Red Cell Volume Distribution Width as Another Biomarker

Login or register to view PDF.
Creative Commons Licence
 
Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Artemio García-Escobar, Cardiology Service, Severo Ochoa Hospital, Avenue of Orellana without number, 28911, Leganes, Madrid, Spain. E: dr_garciaescobar@hotmail.com
Received date
16 September 2019
Accepted date
16 September 2019
DOI
https://doi.org/10.15420/cfr.2019.13.1
Open access
This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

To the Editor,

We congratulate Nadar and Shaikh for their excellent review of the use of biomarkers in heart failure (HF), as well as the new biomarkers currently under investigation.1

Red blood cell distribution width (RDW) is a measure of the heterogeneity of distribution of red blood cell size. A high RDW implies a large variation in red blood cell (RBC) size (anisocytosis) and a low RDW implies a more homogeneous population of RBC sizes. RDW is routinely assessed as part of complete blood count and is calculated as RDW = (standard deviation/MCV) × 100, with reference values approximately 11–15%.2 RDW in combination with mean corpuscular volume (MCV) has been used for the classification of anaemias.3 RDW elevation is associated with conditions of impaired haematopoiesis, such as nutritional deficiencies (iron, folate, vitamin B12), some haemoglobinopathies, myelodysplastic syndrome, myelophthisic anaemia (e.g. neoplastic metastases to bone marrow) and liver impairment, as well as in conditions of increased red cell destruction, such as haemolysis, or when different populations of RBC are present, such as after blood transfusion.4

In recent years, many community cohort studies have shown that an increment in RDW is associated with all-cause mortality. The UK Biobank study (n=503,325; HR 3.10, 95% CI [2.57–3.74])5 and the National Health and Nutrition Examination Survey (n=8175) showed that for every 1% increment in RDW, all-cause mortality risk increased by 22% (HR 1.2, 95% CI [1.15–1.30], p<0.001), and that even in non-anaemic participants it remained associated with mortality.6 In addition, patients with high RDW are 1.8 times more likely to develop adverse events after cardiac surgery (OR 0.55, 95% CI [0.365–0.852], p=0.007).7 In another cohort (n=16,631), after non-cardiac surgery, the area under the curve was 0.761 (95% CI [0.736–0.787]) using a cut-off value of RDW 15.7% with a specificity of 89.3% and a negative predictive value of 99% for predicting 30-day mortality.8 In contrast, in another cohort (n=217,567) RDW >14% was associated with metabolic syndrome (OR 1.14; 95% CI [1.07–1.21]; p<0.0001).9

High RDW is an independent predictor for the development of anaemia during hospitalisation due to acute MI in patients without previous anaemia.10 Moreover, RDW >14.9% is associated with increased major bleeding risk (HR 2.41, 95% [CI 1.15–5.02], p=0.02) in non-ST-segment elevation MI (NSTEMI). The addition of RDW to the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) bleeding score had a significant integrated reclassification improvement of 10% (95% CI [6–19]; p=0.02).11 Similarly, another study showed that RDW was a predictor of major bleeding and that with the addition of RDW as a continuous variable to the National Cardiovascular Data Registry risk model, net reclassification improvement increased by 17.3% (95% CI [6.7–28]; p=0.02).12

In the Cholesterol and Recurrent Events (CARE) study of patients with hyperlipidaemia and history of MI, baseline RDW was associated with increased risk of all-cause death per percent increase in RDW, and RDW in the highest quartile was associated with MI, stroke and HF.13 In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program (n=2,679) RDW was associated with morbidity and mortality (HR 1.17 per 1 SD increase, p<0.001) and in the Duke Databank (n=2,140) RDW was associated with all-cause mortality (HR 1.47 per 1-SD, p<0.001) in patients with advanced heart failure.14

Secondary analysis from the Justification for the Use of Statins in Prevention (JUPITER) trial revealed that RDW was associated with all-cause mortality.15 In the United Investigators to Evaluate Heart Failure (UNITE-HF) registry, elevated troponin T was an independent predictor for all-cause mortality and hospitalisation for HF, and detectable troponin T was directly and independently related to increasing RDW.16

In the Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department (PRIDE) registry, in patients with complaints of dyspnoea to the emergency department, RDW was independently associated with haemoglobin, use of loop diuretics and beta-blockers on presentation but not with nutritional deficiencies; in a multivariable analysis, RDW was a significant independent predictor of 1-year mortality and haemoglobin was not.17 In patients with acute HF, those with high RDW received loop diuretics and oral anticoagulation more often, and high RDW was associated with increased all-cause mortality in patients with preserved left ventricular ejection fraction (LVEF).18 In patients with acute HF, baseline RDW level was associated with a higher risk of death in long-term follow-up regardless of haemoglobin levels and anaemia status.19

Studies Related to Red Cell Volume Distribution Width and its Association

Open in new tab
Open ppt

In a study of patients with systolic HF, researchers analysed biomarkers of ineffective erythropoiesis, inflammation and undernutrition.20 Patients with >15.2% RDW had low levels of iron, transferrin saturation, prealbumin, albumin, total cholesterol and estimated glomerular filtration rate, and high levels of soluble transferrin receptor, erythropoietin, interleukin-6 (IL-6), tumour necrosis factor-alpha receptor (TNF-R) I and TNF-R II, increased RDW was a predictor of all-cause mortality. The correlations between high RDW with inflammation, ineffective erythropoiesis, undernutrition and impaired renal function support the understanding of why high RDW is associated with adverse outcomes in HF.20 The Study of Anemia in a Heart Failure Population (STAMINA-HFP) showed high RDW was predictive of mortality and hospitalisation. In addition, increasing RDW correlated with decreasing haemoglobin, increasing IL-6 and impaired iron mobilisation.21

In contrast, RDW is a parameter with a sensitivity of 94% for iron deficiency, and an RDW value within the reference interval can be used to exclude iron deficiency in cases in which the serum ferritin concentration does not accurately reflect the iron stores owing to severe tissue damage, as in inflammation or malignancy.22 In the Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) study, a subanalysis revealed that high RDW was associated with decreased transferrin saturation and increased C-reactive protein, and that treatment with IV ferric carboxymaltose in iron-deficient chronic HF patients decreased RDW (Table 1).23

Belonje et al. showed that in patients hospitalised for HF, those with higher erythropoietin levels at baseline were independently related to increased mortality at 18 months (HR 2.06, 95% CI [1.4–3.04]; p<0.01).24 Ycas et al. showed that the largest changes in RDW (change in RDW >2%) were observed after following diagnoses of acute renal failure, septicaemia, acute post-haemorrhagic anaemia, pulmonary insufficiency and pleural effusion, suggesting that RDW is a biomarker of ineffective erythropoiesis and possibly hypoxaemia.25 Hypoxia affects the regulation of erythropoiesis; hypoxia-induced factor-1-alpha may enhance or replace the effect of glucocorticoids on burst-forming unit-erythroid self-renewal and production of colony-forming unit-erythroid and the erythroblasts are enhanced approximately 170-fold.26

RDW is a parameter included in routine full blood count. It is feasible, quick and easy to obtain at the bedside, and is becoming a handy prognostic marker in patients with HF, indicating the advance of ineffective erythropoiesis, impaired ability to utilise available iron, inflammation and hypoxia. The European Society of Cardiology HF guidelines suggest the use of IV ferric carboxymaltose for patients with iron deficiency (serum ferritin <100 µg/l or ferritin 100–299 µg/l and transferrin saturation <20%) with an indication IIa-A.27 RDW could also be used as a marker of response to iron substitution in patients with HF.

References
  1. Nadar SK, Shaikh MM. Biomarkers in routine heart failure clinical care. Card Fail Rev 2019;5:50–6.
    Crossref | PubMed
  2. Evans TC, Jehle D. The red blood cell distribution width. J Emerg Med 1991;9(Suppl 1):71–4.
    PubMed
  3. Bessman JD, Gilmer PR Jr, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 1983;80:322–6.
    Crossref | PubMed
  4. Ford J. Red blood cell morphology. Int J Lab Hematol 2013;35:351–7.
    Crossref | PubMed
  5. Pilling LC, Atkins JL, Kuchel GA, et al. Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years. PLos One 2018;13:e0203504.
    Crossref | PubMed
  6. Patel KV, Ferrucci L, Ershler WB, et al. Red blood cell distribution width and the risk of death in middle-aged and older adults. Arch Intern Med 2009;169:515–23.
    Crossref | PubMed
  7. Aydınlı B, Demir A, Güçlü CY, et al. Hematological predictors and clinical outcomes in cardiac surgery. J Anesth 2016;30:770–8.
    Crossref | PubMed
  8. Abdullah HR, Sim YE, Sim YT, et al. Preoperative red cell distribution width and 30-day mortality in older patients undergoing non-cardiac surgery: a retrospective cohort observational study. Sci Rep 2018;8:6226.
    Crossref | PubMed
  9. Sanchez-Chaparro MA, Calvo-Bonacho E, Gonzalez-Quintela A, et al. Higher red blood cell distribution width is associated with the metabolic syndrome: results of the Ibermutuamur Cardiovascular RIsk assessment study. Diabetes Care 2010;33:e40.
    Crossref | PubMed
  10. Salisbury AC, Amin AP, Reid KJ, et al. Red blood cell indices and development of hospital-acquired anemia during acute myocardial infarction. Am J Cardiol 2012;109:1104–10.
    Crossref | PubMed
  11. Sánchez-Martínez M, López-Cuenca A, Marín F, et al. Red cell distribution width and additive risk prediction for major bleeding in non-ST-segment elevation acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2014;67:830–6.
    Crossref | PubMed
  12. Fatemi O, Torguson R, Chen F, et al. Red cell distribution width as a bleeding predictor after percutaneous coronary intervention. Am Heart J 2013;166:104–9.
    Crossref | PubMed
  13. Tonelli M, Sacks F, Arnold M, et al. Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease. Circulation 2008;117:163–8.
    Crossref | PubMed
  14. Felker GM, Allen LA, Pocock SJ, et al. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM program and the Duke Databank. J Am Coll Cardiol 2007;50:40–7.
    Crossref | PubMed
  15. Horne BD, Anderson JL, Muhlestein JB, et al. Complete blood count risk score and its components, including RDW, are associated with mortality in the Jupiter trial. Eur J Prev Cardiol 2015;22:519–26.
    Crossref | PubMed
  16. Adams KF Jr, Mehra MR, Oren RM, et al. Prospective evaluation of the association between cardiac troponin T and markers of disturbed erythropoiesis in patients with heart failure. Am Heart J 2010;160:1142–8.
    Crossref | PubMed
  17. Van Kimmenade RR, Mohammed AA, Uthamalingam S, et al. Red blood cell distribution width and 1-year mortality in acute heart failure. Eur J Heart Fail 2010;12:129–36.
    Crossref | PubMed
  18. Sotiropoulos K, Yerly P, Monney P, et al. Red cell distribution width and mortality in acute heart failure patients with preserved and reduced ejection fraction. ESC Heart Fail 2016;3:198–204.
    Crossref | PubMed
  19. Pascual-Figal DA, Bonaque JC, Redondo B, et al. Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients. Eur J Heart Fail 2009;11:840–6.
    Crossref | PubMed
  20. Förhécz Z, Gombos T, Borgulya G, et al. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009;158:659–66.
    Crossref | PubMed
  21. Allen LA, Felker GM, Mehra MR, et al. Validation and potential mechanisms of red cell distribution width as a pronostic marker in heart failure. J Card Fail 2010;16:230–8.
    Crossref | PubMed
  22. Van Zeben D, Bieger R, Van Wermeskerken RK, et al. Evaluation of microcytosis using serum ferritin and red blood cell distribution width. Eur J Haematol 1990;44:106–9.
    PubMed
  23. Van Craenenbroaeck EM, Conraads VM, Greenlaw N, et al. The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study. Eur J Heart Fail 2013;15:756–62.
    Crossref | PubMed
  24. Belonje AM, Voors AA, Van Der Meer P, et al. Endogenous erythropoietin and outcome in heart failure. Circulation 2010;121:245–51.
    Crossref | PubMed
  25. Ycas JW, Horrow JC, Horne BD. Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia? Clin Chim Acta 2015;448:107–17.
    Crossref | PubMed
  26. Hattangadi SM, Wong P, Zhang L, et al. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 2011;118:6258–68.
    Crossref | PubMed
  27. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2129–2200.
    Crossref | PubMed