Primed to Fail

Corresponding Author

Thrombosis and bleeding rarely occur in the same patient, but chronic kidney disease (CKD) is a notable and confounding exception that significantly complicates hemostatic therapy. In this issue of JACC: Basic to Translational Science, Baaten et al¹ revisit this paradox and suggest that platelets are preactivated in CKD, rendering them functionally exhausted and less responsive to physiological agonists.

The work highlighted in this issue builds on a meta-analysis by the same group in 2021,² which concluded that although most previous studies report impaired platelet function in CKD, results were widely inconsistent because of diverse methodology, the confounding effects of antithrombotic therapy, and heterogeneous patient populations. This latest study directly addresses these issues by stratifying patients with different CKD stages into defined clinical cohorts and excluding individuals receiving anticoagulants or antiplatelet drugs, apart from a dedicated aspirin cohort.

Using ex vivo microfluidic assays that measure thrombus formation under arterial shear, Baaten et al¹ demonstrate that platelets from patients with advanced CKD exhibit impaired adhesion to collagen. This impairment, which was validated by reduced integrin α_IIbβ₃ activation and P-selectin surface exposure in response to collagen-related peptide, was not observed following stimulation with ADP, suggesting a selective dysfunction in glycoprotein (GP)VI signaling in CKD.

Despite typical baseline levels of activated α_IIbβ₃ and P-selectin on the platelet surface, plasma samples from late-stage CKD patients suggested systemic platelet activation, with increased levels of soluble GPVI, which is shed from the surface of activated platelets, as well as thromboxane B₂, the stable precursor of thromboxane A₂. These findings led the authors to hypothesize that late-stage CKD patients exhibit “platelet exhaustion,” where chronic or sustained activation desensitizes platelets to further stimulation. Although platelet exhaustion has previously been described in trauma³ and COVID-19,⁴ its role in platelet dysfunction during CDK remains understudied.

In the context of this work, one naturally raises the question of what triggers platelet exhaustion in CKD? The authors demonstrate that incubating healthy blood with a cocktail of the 7 most up-regulated uremic toxins in advanced CKD reduced thrombus formation on collagen and caused spontaneous aggregation. Although this supports a causative role for uremic toxins, direct correlations between individual toxins and platelet function were not found, highlighting the need for more detailed mechanistic investigation into not only the >130 uremic toxins thought to be up-regulated in CKD, but also other potential causes, including products of inflammation and endothelial dysfunction.

One of the more striking findings of the study is the apparent improvement of platelet dysfunction in late-stage CKD patients taking aspirin, who exhibited higher platelet adhesion and aggregation under flow conditions. This effect was somewhat mirrored in a mouse model of CKD, where aspirin treatment preserved ex vivo thrombus formation to collagen, but not in vivo responses to ferric chloride-induced vascular injury. Notably, adding aspirin to platelets ex vivo did not replicate improved platelet responses, suggesting a chronic in vivo effect, possibly through attenuation of thromboxane-mediated preactivation. These observations add to the contentious role of aspirin in CKD,^5,6 and will hopefully be clarified by clinical trials such as ATTACK (Aspirin to Target Arterial Events in Chronic Kidney Disease) (NTC03796156), which will assess if daily aspirin use prevents heart attacks and strokes in CKD.⁷

The authors are careful not to overstate their conclusions when describing their findings in a clinical context, acknowledging that the assays used do not fully recreate the hemostatic complexity of CKD patients. Although their study does not entirely resolve the paradox of simultaneous thrombosis and bleeding, it does add a plausible piece to the puzzle, where platelets may be preconditioned and still respond under certain stimuli, but demonstrate impaired activation at collagen-rich sites of vascular injury.

In summary, Baaten et al¹ provide a well-designed and thoughtful investigation into abnormal platelet function in CKD, suggesting that the preactivation or “exhaustion” of platelets accounts for impaired platelet responses, which may be prevented by aspirin treatment. This work will hopefully support further studies exploring more nuanced and personalized strategies aimed at preserving platelet functionality in CKD.

Funding Support and Author Disclosures

Dr Roweth has reported that he has no relationships relevant to the contents of this paper to disclose.