Research reveals unique platelet population linked to aging and blood clotting diseases

As people get older, they become more susceptible to blood clotting diseases, when blood cells called platelets clump together when they don’t need to, and this can cause major problems like stroke and cardiovascular disease. For decades, scientists have studied why the blood cells of the elderly behave this way. They used their insights to develop the numerous blood-thinning medications now on the market to treat the leading cause of death in the United States.

Now Camilla Forsberg, professor of biomolecular engineering at the University of Santa Cruz, and her research group have discovered a distinct, secondary population of platelets that appears with aging and has hyper-reactive behavior and unique molecular properties, making them easier to target with drugs. The researchers traced this platelet population back to the stem cell origins and found what they identify as the very first age-specific developmental pathway from a stem cell to an individual adult platelet cell.

The question has been asked for decades: Why are older people at such a high risk for excessive blood clotting, stroke and cardiovascular disease? We have this discovery of a completely new pathway that gradually appears with aging -; troublemakers! That was never part of the discussion.”

Camilla Forsberg, professor of biomolecular technology, UC Santa Cruz

The research group presented their findings in an article published in the prestigious journal Cell. First author Donna Poscablo, Forsberg’s former Ph.D. student who is now a postdoctoral researcher at Stanford University, and her colleagues conducted these experiments using the resources and training environment of the Institute for the Biology of Stem Cells (IBSC) at UC Santa Cruz.

Understanding platelets

Platelet cells are one of three types of blood cells produced by the body, with red and white blood cells being the other two. Millions of these cells are constantly floating around in the blood, and when internal or external injury occurs, they clump together to form a natural, living patch. Platelet dysregulation, which is known to increase with age, occurs when these cells are hyper-reactive and form clots too often, or underperform. In both cases, the body cannot properly control bleeding and clotting, although hyper-reactivity is a much more commonly seen problem.

All blood cells begin as hematopoietic stem cells, a special class of stem cells, and then mature through a series of intermediate steps, a so-called ‘differentiation pathway’, that lead them to their fate as platelets, red blood cells or white blood cells. It has been known for decades that these hematopoietic stem cells decline with age, but that presents a contradiction for scientists: if the hematopoietic cells are less healthy, why are the platelets they create hyper-reactive?

A ‘shortcut’ path

As stem cell biologists, UC Santa Cruz researchers approached this question by examining hematopoietic stem cells.

They conducted experiments that allowed them to trace the lineages of these stem cells in mouse models, and found that in old mice, some of their platelets did not travel along the differentiation pathway. Instead, they took what the UCSC researchers called a “shortcut,” skipping the intermediate steps and immediately becoming megakaryocyte precursor cells, the stage of blood cells immediately before platelet production. As far as the researchers know, this is the first age-specific stem cell pathway ever discovered.

“People think of (platelets and red blood cells) as one line that shares regulation and intermediate stages until the end,” Forsberg said. “It was really surprising to see that (the secondary platelet population) was completely separated from the stem cell level, only in older mice.”

Although the population of platelets produced by the shorter route is hyper-reactive, the platelets produced by the main route continue to behave like the platelets in young people.

“The gradual differentiation cascade retains a youthful quality, and I think that in itself is surprising,” Poscablo said.

They found that the hyper-reactive secondary platelets are produced in the mice around mid-life, with their population gradually growing as they age. So far, researchers have not found a trigger that initiates the production of this secondary pathway. But unexpectedly, it does not appear to be caused by the aging environment itself: when a young hematopoietic stem cell is transferred to an aging environment, it does not appear to activate the shorter pathway; and when an aged hematopoietic stem cell is placed in a young environment, the old stem cells continue to function as old stem cells.

“That was surprising, the age resilience of the other path,” Forsberg said. “One of the platelet populations is not affected at all (by aging), while the one we discovered – the whole phenomenon is not primarily caused by the environment, but by the differentiation pathway.”

Choosing better treatments

Knowing that this secondary population of platelets exists will help researchers find new ways to target and regulate these problematic cells through their stem cells. Previously, researchers have not attempted to target these upstream cells.

“From our expertise, we can ask the questions about how we can target the hematopoietic stem cell and now the megakaryocyte precursor, which has never really been highlighted as a target before,” Poscablo said.

Targeting these cells may not require the creation of new drugs, but simply the prescription of existing blood thinners such as aspirin, which treat different patients to varying degrees, even if they exhibit similar clotting-related symptoms. Using their mouse models, the researchers will identify which of the two stem cell populations are more sensitive to aspirin and the numerous other platelet drugs on the market.

The UCSC researchers are also currently working to find this secondary population of platelets in human cells with the support of a grant from the California Institute for Regenerative Medicine (CIRM). In the mouse models, they will continue to study how to manipulate and control the shortcut, with funding from the National Institutes of Health (NIH).

Collaborators on this study included UCSC assistant professor of applied mathematics Vanessa Jönsson and Reheman Adili and Michael Holinstat of the University of Michigan Medical School. Current and former IBSC scientists who worked on this project included Atesh Worthington (now at UC San Francisco), Stephanie Smith-Berdan, Marcel Rommel, Bryce Manso, Lydia Mok, Roman Reggiardo, Taylor Cool, Raana Mogharrab, Jenna Myers , Steven Dahmen, Paloma Medina , Anna Beaudin (now at the University of Utah, Salt Lake City), and Scott Boyer.