Recent advances in the mechanisms and treatment of immune thrombocytopenia

Abstract

Primary immune thrombocytopenia is an autoimmune disease associated with a reduced peripheral blood platelet count. The phenotype is variable with some patients suffering no bleeding whilst others have severe bleeding which may be fatal. Variability in clinical behaviour and treatment responses reflects its complex underlying pathophysiology. Historically the management has relied heavily on immune suppression. Recent studies have shown that the older empirical immune suppressants fail to alter the natural history of the disease and are associated with a poor quality of life for patients. Newer treatments, such as the thrombopoietin receptor agonists, have transformed ITP care. They have high efficacy, are well tolerated and improve patients' quality of life. A greater understanding of the underlying pathophysiology of this disorder has helped develop a number of new targeted therapies. These include inhibitors of the neonatal Fc receptor inhibitors, Bruton tyrosine kinase and complement pathway. Here we discuss the mechanisms underlying ITP and the new approach to ITP care.

Keywords: immune suppression; immune thrombocytopenia; thrombopoietin receptor agonists.

Figure 1

Immune effector mechanism in ITP. Due to a breakdown in self-tolerance, APC (including megakaryocytes) process and present platelet autoantigens to autoreactive T cells, which then begin a cascade of events including stimulation of autoantibody production and cytotoxic T cell activation. These two mechanisms lead to peripheral platelet destruction and megakaryocyte inhibition in the bone marrow. In addition, autoantibody-opsonized platelets may come under the attack of the complement cascade.

Figure 2

Potential mechanisms of self-tolerance breakdown in ITP. Dendritic cell abnormalities may play a central role in inhibiting Treg and Breg suppressive activities while stimulating autoreactive effector mechanisms (Figure 1). In addition, defects in NK cells and MDSCs may also contribute to autoimmune generation.

Figure 3

Native TPO binds to the extracellular domain of the TPO receptor (left). After a change in configuration the JAK-STAT pathway is activated. TPO-RAs mimic native TPO by binding to the extracellular domain (romiplostim) or transmembrane region (eltrombopag and avatrombopag) of the TPO receptor.

Figure 4

Simplified schema of ITP pathogenesis showing the sites of action of new therapies for ITP. Stimulatory drugs are in green and inhibitory agents are shown in red. BTKIs, Bruton tyrosine kinase inhibitors; CTLA4-Ig, Cytotoxic T Lymphocyte Antigen 4 immunoglobulin G1 fusion protein; Anti-BLys, B lymphocyte stimulator; BAFF, B cell Activating Factor.