Cyclic thrombocytopenia with statistically significant neutrophil oscillations

Abstract

Key Clinical MessageCyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb‐Scargle periodogram).

A Blueprint for Identifying Phenotypes and Drug Targets in Complex Disorders with Empirical Dynamics

“…For instance, it is clear from comparing subjects A and B that a particular genetic mutation ( c-mpl ) is not sufficient to induce thrombocytopenia, corroborating the knowledge that, unlike cyclic neutropenia, CTP is not easily treated by targeting a single cell type or signaling pathway. 29 From comparing both the CCM networks and periodograms for subjects A and C, it is also clear that within CTP there are different phenotypic presentations. However, these dimensionally reduced models also suggest a potential common axis rooted in control of Th cell differentiation.…”

“…CTP is also of immediate clinical relevancy due to difficulty of treatment, 29 especially compared with other blood disorders in which biomarkers are oscillating (such as cyclic neutropenia). 30 Despite frequently being associated with disrupted TPO receptor interactions, 24 , 31 , 32 regular treatment with exogenous TPO (the principal protein regulating the megakaryocyte/platelet axis) mimetics is generally ineffective.…”

“… 30 Despite frequently being associated with disrupted TPO receptor interactions, 24 , 31 , 32 regular treatment with exogenous TPO (the principal protein regulating the megakaryocyte/platelet axis) mimetics is generally ineffective. 29 This suggests that CTP may be mechanistically distinct from the other diseases, which are more easily treated with mimetics for the defective protein.…”

Dynamics of a Mathematical Hematopoietic Stem-Cell Population Model

“…CT typically involves oscillations of just the platelets 23 , though one case of multi-lineage CT has recently been reported 36 , while for CN and PCML oscillations of all of the major blood cell groups are observed 23 . This suggests that for CN and PCML the cycling in all cell lineages may be due to a dynamic destabilization at the stem cell level 23 .…”

“…The red curve shows a solution to(29) computed numerically using a segment of the solution of the nonlinear DDE (1) for t ∈ [−2.8, 0] to define the initial function. The green curve shows a solution of (29) defined by(36) with βj = γj = 0 for all j, except γ1 = 0.003935.…”