Platelet Function in CKD: A Systematic Review and Meta-Analysis

Abstract

Background: Patients with CKD are at high risk for thrombotic and hemorrhagic complications. Abnormalities in platelet function are central to these complications, but reports on platelet function in relation to CKD are conflicting, and vary from decreased platelet reactivity to normal or increased platelet responsiveness. The direct effects of uremic toxins on platelet function have been described, with variable findings.

Methods: To help clarify how CKD affects platelet function, we conducted a systematic review and meta-analysis of platelet activity in CKD, with a focus on nondialysis-induced effects. We also performed an extensive literature search for the effects of individual uremic toxins on platelet function.

Results: We included 73 studies in the systematic review to assess CKD's overall effect on platelet function in patients; 11 of them described CKD's effect on ex vivo platelet aggregation and were included in the meta-analysis. Although findings on platelet abnormalities in CKD are inconsistent, bleeding time was mostly prolonged and platelet adhesion mainly reduced. Also, the meta-analysis revealed maximal platelet aggregation was significantly reduced in patients with CKD upon collagen stimulation. We also found that relatively few uremic toxins have been examined for direct effects on platelets ex vivo; ex vivo analyses had varying methods and results, revealing both platelet-stimulatory and inhibitory effects. However, eight of the 12 uremic toxins tested in animal models mostly induced prothrombotic effects.

Conclusions: Overall, most studies report impaired function of platelets from patients with CKD. Still, a substantial number of studies find platelet function to be unchanged or even enhanced. Further investigation of platelet reactivity in CKD, especially during different CKD stages, is warranted.

Keywords: bleeding; chronic kidney disease; platelets; thrombosis; uremic toxins.

Graphical abstract

Figure 1.

Schematics of platelet adhesion, activation, and aggregation, as implicated in hemostasis and thrombus formation. Readouts of platelet activation status and functionality are displayed. Important receptors involved in platelet adhesion to extracellular matrix include GPIbα and GPVI for binding to vWF and collagen, respectively. Platelet aggregation is mediated by fibrinogen binding to GPIIbIIIa. Platelet activation induces the production of TXA₂, granule secretion, and surface expression of P-selectin. For more details, see text. AA, arachidonic acid; α and δ granules, alpha and dense granules; Fg, fibrinogen; GPVI, glycoprotein VI; GPIb-V-IX, glycoprotein Ib-V-IX; GPIIbIIIa, glycoprotein IIbIIIa (integrin αIIbβ3).

Figure 2.

Flowchart of literature search. Flowchart of the literature search for part 1 depicting the number of included and excluded studies throughout the process.

Figure 3.

Meta-analysis of the effects of CKD on platelet aggregation. Pooled estimate of the CKD effect on (A) collagen or (B) ADP-mediated platelet aggregation, comparing patients with CKD with controls. Results were calculated using a random effects model (Hartung-Knapp-Sidik-Jonkman) and presented as a forest plot.