Platelets offer promising treatment target


Biophoto Associates/ ScienceSource

Platelets and their microparticles play important roles in the pathogenesis of lupus and therefore represent promising clinical targets.

Platelet system activation not only denotes disease activity but also induces immune dysregulation and tissue damage in systemic lupus erythematosus (SLE). Understanding the intricate roles platelets play in inflammation and autoimmunity could reveal “new potent therapeutic pathways,” Marc Scherlinger, MD, of Centre Hospitalier Universitaire in Bordeaux, France, and his associates (Autoimmun Rev. 2018;17:625-35).

For decades, platelets were considered “merely circulating cell fragments” whose function was limited to hemostasis and thrombosis. More recent studies paint a different picture, showing that platelets and platelet-derived microparticles (PMPs) also exhibit complex inflammatory and immune activity. Furthermore, patients with SLE have heightened levels of platelet activation.

In one analysis, flow cytometry of blood samples from 30 patients with SLE identified significantly higher expression of CD63, a marker of platelet activation, compared with healthy controls (Br J Haematol. 2001;115(2):451-9). In a more recent study, the platelets of patients with SLE aggregated with monocytes and leukocytes and induced endothelial expression of the adhesion molecule interleukin-8 significantly more often than did the platelets of controls (Arterioscler Thromb Vasc Biol. 2017;37:707-16).

Other studies have linked SLE with heightened expression of two markers of platelet activation: P-selectin, an adhesion molecule, and CD154, a member of the tumor necrosis factor (TNF) superfamily. Preliminary data also indicate that platelet activation increases the production of PMPs, which, in turn, correlate with increased SLE disease activity and with large-vessel endothelial dysfunction.

“These data underline the potential use of PMPs as biomarkers of disease activity and organ damage, but additional studies are required to validate their use,” Dr. Scherlinger wrote.

Platelet activation in SLE is multifactorial. Serum from affected patients has above-normal levels of immune complexes, large antigen-antibody aggregates that activate platelets by recognizing the Ig receptor Fc gamma RIIA (CD32). Immune complexes also activate Toll-like receptor 7, a functional component of platelets. The surface of PMPs in patients with SLE also has increased levels of bound IgG, which acts as an auto-antibody. Platelet-bound immunoglobulin G is associated with platelet activation and expression of P-selectin, both of which promote immune dysregulation and autoimmunity.

Another mechanism of platelet activation in SLE involves antiphospholipid antibodies, which are present in about one third of patients and which increase the risk of poor SLE outcomes. Autoantibodies activate platelets directly by binding platelet receptors such as GP-Ib alpha and by inducing complement deposition on the platelet surface, Dr. Scherlinger noted. Two more mechanistic players are collagen I, which activates platelets when exposed through endothelial damage, and ischemia-reperfusion associated with Raynaud phenomenon, which affects up to half of patients with SLE and is characterized by increased MPV and heightened expression of P-selectin.

Once activated, platelets induce neutrophils extracellular trap (NET), CD154 activity, autoantigenicity, damage-associated molecular patterns (DAMPs), the release of serotonin (5-HT), and the transfer of pro-inflammatory nuclear material, all of which can induce immune dysregulation. But platelets also function directly in SLE-mediated tissue and organ damage. Vascular damage, “a central component” of SLE, increases when activated platelets and PMPs release bioactive molecules such as interleukin-1b, which upregulates pro-inflammatory gene expression and is involved in endothelial plaque formation.

Platelet activity also activates complement, which can lead to endothelial dysfunction, and exposes P-selectin and DAMPs that support leukocyte recruitment and local vascular inflammation. Studies also link platelet activity to renal damage in SLE, both through direct cell-to-cell interactions and by releasing cytokines and PMP. These processes induce mesangial proliferation and fibrosis and the recruitment of monocytes in lupus nephritis, the experts noted.

Taken together, these findings identify several possible therapeutic targets in SLE. Hydroxychloroquine, which already is “universally” used in SLE, helps prevent thrombotic events and demonstrates antiplatelet activity. Aspirin, an irreversible cyclooxygenase 1 (COX-1) inhibitor, might help counteract thromboxane A2, a metabolite produced by COX-1 of activated platelets that has been measured at increased levels in patients with SLE. Thus far, studies indicate that aspirin has limited effects on thromboxane A2 in patients with SLE c compared with controls. However, aspirin might benefit patients as part of a multimodal antiplatelet regimen, the experts hypothesized.

Another candidate for treating SLE is clopidogrel, an antagonist of the P2Y12 receptor that is activated by adenosine diphosphate (ADP) and plays a central role in platelet activation. Iloprost, a synthetic analogue of prostacycline (PGI2), decreases platelet activation in pathophysiologically similar conditions such as heparin-induced thrombocytopenia (HIT), which, involves immune complex formation and subsequent platelet activation. Metformin diminishes platelet activation, decreases associated release of mtDNA, and reduces flares and the use of prednisone among SLE patients, while dapirolizumab targets CD154 and its interaction with CD40. Results from early-phase trials suggest that both metformin and dapirolizumab can positively affect standard clinical endpoints in SLE.
Dr. Scherlinger and his associates reported having no conflicts of interest.

Amy Karon is a freelance reporter with MDedge News