Hallmarks for Thrombotic and Hemorrhagic Risks in Chronic Kidney Disease Patients

Abstract

Chronic kidney disease (CKD) is a global health issue causing a significant health burden. CKD patients develop thrombotic and hemorrhagic complications, and cardiovascular diseases are associated with increased hospitalization and mortality in this population. The hemostatic alterations are multifactorial in these patients; therefore, the results of different studies are varying and controversial. Endothelial and platelet dysfunction, coagulation abnormalities, comorbidities, and hemoincompatibility of the dialysis membranes are major contributors of hypo- and hypercoagulability in CKD patients. Due to the tendency of CKD patients to exhibit a prothrombotic state and bleeding risk, they require personalized clinical assessment to understand the impact of antithrombotic therapy. The evidence of efficacy and safety of antiplatelet and anticoagulant treatments is limited for end-stage renal disease patients due to their exclusion from major randomized clinical trials. Moreover, designing hemocompatible dialyzer membranes could be a suitable approach to reduce platelet activation, coagulopathy, and thrombus formation. This review discusses the molecular mechanisms underlying thrombotic and hemorrhagic risk in patients with CKD, leading to cardiovascular complications in these patients, as well as the evidence and guidance for promising approaches to optimal therapeutic management.

Keywords: anticoagulants; antiplatelets; chronic kidney disease; hemodialysis membranes; hemostatic dysfunction.

Figure 1

Pathophysiology of cardiovascular diseases in patients with chronic kidney failure. Several risk factors, both modifiable and non-modifiable, contribute to the pathological mechanisms leading to CV events in patients with chronic kidney failure. On the other hand, CVD often contributes to worsened kidney function, accounting for the complex relationship between heart and kidney pathophysiology. CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate.

Figure 2

Mechanisms of platelet hyperreactivity in patients with chronic kidney disease. Uremic toxin triggers platelet hyperreactivity, induces release of platelet-derived MPs, results in overexpression of GP IIb/IIIa and P-selectin, and enhances platelet monocyte aggregation. GPIb-V-IX receptors on platelets are involved in platelet adhesion to vWF and collagen, as unveiled on damaged endothelium. Activated platelets recruit other circulating platelets by releasing mediators such as ADP and TXA₂, leading to thrombus formation. The binding of fibrinogen with platelets is mediated by activated GP IIb/IIIa, which induces platelet aggregation. C-reactive protein is associated with increased fibrinogen plasma level. Exposed TF on the disrupted vessel wall triggers thrombin generation, which consequently converts fibrinogen to fibrin to form a stable clot. vWF exhibits a prothrombotic effect by carrying FVIII and facilitating platelet aggregation and adhesion. Reduced NO level induces platelet activation and aggregation. The decreased levels of thrombomodulin and protein C increase the coagulation tendency and thrombotic risk. ADP = adenosine diphosphate; NO = nitric oxide; TF = tissue factor; TXA₂ = thromboxane A₂; vWF = von Willebrand factor; upward black arrow = increase; downward black arrow = decrease.

Figure 3

Mechanism of platelet dysfunction in patients with chronic kidney disease. Uremic toxins impair the binding of platelets to endothelial cells via the vWF–GPIb-IX-V receptor complex. The high production of PGI₂ causes the inhibition of platelet aggregation. In this condition, the numbers and functions of GP IIb/IIIa receptors decline, and reduced production of TXA₂ and ADP occurs. The carbamylation of GP IIb/IIIa inhibits the binding of fibrinogen with platelets, thereby inducing bleeding. The increased level of GDF-15 is associated with major bleeding. The elevated thrombomodulin level is involved in clot dissolution, with subsequent bleeding risk. The increased plasma NO level in CKD patients decreases platelet aggregation. The synergistic effect of anemia and CKD imposes a worsening effect with regard to platelets abnormalities. ADP = adenosine diphosphate; GDF-15 = growth differentiation factor 15; NO = nitric oxide; PGI₂ = prostacyclin; TXA₂ = thromboxane A₂; vWF = von Willebrand factor; upward black arrow = increase; downward black arrow = decrease.

Figure 4

Thrombus formation on hemodialysis membrane after exposure to blood during dialysis. The bioincompatible membrane causes rupturing of red blood cells during HD and induces platelet adhesion and protein adsorption, which induces a coagulation cascade to form a thrombus. After adsorption on the dialyzer membrane, fibrinogen and vWF undergo conformational changes. The conformational changes in fibrinogen and vWF uncover more binding domains to platelets and trigger activation of platelets, blood coagulation, and thrombosis. vWF = von Willebrand factor.