Baseline Mean Corpuscular Volume Research Articles

MO673: Association of Mean Corpuscular Volume with Mortality in Kidney Failure Patients: Opposite Findings in Chinese and Swedish Kidney Failure Patients

Abstract BACKGROUND AND AIMS Higher mean corpuscular volume (MCV), a measure of the average size of the circulating erythrocyte used for differential diagnosis of anemia or for monitoring macrocytosis, is associated with higher mortality in various clinical settings including in patients (pts) with kidney failure; however, results are not consistent and a study from Japan (Honda et al. Low rather than high mean corpuscular volume is associated with mortality in Japanese patients under hemodialysis. Sci Rep. 2020; 10(1): 15 663) found that low MCV associated with mortality in 8571 hemodialysis pts (mean age 62.5 ± 12.7 years, 37.2% female, median MCV 96.1 fL) pts. We investigated the relationship between MCV with all-cause and cardiovascular mortality in two cohorts of kidney failure pts from China and Sweden. METHOD In 731 incident Chinese peritoneal dialysis pts (median age 50 years, 57% males) and 404 Swedish kidney failure pts (median age 56 years, 62% males), baseline MCV and other biochemical and metabolic biomarkers were analysed in relation to mortality during follow-up period of up to 5 years. All-cause and cardiovascular disease (CVD) mortality risk were analysed with competing-risk regression models with transplantation as competing risk adjusting for age, sex, smoking, diabetes, serum albumin, hemoglobulin and calendar year. RESULTS Chinese pts were significantly younger (P < 0.01) and had lower body mass index (P < 0.01) and Framingham risk score (P < 0.01) than Swedish pts while gender distribution was similar. In univariate analysis, MCV was associated with body mass index (P < 0.01) and mean arterial blood pressure (P < 0.01) in both cohorts. ‘Chinese pts’: During median 3.6 years of follow-up, all-cause mortality rate was 16%, and 52 (46%) of 111 deaths were caused by CVD. Low MCV (<94 fL) was associated with significantly higher all-cause [Fig. 1A; sub-hazard ratio, sHR (95% CI) 2.15 (1.14–4.06)] but not CVD mortality (Fig. 2A) when adjusting for all confounders. ‘Swedish pts’: During median 2.1 years of follow-up, all-cause mortality rate was 30%, and 53 (44%) of the 120 deaths were caused by CVD. In contrast to the Chinese cohort, pts low MCV (<94 fL) was associated with lower both all-cause [Fig. 1B; sHR 0.62 (0.39–0.97)] and CVD mortality [Fig. 2B; sHR 0.49 (0.26–0.94)] when adjusting for all confounders. CONCLUSION In Chinese kidney failure pts low MCV was associated with higher all-cause mortality risk while in Swedish kidney failure pts low MCV was associated with pts lower all-cause and CVD mortality risk, independently of all confounders. Further studies are needed to explore if this difference may reflect regional differences in factors affecting MCV.

First Report of Reversible Macrocytic Anemia with Dysplastic Features Associated with Palbociclib Use in Patients with Metastatic Breast Cancer

Palbociclib is a reversible cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor that is approved for the treatment of hormone-receptor positive metastatic breast cancer (ER+/HER2- MBC). CDK4/6 inhibitors exert their anti-tumor effect by preventing the G1 to S phase cell cycle transition, resulting in G1 cell cycle arrest. The most commonly reported hematologic side effect of palbociclib is neutropenia. Here we report 3 cases of reversible macrocytic anemia with dysplastic changes as a result of palbociclib use. Next, we present a retrospective study of 32 patients treated with palbociclib. Finally, CDK4 and CDK6 levels were measured in CD34+ stem/progenitor cells (HSPC) from myelodysplastic syndrome (MDS) patients and compared to healthy controls.Methods & ResultsFour months into starting treatment with palbociclib plus an aromatase inhibitor for refractory ER+/HER2- MBC, 3 female patients developed macrocytic anemia, with a mean corpuscular volume (MCV) of >100 femtoliters per cell (fL) and a decrease in hemoglobin (Hb) by 2 grams per deciliter (g/dL). Work-up for macrocytosis was unrevealing except for peripheral blood smears showing dysplastic changes including pseudo-Pelger-Huёt anomaly, suggestive of MDS (see Figure (Fig) 1). Bone marrow aspirates were obtained, which also showed morphology similar to MDS including hypocellular marrow (10% cellularity), dysplastic erythroid forms including binucleated forms and nuclear budding, and small hypolobated megakaryocytes (see Fig 2). Cytogenetic, molecular, and flow analyses were normal. Patients were managed expectantly, and when palbociclib was discontinued for breast cancer progression, the macrocytic anemia resolved to baseline Hb and MCV values within 4 months of stopping therapy.A retrospective study to assess hematological characteristics of 32 patients with ER+/HER2- MBC treated with palbociclib for more than 3 months between 1/1/2015 to 3/1/2017 was performed. Statistical analysis included Wilcoxon signed-rank test and Kaplan Meier estimator. Median age was 65 years and 10 (31%) patients had received prior chemotherapy (see Table 1). Median baseline MCV was 89.75 fL compared to 100.5 fL post palbociclib (p <0.0001), and 16 (52%) patients developed macrocytosis (MCV >100 fL). The median progression-free-survival (PFS) for patients who developed a significant MCV increase (highest MCV >10 fL from baseline MCV) was 422 days compared to 216 days for those without a significant MCV increase (highest MCV ≤10 fL from baseline MCV) (HR 0.29, p=0.035). However, this PFS difference was not seen when the change in MCV was analyzed as a time-dependent variable.As palbociclib treatment appears to induce hematologic and bone marrow changes phenotypically similar to MDS, we examined whether alterations in CDK4/6 expression is observed in human MDS. We evaluated CDK4 and CDK6 expression by qRT-PCR in 183 samples from MDS patient-derived HSPC and 17 healthy marrow control HSPC and found that CDK6, but not CDK4, expression was significantly decreased in MDS HSPC when compared to healthy HSPC (p=0.04) (see Fig 3). We then evaluated MDS phenotype by high (>median) and low (≤median) CDK6 expression, and found that patients with low CDK6 expression had a 1 g/dL lower Hb at presentation when compared to those with high CDK6 expression (p=0.001). Further, when healthy marrow HSPC were treated with palbociclib in vitro, we observed a dose dependent decrease in erythroid colony formation and maturation, replicating the anemia phenotype seen in patients.In conclusion, palbociclib treatment can cause a reversible macrocytic and dysplastic anemia. Macrocytosis is a potential indicator of in vivo CDK4/6 inhibition that could be associated with increased PFS in patients with ER+/HER2- MBC who are treated with palbociclib. Low CDK6 expression in MDS correlates with a worsened anemia phenotype. Further clinical studies with larger sample sizes are needed. Continued safety monitoring of patients on palbociclib is suggested. [Display omitted] DisclosuresSteidl:Aileron Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Bayer Healthcare: Consultancy.

Low rather than high mean corpuscular volume is associated with mortality in Japanese patients under hemodialysis

Recent studies have reported that high mean corpuscular volume (MCV) might be associated with mortality in patients with advanced chronic kidney disease (CKD). However, the question of whether a high MCV confers a risk for mortality in Japanese patients remains unclear. We conducted a longitudinal analysis of a cohort of 8571 patients using data derived from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phases 1 to 5. Associations of all-cause mortality, vascular events, and hospitalization due to infection with baseline MCV were examined via Cox proportional hazard models. Non-linear relationships between MCV and these outcomes were examined using restricted cubic spline analyses. Associations between time-varying MCV and these outcomes were also examined as sensitivity analyses. Cox proportional hazard models showed a significant association of low MCV (< 90 fL), but not for high MCV (102 < fL), with a higher incidence of all-cause mortality and hospitalization due to infection compared with 94 ≤ MCV < 98 fL (reference). Cubic spline analysis indicated a graphically U-shaped association between baseline MCV and all-cause mortality (p for non-linearity p < 0.001). In conclusion, a low rather than high MCV might be associated with increased risk for all-cause mortality and hospitalization due to infection among Japanese patients on hemodialysis.

PS1569 COMMON SINGLE NUCLEOTIDE POLYMORPHISM OF TMPRSS6 DETERMINES VARIATION OF RED BLOOD CELL INDICES FOUND IN HETEROZYGOUS ALPHA‐THALASSEMIA

Background:Globally, many screening programs for severe thalassemia (thal) syndromes use red blood cell (RBC) indices; mean corpuscular volume (MCV) &lt;80 fl and/or mean corpuscular hemoglobin (MCH) &lt;25 pg as cut‐off to identify thal disease and carriers. These criterion seem to be sensitive for individual with α°‐thal by two α‐globin gene deletions (‐‐/αα) and β‐thal traits. However this approach cannot be used for confidential identification α+‐thal trait (‐α/αα) due to a wide variation of baseline MCV and MCH. Recently, a single nucleotide polymorphism (SNP) of an iron regulation gene; tmprss6 involved in substitution a nucleotide between thymine (T) and cytosine (C) in exon 17 resulted to amino acid change from valine to alanine (V736A) has been described to associate with RBC indices. However its role on thalassemic RBC remains largely unknown.Aims:To determine the effects of common SNP rs855791 of tmprss6 on RBC indices variation in deletional α‐thal carriersMethods:EDTA whole blood samples were collected from Thai healthy volunteers in cohort and measured complete blood count, RBC indices, hemoglobin typing and comprehensive molecular analysis panel covered &gt; 98% of common globin mutations (α‐thal, β‐thal, Hb E) found in Thailand. SNP rs855791 genotypes of tmprss6 were analyzed by PCR‐RFLP with StuI restriction enzyme. Statistical analysis for average (mean), standard deviation (SD) and comparisons was performed by using PASW Statistics 18. The significant difference was determined by p ≤ 0.05.Results:Total 433 cases (age: 23.0 ± 8.7 years old, male: N = 141 (32.6%), female: N = 292 (67.4%)) of normal β‐globin gene (ββ) included three genotypes of α‐globin gene; normal (αα/αα) (N = 357, 82.4%), ‐α/αα (N = 61, 14.1%), and ‐‐/αα (N = 15, 3.5%) (Table 1). The allele frequency of SNP rs855791 of Thai population showed T:C as 0.6 to 0.4 that similar to other Asian population and consistent across different globin genotypes (Table2). The MCV and MCH ranges of two α‐globin genotypes; αα/αα and ‐α/αα showed an overlapping feature. Interestingly, we found no effect of either C or T polymorphism on RBC indices mainly MCV and MCH in individuals with normal globin genes. However the effects of SNP rs855791 genotypes on MCV and MCH were demonstrated in α‐thal traits. Increased MCV and MCH gradually expressed by SNP genotype C/C &gt; C/T &gt; T/T both in α+‐ and α°‐thal trait (Figure 1 and 2). Comparing the level of serum ferritin among different tmprss6 genotypes; the C/C seemed to have higher iron status followed by C/T and T/T, however there was no statistical significance (data not shown). Therefore this epistatic effect of tmprss6 on determining RBC indices in α‐thal carriers may operate through other mechanism.Summary/Conclusion:For the first time, we have identified that tmprss6 polymorphism can determine RBC size and hemoglobinization in carrier of α‐thal. The genetic mechanism of tmprss6 involved in the determination RBC indices in α‐thal mutations would be further studied.image

Mean Corpuscular Volume and Mortality in Incident Hemodialysis Patients

Background/Aims: Anemia is common in patients with advanced chronic kidney disease (CKD). A proportion of patients present with macrocytic anemia, manifested by elevated mean corpuscular volume (MCV), which has been associated with worse outcomes in CKD patients. However, it is unknown whether elevated MCV is associated with higher mortality risk in incident hemodialysis (HD) patients. Methods: This retrospective observational cohort study examined all-cause, cardiovascular, and infectious mortality associations with both baseline and time-varying MCV in 109,501 incident HD patients using Cox proportional hazards models with 3 levels of hierarchical multivariable adjustment. Odds ratios of high versus low baseline MCV were evaluated using logistic regression. Results: The mean age of patients was 65 ± 15 (standard deviation) years and the cohort was 44% female, 58% diabetic, and 31% African American. Higher MCV was associated with older age, female sex, non-Hispanic White race-ethnicity, alcohol consumption, and having a decreased albumin or protein intake. Patients with higher MCV levels (> 98 fL) had a higher all-cause, cardiovascular, and infectious mortality risk in both baseline and time varying models, and across all levels of adjustment. In the fully adjusted models, compared to a reference of MCV 92–< 94 fL, patients with a baseline MCV > 100+ fL had a 28% higher risk of all-cause mortality (hazard ratio [HR] 1.28, 95% CI 1.22–1.34), 27% higher risk of cardiovascular mortality (HR 1.27, 95% CI 1.18–1.36), and 18% higher risk of infectious mortality (HR 1.18, 95% CI 1.02–1.38). Associations of higher MCV with these adverse outcomes persisted across all examined subgroups of clinical characteristics. Conclusions: Higher MCV was associated with higher all-cause, cardiovascular, and infectious mortality in HD patients. Further investigation is necessary to understand the underlying nature of the observed association.

Gradient Relationship between Increased Mean Corpuscular Volume and Mortality Associated with Cerebral Ischemic Stroke and Ischemic Heart Disease: A Longitudinal Study on 66,294 Taiwanese

The gradient relationship between mean corpuscular volume (MCV) and mortality due to ischemic vascular disease has not been researched using a large-scale population-based study. This study evaluated the association between MCV and death attributable to cerebrovascular disease (CVD) and cardiovascular disease (CAD) in a large population- and community-based Taiwanese cohort. A longitudinal study with a 9-year follow-up was conducted to evaluate individuals aged 20 years or older who had participated in the Keelung (the northernmost city in Taiwan) community-based integrated screening (abbreviated as KCIS) program since September 1999. The mortality rates associated with CVD and CAD were classified across a range of different MCV levels. Increased MCV levels were associated with an increased risk of CVD/CAD-related death (adjusted hazard ratio [aHR] = 1.42, trend test P = 0.0119). Marginally statistically significant associations were noted for specific deaths from ischemic heart disease (aHR = 1.44, trend test P = 0.0992) and cerebral ischemic stroke (aHR = 1.66, trend test P = 0.0667), respectively, but no significant gradient relationship was noted for death from cerebral hemorrhage stroke (aHR = 1.23, trend test, P = 0.6278). A gradient relationship between baseline MCV level and CVD/CAD-related death was noted, but whether such gradient relationships existed for two specific deaths and how these relationships may be confounded by extraneous factors that were not considered here should be investigated in the future.

Biochemical and Haematological Predictors of Reduced Neutrophil Granulocyte Count associated with Intravenous Ceftriaxone Treatment.

Background: Intravenous treatment with ceftriaxone, a commonly used third-generation cephalosporin, is associated with a risk of the potentially fatal side-effect of neutropenia.Objective: The first systematic study to determine whether six to 12 days’ intravenous ceftriaxone treat-ment is associated with a reduction in the neutrophil count and the extent to which biochemical and/or haematological parameters routinely measured at baseline predict such a fall.Method: Baseline and follow-up haematological and biochemical blood indices were measured in 86 pa-tients (mean age 39.4 years; 55 female) receiving 2 g intravenous ceftriaxone daily.Results: At follow-up, the mean (standard error) neutrophil count had fallen from 3.93 × 109 (0.16 × 109) L-1 to 3.15 × 109 (0.15 × 109) L-1 (p < 0.000001). This reduction was predictable according to the following multifactor linear regression model: (baseline neutrophil count (× 109 L-1)) – (follow-up neu-trophil count (× 109 L-1)) = 76 + 159.2(baseline haematocrit) – 14.5(baseline red blood cell count (× 1012 L-1)) – 0.724(baseline mean corpuscular volume (fL)) + 0.474(baseline neutrophil count (× 109 L-1)) + 0.0448(baseline total iron binding capacity (μM)) + 7.15(baseline calcium ion concentration (mM)) – 13.2(baseline corrected calcium ion concentration (mM)) + 0.0166(baseline alkaline phosphatase (IU L-1)). The residuals were normally distributed and model testing by random partition of the original data into two parts, with training of the model using the first part and model testing with the second part, gave highly satisfactory results.Conclusion: Intravenous ceftriaxone treatment is associated with a fall in neutrophils, which can be pre-dicted by routine baseline blood indices

The effects of blood transfusion on red blood cell distribution width in critically ill patients: a pilot study.

Red blood cell distribution width (RDW) is a measure of anisocytosis, generally used in the differential diagnosis of anemia. Recently, RDW was associated with increased mortality in critically ill patients. Red blood cell (RBC) transfusions are potential confounders on RDW values interpretation. The aim of this study was to analyze the changes in RDW after RBC transfusion in intensive care unit (ICU) patients. This was a prospective, observational study including patients admitted to ICU requiring 1 RBC unit. We analyzed RDW values of the patients at four study points: before RBC transfusion (T1), immediately after transfusion (T2), 24hours after transfusion (T3), and 48 hours after transfusion (T4). We also collected laboratory data from donors and RBC units. Changes of RDW (ΔRDW) were computed as the difference between baseline RDW value and RDW at each time point after transfusion. We enrolled 36 patients. RDW values increased after transfusion (p<0.001 at all points vs. baseline), with the highest level at T3. At T3, 34 of 36 patients (94%) had an abnormal RDW value (vs. 26/36, 72%) at baseline (p=0.023). The maximum ΔRDW for each patient was moderately correlated with the difference between mean corpuscular volume (MCV)donors and MCVpatient (r=0.478, p=0.005). Subgroups analysis showed that the maximum ΔRDW was greater in patients with baseline MCV lower than 80 fL or higher than 100 fL (n=7) or baseline RDW of more than 14.5% (n=19). RBC transfusion significantly increased RDW values. This intervention should be accurately reported in the studies evaluating the prognostic role of RDW.

Hemocytometric Measures Predict the Efficacy of Oral Rehydration for Children with Postural Tachycardia Syndrome

To explore whether hemocytometric measures could be qualified predictors for the effect of oral rehydration salts (ORS) in children with postural tachycardia syndrome (POTS). Thirty-five children with POTS and 29 healthy children were enrolled. General information, hemodynamic status, and baseline hemocytometric variables were collected. Children with POTS received ORS therapy and were followed up for 3 months. The independent risk factors of developing POTS were explored. A receiver-operating characteristic curve was used to evaluate predictive value of hemocytometric variables for therapeutic effectiveness of ORS therapy. Children with POTS had larger mean corpuscular volume (MCV) and lower mean corpuscular hemoglobin concentration (MCHC) values than controls (P < .05). The baseline MCV values positively correlated with heart rate elevation from supine to upright (r = 0.294, P < .05). Both larger MCV and lower MCHC values were independent risk factors of developing POTS (for MCV, P < .05, OR 1.222; for MCHC, P < .05, OR 0.936). In children with POTS, responders to ORS had baseline lower MCV and higher MCHC than nonresponders (P < .05). The receiver-operating characteristic curve for the predictive value of MCHC showed that area under the curve was 0.73. MCHC values could be used to predict the effectiveness of ORS for treating POTS in children.

Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.

The klf10 gene could indirectly modify γ-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of β-hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in β-thalassemia major (B-TM), β-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. This cross-sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRα) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among β-hemoglobinopathies.

D43 - Capecitabine and Regorafenib-related increased mean corpuscular volume of red blood cell may be a predictive marker of treatment response and survival in patients with metastatic colorectal cancer

Background: Erythrocyte mean corpuscular volume (MCV) increase has been described in patients treated with capecitabine. Moreover, tyrosine kinase inhibitors have been shown to induce macrocytosis in patients with renal cancer cell and gastrointestinal stromal tumors, presumably via the inhibition of erythroid progenitor cells of the bone marrow. Therefore, the aim of our study was to evaluate the potential association of the erythrocyte MCV increase with tumor response and survival in patients with metastatic colorectal cancer (mCRC) treated with capecitabine and regorafenib. Patients and methods: A retrospective review of 30 patients with mCRC who were treated with capecitabine or regorafenib for at least 3 months at the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy. Complete blood count (CBC) including red blood cell indices were recorded at baseline and after 4, 8 and 12 weeks from capecitabine or regorafenib treatment. Results: Baseline MCV levels and MCV levels after 4, 8 and 12 weeks were registered for each patient treated with capecitabine or regorafenib. Median ΔMCV [(post-treatment MCV values after 12 weeks) - (baseline MCV values)] was calculated. Patients were grouped according to ΔMCV into two groups in order to carry out survival analysis and correlation with tumor response. Moreover, univariate and multivariate analysis was performed to investigate if MCV increase was independently associated with favorable survival outcomes. Conclusions: Erythrocyte MCV increase may be used as a predictive marker for treatment response, PFS and OS in patients with mCRC treated with capecitabine or regorafenib. In the future, response to TAS-102 (trifluridine-tipiracil) and MCV increase will be also evaluated.

Increased mean corpuscular volume as a predictor of response during bevacizumab treatment

Background: Remission during sunitinib (a multikinase inhibitor and antiangiogenic drug) treatment correlates with appearance of macrocytosis. There are some suggestions that bevacizumab, an antiangiogenic drug, may result in macrocytosis as well. There are no published data available on the influence of bevacizumab on macrocytosis. This paper attempted to answer the question: does bevacizumab induce macrocytosis being a predictor of the response? Methods: Between August 2008 and August 2011, 53 patients (29 male and 24 female) were treated with bevacizumab in the combination with chemotherapy at the Oncological Department, University Hospital in Krakow, Poland. Efficacy of bevacizumab was assessed on the basis of the computer tomography scans performed every 3 months within the period of 12 months. Concurrently, mean corpuscular volume (MCV) was evaluated and correlated to the response of the treatment. Results: The percentage increase of MCV compared to baseline at 3, 6, 9 and 12 months was 3.7%, 9.2%, 8.7% and 11.8% respectively. The mean value of baseline MCV was 85.3 fl. The mean value of MCV at 3, 6, 9 and 12 months was 90.5 fl, 93 fl, 91.8 fl and 93.1 fl respectively. Macrocytosis did not occur in our study but an increase of MCV was observed within bevacizumab therapy. It was closely related to the response of the treatment. It seems that an increase of MCV can be a predictive agent of bevacizumab response. Conclusion: Bevacizumab does not induce macrocytosis. Increased MCV after treatment with bevacizumab is related to the treatment response. MCV can be a predictor of the response during bevacizumab treatment. A small number of the observed patients requires further investigations.