Platelets shift into high gear in active ITP, study shows
Findings provide new insights into how the blood disorder develops
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Platelets in active immune thrombocytopenia (ITP) have unique changes in genetic activity that make them more activated than platelets from healthy people or from patients with fewer platelets than normal due to chemotherapy, according to a study that provides new insights into how the disease develops.
“Platelets may reflect, and potentially contribute to, the immune and hemostatic [stopping and preventing bleeding] landscape of ITP,” researchers wrote in “RNA Sequencing Indicates Distinct Platelet Transcriptomic Changes in Immune Thrombocytopenia,” which was published in the Journal of Thrombosis and Haemostasis.
Platelets from patients with active ITP contained more total RNA
In ITP, the immune system mistakenly destroys platelets, cell fragments that normally help blood to clot. As a result, patients are at an increased risk of bleeding and easy bruising. Although ITP is known to involve the immune system, it is not fully understood whether the platelets themselves also have changes that contribute to the disease.
Even though platelets do not have a nucleus, which is the main structure in cells containing DNA, they still contain RNA, which transcribes genetic instructions to produce proteins. Using a sequencing technique to read through and measure RNA transcripts in platelets, the researchers looked at whether they may have a unique pattern of activity in ITP.
The study included samples of purified platelets from six patients with active ITP, six patients whose platelets were low due to chemotherapy, six patients with ITP who were in treatment-free remission, meaning they showed no symptoms or signs of the disease, and eight healthy volunteers as controls.
Platelets from patients with active ITP contained more total RNA than those from healthy controls. Young platelets, which have recently been released from the bone marrow, naturally contain more RNA than older platelets. This finding suggests that active ITP causes the body to produce and release more young platelets to replace those being destroyed.
The RNA sequencing data were high quality and confirmed that the samples contained almost only platelets, with very little contamination from white or red blood cells. The overall RNA activity patterns clearly separated patients with active ITP from healthy controls, while patients in remission had patterns that fell between those two groups.
Platelets in active ITP had unique changes in RNA activity
In active ITP, many increased RNA transcripts were linked to activation of platelets, the process that prepares platelets to adhere to one another and form blood clots after an injury. Activated platelets showed increased activity in integrin-related pathways. Integrins are proteins that allow platelets to adhere to one another and to damaged blood vessels.
Platelets from patients with active ITP also had RNA transcripts linked to the cytoskeleton, the framework that allows platelets to change shape during clotting, as well as vesicle trafficking, the movement of small sacs that transport material inside and outside cells.
“This indicates selective, bidirectional transcript changes within vesicle- and cytoskeleton-associated pathways,” the researchers wrote.
At the same time, platelets from patients with active ITP showed reduced levels of RNA transcripts linked to mitochondria, the structures that produce most of the energy used by cells. They also had lower levels of mitochondrial RNA, suggesting reduced energy-producing activity and altered metabolism within the platelets.
The researchers also detected changes in several long non-coding RNAs, which do not encode proteins but rather help control which genes are active and which are not. Although some small RNAs, including microRNAs, also appeared to differ between groups, the study was not designed to accurately measure these molecules, so conclusions could not be drawn.
Unlike patients with active ITP, those whose platelets were low due to chemotherapy did not show increased RNA levels in platelet activation pathways, indicating that this molecular signature is specific to ITP rather than simply a result of increased production of new platelets in the bone marrow. Patients with ITP who were in treatment-free remission had RNA patterns that were much closer to those of healthy controls.
Overall, this study found that platelets in active ITP had unique changes in RNA activity characterized by an increase in RNA transcripts linked to platelet activation and reduced mitochondrial activity. These changes appear to be specific to active ITP. As patients enter remission, many of these changes partially return toward normal.
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