Oscillating platelet counts in healthy individuals: Experimental investigation and quantitative evaluation of thrombocytopoietic feedback control

Abstract

Peripheral platelet counts of 5 healthy women and 5 healthy men were studied over 54 to 100 d to assess whether statistically significant fluctuations could be detected. Low amplitude fluctuations were found in 7 of the 10 individuals with mean periods of 28.3 ± 3.4 d, using autocorrelation analysis. To understand the origin of such fluctuations, a simple linear feedback model of thrombocytopoiesis was formulated and quantitatively analyzed. This model, together with literature data on platelet‐turnover in healthy individuals and patients with idiopathic thrombocytopenic purpura (ITP), predicts states in which oscillations are likely to occur and explains these as a result of optimum tuning of the feedback system to respond quickly to disturbances in the platelet pool. Both in healthy individuals and patients with cyclic thrombocytopenia, the typical periods of the fluctuations predicted by the model of about 25 d are in good agreement with the data.

Normal and pathological dynamics of platelets in humans

“…We have also identified three published data sets indicating significant oscillations in platelets in apparently healthy male subjects without any obvious platelet pathology [54], [63]. Interestingly in all three of these documented cases the oscillations are in the normal range of platelet levels.…”

“…The results presented in Sect. 5 indicate that highly significant reductions (factor of 1000 and 100, respectively) in α T and k T , which are responsible for the platelet and megakaryocyte-dependent TPO removal rates, are necessary to induce oscillations roughly corresponding to those of CT. Those changes were also necessary to fit the data of Morley [54] and von Schulthess and Gessner [63], in which the apparently healthy subjects maintain platelet levels in the normal range in the face of statistically significant oscillations. In addition, changes in τ e (which represents the duration of the megakaryocyte maturation stage) as well as in α P (which is responsible for the maximum removal rate of platelets due to macrophages) allow the accurate replication of clinical data on platelet and thrombopoietin dynamics.…”

Cyclic thrombocytopenia with statistically significant neutrophil oscillations

“…One of the earliest was that of Wichmann et al 21 which was followed by an exposition of their complete model for hematopoiesis. 22 Von Schulthess et al, 23 noting the existence of oscillations in the platelet counts of normal humans, put forward a conceptually different model of thrombopoiesis, which was followed by Bélair and Mackey. 24 Building on this work, Santillan et al 20 refined the model attempting to understand cyclical thrombocytopenia, and this was subsequently modified by Apostu and Mackey 10 and Langlois et al, 25 again to understand the origins of cyclical thrombocytopenia.…”

Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide

“…Because of the previous apparent association of blood count oscillations with myeloproliferative disease states, numerous theories attributed the mechanism of these oscillations to malignant or pre‐malignant specific pathobiology. While there is some evidence that even in normal individuals there may be a continuous stable oscillation of every haematopoietic cell lineage (Morley et al , , ; Von Schulthess & Gessner, ; Moser et al , ), the myeloproliferative disease‐centric theories postulate that clonal bone marrow progenitor cells present in myeloproliferative diseases may be abnormally sensitive to lineage‐specific growth signals, hydroxycarbamide therapy, or a combination of factors (Zent et al , ; Santillán et al , ; Tefferi et al , ; Steensma et al , ). These neoplastic alterations in signalling pathways are thought to manifest as oscillations apparent in macroscopic measures, such as peripheral blood counts.…”