Abstract
Reticulated platelets are immature platelets freshly released from the bone marrow into the circulation and contain vestigial amounts of ribonucleic acid. Thus, they can serve as an indicator for the activity of thrombopoiesis. Despite the current lack of a standardized reference method, two types of hematology analyzers have incorporated a fully automated measurement of reticulated platelets. The “immature platelet fraction” (IPF; Sysmex XE-/XN-series) has some clinical utility in the differential diagnosis of thrombocytopenia. This is less clear for “reticulated platelets” (retPLT; Abbott CELL-DYN Sapphire/Alinity HQ). The usefulness of these parameters in the prediction of platelet recovery after chemotherapy or stem cell transplantation and as a decision aid for platelet transfusions has not been unequivocally confirmed. Recent findings have shown an association of reticulated platelets with an adverse risk in patients with coronary artery disease and stroke as well as resistance to anti-platelet therapy. Furthermore, a role of reticulated platelets for the prediction of sepsis was indicated. However, validation in larger prospective trials is necessary to establish the clinical benefit of reticulated platelets in these conditions. This review gives an overview of the available analytical methods and summarizes the current knowledge regarding the clinical application of reticulated platelets.
Brief summary
Reticulated platelets represent the most immature platelets recently released from the bone marrow into the circulation and indicate the activity of megakaryopoiesis. Their measurement may have clinical utility to assess the etiology of thrombocytopenia. Whereas an international reference has yet to be defined, two fully automated methods to measure reticulated platelets are commercially available.
Formation of platelets by megakaryopoiesis
Platelets represent the final stage of megakaryopoiesis and constitute an integral element of hemostasis. In the process of megakaryopoiesis pluripotent hematopoietic stem cells in the bone marrow proliferate and differentiate to become megakaryoblasts and eventually megakaryocytes. Megakaryocytes then form proplatelet projections that fragment into new platelets. In healthy humans roughly 1×1011 platelets are produced per day, whereas this rate can be accelerated up to 10-fold in conditions of increased demand [1]. While the platelet count varies greatly between healthy individuals (150–400×109/L), the platelet count in any one individual is more stable throughout life [2]. Furthermore, an inverse relationship between platelet count and mean platelet volume (MPV) exists during steady-state conditions, keeping the total platelet mass (i.e. platelet count adjusted for MPV) constant [2], [3]. Similar to reticulocytes, the newly generated platelets still contain residual ribonucleic acid (RNA) and are thus termed reticulated platelets [4]. Whereas mature platelets persist in the circulation for 7–10 days, reticulated platelets have a much shorter lifespan of <1 day [5]. Thereby, these newly released platelets reflect the activity of megakaryopoiesis.
Measurement of reticulated platelets by flow cytometry
In 1969 Ingram and Coopersmith discovered in a canine model that newly released platelets following acute blood loss contain coarse condensations of residual RNA, which can be stained supravitally with methylene blue and counted microscopically [6]. Kienast and Schmitz were the first to introduce flow cytometric measurement of reticulated platelets based on thiazole orange staining [7]. However, this flow cytometric determination of reticulated platelets by research protocols is time-consuming and requires considerable expertise. Standardization remained difficult even when the same dyes and protocols were used and the reference range for reticulated platelets of healthy individuals, as measured by custom made flow cytometry, has not been clearly defined [8], [9], [10], [11]. Multiple factors contributing to this analytical issue were identified: the type and concentration of fluorescent dye, incubation time and temperature, fixation, RNAse treatment and the flow cytometric data analysis [9], [11], [12], [13], [14]. One of the major obstacles is the non-RNA specific binding of fluorescent dyes due to uptake in alpha dense granules, resulting in high background staining [9], [10], [15]. As the content of these dense granules is dependent on platelet size this problem may partly be solved by optimizing the assay conditions, i.e. degranulation by synthetic thrombin receptor ligand, and by applying a two-dimensional gating process [9], [10].
Automated determination of reticulated platelets
The first fully automated method to measure reticulated platelets based on flow cytometric analysis was established with the R-3000 reticulocyte analyzer (Toa Medical, later Sysmex Corporation, Kobe, Japan) equipped with special software using auramine O as fluorescence dye and a 488 nm argon laser [16], [17]. These early studies recognized a strong positive correlation between the percentage of reticulated platelets and the fraction of large platelets as well as for large platelets and MPV [17]. Sysmex later integrated the measurement of reticulated platelets as a parameter called “immature platelet fraction” into the XE-2100 and XE-5000 hematology analyzers (Sysmex Corporation, Kobe, Japan) within the reticulocyte count (RET/PLT channel) [18]. The later instruments operate a 633 nm semiconductor diode laser and use a proprietary fluorescence dye containing polymethine, which passes the cell membrane and stains residual RNA in reticulated platelets. In the scatterplot displaying cell size (forward light scatter) vs. RNA content (fluorescence) immature platelets are defined by a fixed gate as platelets with large cell size and the highest fluorescence intensity. IPF is given as the percentage of thus defined immature platelets of the total platelet count (IPF) as well as absolute immature platelet count (absolute IPF). This method has been shown to produce reliable results in a number of studies and reference values for healthy individuals with a mean IPF of 3.4% (range 1.1%–6.1%) were established [18], [19], [20], [21], [22], [23]. The latest Sysmex XN-series of hematology analyzers determines the IPF within a dedicated fluorescence platelet assay (PLT-F) using a proprietary oxazine fluorescence dye [24]. Again, the scatterplot of cell size (forward scatter) vs. RNA content (fluorescence intensity) is applied to quantify the IPF (Figure 1) [24]. For the Sysmex XN system reference values for healthy individuals with a median IPF of 2.6% (range 1.0%–7.3%) were established [25]. Hematological conditions pose a special challenge for correct counting of platelets. It was noted that fragments of apoptotic blood cells (e.g. in leukemic blood samples) might interfere with the IPF measurement and give falsely high results due to staining with the reticulocyte stain in the Sysmex XE-series [24], [26], [27]. These artifacts seem to be limited with the XN-series analyzers [24], [28]. The oxazine fluorescence dye used with the new PLT-F channel of the Sysmex XN-series strongly stains intra-platelet structures as mitochondria and cytosolic RNA, but plasma membranes of platelets, erythrocytes and red cell fragments are only slightly labeled [29]. In contrast, the polymethine fluorescence dye applied with the RET/PLT-channel by the predecessor Sysmex XE-series analyzers stains not only platelets, but also plasma membranes of erythrocytes effectively [29]. These improved staining properties of the oxazine fluorescence dye enable a better separation of immature platelets from other populations of similar size (e.g. red cell “ghosts”) in the scatterplot of cell size (forward light scatter) vs. RNA content (fluorescence intensity). The XN-series also shows improved precision of platelet counts below 50×109/L and better correlation (r2 ≥ 0.80) with the flow cytometric reference method for platelet enumeration due to a 5 times larger sample volume analyzed [24], [27], [28], [30], [31], [32]. This progress in the XN-series may account for the moderate correlation of IPF between the XE-2100 and the XN-2000 (r2≥0.60) [24], [27] and potentially improves the utility of IPF especially in hematological patients with very low platelet counts and in clinical settings with interference of aberrant cell populations and debris (e.g. chemotherapy, thrombotic-thrombocytopenic purpura).
Scatterplot of reticulated thrombocyte measurement by Sysmex XN automated hematology analyzer.
Sysmex XN-series determines immature platelet fraction within a dedicated platelet fluorescence assay (PLT-F channel) by forward light scatter vs. sideward fluorescence. FSC, forward scatter; IPF, immature platelet fraction; PLT-F, platelets; RBC, red blood cells; SFL, sideward fluorescence; WBC, white blood cells. Reprinted from Sysmex Europe GmbH with permission.
Abbott also introduced a method to quantify reticulated platelets, called “reticulated platelet”, based on RNA staining as integral part of the reticulocyte assay with the CELL DYN-Sapphire (Abbott Diagnostics, Santa Clara, CA, USA) [33]. This assay uses a 488 nm laser and the proprietary RNA fluorescence dye CD4K530 [34] to separate platelets and red blood cells by an embedded multi-dimensional analysis of three angles of light scatter (0°, 70° and 90°) and fluorescence intensity. First a variable gate adjusted to the red cell population is applied to identify the platelet population. Within the platelet gate, mature and reticulated platelets are discriminated by fluorescence intensity vs. 7° intermediate angle scatter. This algorithm allows correcting for size-dependent background fluorescence of platelets as already suggested earlier [9]. The gating strategy is depicted by Hoffmann et al. [33]. Reticulated platelets are given as a fraction of the total platelet count (retPLT) as well as absolute count of reticulated platelets (absolute retPLT). For healthy individuals reference values with a mean retPLT between 1.4% and 2.2% (reference range 0.4% to 2.8%–6.0%) were established [33], [35], [36], [37], [38]. The recently released Abbott Alinity HQ hematology analyzer determines reticulated platelets (%rP) by a multidimensional analysis of light scatter (axial light loss, polarized side scatter, depolarized side scatter and four intermediate angles of light scatter) and fluorescence intensity [39]. This enables a reliable separation of platelets and red blood cells. However, a performance evaluation of the Abbott Alinity HQ regarding reticulated platelets is lacking thus far.
As for other hematological parameters all automated analyzers use whole blood samples anticoagulated with ethylenediaminetetraacetic acid (EDTA-K2) for the measurement of reticulated platelets (IPF and retPLT). After blood collection stability of IPF (Sysmex XE-2100) ranges between 24 and 48 h [18], [40] and of retPLT (Abbott CELL DYN-Sapphire) between <6 h [38] and at least 26 h [33], provided samples are kept at room temperature. When blood samples are kept at 4 °C, IPF increases linearly within the first 24 h, which can be corrected for by a simple algorithm [41], [42], [43]. With the Sysmex XN stability of platelet enumeration in the PLT-F channel decreases over time when samples are stored at room temperature (mean difference −6.6% and −14.4% after 48 h and 72 h) [27].
Clinical applications of reticulated platelets
Differential diagnosis of thrombocytopenia
First the clinical application of reticulated platelets focused on the diagnostic work-up of thrombocytopenia of unknown etiology. While bone marrow biopsy still remains the gold standard to estimate the activity of megakaryopoiesis, the fully automated measurement of reticulated platelets enables a fast and non-invasive evaluation of thrombopoiesis and can be carried without specialized hematological expertise. As thrombocytopenia due to peripheral consumption (e.g. immune thrombocytopenia [ITP], microangiopathic disease) results in compensatory increased megakaryopoiesis, a consecutive elevation of reticulated platelets is expected. In contrast, decreased amounts of reticulated platelets due to low megakaryopoietic activity are anticipated in bone marrow failure (BMF; e.g. myelodysplastic syndrome [MDS], aplastic anemia [AA], neoplastic disease, chemotherapy-induced thrombocytopenia [CIT]). A number of studies reported markedly elevated reticulated platelets by custom-made flow cytometry methods [7], [44], [45] as well as by automated hematology analyzers [18], [19], [21], [22], [38], [46], [47], [48], [49] in patients with ITP (median IPF 7.7–25.2%, median retPLT 9.1%). However, multiple studies also described increased levels of reticulated platelets in patients with MDS and AA [22], [47], [50], [51], [52], [53]. In the largest cohort of patients with AA (n=51) the level of immature platelets was moderately elevated to a mean IPF of 3.5% (range 0.6%–12.9%; healthy individuals: mean IPF of 1.2%, range 0.3–5.9%, n=2039) as measured by Sysmex XE-2100 (Figure 2) [22]. This increase of immature platelets in AA was less pronounced and significantly different (p<0.0001) from patients with ITP (mean IPF of 7.7%, range 1.0%–33.8%; n=150) [22]. Despite considerable overlap regarding the level of immature platelets in both patient groups, the authors were able to define a cut-off value of IPF≥7.3% to differentiate patients with ITP from those with AA with reasonable sensitivity and specificity of 54.0% and 92.2%, respectively [22]. Higher IPF in BMF and thus a lower discriminatory power was found in another prospective study [52]. A smaller study recently described an improved discrimination between BMF due to AA (n=18) or CIT (n=10) and ITP (n=47) with the Sysmex XN-1000 applying a cut-off of IPF>5.8% (sensitivity 85.1%, specificity 89.3%) [54]. Only one study investigated the role of automated measurement by the Abbott CELL-DYN Sapphire to distinguish between ITP and BMF (AA, MDS, acute myeloid leukemia) [52]. The levels of reticulated platelets showed considerable overlap between both groups and had no discriminatory power at all, whereas in a side-by-side analysis of the same samples IPF (Sysmex XE-5000) had some diagnostic relevance [52]. The authors suggested that this lack of discriminatory power with the Abbott CELL-DYN Sapphire was likely related to the dynamic threshold applied for the correction of size-dependent background fluorescence [11], [52]. The adjustment for platelet size by the Abbott CELL-DYN Sapphire algorithm thus rather seems to be a disadvantage of this analytical method compared to the strategy without correction for platelet size as used by Sysmex. There are only a few reports on the role of reticulated platelets in MDS. When reticulated platelets were determined by custom-made flow cytometry, comparable levels (p=0.28) in patients with MDS (mean 8%, range 4%–17%, 95% confidence interval [CI]: 2–13%, n=6) and healthy individuals (mean 5%, range 0%–26%, 95% CI: 4%–6%, n=71) were reported, whereas patients with ITP had markedly increased levels (mean 23%, range 5%–58%, 95% CI: 14%–32%, p<0.0001) [44]. In contrast, a number of studies using automated measurement of immature platelets described normal or increased levels as compared to healthy individuals [50], [51], [52], [53]. Sugimori et al. reported a mean IPF of 8.80% in a larger cohort of MDS patients (n=51) as compared to 2.07% (p<0.01) in healthy individuals (n=170) as measured with the Sysmex XE-2100 (Figure 3) [51]. The authors noted an increased IPF>10% in 16 out of 51 MDS patients, while 19 patients had IPF levels within the range of healthy individuals [51]. Whereas there was an inverse correlation between platelet count and IPF in healthy individuals and ITP, this was not reproduced in this report focusing on MDS [51]. The authors further speculated that a prominent dysmegakaryopoiesis indicated by a high IPF may be linked to a poor prognosis in MDS [50], [51], [53], but this has not been independently confirmed in larger cohorts of patients.
![Figure 2:
Immature platelet fraction in healthy individuals and patients with aplastic anemia [22].
Immature platelet fraction in patients with immune thrombocytopenia (n=150, mean IPF of 7.7%, range 1.0%–33.8%) is significantly higher than in healthy individuals (n=2039, mean IPF of 1.2%, range 0.3–5.9%) and patients with aplastic anemia (n=51, mean IPF of 3.5%, range 0.6%–12.9%). AA, aplastic anemia; IPF, immature platelet fraction (Sysmex); ITP, immune thrombocytopenia; normal, healthy individuals. Reprinted from Korean J Lab Med 2010;30:455 with permission.](/document/doi/10.1515/labmed-2019-0166/asset/graphic/j_labmed-2019-0166_fig_002.jpg)
Immature platelet fraction in healthy individuals and patients with aplastic anemia [22].
Immature platelet fraction in patients with immune thrombocytopenia (n=150, mean IPF of 7.7%, range 1.0%–33.8%) is significantly higher than in healthy individuals (n=2039, mean IPF of 1.2%, range 0.3–5.9%) and patients with aplastic anemia (n=51, mean IPF of 3.5%, range 0.6%–12.9%). AA, aplastic anemia; IPF, immature platelet fraction (Sysmex); ITP, immune thrombocytopenia; normal, healthy individuals. Reprinted from Korean J Lab Med 2010;30:455 with permission.
![Figure 3:
Immature platelet fraction in healthy individuals and patients with myelodysplastic syndrome [51].
Immature platelet fraction in healthy individuals and patients with thrombocytopenia. IPF values as determined by Sysmex XE-2100 are plotted for healthy individuals (mean IPF of 2.07%, SD±1.06%), patients with myelodysplastic syndrome (mean IPF of 8.80%, SD±8.09%) and patients with immune thrombocytopenia (mean IPF of 18.1%, SD±11.5%). IPF, immature platelet fraction (Sysmex); ITP, immune thrombocytopenia; MDS, myelodysplastic syndrome; SD, standard deviation. Reprinted from [51] with permission.](/document/doi/10.1515/labmed-2019-0166/asset/graphic/j_labmed-2019-0166_fig_003.jpg)
Immature platelet fraction in healthy individuals and patients with myelodysplastic syndrome [51].
Immature platelet fraction in healthy individuals and patients with thrombocytopenia. IPF values as determined by Sysmex XE-2100 are plotted for healthy individuals (mean IPF of 2.07%, SD±1.06%), patients with myelodysplastic syndrome (mean IPF of 8.80%, SD±8.09%) and patients with immune thrombocytopenia (mean IPF of 18.1%, SD±11.5%). IPF, immature platelet fraction (Sysmex); ITP, immune thrombocytopenia; MDS, myelodysplastic syndrome; SD, standard deviation. Reprinted from [51] with permission.
A reciprocal relationship of low platelet counts and increased levels of immature platelets irrespective of the cause of thrombocytopenia was noted by in the number of reports [22], [38], [47], [48], [52], [55], [56]. It was hypothesized that in severe thrombocytopenia a shift might take place towards even more immature forms of reticulated platelets, which are released into the circulation [52]. Thus, the lifespan of these reticulated platelets would be increased, comparable to a phenomenon called “reticulocyte shift” in anemia [52], [57], [58]. This reciprocal interaction restrains the usefulness of reticulated platelets in the differential diagnosis of thrombocytopenia. Moreover, enhanced platelet turnover due to peripheral consumption of platelets caused by autoantibodies is only one component in the multi-causative pathogenesis of ITP. However, platelet turnover may also be normal or even decreased [59], [60], [61]. In ITP autoantibodies, including anti-glycoprotein IIb/III and anti-glycoprotein Ib/IX antibodies, interfere with the platelet production by megakaryocytes in the bone marrow and result in decreased thrombopoiesis [62], [63]. These pathophysiological facts limit the utility of reticulated platelets to distinguish ITP from other causes of thrombocytopenia (i.e. AA, MDS).
Recovery of thrombopoiesis after cytostatic therapy and transfusion management
Intensive cytostatic therapy to treat hematological malignancies and several types of solid tumors as well as hematopoietic progenitor stem cell transplantation (HPSCT) can induce pronounced transient cytopenia and necessitate prophylactic transfusion support. In order to predict recovery of thrombopoiesis and reduce unnecessary platelet transfusions several studies investigated the usefulness of reticulated platelets determined by custom flow cytometry [64], [65], [66], [67] and automated analyzers [20], [55], [56], [68], [69], [70], [71], [72], [73], [74]. In general, these studies observed a rise of reticulated platelets several days before platelet recovery. Although a number of studies used fully automated measurement of IPF, these studies differed in their definition regarding the prediction of platelet recovery (platelet count >20–30×109/L within a median of 1–7 days), investigated heterogeneous patient cohorts (autologous/allogenic HPSCT) and thus identified different thresholds of IPF (3.5%, 5.3%, >5.8%, >6.2%, >7%, >10%, >12.1%) [20], [55], [68], [69], [70], [71], [72], [73]. A consistent cut-off or increment of IPF to reliably predict platelet recovery is therefore still lacking. This is underscored by a systematic analysis of 37 courses of CIT/HPSCT, which demonstrated a poor capacity for both IPF (area under the curve [AUC]=0.57, p=n.s.) and retPLT (AUC=0.57, p=n.s.) as well as for absolute IPF (AUC=0.68, p<0.0001) and absolute retPLT (AUC=0.67, p=0.0002) to predict platelet recovery within the following 2 days [56]. Another recent analysis of 44 allogeneic HPSCT patients demonstrated comparably poor prediction rates of 68.2% for platelet recovery (≥20×109/L) by IPF, whereas other platelet parameters as PDW, MPV and platelet lager cell ratio (P-LCR) showed better prediction rates of 88.6%, 93.2% and 93.2%, respectively [74]. The median time benefit (i.e. the time between first rise of the prediction parameter and platelet recovery) of 4.0, 4.5 and 5.0 days for PDW, MPV and P-LCR, respectively, was also significantly longer than for IPF (1.5 days) [74]. However, the authors noted a large inter-individual variation between the rise of the aforementioned parameters and platelet recovery and concluded, that IPF was not clinically meaningful to predict platelet recovery to >20.0×109/L, which is the critical decision-making level for platelet transfusion [74]. Although earlier studies suggested that reticulated platelets may be used as a parameter to optimize transfusion policies for platelet concentrates in patients undergoing intensive chemotherapy or HPSCT [20], [55], [71], [75], appropriate prospective trials have not been set-up yet. The large inter-individual variation between rise of IPF and platelet recovery and the fact, that IPF significantly drops after transfusion with platelet concentrates, strongly interfere with such strategies in patients who frequently receive platelet transfusions [20], [56], [69], [74], [76].
Acute coronary artery disease
Recently the role of reticulated platelets in acute coronary artery disease has been investigated. Immature platelets have increased cell volume and are metabolically more active than mature platelets [77], [78]. They have a greater prothrombotic potential due to higher levels of intracellular thromboxane A2 as well as increased levels of procoagulant surface proteins such as P-selectin and glycoprotein Ib and IIb/IIIa receptors [79], [80], [81]. In patients with unstable angina as well as non-ST-segment elevation myocardial infarction (non-STEMI) and STEMI significantly elevated levels of reticulated platelets were detected as compared to healthy volunteers by custom flow cytometry [82]. These results were later confirmed in a number of studies using the Sysmex XE-2100 automated analyzer [81], [83], [84], [85]. Conflicting with this, recent studies regarding patients presenting to the emergency department with acute chest pain did not find any significant difference in the IPF between patients with and without acute coronary syndrome (ACS) [86], [87]. However, this discrepancy may be related to the comparison group of patients with chest pain for reasons other than ACS, which might include individuals with elevated IPF due to various other medical conditions (e.g. infection, inflammation) [88]. Immature platelets may serve as a prognostic marker for the outcome of patients with ACS. High levels immature platelets (IPF>6.2%) within 24 h of hospitalization were shown to be an independent risk factor (odds ratio [OR]=2.42, 95% CI: 1.08–5.43, p=0.032) for in-hospital mortality in patients with ACS after adjusting for other covariables (age, diabetes mellitus, heart failure, ST-segment deviation, troponin level) [85]. Three studies investigated the utility of immature platelets in patients with ACS to assess long-term morbidity and mortality. Cesari et al. demonstrated that increased IPF (IPF≥3.1%) within 24–48 h following percutaneous coronary intervention (PCI) for ACS (STEMI, non-STEMI/unstable angina) was able to predict cardiovascular mortality after 1 year follow-up (OR=4.15, 95% CI: 1.24–13.91, p=0.02) in a multivariate model adjusted for Global Registry of Acute Coronary Events (GRACE) risk score [89]. Ibrahim et al. observed that an absolute IPF≥7, 6×106/L in patients with ACS and stable ischemic heart disease (SIHD) was associated with an increased risk to experience a major adverse cardiovascular event (MACE) in a follow-up period of 31 months (hazard ratio [HR] 4.65, 95% CI: 1.78–12.16, p<0.002) [90]. In agreement with this, Freynhofer et al. reported that IPF (cut-off of IPF≥3.35%) distinguished significantly between those patients with and without MACE at 6 months follow-up (p=0.021) in a large observational study of 486 patients with ACS and SIHD, who underwent PCI [91]. However, an independent benefit of IPF beyond that of classical risk factors to identify ACS patients with an increased likelihood for an unfavorable outcome has to be confirmed by further studies before IPF may become relevant for routine clinical practice.
Antiplatelet therapy
Reticulated platelets have also been investigated in response to anti-platelet therapy. Acetylsalicylic acid (ASS) is commonly used as a secondary prophylaxis in cardiovascular disease and transient ischemic attack/ acute ischemic stroke (TIA/AIS). By the means of selective acetylation, it is an irreversible inhibitor of cyclooxygenase-1 (COX-1) and COX-2 and prevents the production of procoagulant thromboxane A2 (TxA2). This irreversible inhibition of COX-1 in anucleate platelets has a sustained effect, as it renders platelets unable to synthesize TxA2 and therefore to aggregate for their entire lifespan (7–10 days) [92]. Similarly, the thienopyridines ticlopidine, clopidogrel and prasugrel permanently inhibit platelet activation by adenosine-diphosphate (ADP) via irreversible binding to the P2Y12-receptor. In-vivo the circulating platelet pool partly recovers the ability to produce TxA2 due to newly produced platelets as early as 4 h after ASS ingestion and full aggregation was demonstrated in in-vitro experiments when only 2.5% ASS-free platelets were present [93]. Consistent with this, a higher platelet turnover, as indicated by higher levels of reticulated platelets, was associated with resistance to antiplatelet therapy with ASS [94]. Higher levels of reticulated platelets also correlated with resistance to anti-platelet therapy with clopidogrel [95], prasugrel [96], [97] and to dual anti-platelet therapy with ASS/thienopyridine [80], [98], [99], [100], [101]. Hypo-responsiveness to clopidogrel (aggregation >50% in response to ADP) in healthy individuals was associated with high numbers immature platelets (upper tertile) and an IPF≥3.6% identified subjects with an impaired response to clopidogrel with a sensitivity and specificity of 85.7% and 81.8%, respectively [95]. A significant relationship between resistance to combined anti-platelet therapy with ASS/clopidogrel and reticulated platelets (retPLT and IPF, respectively), was confirmed in patients with diabetes mellitus type-2 [102], SIHD and ACS [98], [99], [100]. However, during the maintenance treatment with clopidogrel, prasugrel or ticagrelor reticulated platelets did not correlate with an impaired antiplatelet response [99], [103], [104], [105], [106]. Recent studies indicated, that beyond the effect of increased platelet turnover intrinsic properties of immature platelets contribute to the impaired antiplatelet response to thienopyridines [107], [108]. In summary, the studies evaluating the role of reticulated platelets in response to anti-platelet therapy have shown inconsistent results and warrant further research.
Ischemic stroke
TIA and AIS result from embolic or thrombotic occlusion of cerebral vessels and may cause a focal cerebral ischemic injury. Thus far there are only limited studies regarding the role of reticulated platelets in the incidence, pathophysiology and outcome of ischemic cerebrovascular disease [109]. While two preliminary studies reported an increased percentage of reticulated platelets following cardioembolic ischemic stroke [110], [111], McCabe et al. did not find any significant increase in reticulated platelets in patients with AIS or TIA compared with healthy individuals [112]. The small number of patients in the earlier studies and the methodological differences in the custom flow cytometry analysis may account for these divergent results. A recent study using automated measurement of IPF by Sysmex XE-2100 revealed a significantly higher IPF in symptomatic carotid stenosis patients early (at ≤4 weeks) (IPF=5.78%, p<0.001) as well as late (≥3 months) (IPF=5.11%, p=0.01) after TIA/AIS than in asymptomatic patients (IPF=3.48%) [113]. In order to elucidate the role of reticulated platelets in ischemic cerebrovascular disease clearly further research is required.
Infection
Thrombocytopenia is often seen in patients who develop severe infection and sepsis. While the cause of thrombocytopenia in sepsis may be multifactorial, increased platelet consumption due to an uncontrolled procoagulant response with thrombin formation and septic coagulopathy play a main role [114], [115]. In this respect it was recognized that reticulated platelets provide meaningful information for the diagnosis and follow-up of patients with sepsis [116], [117], [118], [119], [120], [121], [122]. Increased levels of IPF were found to significantly correlate with infection as determined by positive blood cultures (positive blood culture: mean IPF 4.86%; negative blood culture: mean IPF 1.79%, p<0.0001) even if patients were non-thrombocytopenic, indicating subliminal platelet consumption [116]. IPF increased before the onset of sepsis by a median of 2 days [117], [119], [121], was independent from other coagulation parameters [118], [120] and predicted mortality [119], [122]. The diagnostic performance of IPF (AUC=0.82 [121], AUC=0.87 [120]) in the discrimination of septic patients from non-septic patients was comparable with current biomarkers of infection such as c-reactive protein (CRP; AUC=0.81 [121], AUC=0.94 [120]) and procalcitonin (AUC=0.92) [120]. Of note, the prognostic efficiency of absolute IPF count to identify patients 2 days before sepsis onset was superior to that of CRP by multivariate analysis [121]. Whereas absolute IPF count displayed a gradual increase from 6 days before the onset of sepsis, the kinetics of CRP fluctuated strongly [121]. Discrepant results were found when IPF was used to assess the severity of sepsis [118], [120]. While IPF correlated with the severity of sepsis in patients treated in an intensive care unit [118], this was not the case in another study that included general ward patients [120]. Larger prospective studies are warranted to confirm these preliminary data and evaluate IPF as a biomarker for the early prediction of sepsis.
Other hematological and non-hematological conditions
Additionally, the utility of immature platelets was assessed in a number of other hematological and non-hematological diseases (Table 1). The scientific evidence for these conditions however is still very limited as most of these findings are described only in a small number of patients and by a single report.
Clinical applications for reticulated platelets.
| Condition | Objective | Reference |
|---|---|---|
| Thrombocytopenia | Differentiate hypo- from hyperproliferative thrombocytopenia | [7], [18], [19], [21], [22], [38], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], 123] |
| Predicting platelet recovery after CIT/HPSCT | [20], [55], [56], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74] | |
| Transfusion management | [20], [55], [56], [69], [71], [74], [75] | |
| Assessing treatment response to thrombopoietic drugs | [124] | |
| Acute coronary syndrome | Predicting outcome | [85], [89], [90], [91] |
| Monitoring of treatment response to antiplatelet therapy | [80], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], 125] | |
| Ischemic stroke | Predicting outcome | [110], [111], [112], [113] |
| Infection | Prediction and diagnosis of sepsis | [116], [117], [118], [119], [120], [121], [122] |
| Miscellaneous conditions with preliminary data | ||
| Myeloproliferative diseases | Assessing platelet turnover in ET | [126] |
| Surrogate for JAK2 V617F mutation in PV and ET | [127], [128], [129] | |
| Prognostic biomarker in MF | [130] | |
| Myelodysplastic syndrome | Prognostic biomarker | [50], [51], [53] |
| Thrombotic thrombocytopenic purpura | Diagnosis and monitoring of treatment response | [131], [132], [133] |
| Disseminated intravascular coagulation | Monitoring severity and predicting mortality | [134] |
| Heparin-induced thrombocytopenia | Predicting presence of anti-platelet factor 4/heparin complexes | [135] |
| Diabetes mellitus | Predicting cardiovascular complications | [136] |
| Pregnancy | Diagnostic biomarker for preeclampsia/HELLP syndrome | [137], [138], [139] |
| Liver disease | Predictive marker for esophageal varices | [140] |
| Dengue fever | Predicting platelet recovery in dengue fever | [141] |
-
CIT, chemotherapy induced thrombocytopenia; ET, essential thrombocythemia; HELLP syndrome, hypertension/elevated liver enzymes/low platelets syndrome; HPSCT, hematopoietic progenitor stem cell transplantation; MF, primary myelofibrosis; PV, polycythemia vera.
Limitations to the use of reticulated platelets
The lack of a standardized reference method to determine reticulated platelets has hindered a broader clinical application until now. Only a single flow cytometry study applied the ICSH reference method to enumerate platelets with the aim to develop a future reference method for reticulated platelets [142], [143]. Therefore, the performance of the aforementioned automated analyzers cannot be independently validated. Two studies showed only a modest correlation of r2=0.38 between the parameters for reticulated platelets (IPF and retPLT) when Sysmex XE-2100/XE-5000 and Abbott CELL-DYN Sapphire were compared directly (Figure 4) [35], [38]. This lack of agreement seems to be related to the different gating algorithm applied by the manufactures, which leads to two slightly differently defined populations of reticulated platelets [38]. Whereas in a study of Meintker et al. there was only weak correlation (r2=0.25) of both IPF (Sysmex XE-5000) and retPLT (Abbott CELL-DYN Sapphire) with other parameters indicative for increased thrombopoiesis as MPV [2], Hoffmann et al. showed a modest, but significant (p<0.001) negative correlation (Spearman’s ρ=−0.399) of retPLT and MPV in healthy individuals [33], [38]. In conclusion the parameters IPF and retPLT are not interchangeable and reference ranges as well as measurement values cannot simply be translated. Furthermore, most of the clinical studies cited above, only used the well-established IPF measurement by Sysmex analyzers. Comparable data for retPLT as determined by Abbott CELL-DYN Sapphire and Alinity HQ are lacking. In summary, a standardized reference method for the measurement of reticulated platelets is urgently needed.
![Figure 4:
Comparison of IPF (Sysmex XE-5000) and retPLT (Abbott CELL-DYN Sapphire) [38].
(A) Correlation. (B) Bland-Altman plot. Reprinted from [38] with permission.](/document/doi/10.1515/labmed-2019-0166/asset/graphic/j_labmed-2019-0166_fig_004.jpg)
Conclusion and future perspectives
Whereas IPF and retPLT are markedly increased in hyperproliferative thrombocytopenia such as ITP, hypoproliferative conditions (e.g. AA, MDS, CIT) frequently also show moderately elevated levels as a reciprocal relationship between reticulated platelets and platelet count irrespective of the cause of thrombocytopenia exists. Thus, the discriminatory power of IPF measurements is only moderate. Improved detection algorithms of the XN analyzers may lead to higher clinical utility, but this should be proven in larger prospective studies, defining IPF thresholds that take patients’ current platelet numbers into account.
Although an IPF-guided transfusion management would be highly desirable to avoid unnecessary platelet transfusions, considerable inter-individual variations between the time period of increasing IPF and platelet recovery has thus far impeded this concept.
Preliminary studies indicated clinical utility of IPF and retPLT for the risk assessment of coronary artery disease and stroke as well as for monitoring of anti-platelet therapy, though validation in larger randomized studies and demonstration of added value compared to conventional parameters are warranted before this might be introduced into clinical practice. Apart from this, the role of reticulated platelets has recently been investigated in several other conditions. The evidence in the majority of these settings is still very limited and additional research is necessary to confirm these findings.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: None declared.
-
Employment or leadership: None declared.
-
Honorarium: None declared.
-
Competing interests: L.M.: Travel costs: Amgen, Astellas, Medac, Merck, MSD, Novartis, Pfizer. S.W.K.: Travel support: Gilead, Alexion, Celgene, Takeda; speaker’s honorary: MSD; research projects (no personal reimbursement): Affirmed, Siemens. The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005;115:3339–47.10.1172/JCI26674Search in Google Scholar
2. Kuter DJ. The physiology of platelet production. Stem Cells 1996;14(Suppl 1):88–101.10.1002/stem.5530140711Search in Google Scholar
3. Ittermann T, Feig MA, Petersmann A, Radke D, Greinacher A, Volzke H, et al. Mean platelet volume is more important than age for defining reference intervals of platelet counts. PLoS One 2019;14:e0213658.10.1371/journal.pone.0213658Search in Google Scholar
4. Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS. The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 1992;98:637–46.10.1093/ajcp/98.6.637Search in Google Scholar
5. Ault KA, Knowles C. In vivo biotinylation demonstrates that reticulated platelets are the youngest platelets in circulation. Exp Hematol 1995;23:996–1001.Search in Google Scholar
6. Ingram M, Coopersmith A. Reticulated platelets following acute blood loss. Br J Haematol 1969;17:225–9.10.1111/j.1365-2141.1969.tb01366.xSearch in Google Scholar
7. Kienast J, Schmitz G. Flow cytometric analysis of thiazole orange uptake by platelets: a diagnostic aid in the evaluation of thrombocytopenic disorders. Blood 1990;75:116–21.10.1182/blood.V75.1.116.116Search in Google Scholar
8. Harrison P, Robinson MS, Mackie IJ, Machin SJ. Reticulated platelets. Platelets 1997;8:379–83.10.1080/09537109777050Search in Google Scholar
9. Matic GB, Chapman ES, Zaiss M, Rothe G, Schmitz G. Whole blood analysis of reticulated platelets: improvements of detection and assay stability. Cytometry 1998;34:229–34.10.1002/(SICI)1097-0320(19981015)34:5<229::AID-CYTO4>3.0.CO;2-2Search in Google Scholar
10. Robinson MS, Mackie IJ, Khair K, Liesner R, Goodall AH, Savidge GF, et al. Flow cytometric analysis of reticulated platelets: evidence for a large proportion of non-specific labelling of dense granules by fluorescent dyes. Br J Haematol 1998;100:351–7.10.1046/j.1365-2141.1998.00563.xSearch in Google Scholar
11. Hoffmann JJ. Reticulated platelets: analytical aspects and clinical utility. Clin Chem Lab Med 2014;52:1107–17.10.1515/cclm-2014-0165Search in Google Scholar
12. Bonan JL, Rinder HM, Smith BR. Determination of the percentage of thiazole orange (TO)-positive, “reticulated” platelets using autologous erythrocyte TO fluorescence as an internal standard. Cytometry 1993;14:690–4.10.1002/cyto.990140615Search in Google Scholar PubMed
13. Richards EM, Baglin TP. Quantitation of reticulated platelets: methodology and clinical application. Br J Haematol 1995;91:445–51.10.1111/j.1365-2141.1995.tb05320.xSearch in Google Scholar PubMed
14. Rapi S, Ermini A, Bartolini L, Caldini A, Del Genovese A, Miele AR, et al. Reticulocytes and reticulated platelets: simultaneous measurement in whole blood by flow cytometry. Clin Chem Lab Med 1998;36:211–4.10.1515/CCLM.1998.036Search in Google Scholar PubMed
15. Balduini CL, Noris P, Spedini P, Belletti S, Zambelli A, Da Prada GA. Relationship between size and thiazole orange fluorescence of platelets in patients undergoing high-dose chemotherapy. Br J Haematol 1999;106:202–7.10.1046/j.1365-2141.1999.01475.xSearch in Google Scholar PubMed
16. Watanabe K, Takeuchi K, Kawai Y, Ikeda Y, Kubota F, Nakamoto H. Automated measurement of reticulated platelets in estimating thrombopoiesis. Eur J Haematol 1995;54:163–71.10.1111/j.1600-0609.1995.tb00209.xSearch in Google Scholar PubMed
17. Koh KR, Yamane T, Ohta K, Hino M, Takubo T, Tatsumi N. Pathophysiological significance of simultaneous measurement of reticulated platelets, large platelets and serum thrombopoietin in non-neoplastic thrombocytopenic disorders. Eur J Haematol 1999;63:295–301.10.1111/j.1600-0609.1999.tb01131.xSearch in Google Scholar PubMed
18. Briggs C, Kunka S, Hart D, Oguni S, Machin SJ. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol 2004;126:93–9.10.1111/j.1365-2141.2004.04987.xSearch in Google Scholar PubMed
19. Abe Y, Wada H, Tomatsu H, Sakaguchi A, Nishioka J, Yabu Y, et al. A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF). Thromb Res 2006;118:463–9.10.1016/j.thromres.2005.09.007Search in Google Scholar PubMed
20. Briggs C, Hart D, Kunka S, Oguni S, Machin SJ. Immature platelet fraction measurement: a future guide to platelet transfusion requirement after haematopoietic stem cell transplantation. Transfus Med 2006;16:101–9.10.1111/j.1365-3148.2006.00654.xSearch in Google Scholar PubMed
21. Cho YG, Lee JH, Kim DS, Lee HS, Choi SI. [Clinical usefulness of the simple technique to diagnose thrombocytopenia using immature platelet fraction]. Korean J Lab Med 2007;27: 1–6.10.3343/kjlm.2007.27.1.1Search in Google Scholar PubMed
22. Jung H, Jeon HK, Kim HJ, Kim SH. Immature platelet fraction: establishment of a reference interval and diagnostic measure for thrombocytopenia. Korean J Lab Med 2010;30:451–9.10.3343/kjlm.2010.30.5.451Search in Google Scholar PubMed
23. Ko YJ, Kim H, Hur M, Choi SG, Moon HW, Yun YM, et al. Establishment of reference interval for immature platelet fraction. Int J Lab Hematol 2013;35:528–33.10.1111/ijlh.12049Search in Google Scholar PubMed
24. Briggs C, Longair I, Kumar P, Singh D, Machin SJ. Performance evaluation of the Sysmex haematology XN modular system. J Clin Pathol 2012;65:1024–30.10.1136/jclinpath-2012-200930Search in Google Scholar PubMed
25. Ko YJ, Hur M, Kim H, Choi SG, Moon HW, Yun YM. Reference interval for immature platelet fraction on Sysmex XN hematology analyzer: a comparison study with Sysmex XE-2100. Clin Chem Lab Med 2015;53:1091–7.10.1515/cclm-2014-0839Search in Google Scholar PubMed
26. Zandecki M, Genevieve F, Gerard J, Godon A. Spurious counts and spurious results on haematology analysers: a review. Part I: platelets. Int J Lab Hematol 2007;29:4–20.10.1111/j.1365-2257.2006.00870.xSearch in Google Scholar PubMed
27. Seo JY, Lee ST, Kim SH. Performance evaluation of the new hematology analyzer Sysmex XN-series. Int J Lab Hematol 2015;37:155–64.10.1111/ijlh.12254Search in Google Scholar PubMed
28. Tanaka Y, Tanaka Y, Gondo K, Maruki Y, Kondo T, Asai S, et al. Performance evaluation of platelet counting by novel fluorescent dye staining in the XN-series automated hematology analyzers. J Clin Lab Anal 2014;28:341–8.10.1002/jcla.21691Search in Google Scholar PubMed PubMed Central
29. Wada A, Takagi Y, Kono M, Morikawa T. Accuracy of a new platelet count system (PLT-F) depends on the staining property of its reagents. PLoS One 2015;10:e0141311.10.1371/journal.pone.0141311Search in Google Scholar PubMed PubMed Central
30. Schoorl M, Schoorl M, Oomes J, van Pelt J. New fluorescent method (PLT-F) on Sysmex XN2000 hematology analyzer achieved higher accuracy in low platelet counting. Am J Clin Pathol 2013;140:495–9.10.1309/AJCPUAGGB4URL5XOSearch in Google Scholar PubMed
31. Park SH, Park CJ, Kim MJ, Han MY, Lee BR, Cho YU, et al. The Sysmex XN-2000 hematology autoanalyzer provides a highly accurate platelet count than the former Sysmex XE-2100 system based on comparison with the CD41/CD61 immunoplatelet reference method of flow cytometry. Ann Lab Med 2014;34:471–4.10.3343/alm.2014.34.6.471Search in Google Scholar PubMed PubMed Central
32. Hummel K, Sachse M, Hoffmann J, van Dun L. Comparative evaluation of platelet counts in two hematology analyzers and potential effects on prophylactic platelet transfusion decisions. Transfusion 2018;58:2301–8.10.1111/trf.14886Search in Google Scholar PubMed
33. Hoffmann JJ, van den Broek NM, Curvers J. Reference intervals of reticulated platelets and other platelet parameters and their associations. Arch Pathol Lab Med 2013;137:1635–40.10.5858/arpa.2012-0624-OASearch in Google Scholar PubMed
34. Kim Y, Kantor J, Landayan M, Kihara J, Bearden J, Sheehan E. A rapid and sensitive reticulocyte method on a high-throughput hematology instrument. Lab Hematol 1997;3:19–26.Search in Google Scholar
35. de Wit N, Oosting J, Hoffmann J, Krockenberger M, van Dun L. Comparative evaluation of the Abbott Cell-Dyn Sapphire reticulated platelets fraction and the Sysmex XE-2100 IPF. Int J Lab Hematol 2009;31(Suppl 1):98.Search in Google Scholar
36. Costa O, Van Moer G, Jochmans K, Jonckheer J, Damiaens S, De Waele M. Reference values for new red blood cell and platelet parameters on the Abbott Diagnostics Cell-Dyn Sapphire. Clin Chem Lab Med 2012;50:967–9.10.1515/cclm-2011-0789Search in Google Scholar PubMed
37. Lang S, David R, Cohen J. Reticulated platelet normal ranges on CELL-DYN Sapphire. Int J Lab Hematol 2013;35(Suppl 1):112.Search in Google Scholar
38. Meintker L, Haimerl M, Ringwald J, Krause SW. Measurement of immature platelets with Abbott CD-Sapphire and Sysmex XE-5000 in haematology and oncology patients. Clin Chem Lab Med 2013;51:2125–31.10.1515/cclm-2013-0252Search in Google Scholar PubMed
39. Van der Beken Y, Van Dalem A, Van Moer G, Segers E, Damiaens S, Hoffmann J, et al. Performance evaluation of the prototype Abbott Alinity hq hematology analyzer. Int J Lab Hematol 2019;41:448–55.10.1111/ijlh.13020Search in Google Scholar PubMed
40. Ruisi MM, Psaila B, Ward MJ, Villarica G, Bussel JB. Stability of measurement of the immature platelet fraction. Am J Hematol 2010;85:622–4.10.1002/ajh.21748Search in Google Scholar PubMed
41. Osei-Bimpong A. The effect of storage on the clinical utility of the immature platelet fraction. Hematology 2009;14:118–21.10.1179/102453309X385098Search in Google Scholar PubMed
42. Osei-Bimpong A, Saleh M, Sola-Visner M, Widness J, Veng-Pedersen P. Correction for effect of cold storage on immature platelet fraction. J Clin Lab Anal 2010;24:431–3.10.1002/jcla.20426Search in Google Scholar PubMed PubMed Central
43. Nishiyama M, Hayashi S, Kabutomori O, Yamanishi H, Suehisa E, Kurata Y, et al. [Effects of anticoagulants and storage temperature on immature platelet fraction % (IPF%) values in stored samples measured by the automated hematology analyzer, XE-5000–utility of CTAD-anticoagulation and room temperature storage]. Rinsho Byori 2011;59:452–8.Search in Google Scholar
44. Thomas-Kaskel AK, Mattern D, Kohler G, Finke J, Behringer D. Reticulated platelet counts correlate with treatment response in patients with idiopathic thrombocytopenic purpura and help identify the complex causes of thrombocytopenia in patients after allogeneic hematopoietic stem cell transplantation. Cytometry B Clin Cytom 2007;72:241–8.10.1002/cyto.b.20163Search in Google Scholar PubMed
45. Monteagudo M, Amengual MJ, Munoz L, Soler JA, Roig I, Tolosa C. Reticulated platelets as a screening test to identify thrombocytopenia aetiology. Q J Med 2008;101:549–55.10.1093/qjmed/hcn047Search in Google Scholar PubMed
46. Kickler TS, Oguni S, Borowitz MJ. A clinical evaluation of high fluorescent platelet fraction percentage in thrombocytopenia. Am J Clin Pathol 2006;125:282–7.10.1309/50H8JYHN9JWCKAM7Search in Google Scholar
47. Pons I, Monteagudo M, Lucchetti G, Munoz L, Perea G, Colomina I, et al. Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. Eur J Haematol 2010;85:158–63.Search in Google Scholar
48. Ferreira FL, Colella MP, Medina SS, Costa-Lima C, Fiusa MM, Costa LN, et al. Evaluation of the immature platelet fraction contribute to the differential diagnosis of hereditary, immune and other acquired thrombocytopenias. Sci Rep 2017;7:3355.10.1038/s41598-017-03668-ySearch in Google Scholar PubMed PubMed Central
49. Van De Wyngaert Z, Fournier E, Bera E, Carrette M, Soenen V, Gauthier J, Preudhomme C, Boyer T. Immature platelet fraction (IPF): A reliable tool to predict peripheral thrombocytopenia. Curr Res Transl Med. 2019; doi: 10.1016/j.retram.2019.04.002 [Epub ahead of print].10.1016/j.retram.2019.04.002Search in Google Scholar PubMed
50. Saigo K, Takenokuchi M, Imai J, Numata K, Isono S, Zenibayashi M, et al. Usefulness of immature platelet fraction for the clinical evaluation of myelodysplastic syndromes. Lab Hematol 2009;15:13–6.10.1532/LH96.09003Search in Google Scholar PubMed
51. Sugimori N, Kondo Y, Shibayama M, Omote M, Takami A, Sugimori C, et al. Aberrant increase in the immature platelet fraction in patients with myelodysplastic syndrome: a marker of karyotypic abnormalities associated with poor prognosis. Eur J Haematol 2009;82:54–60.10.1111/j.1600-0609.2008.01156.xSearch in Google Scholar PubMed
52. Cybulska A, Meintker L, Ringwald J, Krause SW. Measurements of immature platelets with haematology analysers are of limited value to separate immune thrombocytopenia from bone marrow failure. Br J Haematol 2017;177:612–9.10.1111/bjh.14628Search in Google Scholar PubMed
53. Larruzea Ibarra A, Muñoz Marín L, Perea Durán G, Torra Puig M. Evaluation of immature platelet fraction in patients with myelodysplastic syndromes. Association with poor prognosis factors. Clin Chem Lab Med 2019;57:e128–30.10.1515/cclm-2018-0784Search in Google Scholar PubMed
54. Sakuragi M, Hayashi S, Maruyama M, Kabutomori O, Kiyokawa T, Nagamine K, et al. Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders. Int J Hematol 2015;101:369–75.10.1007/s12185-015-1741-0Search in Google Scholar PubMed
55. Yamaoka G, Kubota Y, Nomura T, Inage T, Arai T, Kitanaka A, et al. The immature platelet fraction is a useful marker for predicting the timing of platelet recovery in patients with cancer after chemotherapy and hematopoietic stem cell transplantation. Int J Lab Hematol 2010;32(6 Pt 1):e208–16.10.1111/j.1751-553X.2010.01232.xSearch in Google Scholar PubMed
56. Meintker L, Fritsch JD, Ringwald J, Krause SW. Immature platelets do not reliably predict platelet recovery in patients with intensive chemotherapy or stem cell transplantation. Vox Sang 2017;112:132–9.10.1111/vox.12483Search in Google Scholar PubMed
57. Hillman RS. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest 1969;48:443–53.10.1172/JCI106001Search in Google Scholar PubMed PubMed Central
58. Angenieux C, Maitre B, Eckly A, Lanza F, Gachet C, de la Salle H. Time-dependent decay of mRNA and ribosomal RNA during platelet aging and its correlation with translation activity. PLoS One 2016;11:e0148064.10.1371/journal.pone.0148064Search in Google Scholar PubMed PubMed Central
59. Heyns Adu P, Badenhorst PN, Lotter MG, Pieters H, Wessels P, Kotze HF. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 1986;67:86–92.10.1182/blood.V67.1.86.86Search in Google Scholar
60. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987;80:33–40.10.1172/JCI113060Search in Google Scholar PubMed PubMed Central
61. Strom TS. Numerical analysis of in vivo platelet consumption data from ITP patients. BMC Hematol 2015;15:14.10.1186/s12878-015-0034-4Search in Google Scholar PubMed PubMed Central
62. Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 2003;102:887–95.10.1182/blood-2002-05-1475Search in Google Scholar PubMed
63. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004;103:1364–9.10.1182/blood-2003-08-2672Search in Google Scholar PubMed
64. Macchi I, Chamlian V, Sadoun A, Le Dirach A, Guilhot J, Guilhot F, et al. Comparison of reticulated platelet count and mean platelet volume determination in the evaluation of bone marrow recovery after aplastic chemotherapy. Eur J Haematol 2002;69:152–7.10.1034/j.1600-0609.2002.02702.xSearch in Google Scholar PubMed
65. Wang C, Smith BR, Ault KA, Rinder HM. Reticulated platelets predict platelet count recovery following chemotherapy. Transfusion 2002;42:368–74.10.1046/j.1537-2995.2002.00040.xSearch in Google Scholar PubMed
66. Michur H, Maslanka K, Szczepinski A, Marianska B. Reticulated platelets as a marker of platelet recovery after allogeneic stem cell transplantation. Int J Lab Hematol 2008;30:519–25.10.1111/j.1751-553X.2007.00993.xSearch in Google Scholar PubMed
67. Martinelli G, Merlo P, Fantasia R, Gioia F, Crovetti G. Reticulated platelet monitoring after autologous peripheral haematopoietic progenitor cell transplantation. Transfus Apher Sci 2009;40:175–81.10.1016/j.transci.2009.03.018Search in Google Scholar PubMed
68. Zucker ML, Murphy CA, Rachel JM, Martinez GA, Abhyankar S, McGuirk JP, et al. Immature platelet fraction as a predictor of platelet recovery following hematopoietic progenitor cell transplantation. Lab Hematol 2006;12:125–30.10.1532/LH96.06012Search in Google Scholar PubMed
69. Takami A, Shibayama M, Orito M, Omote M, Okumura H, Yamashita T, et al. Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation. Bone Marrow Transplant 2007;39:501–7.10.1038/sj.bmt.1705623Search in Google Scholar PubMed
70. Goncalo AP, Barbosa IL, Campilho F, Campos A, Mendes C. Predictive value of immature reticulocyte and platelet fractions in hematopoietic recovery of allograft patients. Transplant Proc 2011;43:241–3.10.1016/j.transproceed.2010.12.030Search in Google Scholar PubMed
71. van der Linden N, Klinkenberg LJ, Meex SJ, Beckers EA, de Wit NC, Prinzen L. Immature platelet fraction measured on the Sysmex XN hemocytometer predicts thrombopoietic recovery after autologous stem cell transplantation. Eur J Haematol 2014;93:150–6.10.1111/ejh.12319Search in Google Scholar PubMed PubMed Central
72. Morkis IV, Farias MG, Rigoni LD, Scotti L, Gregianin LJ, Daudt LE, et al. Assessment of immature platelet fraction and immature reticulocyte fraction as predictors of engraftment after hematopoietic stem cell transplantation. Int J Lab Hematol 2015;37:259–64.10.1111/ijlh.12278Search in Google Scholar PubMed
73. Sakuragi M, Hayashi S, Maruyama M, Kiyokawa T, Nagamine K, Fujita J, et al. Immature platelet fraction (IPF) as a predictive value for thrombopoietic recovery after allogeneic stem cell transplantation. Int J Hematol 2018;107:320–6.10.1007/s12185-017-2344-8Search in Google Scholar PubMed
74. Park SH, Park CJ, Kim MJ, Han MY, Lee BR, Cho YU, et al. Evaluation of parameters obtained from the Sysmex XN-2000 for predicting the recovery of the absolute neutrophil count and platelets after hematopoietic stem cell transplantation. Int J Lab Hematol 2016;38:198–208.10.1111/ijlh.12470Search in Google Scholar PubMed
75. Chaoui D, Chakroun T, Robert F, Rio B, Belhocine R, Legrand O, et al. Reticulated platelets: a reliable measure to reduce prophylactic platelet transfusions after intensive chemotherapy. Transfusion 2005;45:766–72.10.1111/j.1537-2995.2005.04286.xSearch in Google Scholar PubMed
76. Bat T, Leitman SF, Calvo KR, Chauvet D, Dunbar CE. Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion. Transfusion 2013;53:1201–4.10.1111/j.1537-2995.2012.03918.xSearch in Google Scholar PubMed PubMed Central
77. Jakubowski JA, Thompson CB, Vaillancourt R, Valeri CR, Deykin D. Arachidonic acid metabolism by platelets of differing size. Br J Haematol 1983;53:503–11.10.1111/j.1365-2141.1983.tb02052.xSearch in Google Scholar
78. Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983;32:443–60.10.1016/0049-3848(83)90255-4Search in Google Scholar
79. Tschoepe D, Roesen P, Kaufmann L, Schauseil S, Kehrel B, Ostermann H, et al. Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest 1990;20:166–70.10.1111/j.1365-2362.1990.tb02264.xSearch in Google Scholar PubMed
80. Guthikonda S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, DeLao T, et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008;52:743–9.10.1016/j.jacc.2008.05.031Search in Google Scholar PubMed
81. Cesari F, Marcucci R, Gori AM, Caporale R, Fanelli A, Paniccia R, et al. High platelet turnover and reactivity in renal transplant recipients patients. Thromb Haemost 2010;104:804–10.10.1160/TH10-02-0124Search in Google Scholar PubMed
82. Lakkis N, Dokainish H, Abuzahra M, Tsyboulev V, Jorgensen J, De Leon AP, et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004;44:2091–3.10.1016/j.jacc.2004.05.033Search in Google Scholar PubMed
83. Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009;101:151–6.10.1160/TH08-03-0186Search in Google Scholar
84. Gonzalez-Porras JR, Martin-Herrero F, Gonzalez-Lopez TJ, Olazabal J, Diez-Campelo M, Pabon P, et al. The role of immature platelet fraction in acute coronary syndrome. Thromb Haemost 2010;103:247–9.10.1160/TH09-02-0124Search in Google Scholar PubMed
85. Lopez-Jimenez RA, Martin-Herrero F, Gonzalez-Porras JR, Sanchez-Barba M, Martin-Luengo C, Pabon-Osuna P. Immature platelet fraction: a new prognostic marker in acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2013;66:147–8.10.1016/j.rec.2012.05.014Search in Google Scholar PubMed
86. Berny-Lang MA, Darling CE, Frelinger 3rd AL, Barnard MR, Smith CS, Michelson AD. Do immature platelet levels in chest pain patients presenting to the emergency department aid in the diagnosis of acute coronary syndrome? Int J Lab Hematol 2015;37:112–9.10.1111/ijlh.12250Search in Google Scholar PubMed PubMed Central
87. Huang HL, Chen CH, Kung CT, Li YC, Sung PH, You HL, et al. Clinical utility of mean platelet volume and immature platelet fraction in acute coronary syndrome. Biomed J 2019;42:107–15.10.1016/j.bj.2018.12.005Search in Google Scholar PubMed PubMed Central
88. Liu QH, Song MY, Yang BX, Xia RX. Clinical significance of measuring reticulated platelets in infectious diseases. Medicine (Baltimore) 2017;96:e9424.10.1097/MD.0000000000009424Search in Google Scholar PubMed PubMed Central
89. Cesari F, Marcucci R, Gori AM, Caporale R, Fanelli A, Casola G, et al. Reticulated platelets predict cardiovascular death in acutecoronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 2013;109:846–53.10.1160/TH12-09-0709Search in Google Scholar PubMed
90. Ibrahim H, Schutt RC, Hannawi B, DeLao T, Barker CM, Kleiman NS. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014;64:2122–9.10.1016/j.jacc.2014.06.1210Search in Google Scholar PubMed
91. Freynhofer MK, Iliev L, Bruno V, Rohla M, Egger F, Weiss TW, et al. Platelet turnover predicts outcome after coronary intervention. Thromb Haemost 2017;117:923–33.10.1160/TH16-10-0785Search in Google Scholar PubMed PubMed Central
92. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982;69:1366–72.10.1172/JCI110576Search in Google Scholar
93. DiMinno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986;68:886–91.10.1182/blood.V68.4.886.886Search in Google Scholar
94. Guthikonda S, Lev EI, Patel R, DeLao T, Bergeron AL, Dong JF, et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007;5:490–6.10.1111/j.1538-7836.2007.02387.xSearch in Google Scholar PubMed
95. Ibrahim H, Nadipalli S, DeLao T, Guthikonda S, Kleiman NS. Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness. J Thromb Thrombolysis 2012;33:137–42.10.1007/s11239-011-0665-7Search in Google Scholar PubMed
96. Perl L, Lerman-Shivek H, Rechavia E, Vaduganathan M, Leshem-Lev D, Zemer-Wassercug N, et al. Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2014;63:513–7.10.1016/j.jacc.2013.07.110Search in Google Scholar PubMed
97. Bernlochner I, Goedel A, Plischke C, Schupke S, Haller B, Schulz C, et al. Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome. Eur Heart J 2015;36:3202–10.10.1093/eurheartj/ehv326Search in Google Scholar PubMed
98. Cesari F, Marcucci R, Caporale R, Paniccia R, Romano E, Gensini GF, et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008;99:930–5.10.1160/TH08-01-0002Search in Google Scholar PubMed
99. Freynhofer MK, Bruno V, Brozovic I, Jarai R, Vogel B, Farhan S, et al. Variability of on-treatment platelet reactivity in patients on clopidogrel. Platelets 2014;25:328–36.10.3109/09537104.2013.827781Search in Google Scholar PubMed
100. Stratz C, Bomicke T, Younas I, Kittel A, Amann M, Valina CM, et al. Comparison of immature platelet count to established predictors of platelet reactivity during thienopyridine therapy. J Am Coll Cardiol 2016;68:286–93.10.1016/j.jacc.2016.04.056Search in Google Scholar PubMed
101. Fabbri A, Marcucci R, Gori AM, Giusti B, Paniccia R, Balzi D, et al. A time course study of high on treatment platelet reactivity in acute coronary syndrome male patients on dual antiplatelet therapy. Thromb Res 2015;136:613–9.10.1016/j.thromres.2015.06.040Search in Google Scholar PubMed
102. Mijovic R, Kovacevic N, Zarkov M, Stosic Z, Cabarkapa V, Mitic G. Reticulated platelets and antiplatelet therapy response in diabetic patients. J Thromb Thrombolysis 2015;40:203–10.10.1007/s11239-014-1165-3Search in Google Scholar PubMed
103. Eisen A, Lerman-Shivek H, Perl L, Rechavia E, Leshem-Lev D, Zemer-Wassercug N, et al. Circulating reticulated platelets over time in patients with myocardial infarction treated with prasugrel or ticagrelor. J Thromb Thrombolysis 2015;40:70–5.10.1007/s11239-014-1156-4Search in Google Scholar PubMed
104. Verdoia M, Pergolini P, Rolla R, Suryapranata H, Kedhi E, De Luca G on behalf of the Novara Atherosclerosis Study Group. Impact of immature platelet fraction on platelet reactivity during prasugrel maintenance treatment. Platlets. 2019;30:915–22.10.1080/09537104.2018.1535707Search in Google Scholar PubMed
105. Verdoia M, Pergolini P, Nardin M, Rolla R, Barbieri L, Schaffer A, et al. Impact of diabetes on immature platelets fraction and its relationship with platelet reactivity in patients receiving dual antiplatelet therapy. J Thromb Thrombolysis 2016;42:245–53.10.1007/s11239-016-1348-1Search in Google Scholar PubMed
106. Verdoia M, Sartori C, Pergolini P, Nardin M, Rolla R, Barbieri L, et al. Immature platelet fraction and high-on treatment platelet reactivity with ticagrelor in patients with acute coronary syndromes. J Thromb Thrombolysis 2016;41:663–70.10.1007/s11239-015-1279-2Search in Google Scholar PubMed
107. Stratz C, Nuhrenberg T, Amann M, Cederqvist M, Kleiner P, Valina CM, et al. Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. Thromb Haemost 2016;116:941–8.10.1160/TH16-03-0191Search in Google Scholar
108. Gruber SC, Freynhofer MK, Willheim M, Weiss TW, Egger F, Hubl W, et al. Twenty-four-hour time dependency of clopidogrel effects in patients with acute coronary syndromes: the CiCAD-study. Platelets 2019;30:506–12.10.1080/09537104.2018.1478399Search in Google Scholar
109. Hannawi B, Hannawi Y, Kleiman NS. Reticulated platelets: changing focus from basics to outcomes. Thromb Haemost 2018;118:1517–27.10.1055/s-0038-1667338Search in Google Scholar
110. Nakamura T, Uchiyama S, Yamazaki M, Okubo K, Takakuwa Y, Iwata M. Flow cytometric analysis of reticulated platelets in patients with ischemic stroke. Thromb Res 2002;106:171–7.10.1016/S0049-3848(02)00131-7Search in Google Scholar
111. Smith NM, Pathansali R, Bath PM. Altered megakaryocyte-platelet-haemostatic axis in patients with acute stroke. Platelets 2002;13:113–20.10.1080/09537100120111559Search in Google Scholar PubMed
112. McCabe DJ, Harrison P, Sidhu PS, Brown MM, Machin SJ. Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack. Br J Haematol 2004;126:861–9.10.1111/j.1365-2141.2004.05137.xSearch in Google Scholar PubMed
113. Murphy SJ, Lim ST, Kinsella JA, Murphy D, Enright HM, McCabe DJ, et al. Increased platelet count and reticulated platelets in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic signal-negative patient subgroups: results from the HaEmostasis In carotid STenosis (HEIST) study. J Neurol 2018;265:1037–49.10.1007/s00415-018-8797-8Search in Google Scholar PubMed
114. Vincent JL, Yagushi A, Pradier O. Platelet function in sepsis. Crit Care Med 2002;30(5 Suppl):S313–7.10.1097/00003246-200205001-00022Search in Google Scholar PubMed
115. Larkin CM, Santos-Martinez MJ, Ryan T, Radomski MW. Sepsis-associated thrombocytopenia. Thromb Res 2016;141:11–6.10.1016/j.thromres.2016.02.022Search in Google Scholar PubMed
116. Di Mario A, Garzia M, Leone F, Arcangeli A, Pagano L, Zini G. Immature platelet fraction (IPF) in hospitalized patients with neutrophilia and suspected bacterial infection. J Infect 2009;59:201–6.10.1016/j.jinf.2009.07.007Search in Google Scholar PubMed
117. De Blasi RA, Cardelli P, Costante A, Sandri M, Mercieri M, Arcioni R. Immature platelet fraction in predicting sepsis in critically ill patients. Intensive Care Med 2013;39:636–43.10.1007/s00134-012-2725-7Search in Google Scholar PubMed
118. Enz Hubert RM, Rodrigues MV, Andreguetto BD, Santos TM, de Fatima Pereira Gilberti M, de Castro V, et al. Association of the immature platelet fraction with sepsis diagnosis and severity. Sci Rep 2015;5:8019.10.1038/srep08019Search in Google Scholar PubMed PubMed Central
119. Muronoi T, Koyama K, Nunomiya S, Lefor AK, Wada M, Koinuma T, et al. Immature platelet fraction predicts coagulopathy-related platelet consumption and mortality in patients with sepsis. Thromb Res 2016;144:169–75.10.1016/j.thromres.2016.06.002Search in Google Scholar PubMed
120. Park SH, Ha SO, Cho YU, Park CJ, Jang S, Hong SB. Immature platelet fraction in septic patients: clinical relevance of immature platelet fraction is limited to the sensitive and accurate discrimination of septic patients from non-septic patients, not to the discrimination of sepsis severity. Ann Lab Med 2016;36:1–8.10.3343/alm.2016.36.1.1Search in Google Scholar PubMed PubMed Central
121. Buoro S, Manenti B, Seghezzi M, Dominoni P, Barbui T, Ghirardi A, et al. Innovative haematological parameters for early diagnosis of sepsis in adult patients admitted in intensive care unit. J Clin Pathol 2018;71:330–5.10.1136/jclinpath-2017-204643Search in Google Scholar PubMed
122. Koyama K, Katayama S, Muronoi T, Tonai K, Goto Y, Koinuma T, et al. Time course of immature platelet count and its relation to thrombocytopenia and mortality in patients with sepsis. PLoS One 2018;13:e0192064.10.1371/journal.pone.0192064Search in Google Scholar PubMed PubMed Central
123. Miyazaki K, Koike Y, Kunishima S, Ishii R, Danbara M, Horie R, et al. Immature platelet fraction measurement is influenced by platelet size and is a useful parameter for discrimination of macrothrombocytopenia. Hematology 2015;20:587–92.10.1179/1607845415Y.0000000021Search in Google Scholar PubMed
124. Barsam SJ, Psaila B, Forestier M, Page LK, Sloane PA, Geyer JT, et al. Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia. Blood 2011;117:5723–32.10.1182/blood-2010-11-321398Search in Google Scholar PubMed PubMed Central
125. Verdoia M, Pergolini P, Rolla R, Barbieri L, Schaffer A, Marino P, et al. Impact of long-term dual antiplatelet therapy on immature platelet count and platelet reactivity. Angiology 2018;69:490–6.10.1177/0003319717736407Search in Google Scholar PubMed
126. Pedersen OH, Larsen ML, Grove EL, van Kooten Niekerk PB, Bonlokke S, Nissen PH, et al. Platelet characteristics in patients with essential thrombocytosis. Cytometry B Clin Cytom 2018;94:918–27.10.1002/cyto.b.21642Search in Google Scholar PubMed
127. Panova-Noeva M, Marchetti M, Buoro S, Russo L, Leuzzi A, Finazzi G, et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood 2011;118:2599–601.10.1182/blood-2011-02-339655Search in Google Scholar PubMed
128. Johnson S, Baker B. A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients. Int J Lab Hematol 2019;41:271–6.10.1111/ijlh.12967Search in Google Scholar PubMed
129. Kissova J, Bulikova A, Ovesna P, Bourkova L, Penka M. Increased mean platelet volume and immature platelet fraction as potential predictors of thrombotic complications in BCR/ABL-negative myeloproliferative neoplasms. Int J Hematol 2014;100:429–36.10.1007/s12185-014-1673-0Search in Google Scholar PubMed
130. Strati P, Bose P, Lyle L, Gaw K, Zhou L, Pierce SA, et al. Novel hematological parameters for the evaluation of patients with myeloproliferative neoplasms: the immature platelet and reticulocyte fractions. Ann Hematol 2017;96:733–8.10.1007/s00277-017-2956-3Search in Google Scholar PubMed
131. Hong H, Xiao W, Stempak LM, Sandhaus LM, Maitta RW. Absolute immature platelet count dynamics in diagnosing and monitoring the clinical course of thrombotic thrombocytopenic purpura. Transfusion 2015;55:756–65.10.1111/trf.12912Search in Google Scholar PubMed
132. Kier YE, Stempak LM, Maitta RW. Immature platelet fraction can help adjust therapy in refractory thrombotic microangiopathic hemolytic anemia cases. Transfus Apher Sci 2013;49:644–6.10.1016/j.transci.2013.07.005Search in Google Scholar PubMed
133. Zheng Y, Hong H, Reeves HM, Maitta RW. Absolute immature platelet count helps differentiate thrombotic thrombocytopenic purpura from hypertension-induced thrombotic microangiopathy. Transfus Apher Sci 2014;51:54–7.10.1016/j.transci.2014.07.004Search in Google Scholar PubMed
134. Hong KH, Kim HK, Kim JE, Jung JS, Han KS, Cho HI. Prognostic value of immature platelet fraction and plasma thrombopoietin in disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2009;20:409–14.10.1097/MBC.0b013e32832b1866Search in Google Scholar PubMed
135. Chen W, Ha JP, Hong H, Maitta RW. Absolute immature platelet counts in the setting of suspected heparin-induced thrombocytopenia may predict anti-PF4-heparin immunoassay testing results. Transfus Apher Sci 2018;57:507–11.10.1016/j.transci.2018.04.001Search in Google Scholar PubMed
136. Lee EY, Kim SJ, Song YJ, Choi SJ, Song J. Immature platelet fraction in diabetes mellitus and metabolic syndrome. Thromb Res 2013;132:692–5.10.1016/j.thromres.2013.09.035Search in Google Scholar PubMed
137. Bernstein U, Kaiser T, Stepan H, Jank A. The immature platelet fraction in hypertensive disease during pregnancy. Arch Gynecol Obstet 2019;299:1537–43.10.1007/s00404-019-05102-2Search in Google Scholar PubMed
138. Moraes D, Munhoz TP, Pinheiro da Costa BE, Hentschke MR, Sontag F, Silveira Lucas L, et al. Immature platelet fraction in hypertensive pregnancy. Platelets 2016;27:333–7.10.3109/09537104.2015.1101060Search in Google Scholar PubMed
139. Everett TR, Garner SF, Lees CC, Goodall AH. Immature platelet fraction analysis demonstrates a difference in thrombopoiesis between normotensive and preeclamptic pregnancies. Thromb Haemost 2014;111:1177–9.10.1160/TH13-09-0746Search in Google Scholar PubMed
140. Rauber P, Lammert F, Grotemeyer K, Appenrodt B. Immature platelet fraction and thrombopoietin in patients with liver cirrhosis: a cohort study. PLoS One 2018;13:e0192271.10.1371/journal.pone.0192271Search in Google Scholar PubMed PubMed Central
141. Dadu T, Sehgal K, Joshi M, Khodaiji S. Evaluation of the immature platelet fraction as an indicator of platelet recovery in dengue patients. Int J Lab Hematol 2014;36:499–504.10.1111/ijlh.12177Search in Google Scholar PubMed
142. Hedley BD, Llewellyn-Smith N, Lang S, Hsia CC, MacNamara N, Rosenfeld D, et al. Combined accurate platelet enumeration and reticulated platelet determination by flow cytometry. Cytometry B Clin Cytom 2015;88:330–7.10.1002/cyto.b.21245Search in Google Scholar PubMed
143. Machin SJ. Development of a consensus standard reference method for immature platelets. Int J Lab Hematol 2013;35:26.Search in Google Scholar
©2020 Stefan W. Krause et al., published by De Gruyter, Berlin/Boston
This work is licensed under the Creative Commons Attribution 4.0 International License.
