A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk, 2023, Verdier et al.

[SNT Gatchaman]

A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk
Verdier, Hippolyte; Thomas, Patrick; Batista, Joana; Kempster, Carly; McKinney, Harriet; Gleadall, Nicholas; Danesh, John; Mumford, Andrew; Heemskerk, Johan W. M.; Ouwehand, Willem H.; Downes, Kate; Astle, William J.; Turro, Ernest

Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, such studies have been limited by small sample sizes (n < 5000) because of the complexity of measuring PR.

We trained a model to predict PR from complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow cytometry–measured PR and a study of a phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with the incidence rates of myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism.

Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.

Key Points
• PR can be predicted from scattergrams generated by hematology analyzers of a type that is in widespread clinical use.

• Genetic analysis of predicted PR reveals associations of PR with the risk of thrombotic diseases, including stroke.


Link | PDF (Blood)

 

[SNT Gatchaman]

PR [platelet reactivity] is typically characterized using light transmission aggregometry (LTA) to measure the aggregation response of platelets to stimulation by agonists. Alternatively, PR to stimulation by an agonist can be measured by flow cytometry (FC), using surface markers of activation, such as the externalization of P-selectin, or the binding of fibrinogen to surface receptors that have undergone conformational change.

Both the LTA and FC approaches are time consuming, difficult to standardize, and require the processing of fresh citrated blood samples soon after venipuncture.

To address the limitations of LTA and FC-measured PR, we explored the possibility of imputing PR phenotypes from measurements made using an alternative technology in widespread clinical use. Sysmex XN hematology analyzers are sophisticated, high-throughput, clinically standardized instruments containing a miniaturized flow cytometer, a device to measure cellular impedance, and a spectrophotometer. The primary function of a Sysmex analyzer is to generate a complete blood count (CBC) from the data measured by these internal devices. A CBC is a standard clinical report that summarizes cellular and biochemical properties of the blood, including cell concentrations, cell volume distributions, and the concentration of hemoglobin. We hypothesized that the cell-level measurements of platelets generated by the internal flow cytometer of a Sysmex instrument carry information that could be exploited to study PR in large genotyped cohorts.