Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia?

doi:10.1016/j.cca.2015.05.021

Clinica Chimica Acta

Volume 448, 25 August 2015, Pages 107-117

https://doi.org/10.1016/j.cca.2015.05.021 Get rights and content

Highlights

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Hypoxia-induced erythropoietin responses could potentially create a fingerprint of large red blood cells.
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A fraction of large cells will increase red-cell distribution width (RDW).
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In a survey of 798 diseases in a ‘big database’, RDW increases following acute hypoxigenic diseases.
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RDW elevations last for 3 months after disease onset.
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Red blood cell size distribution may encode subtle signals that reveal a patient's recent hypoxic history.

Abstract

Background

A biomarker of hypoxic exposure would be useful in clinical diagnosis and prognosis. Acute hypoxia stimulates large increases in serum erythropoietin (EPO), and EPO induces formation of characteristic enlarged red blood cells (RBCs). The presence of large RBCs perturbs red cell distribution width (RDW).

Methods

Using a > 2 M patient medical claims database, the human pathome was scanned for diseases where RDW rose 0–50 days following a new diagnosis. The course of RDW after selected diagnoses was visualized by registering RDW measurements by diagnosis date.

Results

Acute hemorrhage, which provokes EPO-driven erythropoiesis, is followed by increases in RDW but not mean cell volume (MCV). Similar RDW increases follow many acute diseases with risk of hypoxia, including heart failure, pneumonia, atelectasis, pulmonary embolism, pneumothorax, and sepsis. Elevations reach maximum within 1 month after onset and subside to pre-disease levels about 6 months later. Unlike the case with iron-deficiency anemia (IDA), RDW elevations after hypoxia-associated diseases are unaccompanied by discernible change in average RBC size.

Conclusions

As predicted by a model risk pathway linking hypoxia to formation of enlarged RBCs via EPO, acute hypoxemia-related disease episodes induce change in RBC size distribution. Further study is needed to explore whether a more sensitive and specific signal can be extracted from the fine structure of the RBC size distribution routinely measured in automated hemocytometers.

Introduction

Even brief interruptions of oxygen supply can threaten irreversible tissue injury and may reflect serious underlying pathologies. Acute or chronic hypoxemia presents with shortness of breath, cyanosis, and as decreased peripheral blood oxygen saturation (SaO₂) via pulse oximetry. Hypoxemia that is chronic but intermittent can escape routine clinical examination, yet cause incremental tissue ischemia, provoke pathological compensatory responses, and herald overall poor prognosis. A reliable biomarker for chronically episodic hypoxia would be a useful clinical tool. In this investigation we explore a hypothesis that transient hypoxic episodes can leave a durable residual signal in the form of a subpopulation of unusually large RBCs. Because RDW is sensitive to the presence of even small numbers of large RBCs, this commonly reported measure can be used to probe the linkage of RBC size distribution to hypoxic diseases.

Section snippets

Model of pathway linking hypoxemia to RDW elevation

Transient oxygen deficiencies stimulate an increase in oxygen carrying capacity through up-regulation of RBC production. In response to decreased oxygen partial pressure (PaO₂), the renal cortex secretes erythropoietin (EPO) into the circulation via hypoxia-inducible transcription factors [1]. EPO increases regardless of the etiology of hypoxemia, e.g., experimentally imposed hypobaria [2], chronic obstructive pulmonary disease (COPD) [3], [4], heart failure [5], interstitial lung disease [6],

RDW

Automated cytometers calculate mean corpuscular volume (MCV) and its standard deviation. RDW is the coefficient of variation (ratio of RBC volume standard deviation to MCV) expressed as a percentage, and typically ranges from 11% to 17%. In a theoretical quasi-normal distribution, an RDW of 13% implies that about two thirds of the cell volumes will be expected to fall within 87% and 113% of the MCV, hence the term ‘width’. Unlike other hematologic measures, RDW does not have a physical

Database

Fully anonymized records of medical encounters submitted as commercial insurance claims are captured in the HealthCore Integrated Research Environment (HIRE) database. All study materials were handled in compliance with the Health Insurance Portability and Accountability Act of 1996, and a limited dataset was used for all analyses, as defined by the Privacy Rule. Records were obtained for encounters between January 1 2007 and October 1 2013.

RDW measurements < 1 y after any record of malignancies,

Distribution of average post-onset RDW increase across the pathome

Fig. 5 displays the estimated size of RDW elevation following a new occurrence of 798 ICD-9 codes for which at least 1250 cases were observed. RDW increases were observed across most codes in the categories of digestive, lower respiratory, circulatory, blood, and metabolic diseases.

No diagnosis showed an RDW decrease of ≥ 1%, but 74 showed increases of > 0.9%. Of these, 17 (23%) were hemorrhage- or blood-related, 13 (18%) were gastrointestinal, 11 (15%) were lower respiratory tract, and 19 (26%)

Pathome-wide survey of RDW response

The EPO risk-pathway model predicts that diseases causing hypoxia will induce increases in RDW. A pathome-wide scan of 798 ICD-9 diagnosis codes finds that RDW increases following acute conditions with high risk of hypoxia. Although the relation of disease codes to hypoxia is somewhat subjective, almost every serious acute disease impacting oxygenation is associated with subsequent RDW increases. In this observational study, confounding with etiology and treatment may occur. Circulatory and

Conclusions

Red cell size variability increases rapidly following acute hemorrhage and most conditions with risk of hypoxia. Elevations in this variability, measured as RDW, persist for several months while MCV changes little, consistent with a model of EPO-driven production of a subpopulation of large RBCs in response to reduced oxygenation. RDW appears to act as a long-term memory of serious disease, possibly via hypoxia. Further study is warranted to directly measure the effects of applied hypobaria and

Acknowledgments

We acknowledge Dr. Ozgur Tunceli for assistance in data extraction.

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View full text

Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia?

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Model of pathway linking hypoxemia to RDW elevation

RDW

Database

Distribution of average post-onset RDW increase across the pathome

Pathome-wide survey of RDW response

Conclusions

Acknowledgments

Egypt J Chest Dis Tuberc

Blood

Chest

Am J Obstet Gynecol

Clin Chem Acta

Am J Cardiol

JACC

J Card Fail

Am J Cardiol

Am J Cardiol

Am J Emerg Med

Am J Emerg Med

Chest

Am Heart J

J Card Fail

Am J Cardiol

Blood

Chest

Regulation of erythropoiesis by hypoxia-inducible factors

Blood Rev

Rate of erythropoietin formation in response to acute hypobaric hypoxia

J Appl Physiol

Anemia in COPD patients and its relation to serum levels of erythropoietin

Tanaffos

Circulating erythropoietin levels and prognosis in patients with congestive heart failure

Arch Int Med

Erythropoietin levels in patients with interstitial lung disease

Chest

A novel method utilizing markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes

Hematologica

Hematological indices of erthropooietin administration in athletes

Int J Sports Med

Validation of the CORB75 (confusion, oxygen saturation, respiratory rate, blood pressure, and age ≥ 75 years) as a simpler pneumonia severity rule

Infection

Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension

Eur Resp J

Elevated nocturnal desaturation index predicts mortality in interstitial lung disease

Sarcoidosis Vasc Diffuse Lung Dis

Serum erythropoietin levels in septic shock

Anaesth Intensive Care