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Platelet phenotypes might help personalise treatment and reduce cardiovascular risk

15 December, 2021  

A test that categorises patients into different phenotypes based on the reactivity of their platelets could be used to better understand an individual’s response to anti-platelet therapy.

An analysis of patients’ platelet function to various agonists important in the clotting process has revealed at least six different phenotypes, potentially leading the way towards more personalised medicine. 

This was the finding of a study by a group of researchers from the Institute for Cardiovascular and Metabolic Research, University of Reading, and the Department of Haematology, University of Cambridge.1 Although platelets have an essential role in haemostasis, these cell fragments are also involved in the clotting process that can lead to a myocardial infarction or stroke. It has been apparent for some time, that an individual’s platelet response to clotting agonists can vary,2 and that these differences might be genetically controlled.3 Nevertheless, the reasons for this heterogeneity in response remains to be determined and the Reading and Cambridge team wanted to get a better understanding of why an individual might be a hypo-responder to one agonist yet a hyper-responder to another. 

In trying to answer this question, the team developed Platelet Phenomic Analysis (PPAnalysis), a platform designed to assess platelet function across a group of individuals. 

The PPAnalysis used multiple clotting agonists over a wide range of concentrations to try and fully characterise platelet reactivity. In validating the PPAnalysis system, the researchers recruited a group of healthy, fasted, blood donors and assessed the sensitivity of samples to various agonists as well as the strength (or capacity) of the platelet response. The team used varying concentrations of 6 agonists: collagen-related peptide (CRP), epinephrine, thrombin receptor activator peptide 6 (TRAP-6), U46619 (a thromboxane A2 analogue and adenosine diphosphate (ADP). Together, these agonists allowed the researchers to assess fibrinogen binding and the exposure of P-selectin on the platelet surfaces, which is a marker of alpha-granule secretion, i.e., adhesive proteins that mediate platelet–platelet interactions. In addition, the team recruited a second group of healthy donors, which included non-fasted individuals who were aged between 18 and 75.

Findings

Overall, the study observed that the sensitivity and capacity for fibrinogen binding and the P-selectin exposure did not correlate, in other words, the two measures were independent. In addition, the sensitivity of fibrinogen binding and P-selectin exposure to the individual agonists did correlate (r > 0.91, p < 0.01) but to a greater degree than the capacity to generate these responses (r < 0.76). Nevertheless, the sensitivity to individual agonists did vary, so that one individual could, for example, be highly sensitive to ADP but not be sensitive to CRP. In a separate analysis, the authors did not find any differences between donor responses based on age, gender, or body mass index.

Based on these results, which were replicated in a second, different donor group, the researchers identified at least six different phenotypes with high capacity and low sensitivity and vice versa. These results suggested that individuals were not simply ‘high’ or ‘low’ platelet responders but that there was a graded response in between these two extremes. When considering the results from the second group of donors, there was no difference in response.

In discussing their findings, the authors noted that the separation of platelet function into sensitivity and capacity was a novel approach, and which could be of value from a clinical perspective rather than adopting the ‘one size fits all’ current approach. For example, individuals with a low sensitivity and capacity might be more prone to bleeding when using anti-platelet drugs or, in contrast, more treatment-resistant when both sensitivity and capacity are high. 

While the present study was preliminary, as part of an ongoing programme, the researchers wanted to investigate the association between phenotypic groups using PPAnalysis and the risk of both bleeding and thrombosis in patients. 

References

  1. Dunster JL et al. Multiparameter phenotyping of platelet reactivity for stratification of human cohorts. Blood Adv 2021;5(20):4017–30.
  2. Panzer S et al. Agonists-induced platelet activation varies considerably in healthy male individuals: studies by flow cytometry. Ann Hematol 2006;85(2):121–5.
  3. Jones CI et al. Mapping the platelet profile for functional genomicstudies and demonstration of the effect size of the GP6 locus. J Thromb Haemost 2007;5(8):1756–65.