JUPITER, Fla.—Scientists at Scripps Research, a non-profit research organization exploring a variety of medical issues affecting broad populations, have located a prospective new treatment for a low blood platelet condition known as thrombocytopenia. A potentially dangerous condition that can lead to life-threatening internal bleeding, thrombocytopenia has several possible causes and is often a side effect of radiation treatment for cancer.
Until now, clinicians may have turned to removal of the spleen, or to a known protein called thrombopoietin (TPO). TPO has shown promising effectiveness in increasing a person’s platelet count, but also has limitations in its clinical effectiveness. TPO is a glycoprotein hormone produced by the liver and kidney which regulates the production of platelets and stimulates the production and differentiation of megakaryocytes, the bone marrow cells that bud off large numbers of platelets. Studies which introduced recombinant thrombopoetin in normal subjects have been shown to have the contraindicated outcome of spurring antibodies to attack TPO. This unintended side effect has raised concerns about its safety in treating thrombocytopenia patients already facing an immune stressor, triggered perhaps by blood disease, radiation or chemotherapy.
Scripps researchers have found a novel approach to treating thrombocytopenia: by harnessing the YRSACT enzyme, already well known for its role in decoding DNA. What the Scripps team found was that in addition to its translational role, YRSACT was also found in high concentrations in blood platelets, and the researchers set out to discover why. They found that the enzyme plays a critical role in one method of platelet production by increasing the production of megakaryocytes, which are the building blocks of platelets. They began by introducing YRSACT to mice with platelet deficiencies, and saw a dramatic increase in their platelet production.
“Our animal study indicated accelerated platelet recovery, not only in antibody-induced thrombocytopenia, but also in radiation-induced thrombocytopenia,” commented first author Dr. Taisuke Kanaji, an institute investigator at Scripps Research.
Proving the utility of YRSACT posed its own significant research challenges. Because cases of organic thrombocytopenia are rare, decoding the blood cells of those presenting patients for an appropriate testing environment was difficult. Immune thrombocytopenia (ITP) happens when the immune system mistakenly activates antibodies that mistakenly destroy platelets. While it may be hereditary, it is rare, and often not serious enough to cause clinically pertinent symptoms.
Through an auspicious connection, the Scripps team linked up with colleagues at the Center for iPS Cell Research and Application at Kyoto University to test a stem cell line harvested from a thrombocytopenia patient.
“I think this was a beautiful collaboration of groups having distinct expertise to work together to accomplish our goal,” Dr. Sachicko Kanaji, co-first author and a staff scientist at Scripps Research, remarked in a news release.
Most significantly, they found that platelet replenishment by YRSACT is independent of TPO. According to the abstract of the paper initially published in the journal Proceedings of the National Academy of Sciences (PNAS), expansion of megakaryocyte-biased hematopoiesis induced by YRSACT offers new approaches for treating thrombocytopenia, boosting yields from cell-culture production of platelet concentrates for transfusion and bridging therapy for hematopoietic stem cell transplantation, even in patients deficient in TPO signaling.
While thrombocytopenia may be rare, it does present significant risk for an already vulnerable population. “This opens up new options for treating diseases of the blood,” said Dr. Paul Schimmel, professor at Scripps Research and co-senior author of the PNAS study.
According to Kanaji, the next step in the research is to decode the specific conditions—whether a response to radiation or infection—that might prompt the body to activate YRSACT on its own.