The highs and lows of cyclic thrombocytopenia

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. Normal thrombopoiesis is oscillatory upon perturbation due to thrombopoietin-mediated platelet homeostasis regulation. Cyclic thrombocytopenia (CTP) exhibits exaggerated reciprocal platelet/thrombopoietin oscillations. CTP occurs on either thrombocytopenia or thrombocytosis baseline. While the aetiology of CTP remains uncertain, we propose a two-hit model where CTP patients possess pathogenic risk factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate CTP. The risk factors of thrombocytopenia-based CTP may include humoral and cell-mediated autoimmunity, and genetic variants in MPL or STAT3. Thrombocytosis-based CTP mostly occurs during hydroxyurea treatment in patients with myeloproliferative diseases with underlying JAK2 V617F or BCR::ABL1 translocation.image