Blood platelets are like the sand bags of the body. Got a cut? Platelets pile in to clog the hole and stop the bleeding.

But genetic mutations, infections and even radiation from cancer treatments can slash platelet numbers, leading to a condition called thrombocytopenia and putting people at risk for internal bleeding.

Now scientists have uncovered a new approach for treating thrombocytopenia. As reported in the journal Proceedings of the National Academy of Sciences, they found that an enzyme can boost platelet production and may work as a future therapeutic.

"This opens up new options for treating diseases of the blood," says co-senior author of the study.

Previous research had shown that while the enzyme YRSACT (tyrosyl-tRNA synthetase) has a crucial role in decoding DNA (a process called translation), it appears to have additional jobs in the cell. YRSACT was abundant in blood platelets, the cells that let wounds clog and heal. So, the the team sought to uncover why.

Their study is the first to show that YRSACT is key to one method of platelet production. The authors worked with a platelet-deficient mouse model. Animals injected with YRSACT showed a dramatic increase in platelet production, especially under stressful conditions, such as radiation similar to what cancer patients face.

"Our animal study indicated accelerated platelet recovery, not only in antibody-induced thrombocytopenia, but also in radiation-induced thrombocytopenia," says study first author.

So how does YRSACT work? The researchers found that YRSACT increases the production of large bone marrow cells called megakaryocytes, which are the precursors to platelets. YRSACT targets monocytic cells to induce secretion of transacting cytokines that enhance megakaryocyte expansion stimulating the Toll-like receptor/MyD88 pathway.

Until this discovery, thrombopoietin (TPO) was previously the only other protein known to increase platelets. Co-senior author says a version of TPO is currently used as a drug to treat some cases of thrombocytopenia. However, TPO has limitations, making it unsuitable and hazardous in some clinical settings.

Showing that YRSACT could be useful in human patients posed its own challenges. Congenital thrombocytopenia is rare, and even finding the right blood cells to test in thrombocytopenia patients is like finding a needle in a haystack.

Remarkably, the researchers were able to team up with a group at the Center for iPS Cell Research and Application at Kyoto University to test a stem cell line developed from a thrombocytopenia patient.
"I think this was a beautiful collaboration of groups having distinct expertise to work together to accomplish our goal," says study co-first author.

Their findings in these human cells further confirmed that YRSACT can control a mechanism in cells to produce life-saving platelets.

The next step in the research is to understand the conditions-from infections to radiation-that prompt the body to activate YRSACT on its own.

https://www.scripps.edu/news-and-events/press-room/2018/20180814-platelet-enzyme-bleeding.html

http://www.pnas.org/content/early/2018/08/07/1807000115