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The RDW is an important biomarker for vascular health and inflammation.
Here is an excerpt from my upcoming book that explains the RDW biomarker in great detail.
Red Blood Cell Distribution Width (RDW)
RDW is more complicated to interpret compared to WBC because it is less specific as explain earlier in this chapter. Red cell distribution width‐coefficient of variation (RDW—CV) is a routine component of the complete blood count, automatically generated by most hematology analyzers at no extra cost. It is a very inexpensive test. RDW is a quantitative estimation of the heterogeneity of volume of red blood cells (RBCs), commonly known as anisocytosis. Elevated RDW can result from an increase in RBC volume variance and/or a reduction in mean corpuscular volume (MCV). However, the RDW value also reveals inflammation to those who understand the various ranges associated with the RDW value.
The diagnosis of anisocytosis means that your red blood cells are of mixed sizes. Normally, red blood cells should be about the same size – in the range of 11.5 – 12.5 percent. Highly elevated RDW values are classically associated with anemia. WebMD answers the question, “what is the RDW?”[i]
“RDW stands for the red blood cell distribution width. This is a standard reported measure on a complete blood count (CBC) lab test. It measures the variability in red blood cell size.
In the normal state, red blood cells are continually being produced and removed from the blood at a steady rate. The young, immature red blood cells are larger than mature red blood cells. There are predictable proportions of large and small red blood cells, which can be plotted on a graph as the normal values.
In certain forms of anemia, the RDW may be higher than normal because there are more immature or abnormal red blood cells skewing the statistical range of values.
The RDW result is nonspecific. If a doctor suspects an unusual form of anemia, there are more sophisticated tests that can make the diagnosis.”
WebMD used “the kiss of death” term for RDW – “nonspecific.” Nonspecific means the marker goes up in many conditions. In standard-of-care lingo it means doctors do not have a drug specifically made to treat elevated RDW. This creates a problem for medical providers as there is no expedient way to lower RDW. They prefer convenient diagnoses like “cholesterol” so they can quickly prescribe a pill and send you on your way, often to poorer health. Sixty percent of Americans have at least one chronic condition for a reason.
Nonspecific, however, is what chronic diseases are. Governments, societies, consensus groups, and insurance actuaries come up with categories of disease. The chapter on immunity shows that are only 5 types of white blood cells defending our health – yet there are 77,000 named diseases in the 2020 coding book ICD-10. Why do we not have 77,000 different types of immune responses? Keep in mind that in 1979, ICD-9 was established with just 14,000 diagnostic codes. Since 1979, have 63,000 new disease-fighting mechanisms been acquired by humans, or have there been 63,000 new drugs marketed? In fact, in 2022 there are over 20,000 drugs approved for marketing by the FDA. The point is, almost every chronic disease overlap in terms of immune response. Who is right, ICD-10 or immunity?
Markers that are non-specific are a blessing, especially if there are ways to improve them. Imagine lowing your RDW value and, at the same time, lower your risk for heart disease, cancer, diabetes, and Alzheimer’s. Who would be against that?
Upon careful review of the science behind the “life and times” of red blood cells, four health ranges emerge for this biomarker: low, optimal, inflammation, and anemia. The inflammation range is not considered in the standard of care and current references ranges for RDW consider the inflammatory range “normal,” Figure 7.
RDW is a profound indicator of your current health risk and future prognosis. It is an indication of vessel health. In the inflammation zone, the inflammatory marker C reactive protein (CRP) is usually elevated above the scientific normal value by approximately the same amount as the RDW. CRP is a protein made by the liver and sent into the bloodstream in response to inflammation. The test pair is quite indicative of the health of your capillaries where most of your physiological activity is occurring outside of cells, Figure 8.
Figure 8. Red blood cells traveling single-file through a capillary. The biomarker, CRP, elevates with inflammation within the vessel.
Anemia is not a deadly disease; however, mortality risk sweeps sharply up with increasing RDW, Figure 9. Figures 9A and 9B are from two completely different studies. The trend is clear that higher RDW predicts higher mortality. Since anemia is not responsible for the consistent elevation in early mortality, inflammation and associated chronic infections are the logical causes.
Figure 9A. Survival curves for mortality rates from all causes and hospital re-admission, stratified according to red blood cell distribution width quartiles among 488 patients.[ii] Rates of reaching endpoints were significantly higher among those with higher red blood cell distribution width and the data meets statistical validation criteria.
Figure 9B. Association of red blood cell distribution width (RDW) with mortality in the Third National Health and Nutrition Examination Survey (NHANES III).[iii] Rates of all-cause, cardiovascular, cancer, and chronic lower respiratory tract disease deaths increase 500% from the lowest to highest RDW quintile.
A complete blood cell count with differential includes the RDW data. However, since it is viewed as marker of anemia, doctors glance at the value to see if it is in the anemia zone. That is, it is either viewed as normal or high for anemia without regard for what this biomarker is actually conveying, which is a continuum of inflammation and risk of dying young.
A group from Beijing explain why RDW values define a continuum of risk for early mortality, at least in standard of care speak. In their paper, ”High red blood cell distribution width is closely associated with risk of carotid artery atherosclerosis in patients with hypertension,”[iv] they explain that RDW is associated with adverse cardiovascular outcomes. Elevation in RDW tracked linearly with carotid artery atherosclerotic plaque and carotid intima media thickness (IMT) to inner diameter ratio. These are measurement to determine the degree of atherosclerosis (hardening of the arteries). Not surprising, they also showed increases in white blood cell count was a significant and independent contributor to the RDW elevation. This substantiates that the process of heart disease is infectious that stimulated the inflammatory immune response.
Indeed, RDW is known within the medical research community as an indicator of a variety of chronic diseases with cardiovascular diseases leading the list. A PubMed search that includes the term “red blood cell distribution width,” in the “title only” yielded 445 articles. Many of the articles discuss the association between RDW and disease. About 42% of the articles linked abnormal RDW and cardiovascular diseases and 15% associated abnormal RDW with early mortality. Table 5 shows that this test is specific for cardiovascular disease risk and that, when RDW is abnormal, many diseases may crop up in a person. This table further illustrates the connectivity of diseases and shows that the WebMD statement that this is a test for anemia is WAY OFF BASE.
Table 5. Abnormal red blood cell distribution width and disease based on a review of 445 published articles.
Since the onset of COVID-19, 32 scientific articles on the association between RDW levels and COVID-19 outcomes have been published when using a title-only search. That constitutes 7 percent of the total number of references on RDW when using the same search strategy. RDW is a logical biomarker to measure in COVID-19. SARS‐CoV‐2 infection can cause both direct injury to the peripheral circulating RBCs or erythroblasts in bone marrow and an indirect injury to RBCs due to hemolytic anemia or intravascular coagulopathy, and disturbances in iron metabolism.
The spike protein has been shown to physically damage cells, specifically red blood cells, leading to elevation of the d dimer clotting biomarker. Elevated RDW for COVID-19 patients admitted to a hospital portended higher mortality. In a report of 622 hospitalized individuals, death rates jumped 100 percent when RDW was >14.5 compared to those with lower RDW values.[v]
Clearly, if the study looked at three ranges including a range of <12.5, rather than just two ranges, the mortality trends most likely would have trended as illustrated in Figure 9. In the article, the author state, “Of the 97 patients with a fatal outcome, 53% (51/97) had an elevated RDW on admission and 47% (46/97) had a normal RDW (P < .001).” This data substantiates that the RDW value of >14.5, as a starting point for a group, is already well above a true scientific normal value. When comparing groups above and below 14.5, but both levels include people well into the inflammation zone. The cohorts overlap. Another way to view this - were the 47% in the low (presumed normal) group at some type of special risk not explained by the RDW value or is the normal range wrong? Further evidence for the need to view biomarkers on a continuum rather than in groups encompassing broad ranges of a biomarker.
But the madness continues. In a trial including 1641 patients with COVID‐19, RDW was associated with increased mortality risk of, again, 100 percent.[vi] Two RDW ranges, >14.5% versus ≤14.5% were used. In a group of 294 hospitalized COVID‐19 patients, RDW was associated with increased mortality of 450% after adjustment for age, anemia, and co‐morbidities. In this analysis, two RDW ranges were used, ≤14.6% versus >14.6%.[vii]
Another fairly obvious problem emerges when using a non-science-based “normal” values to compare to abnormal values in research studies. When the true normal value for RDW is not known or appreciated, then studies wind up comparing sick people to other sick people rather than sick to healthy people. The data, therefore, is not representative of actual risk. In most cases, studies will present much lower risks for the elevation of the biomarker because of this important error.
To support the assertion that the RDW biomarker predicts early mortality, here is a summary from a couple of key published studies:
A Harvard Medical School and Harvard School of Public Health team published, "Red blood cell distribution width and mortality risk in a community-based prospective cohort." [viii] Their conclusion is simple (sort of):
“Higher RDW was associated with increased mortality risk in this large, community-based sample, an association not specific to CVD. Study of anisocytosis may therefore yield novel pathophysiological insights, and measurement of RDW may contribute to risk assessment.”
They also state:
“The highest quintile of RDW, compared with the lowest, was significantly associated with 134% increased risk of cardiovascular mortality after multivariable adjustment” and
“The highest quintile of RDW, compared with the lowest, was significantly associated with an 88% increased risk of death due to cancer.”
It is interesting but not unusual to see one biomarker, in this case RDW, associated with both cancer and cardiovascular disease. This type of clear correlation hints at the possibility that the causes of these two diseases may overlap.
Red blood cells do not form into “abnormal” sizes without a reason.  What could the cause(s) of this abnormality be? Well, both cancer and cardiovascular diseases are chronic diseases. And we started this book by saying inflammation is at (or, more correctly, close to) the root of all chronic diseases. It should be of no surprise that the Harvard team found “a possible role for inflammation.” Here is what Harvard had to say:
“We hypothesized that the association of RDW with mortality risk may be due to underlying inflammation, as inflammation is increasingly appreciated to contribute to the pathogenesis of chronic disease. Our data support an association of anisocytosis with inflammation, and suggest that the association of RDW with mortality risk may in part be due to an effect of inflammation on both anisocytosis and risk. We did not find that the association of RDW with mortality risk is entirely dependent upon inflammation, as the risk associated with RDW was not significantly diminished in participants with a low CRP level compared with those with a high CRP level.”
The Harvard group is making a slight misinterpretation on their measurement of inflammation. Measuring CRP is a very good way to measure inflammation, but it is not the only way. CRP is really a measure of vascular inflammation specifically. White blood cell counts and a variety of other parameters should be included in a complete evaluation of inflammation.
Three important lessons are learned from this elegant study:
1. Abnormal RDW is a strong predictor of future serious deadly chronic disease.
2. Inflammation is connected with chronic disease and with abnormal RDW.
3. The correlation in 2. above is not absolute thus, no single test, either CRP or RDW are definitively predictive as stand-alone tests.
You can help expand us help you gain access to better testing. Do this by creating “pull through” marketing. If enough educated people ask for appropriate tests, maybe healthcare will do the right thing by our children, if not us, and make tests and interpretations like this more available. But you have to ask. You have to become involved.
Harvard Medical School does not hold exclusive knowledge on the RDW, disease, and death connection. What follows is a short list or research titles on this topic and includes their affiliations:
“Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.”[ix] Duke Clinical Research Institute, Durham, North Carolina; London School of Hygiene and Tropical Medicine, London, United Kingdom; University of Glasgow, Glasgow, United Kingdom; Brigham and Women’s Hospital, Boston, Massachusetts; McMaster University, Hamilton, Ontario, Canada; AstraZeneca LP, Wilmington, Delaware.
“Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People with Coronary Disease.”[x] Department of Medicine, Division of Nephrology, University of Alberta, Alberta, Edmonton, Canada; Harvard School of Public Health, Boston, Mass; London Health Sciences Center, London, UK; University of Texas School of Public Health, Austin; and Brigham and Women’s Hospital, Boston, Mass.
“Red cell distribution width and mortality in predominantly African-American population with decompensated heart failure.”[xi] Detroit Medical Center at Wayne State University, Detroit, MI.
“Red blood cell distribution width and the risk of cardiovascular morbidity and all-cause mortality: a population-based study.”[xii] Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Medical division, Maccabi Healthcare Services, Tel Aviv, Israel.
“Red Blood Cell Distribution Width and Risk of Cardiovascular Events and Mortality in a Community Cohort in Taiwan.”[xiii] Prof. Yuan-Teh Lee, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung Shan South Road, Taipei 100, Taiwan.
“Increased Red Blood Cell Distribution Width Associates with Cancer Stage and Prognosis in Patients with Lung Cancer.”[xiv] Respiratory Center, Shinko Hospital, Kobe-city, Hyogo, Japan.
“Red cell distribution width: an inexpensive and powerful prognostic marker in heart failure.”[xv] Department of Cardiology, Division of Cardiovascular and Respiratory Studies, Postgraduate Medical Institute, Castle Hill Hospital, Kingston-Upon-Hull, East Yorkshire, UK.
The RDW biomarker predicts adverse outcomes across a broad range of diseases. It is a strong indicator of underlying inflammation, and possibly infection. Do not expect to get an evidence-based explanation of RDW from the standard of care. Thus, arm yourself with the information provided here and seek further testing into the cause of the inflammation.
Footnotes  RBC and the hemoglobin molecule are formed at an extraordinary rate (one trillion hemoglobin molecules per second). Every red blood cell in our bodies is replaced every 4 months because they become damaged from continuous circulation and squeezing through capillaries. If the bone marrow is not healthy, the red blood cells may be produced in different sizes.
Endnotes [i]http://answers.webmd.com/answers/1198043/what-is-rdw, March 21, 2011. [ii] Dai, Yuxiang, et al. "Red cell distribution width predicts short-and long-term outcomes of acute congestive heart failure more effectively than hemoglobin." Experimental and therapeutic medicine 8.2 (2014): 600-606. [iii] Perlstein, Todd S., et al. "Red blood cell distribution width and mortality risk in a community-based prospective cohort." Archives of internal medicine 169.6 (2009): 588-594. [iv] Wen, Yang. "High red blood cell distribution width is closely associated with risk of carotid artery atherosclerosis in patients with hypertension." Experimental & Clinical Cardiology 15.3 (2010): 37. [v] Soni, Mamta, and Ram Gopalakrishnan. "Significance of RDW in predicting mortality in COVID‐19—An analysis of 622 cases." International journal of laboratory hematology (2021). [vi] Foy, Brody H., et al. "Association of red blood cell distribution width with mortality risk in hospitalized adults with SARS-CoV-2 infection." JAMA Network Open 3.9 (2020): e2022058-e2022058. [vii] Ramachandran P, Gajendran M, Perisetti A, et al. Red Blood Cell Distribution Width in Hospitalized COVID-19 Patients. Front Med (Lausanne). 2022;8:582403. Published 2022 Jan 7. doi:10.3389/fmed.2021.582403 [viii] Perlstein, Todd S., et al. "Red blood cell distribution width and mortality risk in a community-based prospective cohort." Archives of internal medicine 169.6 (2009): 588-594. [ix] Felker, G. Michael, et al. "Red Cell Distribution Width as a Novel Prognostic Marker in Heart FailureData From the CHARM Program and the Duke Databank." Journal of the American College of Cardiology 50.1 (2007): 40-47. [x] Tonelli, Marcello, et al. "Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease." Circulation 117.2 (2008): 163-168. [xi] Zalawadiya, Sandip K., et al. "Red cell distribution width and mortality in predominantly African-American population with decompensated heart failure." Journal of cardiac failure 17.4 (2011): 292-298. [xii] Arbel, Yaron, et al. "Red blood cell distribution width and the risk of cardiovascular morbidity and all-cause mortality: a population-based study." European Heart Journal 34.suppl 1 (2013): P1549. [xiii] Chen, Pei-Chun, et al. "Red blood cell distribution width and risk of cardiovascular events and mortality in a community cohort in Taiwan." American journal of epidemiology (2009): kwp360. [xiv] Increased Red Blood Cell Distribution Width Associates with Cancer Stage and Prognosis in Patients with Lung Cancer [xv] Al‐Najjar, Yahya, et al. "Red cell distribution width: an inexpensive and powerful prognostic marker in heart failure." European journal of heart failure 11.12 (2009): 1155-1162.
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