Platelet Abnormalities in CKD and Their Implications for Antiplatelet Therapy

Abstract

Patients with CKD display a significantly higher risk of cardiovascular and thromboembolic complications, with around half of patients with advanced CKD ultimately dying of cardiovascular disease. Paradoxically, these patients also have a higher risk of hemorrhages, greatly complicating patient therapy. Platelets are central to hemostasis, and altered platelet function resulting in either platelet hyper- or hyporeactivity may contribute to thrombotic or hemorrhagic complications. Different molecular changes have been identified that may underlie altered platelet activity and hemostasis in CKD. In this study, we summarize the knowledge on CKD-induced aberrations in hemostasis, with a special focus on platelet abnormalities. We also discuss how prominent alterations in vascular integrity, coagulation, and red blood cell count in CKD may contribute to altered hemostasis in these patients who are high risk. Furthermore, with patients with CKD commonly receiving antiplatelet therapy to prevent secondary atherothrombotic complications, we discuss antiplatelet treatment strategies and their risk versus benefit in terms of thrombosis prevention, bleeding, and clinical outcome depending on CKD stage. This reveals a careful consideration of benefits versus risks of antiplatelet therapy in patients with CKD, balancing thrombotic versus bleeding risk. Nonetheless, despite antiplatelet therapy, patients with CKD remain at high cardiovascular risk. Thus, deep insights into altered platelet activity in CKD and underlying mechanisms are important for the optimization and development of current and novel antiplatelet treatment strategies, specifically tailored to these patients who are high risk. Ultimately, this review underlines the importance of a closer investigation of altered platelet function, hemostasis, and antiplatelet therapy in patients with CKD.

Keywords: blood platelet disorders; chronic kidney disease; platelet aggregation inhibitors; platelets; thrombosis.

Figure 1.

The process of thrombus formation and summary of CKD-induced platelet abnormalities and contributing factors. (A) Whereas healthy endothelium protects from platelet adhesion and activation, vascular injury triggers the formation of thrombi through platelet adhesion, activation, and aggregation. Furthermore, tissue factor exposed by the injured vessel wall triggers the production of thrombin, which converts fibrinogen to fibrin, resulting in the formation of a stable, fibrin-rich clot. (B) Besides a reduction in platelet number in patients with CKD, alterations have been described in stimulation-induced platelet adhesion, aggregation, granule secretion, thromboxane A2 (TXA₂) generation, and platelet-mediated clot retraction. CKD may directly affect platelet responses and thrombus formation in CKD through uremic toxin accumulation and a chronic low-grade inflammation, and indirectly through dialysis, vascular inflammation, and reduced vascular integrity, hypercoagulability, and anemia. For more details, see text. Ca²⁺, calcium; Fg, fibrinogen; GPIb-V-IX, glycoprotein Ib-V-IX; GPVI, glycoprotein VI; NO, nitric oxide; PAR1/4, protease-activated receptor 1/4; TP, thromboxane receptor; TXA₂, thromboxane A₂; α₂, α₂ adrenergic receptor; α and δ granules, alpha and dense granules.

Figure 2.

Working mechanism of antiplatelet drugs. (A) Antiplatelet drugs reduce platelet activation by either preventing thromboxane A₂ synthesis, inhibiting P2Y₁₂ signaling, or increasing intraplatelet levels of cAMP and cyclic guanosine monophosphate. Also interfering with thrombin signaling (by blocking the thrombin receptor protease-activated receptor 1 (PAR-1) or interfering with thrombin production) can have antiplatelet effects. (B) Schematic overview of the effect of the different antiplatelet agents on cardiovascular risk and bleeding risk in CKD, and on efficacy (in terms of cardiovascular risk reduction) and HTPR in patients with CKD compared with patients without CKD. For more details, see text. cGMP, cyclic guanosine monophosphate; CV risk, cardiovascular risk; HTPR, high on-treatment platelet reactivity; PGH₂, prostaglandin H₂; PDE, phosphodiesterase; TP, thromboxane receptor; TXA₂, thromboxane A₂.

Figure 3.

Underrepresentation of patients with CKD ≥4 from clinical trials investigating the efficacy of P2Y₁₂ inhibitors. For randomized controlled trials (A) and observational studies (B) examining P2Y₁₂ antiplatelet therapy, the number of included patients were categorized according to CKD stadium. Studies that excluded patients requiring dialysis are indicated with an asterisk (*).