Because blood vessels are present in all organs and tissues, vascular disease is not restricted to a limited group of signs and symptoms. All organs and tissues are potential targets of injury in vascular disease, and most patients present with signs and symptoms indicative of injury to a specific organ or tissue, usually as a result of diminished blood flow. For example, if there is decreased blood flow to the heart, the patient presents with signs and symptoms related to cardiac dysfunction. The decrease in blood flow could be the result of a lesion that originates in the blood vessel wall, and therefore a vascular disease, or an obstruction by a blood clot inside the blood vessel. The disorders originating within the blood vessel wall include atherosclerotic vascular disease, hypertensive vascular disease, vasculitis, tumors, and aneurysms. Blood vessel disorders that may result from an abnormality that is not within the blood vessel wall include deep vein thrombosis (DVT), and what the DVT may generate if any of the clot moves to the lungs, pulmonary embolism (PE). DVT and PE are also discussed in this chapter. A first-time DVT or PE is nearly always the result of clot formation inside a normal vein. However, if an abnormality in vein anatomy exists, such as congenital atresia of the inferior vena cava, such defects within the blood vessels themselves can be highly contributory to the development of a DVT.

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  Atherosclerotic vascular disease is one of the most predominant illnesses in the Western world. The goal of clinical laboratory testing is to identify the cause of atherosclerosis. This is usually related to excess dietary lipid or a disorder of lipid metabolism. This chapter provides information on disorders of lipid metabolism that lead to atherosclerosis.

  
  
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  Hypertensive vascular disease is also common. The role of clinical laboratory testing is to determine if there is a correctable cause for hypertension. Because more than 90% of hypertension cases are “essential,” there is currently no correctable cause. Treatment with antihypertensive medical therapy is important and beneficial, but it does not treat the underlying cause for hypertension in most cases. Some causes of hypertension, however, are identifiable and correctable, often surgically. An example of a surgically correctable form of hypertension is one in which a tumor secretes a hormone responsible for the elevation of blood pressure. Removal of the tumor typically results in normalization of the blood pressure. The section “Hypertension” focuses on the correctable causes of hypertension and the laboratory tests useful in identifying them.

  
  
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  Vasculitis represents a less commonly encountered group of disorders with inflammation in the blood vessel wall. Clinical laboratory testing has a limited role in establishing the diagnosis of a particular form of vasculitis. The diagnosis is made by the specific clinical features of the patient, the results of antineutrophil cytoplasmic antibody (ANCA) testing for some forms of vasculitis, and, on occasion, histopathologic review of a blood vessel biopsy specimen.

  
  
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  DVT and PE are primarily diagnosed with imaging studies. However, an important test in the clinical laboratory, used primarily to rule out DVT and PE when the result is negative, is the D-dimer test.

Description

Atherosclerotic vascular disease is a major cause of mortality and morbidity in the Western world. It is the consequence of an accumulation of lipid in large arteries including the aorta and, thereby, a narrowing of the lumen of the arteries, which results in decreased blood flow. When an atherosclerotic plaque ruptures, a thrombus can form over the ruptured plaque and totally occlude blood flow. Atherosclerotic disease is vascular in origin in that lipid deposition and cell proliferation occur within the blood vessel wall. The end-organ damage depends on the anatomic location of the occluded artery. It is common to have generalized atherosclerosis with multiple vascular beds affected.

The causes of atherosclerotic vascular disease include:

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  Ingestion of excess or atherogenic dietary fat, which is primarily saturated fatty acids and cholesterol. This is the most common cause of atherosclerotic vascular disease.

  
  
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  Primary lipid disorders, also known as primary hyperlipidemias, which result in an increase in cholesterol, triglyceride, or both in the plasma. Many of these disorders are a result of genetic mutations that perturb the metabolism of cholesterol. They are not uncommon.

  
  
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  Nonlipid disorders causing elevations in the concentration of plasma lipids, usually cholesterol and/or triglyceride. These are called secondary hyperlipidemias. Disorders or conditions that adversely affect lipid metabolism include hypothyroidism, nephrotic syndrome, liver disease, diabetes, obesity, and alcohol abuse. In addition, many medications can alter plasma lipid levels.

  
  
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  Though not common, elevated levels of lipoprotein(a) (Lp(a) and pronounced “L-P-little a”) with or without other lipid or lipoprotein abnormalities.

  
  
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  Also not common, disorders that are associated with direct damage to the blood vessel wall, independent of lipid levels, such as high circulating concentrations of homocysteine.

Diagnosis

The initial approach to the patient for routine evaluation or for monitoring the status of atherosclerotic vascular disease is to determine if the patient has an elevation in serum or plasma cholesterol, and if so, to first determine if the cause is excess intake of dietary fat.

An elevated total cholesterol level (>200 mg/dL) prompts the need to determine the plasma or serum concentrations of low-density lipoprotein (LDL) cholesterol (a high level is bad) and high-density lipoprotein (HDL) cholesterol (a high level is good). Table 8–1 describes the lipoproteins that transport lipids in the plasma.

Late in 2013, the American College of Cardiology and the American Heart Association, in conjunction with the National Heart, Lung, and Blood Institute, developed new guidelines. These contained substantial changes from the previous guidelines that were established more than a decade earlier by the Adult Treatment Panel III(ATP III). Previous targets for LDL cholesterol of 100 mg/dL, with the optional goal of less than 70 mg/dL, were removed as indicators of treatment success. Instead, 4 treatment groups for statin therapy have been identified. They are individuals with clinical atherosclerotic vascular disease; those with LDL cholesterol levels greater than 190 mg/dL; those with diabetes between 40 and 75 years old with LDL cholesterol levels between 70 and 189 mg/dL without evidence of atherosclerotic vascular disease; and individuals without evidence of cardiovascular disease or diabetes who have LDL cholesterol levels between 70 and 180 mg/dL and a 10-year risk of atherosclerotic vascular disease greater than 7.5%. The risk for stroke has been added to the coronary events traditionally covered by cardiovascular risk assessments. Specific recommendations on lifestyle for cardiovascular disease prevention include eating a diet rich in fruits, vegetables, whole grains, fish, low-fat dairy, lean poultry, nuts, legumes, non-tropical vegetable oils with restriction of saturated fats, trans fats, sweets, sugar sweetened beverages, and sodium; and engaging in aerobic physical activity of moderate to vigorous intensity lasting 40 minutes per session 3 to 4 times per week. With regard to weight loss, the new recommendation is that patients with a BMI of 25, not 30 as in the past, who have even one comorbidity, such as an elevated waist circumference, should begin treatment for weight loss.

LDL Cholesterol

The most common method for determining LDL cholesterol is a calculation that requires the use of a fasting sample with a triglyceride level less than 400 mg/dL. The LDL is calculated according to the Friedewald formula, which is: calculated LDL cholesterol = total cholesterol – HDL cholesterol – (triglycerides/5). The very-low-density lipoprotein (VLDL) fraction is represented by (triglycerides/5) with the assumption that there is very little triglyceride in LDL and HDL. Because the plasma and serum triglyceride concentration increases with ingestion of dietary fat, a fasting sample is required for an accurate calculation of LDL cholesterol using the Friedewald formula. Although it is acceptable to drink water, the patient may not ingest any calories 8 to 12 hours before the blood sample is collected. If the patient does not fast, and the triglyceride is elevated above baseline, the calculated LDL cholesterol will be falsely low. Another challenge to an accurate determination of LDL cholesterol is that there is substantial biological variability, independent of any change in dietary habits, in the total cholesterol level. This would also have a significant impact on the calculated LDL value. For that reason, testing for total cholesterol and LDL cholesterol should be repeated on a second sample drawn 1 to 8 weeks later. The mean value from these 2 samples is used, as long as the differences between them are less than 30 mg/dL in total cholesterol. If the difference is greater than 30, a third sample should be obtained and the mean of the 3 samples calculated. The day-to-day variability in total cholesterol within a single individual is typically at least 10% and can be as high as 30%. This level of variability, in a patient whose LDL cholesterol is calculated using the Friedewald formula, could span a range of values from 125 to 165 mg/dL if the patient has a true value of 145 mg/dL. The Friedewald calculation fails if the triglyceride concentration in the fasting sample is higher than 400 mg/dL. At such high concentrations, the (triglyceride concentration/5) is no longer a reasonable estimate of the VLDL cholesterol concentration.

Assays that directly measure LDL are also available. These are not dependent on the Friedewald formula, and therefore independent of the triglyceride concentration. For that reason, fasting is not required if a direct LDL assay is performed. The direct LDL cholesterol assay circumvents the issues associated with the calculated LDL cholesterol when it is greater than 400 mg/dL. However, even though these assays are routinely used, some studies have shown substantial imprecision with the assay, although this conclusion has been challenged by other studies. In addition, direct LDL cholesterol measurement is not useful in patients with a dyslipidemia.

HDL Cholesterol

Low levels of HDL cholesterol (<40 mg/dL) represent a cardiac risk factor. However, an elevated HDL cholesterol concentration greater than or equal to 60 mg/dL reduces cardiovascular risk, and if present, it allows subtraction of 1 risk factor from the sum of the risk factors. The patient does not need to fast prior to sample collection for performance of the HDL cholesterol.

Total Cholesterol

The total cholesterol concentration is the sum of HDL cholesterol, LDL cholesterol, VLDL cholesterol, intermediate-density lipoprotein cholesterol (IDL cholesterol), and cholesterol associated with LP(a). In the vast majority of patients, the cholesterol in IDL and in LP(a) is very small relative to the other lipoproteins. The patient does not need to fast prior to sample collection for performance of the total cholesterol. Like HDL cholesterol, total cholesterol is not affected by recent dietary intake.

Non-high-density Lipoprotein Cholesterol

Non-HDL cholesterol is the difference between the total cholesterol concentration and the HDL cholesterol concentration. The remaining lipoprotein particles—LDL, VLDL, IDL, and LP(a)—are all atherogenic. In some clinical trials, non-HDL cholesterol was shown to be superior over LDL cholesterol as a measurement of cardiovascular risk. Because neither the total cholesterol nor the HDL cholesterol is affected by the triglyceride level or ingestion of dietary fat, non-HDL cholesterol can be calculated on nonfasting specimens. Use of non-HDL cholesterol measurements instead of calculated LDL cholesterol measurements avoids the problem of calculating LDL cholesterol in patients who have triglyceride concentrations greater than 400 mg/dL.

High-sensitivity C-reactive Protein

The level of persistent inflammatory processes relates to the risk of cardiovascular events. Patients who have an existing inflammatory process typically have CRP levels greater than 3.0 mg/L. Transient elevations in CRP associated with benign processes occur frequently, and for that reason repeat testing within 2 weeks of an elevated value is recommended to determine if the CRP level exceeds 3.0 mg/L. The American Heart Association and the National Cholesterol Education Panel concur that CRP levels should be measured only after traditional lipid parameters have been assessed completely, with the CRP levels used to classify only those patients who are considered to have borderline cardiovascular risk. Values for CRP of less than 1.0 mg/L represent low risk; 1.0 to 3.0 mg/L is intermediate cardiovascular risk; in patients with greater than 3.0 mg/L CRP is considered to be at high cardiovascular risk. The CRP assay was not originally designed for a high-sensitivity analysis, and previously was only used to measure much higher values than the levels used in cardiovascular risk assessment.

Tests Not Included for Cardiovascular Risk by the 2010 American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines for Asymptomatic Individuals

Homocysteine, LP(a) (primarily because of lack of standardized assays), fibrinogen (although immunoassays appear to provide better predictive data than functional clot-based assays), apolipoproteins (even though low apo A-I levels, associated with HDL, and high apo B-100 levels, associated with LDL, are found in patients with increased cardiac risk, neither parameter adds information beyond what is provided by HDL cholesterol and LDL cholesterol), lipoprotein particle size, lipoprotein density, natriuretic peptides, and genomic testing.

Metabolic Syndrome