Insight into how chemotherapy causes low platelets

Chemotherapy kills cancer cells, but it’s not without cost. One serious side-effect of chemotherapy is it causes platelet numbers to drop, resulting in a higher chance of bruising and bleeding.

Now new research from scientists at the Walter and Eliza Hall Institute has revealed how chemotherapy has its deleterious effect on platelets.

Platelets are formed by a process called ‘shedding’ where small fragments break off megakaryocytes, which are large cells normally found in the bone marrow. However until now it has been unclear precisely how this process unfolds.

The WEHI researchers found the shedding is governed by the Bcl-2 family of proteins, which are involved in the process of apoptosis, or programmed cell death.

Some ‘pro-death’ Bcl-2 family proteins cause cells to die, while an opposing ‘pro-survival’ faction prevents cell death, allowing cells to survive.

In the past decade it has been thought that platelets are formed by megakaryocytes through a process similar to cell death, where they form the platelets internally then release them by breaking up.

“Our research tested this assumption by examining the molecules that are required for programmed cell death,” said Dr Emma Josefsson, one of the study authors. “We found that, at a molecular level, platelet formation does not occur by a death-like process.

“We found that pro-death Bcl-2 family proteins were not required for platelet formation from megakaryocytes. In fact, pro-survival Bcl-2 family proteins are essential for keeping megakaryocytes alive so they can make platelets.”

Low platelet numbers are a side-effect of chemotherapy and, whilst this has long been ascribed to the death of megakaryocytes and their precursors, the mechanisms responsible have remained unclear.

The WEHI team showed that chemotherapy kills megakaryocytes by its action on Bcl-2 family proteins, Dr Josefsson said. “Our work has shown that chemotherapy activates ‘pro-death’ Bcl-2 proteins to kill megakaryocytes, meaning patients are less capable of producing platelets as they recover from cancer treatment.”

Institute scientist Professor Don Metcalf has researched blood formation for the past 50 years and was part of the research team. “For the past decade many researchers around the world have been wondering what role Bcl-2-family proteins play in platelet formation,” he said.

“This study is important for resolving a longstanding debate about platelet formation, and in the long term may lead to new strategies to prevent chemotherapy-induced thrombocytopenia.”

The insight, which was published today in the Journal of Experimental Medicine, offers hope for new treatments that can counteract the effects of chemotherapy on platelet formation.