Clinical applicability of reticulated platelets

Imetelstat (GRN163L) is a specific telomerase inhibitor that has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report, we investigated the potential mechanisms that account for imetelstat’s beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers. Using a well-established system of ex vivo megakaryopoiesis, we demonstrated that imetelestat treatment affects normal megakaryocyte (MK) development by exclusively delaying maturation of MK precursor cells. By contrast, additional stages along MPN MK development were affected by imetelstat resulting in reduced numbers of assayable colony-forming unit MK and impaired MK maturation. In addition, treatment with imetelstat inhibited the secretion of fibrogenic growth factors by malignant but not by normal MK. Our results indicate that the delay observed in normal MK maturation may account for imetelstat-induced thrombocytopenia, while the more global effects of imetelstat on several stages along the hierarchy of MPN megakaryopoiesis may be responsible for the favorable clinical outcomes reported in MPN patients.

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“…Platelet release by immature MKs has been previously reported in disease conditions associated with increased platelet demand. 25,26 …”

Section: Resultsmentioning

confidence: 99%

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

Mosoyan

Kraus

et al. 2017

Leukemia

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“…23 MPV is associated with cardiovascular risk factors, such as smoking, obesity, arterial hypertension and hyperlipidaemia. 8 In contrast, MPV is only a measure of platelet size and only resembles a surrogate for platelet turnover, as not all large platelets are reticulated/young platelets. 10,24 Our data, however, do not indicate an association of MPV with adverse outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Sustained high residual platelet reactivity due to insufficient response to antithrombotic agents is critically linked to future outcome. 4,8 Comparing established predictors of platelet reactivity, reticulated platelet count (RPC) has been shown to be the strongest independent predictor of platelet response during dual antiplatelet therapy (DAPT). [3][4][5][6][7] Reticulated platelets are larger in size, denser, have greater prothrombotic potency and are less susceptible for inhibition than their older counterparts.…”

Section: Introductionmentioning

confidence: 99%

Impact of platelet turnover on long‐term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention

Tscharre

Farhan

Bruno

et al. 2019

Eur J Clin Investigation

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Background: Increased platelet turnover and high platelet reactivity are associated with short-term major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). We investigated the impact of platelet turnover on long-term MACE. Methods: Consecutive patients presenting with ACS or SCAD undergoing PCI between 2009 and 2010 were included. All patients received clopidogrel and aspirin as dual antithrombotic therapy regimen. Multivariable Cox proportional hazard models were applied to assess the prognostic impact of platelet turnover (reticulated platelet count [RPC], mean platelet volume [MPV]) and function on long-term MACE, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. Results: In total, 477 patients were eligible. Mean age was 64.3 ± 12.7 years, 68.8% were male. Median follow-up was 5.8 (IQR 4.2-6.5) years. Median RPC was 7.6 (IQR 5.6-10.4) g/L and median MPV was 10.7 (IQR 10.1-11.3) fL. In univariable analysis, RPC was associated with MACE, both as continuous (HR 1.064 [95%CI 1.021-1.111]; P = .006) and dichotomized (HR 1.693 [95%CI 1.156-2.481]; P = .006) variable. After adjustment, continuous RPC (HR 1.055 [95%CI 1.012-1.099]; P = .010) and dichotomized RPC (HR 1.716 [95%CI 1.152-2.559]; P = .007) remained significantly associated with MACE. Neither MPV nor platelet function testing was associated with long-term adverse outcome.

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“…Several mechanisms have been hypothesized to impact on platelet aggregability in smokers, including lipid oxidation products, 31 reduced release of platelet-derived nitric oxide, 32 higher sensitivity of GPIIB/ IIIA to fibrinogen, 30 and impaired balance of thromboxane A2 and prostaglandin I2. 34,35 Immature platelet fraction (IPF) is a parameter allowing the identification of the fraction of reticulated platelets 7 with a cheap, reliable and easy-to-obtain analysis, using traditional cell counters. 34 Reticulated platelets display a larger size, higher alpha-granules and RNA content and increased capability of protein synthesis and then a potentially enhanced reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…34 Reticulated platelets display a larger size, higher alpha-granules and RNA content and increased capability of protein synthesis and then a potentially enhanced reactivity. 34,35 Immature platelet fraction (IPF) is a parameter allowing the identification of the fraction of reticulated platelets 7 with a cheap, reliable and easy-to-obtain analysis, using traditional cell counters. 36 Some authors have reported that high levels of circulating immature platelet are associated with a prothrombotic condition.…”

Section: Discussionmentioning

confidence: 99%

Impact of active smoking on the immature platelet fraction and its relationship with the extent of coronary artery disease

Nardin

Verdoia

Negro³

et al. 2020

Eur J Clin Investigation

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Introduction:Smoking represents a major cardiovascular risk factor, due to the induction of oxidative stress and low-grade, continuous, inflammation that contribute to promote atherothrombosis. However, the mechanisms leading to increased platelet aggregability associated with smoking are only partially defined. A potential role has been hypothesized for immature platelets, a younger and potentially more reactive fraction, previously associated with the main determinants of coronary artery disease (CAD). Therefore, the aim of our study was to define the impact of smoking on the immature platelet fraction (IPF) and its relationship with prevalence and extent of coronary artery disease. Methods: We enrolled a cohort of consecutive patients undergoing coronary angiography in a single centre. Significant CAD was defined as at least 1 vessel stenosis >50%, while severe CAD was defined as left main and/or three-vessel disease. IPF was measured at admission by routine blood cell count (Sysmex XE-2100). Results: We included in our study 2553 patients who were divided according to smoking status (active smokers: 512; nonactive smokers: 2041). Smokers were younger, more frequent males, with lower rate of diabetes mellitus, previous PCI and previous CABG (P < .001, respectively) and were in treatment less often with ARB, BB, nitrates, statins, ASA, clopidogrel, CCB and diuretics (P < .001, respectively) as compared to nonactive smokers. Higher percentage of smokers was observed in patients with higher IPF values, and at multivariate analysis, active smoking resulted as an independent predictor of higher IPF (adjusted OR [95% CI] = 1.59[1.03-2.45], P = .035). Among smokers, higher IPF was associated with lower ejection fraction (P = .034), percentage of acute coronary syndrome (P = .002) and platelet count (P < .001) compared to ones with lower IPF. However, the IPF (according to quartiles values) was not associated with the prevalence and extent of CAD (82.5%, 80.4%, 86.1% and 80.9%, from 1st to 4th quartile, respectively, adjusted OR[95% CI] = 0.98[0.79-1.23], P = .89) and severe CAD (31%, 31.1%, 39.1% and 35.2%, from 1st to 4th quartile, respectively, adjusted OR[95% CI] = 1.03[0.86-1.23], P = .76).

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Clinical applicability of reticulated platelets

Cited by 32 publications

References 60 publications

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis

Impact of platelet turnover on long‐term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention

Impact of active smoking on the immature platelet fraction and its relationship with the extent of coronary artery disease

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