing cancer drugs, CXCL12 also loses its effect.

Dr von Hundelshausen said their findings suggest that the new inhibitor could be beneficial to heart attack patients. After a heart attack, patients are given acetylsalicylic acid plus clopidogrel to prevent new blood clots from forming, but these lead to incomplete platelet inhibition.

It means in certain situations, such as additional platelet activation by collagen, “the new inhibitor could offer additional benefits without increasing the risk of bleeding,” he added.

Source: Leberzammer J, Agten SM, Blanchet X, Duan R, Ippel H, Megens RTA, Schulz C, Aslani M, Duchene J, Döring Y, Jooss NJ, Zhang P, Brandl R, Stark K, Siess W, Jurk K, Heemskerk JWM, Hackeng TM, Mayo KH, Weber C, von Hundelshausen P. (2022) “Targeting platelet-derived CXCL12 impedes arterial thrombosis.” Blood, doi: 10.1182/blood.2020010140

Link: https://ashpublications.org/blood/article/doi/10.1182/blood.2020010140/484442/Targeting-platelet-derived-CXCL12-impedes-arterial

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