Hyperactive platelets to blame for African-American cardio risk?

A molecular pathway through which platelets, the clot-forming cells of the blood, are activated could outline the road to heart disease and stroke for people of African-American descent, said researchers led by those from Baylor College of Medicine in Houston and Jefferson Medical College of Thomas Jefferson University in Philadelphia.

African-Americans in the United States face significantly higher risks of dying from coronary heart disease and stroke than their white counterparts. While much of the disparity is attributed to racial bias, higher prevalence of risk factors and differences in socioeconomic status, access to health care and environment, there are differences for which these factors do not account. In a report that appears in the journal Nature Medicine, Drs.Chad Shaw of BCM and Paul Bray of Jefferson Medical College and their colleagues describe a racial difference in platelet reactivity and a protein (PC-TP, phosphatidylcholine transfer protein) that speeds the activation of platelets through one of two human thrombin activation receptors (PAR4).

When they analyzed the platelets from 70 African-American and 84 white subjects, they unexpectedly found that platelets from the African-Americans clotted faster and to a greater extent in response to thrombin, an agent that activates PAR4 in platelets.  African Americans also expressed significantly higher levels of PC-TP in their platelets.

“It appears that this may be a contributor to the racial differences in blood clotting,” said Shaw, assistant professor of molecular and human genetics at BCM and a corresponding author of the report. They also identified a microRNA (miR-376c) that can silence the expression of PC-TP and thus reduce the activity of PAR4. This microRNA is expressed at higher levels in the platelets of whites than in those of African-Americans. (MicroRNAS are short sequences, about 22 or 23 nucleotides long of the genetic material RNA that can act as switches, often turning genes off.)

The finding has particular significance in terms of developing drugs and evaluating those already underway, Shaw said. For example, many drugs, including aspirin, are currently in use to prevent the formation of blood clots, which can lead to heart attack and stroke. These medicines work by inhibiting the blood’s ability to form clots, an activity of the platelets. Other drugs currently under development interfere with the activity of platelet PAR1, a sister protein to PAR4. However, studies by the BCM-Jefferson team showed that that when PAR1 is inhibited, thrombin can more potently activate PAR4 in African-Americans.

These kinds of differences are important in understanding disease and how it differs among people, said Shaw. It is also important in understanding how to use certain drugs and how to personalize drugs based on patient information, he said.

Others who took part in this study include: Lukas M. Simon, Edward S. Chen and Angela Bergeron, all of BCM; Leonard C Edelstein, Raúl Teruel Montoya, Michael Holinstat, Xianguo Kong, Srikanth Nagalla and Paul F. Bray (another corresponding author) all of Jefferson Medical College; Narla Mohandas of New York Blood Center; David E Cohen of Brigham and Women’s Hospital in Boston; and Jing-fei Dong of Puget Sound Blood Center in Seattle, Washington.

Funding for this work came from the U.S. National Institutes of Health (Grant HL102482 ) and the Cardeza Foundation for Hematologic Research.

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