Introduction

The erythrocyte sedimentation rate (ESR), the rate at which erythrocytes settle out of nonclotted blood in 1 hour, has been one of the most widely performed laboratory tests in the past 65 years. Used primarily to detect occult processes and monitor inflammatory conditions, the ESR test has changed little since 1918 when Fahraeus discovered that erythrocytes of pregnant women sedimented in plasma more rapidly than they did in nonpregnant women. Since its incorporation into standard laboratory diagnosis, the ESR has been shrouded with medical myths and is often misinterpreted or misused. This chapter provides a rational guideline for its use as a nonspecific measure of inflammatory, infectious, neoplastic, and cardiovascular diseases.¹^–⁴

Erythrocyte Aggregation

Normally, erythrocytes settle quite slowly as the gravitational force of the erythrocyte’s mass is counteracted by the buoyant force of the erythrocyte’s volume. However, when erythrocytes aggregate, they sediment relatively rapidly because the proportional increase in their total mass exceeds the proportional increase in their volume.¹^–⁴

Therefore, the major determinant in the sedimentation rate of erythrocytes is erythrocyte aggregation, which usually occurs along a single axis (rouleaux formation). The aggregation of erythrocytes is largely determined by electrostatic forces. Under normal circumstances, erythrocytes have a negative charge and therefore repel each other. However, many plasma proteins are positively charged and neutralize the surface charge of erythrocytes, thereby reducing repulsive forces and promoting aggregation.¹^–³

The relative contribution of the various “acute phase” reactant proteins to aggregation is shown in Table 12-1. One protein that has no direct effect on the ESR in physiologic concentrations, but which is associated with certain inflammatory, degenerative, and neoplastic diseases, is C-reactive protein (CRP). Its major function is facilitation of the complement system. Like ESR, measurement of CRP is used in the monitoring of patients with chronic inflammatory conditions.¹ An elevated CRP provides evidence of an inflammatory process despite a normal ESR. Therefore, when used in conjunction with the ESR, it greatly increases the sensitivity in detecting inflammatory and/or infectious processes, especially when variables such as anemia confound the ESR.

TABLE 12-1 Relative Contribution of Acute-Phase Reactant Proteins to Erythrocyte Aggregation

BLOOD CONSTITUENT	RELATIVE CONTRIBUTION
Fibrinogen	10
β-Globulin	5
α-Globulin	2
Albumin	1

The ESR is also elevated in patients with proteinemias (myeloma, macroglobulinemia, cryoglobulinemia, and cold agglutinin disease).¹^–⁴ Disorders of erythrocytes such as various anemias will alter the ESR and may interfere with accurate interpretation.¹^–⁴ Because the ESR is directly proportional to the mass of the erythrocyte and inversely proportional to its surface area, large erythrocytes sediment more rapidly than smaller cells. Therefore, in macrocytic anemia, there is an increased ESR, and in microcytic anemia, there is a decreased ESR.

Although the usefulness of ESR determination has decreased as new methods of evaluating disease have been developed, it remains quite helpful in the diagnosis of some diseases, such as temporal arteritis and polymyalgia rheumatica. Perhaps more useful is its ability to monitor these conditions as well as others, including chronic inflammatory diseases such as rheumatoid arthritis (RA), Hodgkin’s disease, and other cancers. Although the use of the ESR as a screening test to identify patients who have serious disease is not supported by the literature, it does provide a general gauge of inflammatory processes in the body. It is well accepted that an extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease, or metastatic malignancy. Recently, there has been a growing appreciation of the value of the ESR as a marker for atherosclerosis and coronary artery disease.^5,⁶ In addition, as a sign of chronic low-grade inflammation, it may be helpful as a marker for other conditions as well. For example, in a study of 49,321 Swedish males aged 18 to 20 years, screened for general health and for mental and physical capacity at compulsory conscription examination before military service, there was an inverse correlation between ESR and performance on an IQ test.⁷ This result indicated that low-grade inflammation, as indicated by the ESR, was associated with reduced cognitive abilities at ages 18 to 20 years.