Inhibiting Platelets to Treat a Disorder of Hemoglobin

Sickle cell disease (SCD) is, fundamentally, a disorder of hemoglobin and red blood cells, but complex and dynamic interactions between erythrocytes, platelets, leukocytes, and endothelial cells underlie the pathophysiology of the vaso-occlusive ischemia and tissue infarction that account for much of morbidity and mortality of SCD. Inflammation also contributes to these processes, and there is compelling laboratory evidence that SCD is a hypercoagulable state. In particular, aberrant platelet function appears to play a role in the pathophysiology of SCD. Thrombocytosis occurs commonly in patients with SCD and is often exacerbated during vaso-occlusive events, and there is evidence of platelet activation at baseline (i.e., under steady-state conditions), with markers of activation increasing during acute vaso-occlusive events. The plasma concentration of ADP is abnormally high in SCD, and ADP may promote thrombosis and inflammation by directly activating platelets and by inducing release from platelets of CD40 ligand, respectively. Together, these observations provide a rationale for studying anti-platelet agents in the treatment of SCD.

Anti-platelet therapy for SCD is not a new idea, and several trials of aspirin or ticlopidine, a first-generation ADP-receptor antagonist, were conducted about 30 years ago.^1-4  In aggregate, those studies showed evidence of clinical benefit or a response based on assessment of biomarkers, or both, but the impact of those studies on the field was muted because of limitations in experimental design (e.g., small sample size, short duration of therapy). As such, the role of anti-platelet therapy in the management of SCD has remained uncertain. However, with the advent of newer anti-platelet agents, this question is being readdressed. Prasugrel is an oral, third-generation platelet P2Y₁₂ ADP-receptor antagonist. It irreversibly inhibits ADP-mediated platelet activation and aggregation, and it is currently approved for the treatment of patients with acute coronary syndrome who are managed with percutaneous coronary intervention. In patients with SCD, prasugrel has been tested in one phase I and two phase II studies. The phase I study demonstrated that prasugrel had comparable pharmacokinetics and produced a similar degree of platelet inhibition in patients with SCD compared with healthy volunteers.⁵  One of the phase II studies (conducted in adults) reported that treatment with prasugrel was safe (there were no hemorrhagic events requiring medical intervention), decreased platelet activation based on biomarker analysis, and possibly lessened pain severity. A phase II study has been completed in children, but the results are not yet published. A phase III study is currently recruiting subjects.

The manuscript by Joseph A. Jakubowski and colleagues provides further analysis of data from the phase I study. Cellular and soluble biomarkers of platelet activation and coagulation were compared between adult SCD patients and healthy volunteers at baseline and following 12 days of once daily treatment with prasugrel. The investigators confirmed that patients with SCD had increased platelet activation at baseline compared with healthy volunteers, as measured by percentages of monocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40 ligand. Soluble prothrombin fragment 1.2 (F1.2) and thromboxane B₂ levels were also increased in adults with SCD compared with the volunteer group. A significant reduction in platelet-monocyte aggregates was observed for the patients with SCD treated with prasugrel but not in their control counterparts. Post-treatment, SCD patients also had lower levels of both plateleterythrocyte aggregates and soluble tissue factor, but maintained higher levels of monocyte-platelet aggregates and soluble F1.2 compared with volunteers.