How does uremia affect platelet aggregation?

From the Guidelines

Uraemia significantly impairs platelet aggregation, leading to a pro-hemorrhagic state in patients with chronic kidney disease (CKD). This impairment is multifactorial, involving alterations in platelet synthesis, composition, and activation, as well as dysfunctional platelet-vessel wall interactions 1. The presence of uremic toxins, anemia, and increased oxidative stress all contribute to altered platelet function and activation, compromising hemostasis. Specifically, uremic toxins can directly interfere with platelet function by altering calcium mobilization, reducing thromboxane A2 production, and impairing glycoprotein receptor interactions. Anemia, a common complication of CKD, further exacerbates platelet dysfunction by reducing platelet-endothelial interactions. Additionally, the uremic environment leads to platelet exhaustion, where platelets are chronically partially activated but unable to aggregate effectively when needed.

Key mechanisms underlying the impairment of platelet aggregation in uremia include:

• Alterations in platelet synthesis, composition, and activation
• Dysfunctional platelet-vessel wall interactions, including reduced platelet-vessel wall interaction and decreased ADP release
• Competitive inhibition of the GPIIb/IIIa receptor complex by circulating fibrinogen fragments
• Abnormal von Willebrand factor function, which compromises platelet adhesion to the endothelium
• Anemia, which reduces platelet function and platelet-endothelial interactions

These defects manifest clinically as prolonged bleeding times and increased risk of hemorrhagic complications, particularly in advanced kidney disease. Treatment approaches include maintaining adequate dialysis, correcting anemia with erythropoietin, and using desmopressin for acute bleeding episodes, which temporarily improves platelet function by increasing von Willebrand factor levels 1. Desmopressin is a useful agent in managing uremic platelet dysfunction, particularly in patients with end-stage renal disease, by enhancing platelet function and reducing the risk of bleeding complications.

From the Research

Uraemia and Platelet Aggregation

• Uraemia affects platelet aggregation by reducing the adhesion of platelets to the vascular subendothelial wall due to reduction of GPIb and altered conformational changes of GPIIb/IIIa receptors 2.
• The pathogenesis of uremic bleeding tendency is related to multiple dysfunctions of the platelets, including reduced platelet numbers, increased platelet turnover, and alterations of platelet adhesion and aggregation caused by uremic toxins 2.
• Uremic toxins, increased platelet production of NO, PGI(2), calcium, and cAMP, as well as renal anemia, contribute to the alterations of platelet adhesion and aggregation 2.
• Correction of uremic bleeding can be achieved through treatment of renal anemia with recombinant human erythropoietin or darbepoetin alpha, adequate dialysis, desmopressin, cryoprecipitate, tranexamic acid, or conjugated estrogens 2.

Effect of Conjugated Estrogens on Platelet Aggregation

• Conjugated estrogens shorten bleeding times in uremia and may provide a more sustained hemostatic effect over desmopressin 3.
• Estrogens do not influence the circulating level of von Willebrand factor or change its multimeric structure, and the defective platelet aggregation and thromboxane formation observed in uremic patients are not corrected by estrogens 4.
• Conjugated estrogens are an adequate alternative to cryoprecipitate or desmopressin for the treatment of bleeding associated with renal failure, especially when a longer duration of action is needed and immediate onset of the effect is not essential 4.

Clinical Manifestations and Management

• Uremic patients may develop a number of clinical manifestations, including epistaxis, purpura, and bleeding from the gastrointestinal tract 5.
• Management of uremic bleeding may include dialysis, red-blood-cell transfusions, cryoprecipitate, desmopressin, and conjugated estrogens, with consideration of adverse effects and duration of action 5.
• The most useful clinical laboratory test to assess both bleeding risk and response to therapy is bleeding time, which correlates better with clinical bleeding complications than indices of azotemia or in vitro platelet aggregation tests 6.