Platelet Function and Venous Thrombosis Risk

Editorial

Platelets, together with endothelial cells and circulating coagulation proteins, are crucial mediators of vascular hemostasis and, therefore, they play an important role in VTE [1]. Classically, platelet function has been considered very relevant in arterial thrombosis. However, arterial and venous thromboses are related and share common risk factors [2,3]. Recent studies have demonstrated their fundamental role in the mechanisms of Venous Thromboembolism (VTE), at least in animal models [4-6]. In addition, a review has described platelet features involved in the pathophysiology of VTE in humans [7]. Different methodologies are employed to evaluate platelet function. One of them is the PFA-100^® analyzer (Siemens Healthcare Diagnostics, Marburg, Germany). This is an in vitro assay for the evaluation of overall platelet function.

The PFA-100^® simulates a vessel wall under physiologic shear stress conditions. The device contains a membrane coated with collagen and also with ADP (PFAadp) or with epinephrine (PFAepi). This membrane has a hole through which the anticoagulated blood passes. The presence of these agonists and the high share rates results in platelet adhesion, activation and aggregation, and finally forming a stable platelet plug which occludes the hole. The time required to occlude the hole, in seconds, is reported as Closure Time (CT) and it is inversely proportional to the functional capacity of platelets [8].

Several studies have attempted to develop models for predicting thrombogenicity and thrombus formation. The complex mechanisms behind high shear rate thrombus occlusion have been investigated by Mehrabadi et al. [9]. By using platelet function analyzer, the PFA-100^®, they developed a model for thrombus formation at high shear rates to predict thrombus growth and occlusion times However, the risk of venous VTE has not been associated clearly with an elevated global platelet function and/or aggregation [10]. Considering the hypothesis of a relationship between platelet hyperreactivity and VTE, we have recently published a study deomstrating the relationship between short CT measured by PFA-100^® and VTE risk [11].

Individuals were recruited from the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa) at the Hospital de la Santa Creu i Sant Pau, Barcelona (Spain) between 2012 and 2016. RETROVE is a prospective case-control study that included 400 consecutive adult (=18 years) patients with VTE (according to specific clinical inclusion criteria) and 400 healthy volunteers who serve as controls. For the PFA analysis, the whole blood sample (drawn into 4, 5ml tubes that contained a 3, 8% solution of sodium citrate as anticoagulant) was transferred into the reservoir of the disposable test cartridges (PFAadp and PFAepi), already inserted in the instrument, and both CT were recorded. For the PFAadp and PFAepi, values =10th percentile of the controls were considered as risk factors. Also, we codified the individuals according to a new parameter called Redundant Platelet Function Assay (RPFA) parameter, which identifies individuals at risk when they have both PFAadp and PFAepi =10th percentile.

The unadjusted odds ratio (OR) values =10th percentile for the PFAadp and PFAepi were 4, 02 (95% CI, 2, 76-5, 95) and 3, 33 (2, 27-4, 97), respectively. RPFA showed the highest OR (5, 17, 95% CI 2, 76-5, 95) because it represents de co-joint risk.

Platelet aggregation was also evaluated by multiplate analyzer but did not show an association with VTE risk.

To our knowledge, these analyses offer the first epidemiological evaluation between the risk of VTE and global platelet function, measured by the PFA-100^® analyzer. Our results show a clear association between short CT and VTE risk, for the usual agonists (ADP and epinephrine).

The association between short CT and PFA-100^® in VTE results was independent of age, sex, ABO blood group and FVIII risk levels. It seemed influenced by Von Willebrand levels but, after adjusting the analysis by this phenotype, the association still remained.

Notably, the RPFA parameter that represent the co-joint risk from PFAadp and PFAepi, showed the strongest association with VTE risk. This suggests that the RPFA parameter is also a good marker for the risk of a thrombotic event, which has to be evaluated prospectively. Our findings suggest that an elevated platelet adhesion function, but not platelet hyper aggregability, play an important role in the pathogenesis of VTE. In support of the relationship between platelet function and VTE risk, there exist clinical evidence on the protective effect of antiplatelet therapy in the risk of recurrence of VTE [12- 14]. We believe that our results will provide a firm foundation for additional studies, preferentially prospective, and ultimately find a place in clinical practice.

References

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