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Summary: Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell‐mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL, STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia‐related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea‐induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future. [ABSTRACT FROM AUTHOR]

Summary: Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells. [ABSTRACT FROM AUTHOR]