Components of the Complete Blood Count as Risk Predictors for Coronary Heart Disease

Abstract

Atherosclerosis is an inflammatory disease, and several inflammatory biomarkers, such as C-reactive protein, have been used to predict the risk of coronary heart disease. High white blood cell count is a strong and independent predictor of coronary risk in patients of both sexes, with and without coronary heart disease. A high number of white blood cells and their subtypes (for example, neutrophils, monocytes, lymphocytes, and eosinophils) are associated with the presence of coronary heart disease, peripheral arterial disease, and stroke. The coronary heart disease risk ratios associated with a high white blood cell count are comparable to those of other inflammatory markers, including C-reactive protein. In addition, other components of the complete blood count, such as hematocrit and the erythrocyte sedimentation rate, also are associated with coronary heart disease, and the combination of the complete blood count with the white blood cell count can improve our ability to predict coronary heart disease risk. These tests are inexpensive, widely available, and easy to order and interpret. They merit further research.

Coronary heart disease (CHD) is the leading cause of death in the United States, and it is estimated that the prevalence of cardiovascular disease will increase by approximately 10% over the next 20 years.^1,2 During the past 2 decades, extensive research has established that atherosclerosis is an inflammatory disease,³ a finding that has offered new possibilities for predicting CHD risk. The presence of many types of inflammatory biomarkers, most notably high-sensitivity C-reactive protein (CRP), have been found to be consistent predictors of CHD events.⁴ Although an increasing number of novel inflammatory biomarkers are being studied in this context, many offer little improvement in the current risk-prediction models.⁵ Whereas measurement of CRP and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) have shown promise as predictors of CHD events,⁵ most of the other newly introduced inflammatory risk markers are expensive to test, are not readily available, lack standardization, and have not been confirmed by multiple prospective studies.

We have previously shown that a growing body of evidence supports the usefulness of the white blood cell (WBC) count as a predictor of future coronary events.⁶ Herein, we review the most recent data on the use of the WBC count and other components of the complete blood count (CBC) to predict CHD risk. An elevated WBC is a well-recognized indicator of inflammation.⁶ The total number of WBCs and each subtype (for example, neutrophils, monocytes, lymphocytes, and eosinophils) have been implicated as predictors of CHD.⁶ Nearly all of the cellular elements in the blood, including WBCs, red blood cells (RBCs), and platelets, are involved in the underlying pathogenesis of atherosclerosis.^3,6 These markers not only play a role in the development of CHD in asymptomatic patients, but they predict recurrent events and death in patients who already have CHD.^7,8 In addition to the cellular components, an elevated erythrocyte sedimentation rate (ESR) has been shown to be a weak prognostic factor in CHD patients.^9–11

Total White Blood Cell Count and Coronary Heart Disease

The relationship between white blood cell count and CHD was first suggested more than 80 years ago.¹² Results from multiple studies of patients with and without CHD at baseline have indicated that the WBC count can be used to predict the incidence of coronary events.^13–25

A high WBC count also has been shown to be predictive of future cardiovascular events in individuals who were disease free at baseline (Fig. 1 ^14–25).⁶ Multiple studies have shown that a high WBC count is associated with increased mortality rates in patients who present with unstable angina pectoris,^26,27 acute coronary syndromes (ACS),²⁸ and acute myocardial infarction (MI),^29–32 and in patients who undergo percutaneous coronary interventions (PCIs)³³ or coronary artery bypass grafting (CABG) (Fig. 2 8,29,32,34–40).^34–36,41 Moreover, elevated total WBC and neutrophil and monocyte counts are associated with cerebral ischemia and stroke.^42–45 In 2004, Grau and colleagues³⁸ showed that, in patients who had had an ischemic stroke or MI or who had peripheral arterial disease (PAD), there was a relationship between high WBC counts and the recurrence of vascular events.

Fig. 1 The 95% confidence interval and point estimate for coronary heart disease (CHD) incidence and CHD mortality in patients free of CHD. The solid vertical line denotes a relative risk of 1 (no effect); horizontal lines represent 95% confidence interval; and tick marks show point estimates for relative risk.

Fig. 2 The 95% confidence interval and point estimate for coronary heart disease death in patients with acute coronary syndromes, as determined on the basis of total white blood cell count.

An increase in quartiles of WBC count from baseline over 24 hours after an MI episode has been correlated with an increase in all-cause death after an MI,⁴⁶ and a recent subanalysis of the Ongoing Tirofiban In Myocardial Infarction Evaluation (On-TIME) trial showed that an increase in WBC count (defined as WBC count after 6 or 24 hours minus the WBC count on admission) was a significant predictor of death after PCI.³⁹ In an analysis of 900 patients in the Stent Primary Angioplasty in Myocardial Infarction (Stent PAMI) trial, investigators found that an elevated WBC count upon hospital admission (highest tertile, ≥12) had a strong independent association with reinfarction at 1 year.⁴⁷ Moreover, in a subanalysis using data from the Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study that compared patients with and without stages 3 to 4 chronic kidney disease, investigators found that elevated inflammatory markers, including the WBC count, were associated with an increase in adverse cardiac events and death.²⁵ They also found that, although the risk is additive, the synergy between inflammation and chronic kidney disease was not statistically significant.²⁵ Finally, results from a meta-analysis of 5,337 CHD patients from 7 large studies showed that a high WBC count was associated with a risk ratio of 1.4 (95% CI, 1.3–1.5) for CHD.⁴⁸ This risk ratio is comparable to those seen with other novel inflammatory markers associated with atherosclerosis, including CRP.⁴⁹

Therefore, the relationship between white blood cell count and CHD is strong, consistent, dose-dependent, independent, biologically plausible, and coherent with the current paradigm of the inflammatory origin of atherosclerosis. The association between WBC count and CHD has been consistently observed in different populations with varying degrees of baseline risk—in asymptomatic individuals and symptomatic patients. The association between the WBC count and CHD appears to be independent of other traditional coronary risk factors, including smoking. Although smoking is associated with leukocytosis, studies have shown that the predictive value of a high WBC count for CHD is independent of whether patients are smokers.⁶

Differential White Blood Cell Count and Coronary Heart Disease

Elevated levels of almost all subtypes of WBCs, including eosinophils,^50,51 monocytes,^52–54 neutrophils,^38,55–60 and lymphocytes (an inverse relationship),^52,61–63 have been associated with increased risk of CHD (Fig. 3 16,38,40,52,55,57,64).⁶ In a large, disease-free patient cohort from the Adult Health Study (AHS) of Hiroshima and Nagasaki, results showed a relationship between the total WBC count, including the eosinophil, neutrophil, and monocyte counts, and the incidence of CHD.⁵⁰ Results from the Paris Prospective Study II showed an increased risk of CHD in patients with high monocyte counts.⁵² In the Caerphilly and Speedwell studies, increased coronary risk was associated with high neutrophil, eosinophil, lymphocyte, monocyte, or basophil counts.⁵⁵ A prospective study⁴⁰ of 1,037 patients who experienced an acute MI showed that elevated total WBC, monocyte, and neutrophil counts and low lymphocyte counts were independent predictors of all-cause death. The investigators in that study found that adding the neutrophil count to models of total WBC, monocyte, and lymphocyte counts improved the models' predictive ability.⁴⁰ Furthermore, Papa and colleagues⁶⁵ found that higher neutrophil-lymphocyte counts in patients with angiographically documented coronary artery disease (CAD) increased the risk of cardiac death within a 36-month follow-up period.

Fig. 3 The 95% confidence interval and point estimate for coronary heart disease incidence and mortality rate in disease-free persons and in patients with acute coronary syndromes, as determined on the basis of white blood cell subtypes.

In a large cross-sectional study of middle-aged, asymptomatic participants in the 1999–2002 National Health and Nutrition Examination Survey (NHANES), elevated monocyte and neutrophil counts, along with elevated CRP and fibrinogen levels, were associated with the presence of subclinical PAD.⁶⁴ In another study of patients with PAD, only an elevated neutrophil count was predictive of an increased risk of major adverse cardiovascular events or death within the study's 20-month follow-up period.⁶⁶ However, a study using intravascular ultrasonography showed a direct relationship between the monocyte count and an increase in the volume of atherosclerotic plaque in the arteries of patients who have had an acute MI.⁶⁷ In addition, a higher prevalence of monocytosis has been reported in patients with angiographically documented CAD.⁵⁴ When the relationship between peripheral monocyte count and coronary vasospasm was examined in 180 patients with chest pain, an elevated monocyte count was strongly associated with coronary vasospasm.⁶⁸ A more recent (2008) prospective, observational study in asymptomatic adults showed that, of all the WBC subtypes, the monocyte count had the strongest independent relationship with CHD risk, as estimated by the Framingham and SCORE calculations.⁶⁹ Moreover, several studies have shown that the WBC^70,71 and, more specifically, the monocyte count are independent predictors of subclinical carotid plaque deposition and carotid intima medial thickening.^71,72

In a genetic analysis of the inflammatory role of eosinophils, Gudbjartsson and colleagues⁷³ undertook a genome-wide association scan of the blood of more than 9,000 Icelanders to determine the sequence variants affecting eosinophil counts and to evaluate the association with inflammatory disorders. The analysis revealed that a single nucleotide polymorphism at 12q24, in SH2B3, had a significant association (P < 0.002) with MI in their scan data set and was consistent with 6 replication sets of European ancestry, with an odds ratio of 1.13 (95% CI, 1.08–1.18).⁷³ Further studies are needed to evaluate the consistency of the relationship of WBC subtypes and cardiovascular risk. It should be noted that most of the above-mentioned studies have excluded subjects with hematologic disorders, such as chronic lymphocytic leukemia or aplastic disorders, and the relationship between WBCs and CHD requires separate investigation in those situations.

White Blood Cell Count versus High-Sensitivity C-Reactive Protein as Coronary Heart Disease Risk Markers

High-sensitivity C-reactive protein is increasingly used for coronary risk prediction in clinical settings. With the knowledge that neither CRP nor the WBC count is the “perfect” screening tool, it is noteworthy that the WBC count is comparable in efficacy to CRP for predicting CHD risk (Fig. 4 ^74–80). Both tests are nonspecific markers of systemic inflammation and have comparable power for predicting coronary events. Meta-analyses by Danesh and colleagues^48,49 found that the WBC had an odds ratio of 1.4 (95% CI, 1.3–1.5) and the CRP had an odds ratio of 1.45 (95% CI, 1.2–1.6).

Fig. 4 The 95% confidence interval and point estimate for coronary heart disease (CHD) event risk based on white blood cell count versus C-reactive protein.

PAD = peripheral arterial disease

Unfortunately, there are few head-to-head comparisons of WBC count with CRP for CHD risk prediction (Fig. 4). In a subset of the West of Scotland Coronary Prevention Study, univariate analysis showed that both the WBC count and the CRP were risk predictors of coronary events, with respective risk ratios of 1.15 (95% CI, 1.02–1.31) and 1.21 (95% CI, 1.06–1.31).⁷⁴ However, multivariate analysis showed that only Lp-Pla₂ had significant predictive ability for the risk of a coronary event, with a risk ratio of 1.18 (95% CI, 1.05–1.33).⁷⁴ In a study of the relationship between inflammation and PAD that used data from the 1999–2002 NHANES, the multivariate adjusted odds ratio of PAD was increased for the highest quartiles of both WBC count (OR, 1.67; 95% CI, 0.84–3.31) and CRP (OR, 2.14; 95% CI, 1.41–3.25), compared with the lowest quartiles.⁷⁵ These relations remained significant across different subgroups that were used to evaluate the influence of sex, obesity, and diabetes mellitus.⁷⁵

In a fully adjusted model from the Women's Health Initiative Observational Study,⁷⁶ a comparison of WBC counts in the first and 4th quartiles showed that women in the 4th quartile were at higher risk for CHD events: the odds ratio was 2.36 (95% CI, 1.33–4.19), which was higher than the odds ratio of 1.95 (95% CI, 0.95–4.01) for women with elevated CRP levels. In that study, elevated WBC counts and CRP levels synergistically predicted CHD risk, with an odds ratio of 6.8 (95% CI, 2.7–16.9).⁷⁶ Another study, from the Centers for Disease Control and Prevention (CDC), evaluated 8,355 participants in the 1999–2002 NHANES for lifestyle and emerging risk factors that could contribute to participants' Framingham risk score. Results of the study showed that an elevated WBC count (>7 ×10⁹/L, the population median) was associated with an odds ratio of 1.49 (95% CI, 1.32–1.67) of the highest 10-year CHD risk—as was an elevated CRP level, with an odds ratio of 2.10 (95% CI, 1.74–2.53).⁷⁷ In addition, in a study of outcomes after patients underwent stent placement for unprotected left main coronary artery stenosis, Palmerini and colleagues⁷⁸ found that WBC counts and CRP levels were comparable in predicting outcomes at 9 months.⁷⁸

Conversely, in a study of 270 patients with angiographically documented CAD, results showed that increases in the total WBC count and the neutrophil and eosinophil counts all were significantly associated not only with the presence of CAD but also with its severity, as determined by the number and extent of lesions, whereas levels of CRP and the ESR were not.⁷⁹ Similarly, in a study of patients undergoing diagnostic coronary angiography, the WBC count was independently associated with angiographically documented CAD and multivessel disease, whereas CRP values, tissue inhibitor of metalloproteinases-1 (TIMP-1), and the ESR were not.⁸¹

However, in a subanalysis of the On-TIME trial that evaluated early versus late administration of tirofiban during primary PCI for ST-elevation myocardial infarction (STEMI), results showed that the baseline CRP value was a significant predictor of re-infarction and 1-year death, with an odds ratio of 1.03 (95% CI, 1.01–1.05; P = 0.012), whereas the baseline WBC count was not significantly associated with worse outcomes, with an odds ratio of 1.09 (95% CI, 0.96–1.23; P = 0.202).⁸⁰ Kruk and colleagues⁸² also evaluated patients with STEMI who underwent primary PCI and found that elevated WBC counts and CRP values were independent predictors of in-hospital death.⁸²

In a study of patients who presented at the emergency department with chest pain suggestive of ACS, both the WBC counts and the CRP values were associated with a diagnosis of ACS upon hospital discharge; however, multivariate analysis showed that only the WBC count was actually associated with the presence of ACS, with an odds ratio of 20.9 (95% CI, 3.7–19.5).⁸³ In a prospective cohort study of 128 patients with angina pectoris,⁸⁴ investigators found that WBC counts and CRP levels were significantly higher in patients with unstable angina pectoris than in patients with stable angina (P < 0.0001) and that the circulating level of CRP was strongly associated with the clinical setting of unstable angina, with an odds ratio of 1.56 (95% CI, 1.23–2.0).

Consequently, it appears that both tests are useful in different populations and among men and women and that these tests have comparable weaknesses and strengths in predicting coronary risk. However, the test for WBC count is less expensive and more widely available than is the test for CRP. Obviously, a high WBC count, like other markers of risk such as high cholesterol level and CRP, is not synonymous with the presence of CHD and is one of multiple risk markers used to predict the risk of CHD. Similarly, many subjects with cardiovascular disease have normal WBC counts.

Effect of Statins on White Blood Cell Count

Statins are known to reduce cardiovascular events and related inflammatory markers,⁸⁵ but they also reduce the WBC count. In a study of 1,246 patients with angiographically documented CAD, the use of statins was associated not only with lower WBC counts, but also with reduced levels of CRP, fibrinogen, and von Willebrand factor.⁸⁶ Lower WBC counts and lower values of other inflammatory markers have also been seen in CHD patients who take statins, even in the absence of changes in total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglyceride levels.⁸⁷ In the National Registry of Myocardial Infarction (NRMI)-4 study, the WBC count was an independent predictor of in-hospital death from acute MI and was lower in patients who were taking statins or aspirin.³⁷ Statin use is also associated with a decrease in the neutrophil count in patients with existing peripheral vascular disease.⁸⁸

In a 6-month prospective study of patients with stable CAD, pravastatin significantly lowered the WBC count (8.9% vs baseline; P < 0.01), and multivariate regression analysis showed that the change in WBC count was an independent predictor of coronary plaque regression (14% reduction vs baseline; P < 0.0001).⁸⁹ In the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study,⁹⁰ in patients with stable CAD, the baseline WBC count was associated with greater CHD death in patients who were randomly assigned to receive a placebo, but not in patients given pravastatin. The number of coronary deaths and other cardiac outcomes that were prevented in the statin arm of the study increased, as did baseline WBC quartiles. The WBC count was a stronger predictor of treatment benefit than was the ratio of total cholesterol to HDL-C. Moreover, after statin treatment, the WBC count decreased at 1-year follow-up and remained stable thereafter.⁹⁰

Beyond Leukocytes: Use of the Complete Blood Count to Predict Coronary Heart Disease Risk

Other components of the CBC, such as the RBC and platelet counts and hemoglobin and hematocrit values, also are associated with CHD and can be used in combination with the WBC count to predict coronary risk. Few studies, however, have examined the usefulness of combining multiple CBC elements to predict CHD risk. According to one such study by Ronnow and colleagues,⁹¹ a simple CBC-derived risk score comprising the hematocrit and WBC and platelet counts could be used to predict death in a meaningful way; but an expanded CBC-derived risk score comprising the hematocrit, mean corpuscular volume (MCV), red cell distribution width (RDW), mean corpuscular hemoglobin concentration, and platelet and WBC counts provided substantially greater predictive value. Predictive ability was further improved by adjustment for age, sex, and other traditional risk factors.⁹¹ In another study, the same group showed that in patients with angiographically documented CAD, the total WBC count was an independent predictor of death or MI.⁶² In these patients, good predictive power was provided by high neutrophil or low lymphocyte counts, but the greatest risk prediction was achieved by using the neutrophil-to-lymphocyte ratio.⁶²

Gibson and colleagues⁹² found that, in patients undergoing CABG, the preoperative WBC count was not a predictor of death during their 3.6 years of follow-up, but that the neutrophil-lymphocyte count was a significant predictor of both cardiovascular and all-cause death, especially in the highest quartile (hazard ratio, 2.09; 95% CI, 1.54–2.84).⁹² In an extension of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), Spencer and colleagues⁹³ screened 383 patients with hypertension to determine whether there was a relationship between hematologic factors and global measures of cardiovascular risk. They found that elevated WBC counts and increased levels of fibrinogen and von Willebrand factor significantly correlated with a higher Framingham 10-year CHD risk score and were independent predictors of Framingham CHD risk.⁹³ A lower hematocrit significantly correlated with both the Pocock and Framingham 5-year cardiovascular risk scores.⁹³

Anderson and colleagues⁹⁴ evaluated the predictive ability of the CBC in a prospective cohort of 29,526 patients undergoing coronary angiography and found that the CBC score had discriminatory predictive ability for all-cause death at 30 days, with an area under the curve of 0.75. The age- and sex-adjusted CBC model had an area under the curve of 0.78. In addition, the CBC score showed strong predictive ability at 30 days and at 1, 5, and 10 years when a scalar risk score incorporating age and sex was used (linear trend, P < 0.001).⁹⁴

Red Blood Cell Count and Coronary Heart Disease Risk

Several factors related to RBCs are associated with CHD, including hemoglobin levels and the hematocrit, RDW, and ESR⁹⁵; however, there are not enough data to suggest an association between the RBC count and cardiovascular disease. Although polycythemia vera is associated with an increased risk of macrovascular events,⁹⁶ elevated RBC counts within the upper limits of normal have been reported to have only weak or no association with cardiovascular risk.⁹⁷

Hematocrit and Coronary Heart Disease Risk

Several studies have shown a relationship between the hematocrit and incident cardiovascular events in patients who have had an MI,^98,99 in those with PAD,¹⁰⁰ and in asymptomatic individuals.^101–109 However, results of some studies have not shown a significant relationship between hematocrit and CHD risk.^103,110,111 In fact, while most studies of different patient populations do show an association between increased hematocrit and increased risk of CHD, the observed risk ratios are generally low, and, therefore, the clinical usefulness of hematocrit alone is unclear.

A meta-analysis of 19 prospective studies of hematocrit and CHD risk showed a pooled odds ratio of 1.16 (95% CI, 1.05–1.29) in disease-free subjects, and a risk ratio of 1.81 (95% CI, 1.19–2.76) in patients with vascular disease.⁹⁵ The same meta-analysis also dealt with the value of viscosity and the ESR for CHD risk prediction. The investigators reported a risk ratio of 1.57 (95% CI, 1.34–1.85) for the top tertile of plasma viscosity in population-based studies, and a risk ratio of 2.6 (95% CI, 1.64–4.12) for patients with vascular disease.⁹⁵ Results of a more recent study show that the hematocrit-to-blood viscosity (Hct-BV) ratio had significant negative correlation with the frequency of hospital admission and that a lower Hct-BV ratio was associated with a greater likelihood of cardiac death in CHD patients.¹¹²

Uncertainty remains in regard to the effectiveness of blood transfusion in correcting a low hematocrit in ACS patients.¹¹³ Although an observational study by Wu and colleagues¹¹⁴ suggests that blood transfusion can improve short-term survival in patients who are anemic at presentation, Hebert and colleagues¹¹⁵ found no such benefit, while others^116–118 actually report a harmful effect. A retrospective cohort study (2006) suggests that higher mortality rates in women after CABG are due in part to the more common occurrence of blood transfusions in women, leading to immunomodulation and an increased risk of infection and death after bypass surgery.¹¹⁹ Results from a pooled study of ACS patients from 3 large international trials showed an increased mortality rate after blood transfusion in patients who developed moderate-to-severe bleeding, anemia, or both, during hospitalization.¹¹³ In another analysis involving a subset of 44,242 patients, investigators found an inverse relationship between in-hospital death and nadir hematocrit in non-STEMI patients.¹²⁰ They also found that transfusions were related to significantly increased in-hospital death in the highest hematocrit quartile (Hct >30).¹²⁰ Therefore, it appears that well-designed, randomized, controlled trials of transfusion strategies are needed to provide clear guidelines with regard to blood transfusion in ACS patients. Until then, a cautious approach is warranted in the use of blood transfusion in these patients.

The RDW, a numerical measure of the variability of the size of circulating erythrocytes, is significantly associated with an increased risk of all-cause death, and specifically with death secondary to cardiovascular disease in cross-sectional studies of the population of the United States.^121,122 In addition, the RDW is an independent predictor of death in patients who have had previous MIs¹²³ or stroke¹²⁴ and in men referred for coronary angiography.¹²⁵

Erythrocyte Sedimentation Rate and Coronary Heart Disease Risk

Although the ESR varies among elderly patients, it has a positive correlation with several CHD risk factors, including age, sex, smoking, systolic blood pressure, total cholesterol levels, heart rate, body mass index, diabetes, alcohol consumption, and fibrinogen, hemoglobin, and albumin levels.^126–129 After multivariate adjustment, the ESR is an independent and strong short- and long-term predictor of CHD death.¹²⁸ In young subjects, a moderate but persistent elevation in the ESR has been associated with an increased risk of incident MI.¹³⁰ Other conditions associated with a persistently elevated ESR include chronic infectious states, renal failure, rheumatoid arthritis, and chronic bronchitis.¹³¹ In the Stockholm Prospective Study, there was a positive and independent relationship between the ESR and fatal MI in asymptomatic men and women,¹³² but in NHANES I, the ESR was a risk factor for fatal MI only in men.¹⁰ In the Reykjavik Study, the ESR was an independent long-term predictor of CHD and death due to stroke in both men and women.⁹ Another study found that the ESR was related to the extent of coronary atherosclerosis on angiography and was a predictor of cardiac death in men with ischemic heart disease.¹²⁹ Finally, a meta-analysis of 4 population-based studies showed that an ESR in the top third tertile yielded a risk ratio of 1.33 (95% CI, 1.15–1.54), compared with an ESR in the bottom tertile.⁹⁵

Platelets and Coronary Heart Disease Risk

High platelet counts—such as those seen with hematologic neoplasms—are clearly associated with an increased risk of thrombosis; however, the effect of increased platelet numbers that are still within physiologic ranges remains unclear. A limited number of studies have shown that high platelet counts and a rapid platelet-aggregation response are associated with increased long-term coronary death.¹³³ Conversely, a low platelet count in the presence of an increased mean platelet volume after ischemic cerebral infarction is also associated with increased mortality rate.¹³⁴ In a cross-sectional study of patients undergoing coronary angiography, the mean platelet volume was higher in MI patients than in control patients, and stable angina pectoris correlated with the extent of CHD.¹³⁵

Other studies suggest that platelet counts and aggregation that are within physiologic range are not related to CHD events.¹³⁶ Khandekar and colleagues¹³⁷ found a significant increase in platelet volume indices, mean platelet volume, and platelet distribution width in patients with unstable angina or acute MI, compared with stable CHD patients and healthy matched control patients.¹³⁷

It appears that the role of platelets in the pathogenesis of CHD is due mainly to their functional properties and their interaction with plasma and tissue factors; only a small proportion of their effect—if any—is related to their absolute number. The small number of related positive studies may be the result of a publication bias toward the withholding of negative findings.

Potential Mechanisms

The effect of leukocytosis on CHD can be explained by multiple mechanisms; however, the inflammatory basis of atherosclerosis remains the cornerstone of this relation. Atherosclerotic lesions are inflammatory in nature, occur predominantly in large- and medium-sized arteries, and develop early in life.³ Leukocytosis can be considered a marker of inflammatory changes in atherosclerotic lesions, because leukocytes play a key role in the initiation and progression of the disease. In terms of ACS pathophysiology, leukocytes themselves are directly responsible for myocardial injury. Leukocytes release cytokines, bringing about further macrophage recruitment and the proliferation of smooth muscle cells within the vascular wall. In addition, protease secretion leads to endothelial damage of the coronary vessels, exposing thrombogenic collagen and predisposing the vessels to thrombus formation. Phagocytes release myeloperoxidase, which generates reactive oxygen species that are involved in the generation and progression of atherosclerosis and that contribute to the development of plaque instability in acute MI.³¹

A 2007 study has linked high WBC counts to the presence of vulnerable plaque.¹³⁸ The investigators used optical coherence tomography to visualize lesions in patients undergoing coronary catheterization. An elevated baseline WBC count correlated with the macrophage density of the visualized plaque (r = 0.483; P = 0.001), and it was shown that patients with thin-cap fibroatheromas had higher WBC counts than did those without thin-cap fibroatheromas (11 vs 7.9; P = 0.007).¹³⁸ Other studies^139–148 have shown that leukocytes also play an important role in the pathogenesis of myocardial injury through multiple mechanisms, such as vessel-plugging, decreased perfusion, and abnormal WBC aggregation.

Elevated WBC counts are associated with several coronary risk factors, including smoking, elevated serum triglyceride and cholesterol levels, clotting factors, body mass index, obesity, and diastolic blood pressure.^149–152 Leukocytosis also is associated with several disorders that characterize the metabolic syndrome^153,154 and with micro- and macrovascular complications in patients with diabetes.¹⁵⁵ The different mechanisms by which leukocytosis might affect CHD are listed in Table I.30,75,139–146,148–152,156–161

TABLE I. Possible Mechanisms of Action of White Blood Cells in Coronary Heart Disease

Elevated RBC counts and hematocrit are associated with rheologic effects, such as increased viscosity, which is a risk factor for coronary events.¹⁶² The adenosine diphosphate released from the RBCs enhances platelet aggregation,¹⁶³ and the elevated hematocrit is associated with a concomitant increase in platelet adhesion.^162,164 Aggregation of RBCs is significantly higher in men with proven vascular disease.¹⁶⁵ In addition, RBC indices are associated with a number of CHD risk factors. For example, increased hemoglobin levels are associated with elevated serum cholesterol and triglyceride levels,^166,167 and it is believed that the lipid-rich membranes of RBCs contribute to atheroma formation in the coronary arteries.¹⁶⁸ In an elaborate set of studies in patients who died suddenly of cardiac causes, Kolodgie and colleagues¹⁶⁹ found that an accumulation of erythrocytic membranes within an atherosclerotic plaque increases the risk of plaque destabilization by contributing to the deposition of free cholesterol. A prospective study using data from the Nurses' Health Study showed that a higher total trans-fatty acid content in the erythrocytes is associated with a significantly increased risk of CHD, with the highest quartile of trans-fatty acid content in erythrocytes having a relative risk of 2.7 (95% CI, 1.5–5; P < 0.01 for trend), compared with the lowest quartile.¹⁷⁰ Accordingly, Tziakas and colleagues¹⁷¹ showed that the cholesterol content of erythrocytic membranes was significantly higher in patients with ACS than in patients with stable angina. It is thought that the altered membranes might decrease the fluidity of the RBCs. The different mechanisms by which RBCs might affect CHD are summarized in Table II.89,162–164,166–171

TABLE II. Possible Mechanisms of the Role of Red Blood Cells in Coronary Heart Disease

Inflammation and thrombosis are closely related.¹⁷² Platelets have clear roles in thrombosis and contribute to inflammation.^158,173,174 Under stress, activated platelets help neutrophils adhere to the subendothelial matrix. Chirkov and colleagues¹⁷⁵ have shown that there is increased platelet aggregability and resistance to nitric oxide in patients with stable angina pectoris and ACS, compared with patients without CHD (P < 0.01). Platelets also synthesize interleukin-1 beta (IL-1β), an important mediator of platelet-induced activation of the endothelial cells, which, in turn, induce chemokines that up-regulate the molecules that promote endothelial adhesion of neutrophils and monocytes.¹⁷⁶ This increased total platelet-monocyte binding has been shown in ACS patients.¹⁷⁷ In addition, patients with a larger territorial burden of atherosclerotic disease have shown greater P-selection expression, which promotes inflammation, atherogenesis, and thrombosis.¹⁷⁸ Activated platelets also have been implicated in the oxidative modification of LDL-C that can contribute to proliferation of smooth-muscle cells. Platelets are the source of 90% of the circulating CD40L, which has proatherogenic and prothrombotic functions and is a predictor of incident MI, stroke, and cardiovascular death.¹⁷⁹ The different mechanisms by which platelets might affect CHD are summarized in Table III.^{158,172–179}

TABLE III. Possible Mechanisms of the Role of Platelets in Coronary Heart Disease

Conclusions

Elevated WBC counts, along with other components of the CBC, are associated with CHD morbidity and death. The tests are inexpensive and widely available and warrant further use for the purpose of coronary risk evaluation in the clinical and research settings. Comparative studies are needed of the WBC count and the CBC versus more novel inflammatory markers (such as CRP) for predicting cardiovascular disease risk. In addition to the absolute number of leukocytes and other blood cells, several indices of their activity, such as expression of different leukocytic proinflammatory genes, should also be tested in this context. Such analyses should take into account the intra-individual variability of WBC counts and subtypes, and also the known racial variances in WBC counts.

The WBC count should be further tested as a surrogate marker of outcomes for evaluating the effect of statins and similar pharmacologic interventions. Results of a 2008 study showed that statins can prevent vascular events in patients with high baseline CRP and moderate levels of LDL-C.¹⁸⁰ Future studies and subgroup analyses are needed to determine whether patients with high WBC counts and moderate-to-low LDL-C levels (with either high or low CRP levels) are a new target population that could benefit from statin therapy. Elevated baseline WBC counts or no reduction in WBC counts (or related cell subtypes) during therapy might identify different response patterns and a need for more aggressive or combined therapy. Results from such trials could be used to develop clinical guidelines and to promote the use of these tests in the most appropriate manner.