Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

Abstract

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients.

Keywords: ITP; SYK inhibitors; TPO-RA; pathogenesis; platelet desialylation; rituximab; splenectomy.

Figure 1

Pathogenesis of immune thrombocytopenia and targets for drug action. Immune thrombocytopenia results from peripheral destruction and impaired megakaryopoiesis. The key event is thought to be the production of antiplatelet antibodies that target platelet glycoproteins (GPs), thereby leading to platelet destruction. Platelets coated with antiplatelet antibodies are mainly destroyed in the spleen by splenic macrophages, and this is based on an Fcγ-dependent mechanism, which is controlled by spleen tyrosine kinase (Syk). Antigens from phagocytosed platelets are presented by the major histocompatibility complex class II (MCHII) to T-cell receptors (TCRs), which stimulates autoreactive T cells, i.e., follicular T cells (TFHs). TFHs interact with autoreactive B cells through the CD40/CD154 axis and IL21 production, promoting the differentiation of B cells into autoreactive plasma cells that will produce more antiplatelet antibodies. This autoimmune response is maintained by a deficiency in regulatory T cells (Treg). Opsonized platelets could also activate the classical complement pathway, and desialylated platelets are destroyed in the liver via an Fcγ-independent mechanism, thus promoting peripheral platelet destruction. CD8 cytotoxic T cells (CTLs) can mediate cytotoxicity against platelets, leading to platelet apoptosis, platelet lysis, or platelet desialylation. Impaired platelet production results from an autoimmune response targeting megakaryocytes (both antiplatelet antibodies and CTLs) and inadequate levels of thrombopoietin (TPO), which is the main growth factorof thrombopoiesis. The targets of action of current treatments and some molecules under investigation (not yet approved) are mentioned in this figure by red arrows. Abbreviations: BTK—Bruton’s tyrosine kinase; IL—interleukin; FcγR—IgG Fc receptor; FcRn—neonatal Fc receptor; IVIg—intravenous immunoglobulin; TPO-RA—thrombopoietin receptor agonist; C1s inhibitor—monoclonal antibody targeting C1s; CD—cluster of differentiation.

Figure 2

Therapeutic approach for patients with ITP. The diagnosis of ITP is first evaluated by excluding non-autoimmune causes of thrombocytopenia and secondary ITP. After diagnosis, the need for treatment is assessed. Follow-up is recommended for patients with platelet counts above 20,000 to 30,000/µL and no bleeding. For patients requiring therapy, the first option is administration of corticosteroids, IVIg, anti-D, and platelet transfusion (in emergency situations and for selected patients, TPO-RA). Rare cases of secondary thrombocytopenia are ruled out at first relapse, and one of the options for subsequent treatment is chosen. A lack of response to treatment calls for additional evaluation with genetic testing. In terms of treatment, patients and physicians can choose between combined therapies, innovative therapies being evaluated in ongoing clinical trials, or splenectomy if it has not already been performed. Abbreviations: ITP—immune thrombocytopenia; CBC—complete blood count; HIV—human immunodeficiency virus; HCV—hepatitis C virus; HBV—hepatitis B virus; plt—platelets; IVIgs—intravenous immunoglobulins; TPO—thrombopoietin; TPO-RA—thrombopoietin agonist receptor; ANAs—antinuclear antibodies; APLAs—antiphospholipid antibodies; GP—glycoprotein; EBV—Ebstein Barr virus; CMV—cytomegalovirus.