Heart Health & Cardiovascular

Heart Health & Cardiovascular, Blood Disorders

The thromboplastin reagent used by LabCorp consists of recombinant tissue factor mixed with synthetic phospholipid. Recombinant tissue factor is free from contamination with coagulation factors that can be found in tissue factor extracted from other sources. This serves to increase the PT assay's sensitivity for factor efficiencies. Prothrombin time results are reported in seconds and are also converted to international normalized ratio (INR) values. The INR serves to normalize results obtained from different laboratories for the variable responsiveness of different thromboplastin reagents. Each thromboplastin is assigned an activity Index (ISI) based on comparison to an international reference thromboplastin from the World Health Organization. The formula for calculating the INR isINR = [patient's results / normal patient average](ISI)The ISI of the thromboplastin used in the LabCorp assay is near 1.0. The use of low ISI thromboplastin serves to improve the precision of therapeutic monitoring by enhancing sensitivity of the prothrombin assay.The PT is sensitive to deficiencies of extrinsic and common pathway factors X, VII, V, II, and fibrinogen.6-8The PT is more responsive to deficiencies of factors X and V than is the aPTT. Congenital deficiencies of these factors are relatively rare and cause bleeding disorders of varying severity. Refer to individual test descriptions for more information. Acquired deficiencies of the vitamin K-dependent factors II and VII may occur during warfarin therapy and in patients with vitamin K deficiency. Diminished levels of all the factors of the extrinsic pathway can also occur in consumptive coagulopathies, such as disseminated intravascular coagulation (DIC), and as the result of decreased factor production as can be seen with severe liver disease or malnutrition. Specific inhibitors of extrinsic pathway factors are extremely rare, but may produce a prolonged PT.6-8Lupus anticoagulants (LA) may cause a prolonged PT due to nonspecific factor inhibition. Some individuals with LA can develop antibodies that bind to and increase the rate of clearance of prothrombin (factor II). These patients typically have an extended PT due to reduced factor II level and an increased risk of bleeding.Coumarins, a family of compounds that inhibit the vitamin K-dependent carboxylation of several coagulation factors, are commonly used to limit fibrin clot formation in individuals with increased risk of venous or arterial thrombosis.10-12Warfarin, also referred to as Coumadin®, is the most commonly used coumarin in North America.11Overdosing with warfarin can increase the risk of hemorrhage and inadequate dosing decreases the efficacy of anticoagulation. Unfortunately, a large number of factors can affect the pharmacological potency of these oral anticoagulants. These factors are reviewed in considerable detail in the American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy.12Therapeutic monitoring is essential to maintain the dosage within the appropriate range range. Because the PT is sensitive to deficiencies of vitamin K-dependent factors II and VII, it is used to monitor warfarin therapy.Coumarins inhibit the carboxylation of procoagulant factors II, VII, IX, X, and anticoagulants proteins C and S to a similar extent. Steady-state levels of these proteins are all reduced to a similar degree, based on the dose and effectiveness of the oral anticoagulant given; however, during the initial days of treatment, the rate of decline of factor levels is dependent on their half-life. Since factor VII has a short half-life relative to other vitamin K-dependent factors, the levels of this factor drop much more precipitously than the others.11Superwarfarins, such as brodifacoum, are often found in rat poison and may cause prolongation of the PT. Patients suffering brodifacoum poisoning respond to vitamin K often bringing their PT into the normal range briefly, but since the drug is stored for long periods of time in fat, the PT rises again over time.

Heart Health & Cardiovascular

High CK is found after trauma, surgery, and exercise; these entities may not be accompanied by elevation of CK-MB. To distinguish myoglobinuria from hemoglobinuria, serum CK and LD may be helpful. CK is normal with uncomplicated hemolysis but LD and LD1usually are increased. When myoglobin is released, 40-fold elevation of CK may be anticipated with only moderate increase in serum LD and increased LD5.8

Heart Health & Cardiovascular, Diabetes & Blood Sugar

Investigation of serum lipids is indicated in those with coronary and other arterial disease, especially when it is premature, and in those with family history of atherosclerosis or of hyperlipidemia. In this sense, the expression “premature” is mostly used to include those younger than 40 years of age. Patients with xanthomas should be worked up with lipid panels but not those with xanthelasmas or xanthofibromas in the sense of dermatofibromas. Those whose fasting serum is lipemic should have a lipid panel, but the serum of a subject with high cholesterol (but normal triglyceride) is not milky in appearance. The patient with high cholesterol (>240 mg/dL) should have a lipid panel. Patients with cholesterol levels between 200−240 mg/dL plus two other coronary heart disease risk factors should also have a lipid panel.1In addition to application in screening programs for evaluation of risk factors for coronary arterial disease, lipid profiling may lead to detection of some cases of hypothyroidism.Primary hyperlipoproteinemiaincludes hypercholesterolemia, a direct risk factor for coronary heart disease.Secondary hyperlipoproteinemiaincludes increases of lipoproteins secondary to hypothyroidism, nephrosis, renal failure, obesity, diabetes mellitus, alcoholism, primary biliary cirrhosis, and other types of cholestasis.Decreasedlipids are found with some cases of malabsorption, malnutrition, and advanced liver disease. In abetalipoproteinemia, cholesterol is <70 mg/dL.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

This test measures the serum concentration of triglycerides and provides a calculated value for serum very low-density lipoprotein cholesterol (VLDL-C), which may be used to help assess cardiovascular disease (CVD)-related risk. VLDL is a carrier of serum cholesterol and the main carrier of triglycerides. Often, the VLDL-C test is ordered as part of a lipid profile to provide insight into overall CVD-related risk [1,2].Triglyceride testing is useful in classification of various lipoprotein disorders and aids in the assessment of risk factors for atherosclerosis, coronary heart disease, and metabolic syndrome. VLDL-C consists of triglyceride-rich lipoprotein particles. Upon entering the circulation, these particles are metabolized to intermediate-density lipoprotein cholesterol (IDL-C) and subsequently low-density lipoprotein cholesterol (LDL-C), a key factor in the pathogenesis of atherosclerosis and coronary heart disease [1,2].The results of this test should be interpreted in the context of pertinent clinical and family history as well as physical examination findings.References1. Grundy SM, et al.Circulation. 2019;139(25):e1082-e1143.2. Hilbert T, et al. Lipids and dyslipoproteinemia. In: McPherson RA, et al, eds.Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Saunders Elsevier; 2017:226-248.

Heart Health & Cardiovascular, Blood Disorders

Fibrinogen, also referred to as factor I, is a 340-kilodalton glycoprotein that is produced by the liver.6Fibrinogen has a plasma half-life of about four days. Proteolytic conversion of fibrinogen to fibrin occurs through both the extrinsic and intrinsic pathways.6Severe fibrinogen deficiency should be considered when a patient with bleeding history has both extended protime (PT) and activated partial thromboplastin time (aPTT).7,8Mild deficiency may not produce prolongation of either the aPTT or PT and, therefore, fibrinogen activity should be measured in individuals with a bleeding tendency even when the aPTT and PT are in the normal reference interval.Congenital afibrinogenemia, a condition associated with the complete absence of fibrinogen, is rare with only about 150 cases reported in the literature.6,7Fibrinogen deficiency is inherited as an autosomal recessive trait.7,8Afibrinogenemia occurs in individuals who are homozygous or doubly heterozygous for mutations. These individuals have infinite protime and aPTT results due to the inability to produce fibrin. Approximately 25% of patients with afibrinogenemia have mild thrombocytopenia.7Individuals who are heterozygous for congenital fibrinogen deficiency are usually asymptomatic unless their fibrinogen levels fall to <50 mg/dL.7Both functional (activity) and antigenic levels are diminished in these individuals.7Fibrinogen deficiency affects both males and females with a prevalence that is equal in all ethnic groups.7Acquired deficiencies occur in individuals with significant hepatic dysfunction, renal disease, and after L-asparaginase therapy.6Diminished levels can also be seen in patients with disseminated intravascular coagulation (DIC) or who are undergoing thrombolytic therapy.6Fibrinogen is one of the major determinants of the erythrocyte sedimentation rate and individuals with afibrinogenemia typically have greatly extended sedimentation rates.7Individuals with dysfibrinogenemia have fibrinogen that is qualitatively defective with low functional fibrinogen levels (activity) and normal or decreased antigenic levels.6Congenital dysfibrinogenemia is inherited as an autosomal dominant mutation.6A number of disfibrinogenemic defects have been identified with a variety of manifestations including abnormal fibrin polymerization, impaired fibrinopeptide release, abnormal fibrin stabilization, and abnormal fibrin clot lysis.6,7Fibrinogen activity and antigen levels are useful in the diagnosis of dysfibrinogenemia since these individuals often have diminished activity relative to antigen levels.8Typically, dysfibrinogenemia is associated with an elevated thrombin time and greatly elevated reptilase time.Individuals with afibrinogenemia have a bleeding tendency of varying severity.7Symptoms often start in early infancy with umbilical cord bleeding, intracerebral hemorrhage, or bleeding at circumcision.6-8Individuals with afibrinogenemia also suffer from deep muscle and joint bleeding and other mucous membrane bleeding throughout life.6Women with afibrinogenemia typically do not experience menorrhagia.8Patients with heterozygous hypofibrinogenemia usually have a minimal history of bleeding with symptoms only observed after major surgery or trauma.6,7Approximately 50% of individuals with dysfibrinogenemia are asymptomatic suffering neither bleeding nor thrombosis.6,7These individuals are usually detected when prolonged clotting times are discovered as a result of routine laboratory testing. About one in four will suffer prolonged bleeding after surgery and approximately 20% will have an increased tendency toward thrombosis.6A number of clinical and epidemiological studies have revealed a consistent association between elevated fibrinogen levels and increased risk for atherosclerotic vascular disease;11however, it remains to be determined whether increased fibrinogen acts as a mediator of arterial thrombosis or simply reflects the inflammation associated with atherosclerosis.11

Heart Health & Cardiovascular

See descriptions of individual tests.

Heart Health & Cardiovascular, General Health & Wellness

In the progressive dystrophies, aldolase levels may be 10 to 15 times normal when muscle mass is relatively intact, as in early stages of the disease. When advanced muscle wasting is present, values decline. In the inflammatory myopathies (eg, dermatomyositis) serum aldolase (as well as CK) levels may be applied to monitoring the response to steroid therapy. They are of particular value in guiding tapering of steroid administration.1No elevation is found in muscular dystrophy secondary to alteration of the nerves or nerve centers.Aldolase is present as a tetramer composed of two of three known subunits designated A, B, and C. Of the four isoenzymes, AAAA is predominant in skeletal muscle, BBBB predominates in liver, and CCCC in brain and other tissue. A hybrid isoenzyme, AAAC is present in tissues but at a lower concentration.2The enzymatic method determines total enzyme activity and thus is not specific for muscle aldolase.Elevated aldolase levels may be found with hepatitis, other liver diseases, myocardial infarction, hemorrhagic pancreatitis, gangrene, delirium tremens, and in some cases of neoplasia. In cases of acute viral hepatitis, increase in serum aldolase tends to parallel ALT (SGPT) levels and is usually up to 20 times the average of normal. Normal results are usually obtained in portal cirrhosis and obstructive jaundice. A small fraction of cases of measles in young adults has been reported to have significant elevations of serum CK and aldolase.3,4Serum aldolase and CK may be elevated in the serum of patients who have taken L-tryptophan and develop eosinophilia-myalgia syndrome.5

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

Be sure the patient is not on digitoxin instead of digoxin. Digitoxin is also an active component of digitalis leaf. The 2013 ACCF/HCA Guidelines for Management of Heart Failure suggest a therapeutic range of 0.5 -0.9 ng/mL for digoxin. Ninety percent of nontoxic patients have levels ≤2.0 ng/mL, 87% of toxic patients have levels >2.0 ng/mL. Levels >3.0 ng/mL in adults are strongly suggestive of overdosage. However,digitalis levels must always be interpreted in light of clinical and chemical data. Older, smaller patients require less digoxin. Proportionally lower loading doses are advocated in the elderly.1The primary cause of digoxin toxicity in the aged is decreased renal function. Maintenance doses should be adjusted to the glomerular filtration rate.1Renal failure, hypercalcemia, alkalosis, myxedema, hypomagnesemia, recent MI and other acute heart disease, hypokalemia, and hypoxia may increase sensitivity to the toxic effects of digoxin.Quinidinemay cause elevation of digoxin level by decreasing its excretion.2,3It is recommended that serum digoxin concentration be measured before initiation of quinidine therapy and again in four to six days.When confronted with unexpectedly low digoxin levels, consider thyroid disease, malabsorption, cholestyramine, colestipol, kaolin, pectin, neomycin, sulfasalazine, anticholinergic drug effects, and reduced intestinal blood flow from mesenteric arteriosclerosis. Consider as well congestive failure when low digoxin levels are encountered.Patients withdigitalis resistancemay require larger doses and higher than usual serum levels (eg, patients with hyperthyroidism).The probability that a patient will take a drug exactly as the physician has prescribed it has been shown to be hardly better than half. The probability is less among elderly patients getting a large number of medications. Measure trough, because of variability of peak interval.FAB fragments of digoxin-specific sheep antibodies are available for the treatment of digoxin toxicities but should be limited to potentially life-threatening overdoses.Compounds with “digoxin-like” immunoreactivity are present in a variety of clinical states associated with salt and fluid retention (eg, renal failure, pregnancy third trimester, congestive heart failure) and are also present during the first two weeks of neonatal life. These compounds (DLF−digoxin-like factors, etc) cross react with digoxin-specific immunoassays and give falsely elevated plasma digoxin levels. Laboratories must evaluate new antibody preparations for cross reactivity with the factors.

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

LD levels increased in rheumatoid and infectious arthritis and gout and normal in osteoarthritis.

Heart Health & Cardiovascular

Total LDL and HDL cholesterol, in conjunction with a triglyceride determination, provide valuable information for the risk of coronary artery disease. Total serum cholesterol analysis is useful in the diagnosis of hyperlipoproteinemia, atherosclerosis, hepatic and thyroid diseases.

Heart Health & Cardiovascular, Blood Disorders

Screening test for abnormalities of coagulation factors that are involved in the extrinsic pathway. Also used to monitor effects of Warfarin therapy and to study patients with hereditary and acquired clotting disorders.

Heart Health & Cardiovascular, Fitness & Performance

This test measures creatine kinase (CK), an enzyme found primarily in striated muscle and heart tissue, and may be useful in assessing muscle damage.CK is a dimeric enzyme composed of either 2 B subunits (CK-BB), 2 M subunits (CK-MM), or an M and a B subunit (CK-MB). CK-MM is the primary isoenzyme found in the skeletal muscle and heart tissue. CK-BB is mainly found in the brain and smooth muscle of gastrointestinal tract and urinary bladder. CK-MB is mainly found in the heart with a small amount in skeletal muscle [1]. An elevated level of any isoenzyme results in an elevated total CK level.An increase in the CK level is often observed in inflammatory myopathy (eg, viral myositis, polymyositis, and immune-mediated myopathies), muscular dystrophy (eg, Duchenne sex-linked muscular dystrophy), rhabdomyolysis, or malignant hyperthermia [1]. In patients with neuromuscular disorders, an increased CK level may be the only initial manifestation [1]. Increased CK activity may also be caused by hypothyroidism, acute myocardial infarction, chronic renal failure, direct muscle trauma (eg, surgery and intramuscular injection), excessive exercise, certain medications (eg, statins, fibrates, antiretrovirals, and angiotensin II receptor antagonists), or brain damage or very low birth weight in newborns [1].The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.Reference1. Panteghini M, et al. Serum enzymes. In: Rifai N, et al. eds.Tietz Textbook of Laboratory Medicine. 7th ed. Elservier Inc; 2022:4149-4299.

Heart Health & Cardiovascular, General Health & Wellness

Elevations in serum lactate dehydrogenase occur from myocardial infarction, liver disease, pernicious and megaloblastic anemia, pulmonary emboli, malignancies, and muscular dystrophy. Since lactic dehydrogenase is present in many body tissues, it's diagnosis usefulness is limited. Tissue specificity may be enhanced by isoenzyme analysis.

Diabetes & Blood Sugar, Heart Health & Cardiovascular

Insulin is useful in diagnosing hyperinsulinemia in hypoglycemic patients. Hyperinsulinemia may be due to an insulin-producing tumor (insulinoma), syndrome of insulin resistance, or persistent hyperinsulinemic hypoglycemia of infancy.

Heart Health & Cardiovascular, General Health & Wellness

The Lipid Panel, Standard measures serum cholesterol and triglyceride (TG) levels; it includes evaluation of the cholesterol/HDL-C ratio (calculated), HDL-C, LDL-C (calculated), non-HDL-C (calculated), total cholesterol, and TG. Comprehensive lipid assessment aids in the evaluation of cardiovascular risk and the likelihood of suffering an ischemic event. It is also useful for the prevention and management of atherosclerotic disease, as well as the diagnosis of metabolic syndrome [1].Cardiovascular disease (CVD) is the leading cause of death in the United States. The risk of developing CVD and having an ischemic event is significantly increased in individuals with high LDL-cholesterol (LDL-C) and TG levels [2,3]. The American Heart Association (AHA) recommends that Americans aged 20 and above have their lipid levels tested every 4 to 6 years. Children should have their cholesterol tested for the first time between ages 9 and 11, and again between ages 17 and 21. Testing should start earlier if there is family history of high cholesterol [4].The AHA recommends repeat measurement of LDL-C within 4 to 12 weeks of starting or changing lipid-lowering therapy, to assess response and adherence, and then every 3 to 12 months as appropriate [4].Treatment with N-acetyl cysteine (NAC) for acetaminophen overdose may generate a falsely low result for cholesterol. Venipuncture immediately after or during administration of the painkiller metamizole (dipyrone) may also lead to falsely low results for cholesterol.Note:Any or all individual tests from a panel can be ordered separately.References1. Stone NJ, et al.Circulation. 2014;129(suppl 2):S1-S45.2. CDC. Heart disease fact sheet. Reviewed August 23, 2017.https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_disease.htm3. Arbel Y, et al.Card Diabetol. 2016;15:11.4. AHA. Cholesterol management guide for healthcare practitioners. November 10, 2018.https://www.heart.org/-/media/files/health-topics/cholesterol/chlstrmngmntgd_181110.pdf

Heart Health & Cardiovascular, Diabetes & Blood Sugar

Offered as part of multiple lab tests

Heart Health & Cardiovascular

Measurement of lipoprotein(a) is now recommended in several patient subgroups for whom excess lipoprotein(a) may have important clinical consequences: (1) patients with premature atherosclerosis, (2) patients with a strong family history of premature coronary heart disease (CHD), (3) patients with elevated LDL-C and greater than or equal to two risk factors, (4) patients who have had coronary angioplasty in whom lipoprotein(a) excess may increase the risk of restenosis, and (5) patients who have undergone coronary bypass graft surgery in whom Lp(a) excess may be associated with graft stenosis.2,3Lipoprotein(a) has been called a powerful predictor of premature atherosclerotic vascular disease.2As an independent risk factor for premature coronary artery disease, excess Lp(a) concentrations are associated with an increased risk of cardiac death in patients with acute coronary syndromes and with restenosis after angioplasty (PTCA) and coronary bypass procedures. In general, concentrations greater than or equal to 75 nmol/L of Lp(a) in serum are associated with a two- to sixfold increase in risk, depending on the presence of other risk factors.

Heart Health & Cardiovascular

Phosphorus is sometimes significantly abnormal in lactic acidosis. Creatinine is higher in ketoacidosis than in lactic acidosis, by interference produced by acetoacetic acid on creatinine. Causes of lactic acidosis (usually <45 mg/dL) include carbohydrate infusions, exercise, diabetic ketosis, alcohol. Causes of lactic acidosis (>45 mg/dL) include shock (in which lactic acidosis may occur early, before fall in blood pressure, decrease in urine output), hypoxia (including congestive failure, severe anemia, hypotension) and malignancies. Severe lactic acidosis can develop in minutes. Lactic acidosis can accompany dehydration. Blood lactate concentration correlates negatively with survival in patients with acute myocardial infarction, with persistent elevation, >36 mg/dL for more than 12 hours, being associated with poor prognosis.5At a given bicarbonate level, the average pCO2is lower in lactic acidosis than in diabetic ketoacidosis. Lactic acid determination is generally indicated if anion gap is <20 and if pH is >7.25 and the pCO2is not elevated. (Mizock uses pH 7.35 as a diagnostic criterion.1) The measurement of lactate levels may be indicated in the clinical setting of metabolic acidosis. Serum salicylate, ethanol level, and osmolality may be helpful. Spontaneous lactic acidosis may be fatal. High CSF lactate levels suggest the meningitis is bacterial while low values suggest a viral cause.6

Heart Health & Cardiovascular, Diabetes & Blood Sugar

LDL cholesterol is a key factor in the pathogenesis of atherosclerosis and Coronary Artery Disease (CAD), while HDL cholesterol has often been observed to have a protective effect. Even within the normal range of total cholesterol concentrations, an increase in LDL cholesterol can produce an associated increased risk for CAD. LDL cholesterol binds to receptor sites on macrophages in blood vessel walls inciting several changes to the blood wall which enhance atherosclerotic plaque development.

Heart Health & Cardiovascular

Elevated concentrations of Lp(a) are associated with increased risk of coronary artery disease.

Heart Health & Cardiovascular

Fibrinogen is essential for the formation of a blood clot. Deficiency can produce mild to severe bleeding disorders.

Heart Health & Cardiovascular

The renin-angiotensin system and potassium ion are the major regulators of aldosterone secretion, whereas ACTH and other POMC peptides, sodium ion, vasopressin, dopamine, ANP, α-adrenergic agents, serotonin, and somatostatin are minor modulators.1,2Renin cleaves angiotensinogen, which is synthesized by the liver; to produce angiotensin I. Angiotensin I is, in turn, rapidly cleaved by angiotensin-converting enzyme (ACE) in the lung and other tissues to form angiotensin II. Angiotensin II stimulates aldosterone secretion and vasoconstriction. Factors that decrease renal blood flow, such as hemorrhage, dehydration, salt restriction, upright posture, and renal artery narrowing, increase renin levels which, in turn, raise aldosterone levels. In contrast, factors that increase blood pressure, such as high salt intake, peripheral vasoconstrictors and supine posture, decrease renin and aldosterone levels.3Aldosterone promotes active sodium transport and excretion of potassium.Hypokalemia increases and hyperkalemia decreases renin release.1Potassium also directly increases aldosterone secretion by the adrenal cortex and aldosterone then lowers serum potassium by stimulating its excretion by the kidney. High dietary potassium intake increases plasma aldosterone and enhances the aldosterone response to a subsequent potassium or angiotensin II infusion.3Primary hyperaldosteronism, also referred to as Conn syndrome, is caused by the overproduction of aldosterone by one or both of the adrenal glands.1,2Historically, primary aldosteronism was considered to be an uncommon cause of hypertension. However, recent studies indicate that 10% to 15% of cases are associated with primary hyperaldosteronism.4Secondary hyperaldosteronism is relatively common and can occur as the result of any condition that decreases blood flow to the kidneys (ie, renal artery stenosis), decreases blood pressure, or lowers plasma sodium levels. Secondary hyperaldosteronism may also be seen with cirrhosis, congestive heart failure, and toxemia of pregnancy.Hyperaldosteronism increases reabsorption of sodium and loss of potassium by the kidneys, resulting in an electrolyte imbalance.1,5The condition can be asymptomatic, although muscle weakness can occur if potassium levels are very low. A number of studies have suggested that high-normal aldosterone levels predict development of high blood pressure in normotensive subjects6and that increased aldosterone action contributes to hypertension, cardiovascular fibrosis, and cardiac hypertrophy.5-7

Heart Health & Cardiovascular

In 1971, Alaupovic suggested that apolipoproteins should be measured when assessing the relation of lipids and lipoproteins to CHD.2Many patients with CHD were found to have normal serum and cholesterol levels. It was postulated that the chemical composition of the lipoproteins was more important for understanding the process of CHD than their blood levels.Subsequent studies have demonstrated that apolipoproteins are better discriminators than lipids and lipoproteins in patients with CHD and their relatives.A number of studies have shown that apo A-1 and apo B correlate better with evidence of CHD than do lipoprotein measurements alone. In an investigation of first-degree relatives of patients with CHD, serum apo A-1 levels were significantly lower and apo B levels were significantly higher than those of healthy controls. Apo B was a better discriminator between male relatives, and apo A-1 was a better discriminator between female relatives and CHD patients. Furthermore, the percentage of correctly classified subjects increased by 12% when apo A-1 and apo B measurements were added as variables.Avogaro et al found that serum apo A-1 and apo B levels, as well as various ratios using apolipoprotein measurements, were the variables that best discriminated male myocardial infarction survivors from age- and sex-matched controls.3In 1983, Maciejko et al compared apo A-1 and HDL cholesterol measurements for their ability to identify male patients with angiographically assessed CHD.4Analysis of their results indicated that apo A-1 alone misclassified 12.9% of the individuals compared to a misclassification error of 21.3% for HDL cholesterol alone. When apo A-1 and HDL cholesterol were used in combination, a misclassification error of 10.6% resulted. More recent studies have drawn similar conclusions.When apo A-1, apo B, lipids, and lipoprotein cholesterol were measured in school-aged children (mean age of 10 years), apo A-1 and apo B levels were associated with a history of myocardial infarction in their parents. In striking contrast, the levels of serum lipids and lipoprotein-cholesterol values in these children were not related to myocardial infarction in either parent. Although no definite relationship between childhood apolipoprotein levels and adult CHD can be drawn, the results indicate that apolipoprotein measurements are more related to clinical disease than are conventional lipid measurements.5Although the relationship of triglyceride measurements and CHD remains controversial, apolipoprotein measurements may be of benefit in identifying patients with hypertriglyceridemia who are at risk for CHD. Maciejko has suggested that apo B levels are helpful in differentiating primary causes of hypertriglyceridemia, provided that secondary causes (diabetes, alcohol ingestion, uremia, acromegaly, emotional stress or stress from acute illness, and certain drugs such as estrogen or beta blockers) have been ruled out. In familial endogenous hypertriglyceridemia, the apo B concentrations will be low while the patient with hypertriglyceridemia from familial combined hyperlipidemia will have a high apo B level.Apolipoprotein measurements are also useful in the differentiation of familial hyper- or hypolipidemias. As mentioned, apo B may be used to differentiate familial combined hyperlipidemia from familial hypertriglyceridemia. Apo B measurements will also provide laboratory evidence of hyperapobetalipoproteinemia with excess apo B, whereas apo B deficiency states are found in abetalipoproteinemia, hypobetalipoproteinemia, familial hypobetalipoproteinemia with chylomicronemia, and abetalipoproteinemia with normotriglyceridemia. Apo A-1 deficiency states include Tangier disease, hypoalphalipoproteinemia, and HDL deficiency.These studies indicated that apolipoprotein measurements can provide clarification in a variety of clinical states involving dyslipidemias. The Maciejko, Kottke, and Naito studies have concluded that apolipoprotein concentrations have greater discrimination in classifying patients who have or are predisposed to CHD and are more stable parameters than are lipids and lipoproteins.6Lipids and lipoproteins are dynamic molecules whose concentration and composition are continually changing due to normal biologic variation, whereas apo A-1 and apo B levels are less affected, with change reflecting disease rather than biologic variability. In summary, apo A-1 and apo B measurements may be useful in the presence of the following conditions:• Borderline elevations of cholesterol• High cholesterol:HDL ratio with normal cholesterol• Borderline elevations of LDL• Normolipidemic children with a positive family history• Normolipidemic adults with a positive family history• Primary dyslipoproteinemias

Heart Health & Cardiovascular

Serum myoglobin is rapidly cleared by the kidneys. Urine myoglobin levels were not detected after myocardial infarct.4Elevated myoglobin levels may be associated with cocaine abuse.5Other conditions which cause elevation of serum myoglobin include open heart surgery, exercise, progressive muscular dystrophy, shock, and renal failure.1It is increased in azotemic subjects and not effected by dialysis.6

Heart Health & Cardiovascular, Diabetes & Blood Sugar

LP-IR is a marker of insulin resistance, and as such the LP-IR score predicts a patient's likelihood of future development of T2D.1-4LP-IR is a multimarker index (values 0-100) based on the concentrations of particular lipoprotein subclasses [very large and large triglyceride-rich lipoprotein particles (VLL-TRLP), small low density lipoprotein particles (S-LDLP), large high density lipoprotein particles (L-HDLP), and mean TRL, LDL, and HDL particle sizes (TRLZ, LDLZ, HDLZ)]. The medical decision limits established for LPIR are <50 (low), 50-80 (intermediate), and >80 (high) with these cutpoints corresponding to the 25th and 75th percentiles in a normal population. DRI builds on the effective insulin resistance assessment by LP-IR and adds the measurement of BCAA. Similar to LP-IR, BCAA have also been shown to predict incident T2DM.5,6The analytes contributing to DRI are measured by mathematical deconvolution of the methyl signal region of the plasma/serum NMR spectrum. This algorithm is different from the NMR LipoProfile test in that the methyl region is extended downfield to include signals from the BCAA (valine and leucine).

Heart Health & Cardiovascular, General Health & Wellness

Aids in the diagnosis of primary disease of skeletal muscle myocardial infarction and viral hepatitis.

Heart Health & Cardiovascular, Nutrition & Vitamins

Severe homocysteinemia is typically caused by a rare inborn error of metabolism.1,2The most common defect that can produce levels >100 μmol/L is homozygous cystathionine-β-synthase (CS) deficiency, which occurs with an incidence of 1 per 300,000 live births. About 1% of the population has heterozygous CS deficiency, a condition that typically results in moderate to intermediate hyperhomocysteinemia. Individuals with CS deficiency are at increased risk for occlusive vascular disease.1,2Individuals with a thermolabile variant of the enzyme methylene-tetrahydrofolate reductase can have high normal to moderately elevated levels of homocysteine.1,2Homocysteine can be considered to be an independent risk factor for the development of cardiovascular disease.1-3Patients with cardiovascular disease, including heart disease, stroke, peripheral vascular disease, and thromboembolic disease generally have higher homocysteine levels than matched controls. The results of a large number of epidemiological studies have been analyzed through a meta-analysis.1The increased risk, or odds ratio (OR), for coronary artery disease in patients with increased homocysteine levels was estimated to be 1.7. The OR for stroke was estimated to be 2.5 and the OR for peripheral vascular disease was estimated to be 6.8. Several conditions, other than specific genetic defects or cardiovascular disease, have been associated with hyperhomocysteinemia.1These include vitamin deficiency, advanced age, hypothyroidism, impaired kidney function, and systemic lupus erythematosus. Medications including nicotinic acid, theophylline, methotrexate, and L-dopa have been reported to cause elevated homocysteine levels.

Heart Health & Cardiovascular, Autoimmune & Inflammation

Useful in predicting risk for cardiovascular disease.

Heart Health & Cardiovascular, Blood Disorders

PT/INR:Screening test for abnormalities of coagulation factors that are involved in the extrinsic pathway. Also used to monitor effects of Warfarin therapy and to study patients with hereditary and acquired clotting disorders.aPTT:The aPTT is a screening test that will detect deficiencies or inhibitors to the intrinsic (Factors VIII, IX, XI and XII) and common (Factors II, V, X and Fibrinogen) pathway coagulation factors.

Heart Health & Cardiovascular, Blood Disorders

SeeAntithrombin (AT) Deficiency Profile [015594]for more clinical information.

Heart Health & Cardiovascular

Coagulation activation results in the cleavage of fibrinogen to fibrin monomer.7,8The fibrin monomers spontaneously aggregate to fibrin and are cross-linked by factor XIII; this produces a fibrin clot. In response to the coagulation process the fibrinolytic system is activated resulting in the conversion of plasminogen into plasmin, which cleaves fibrin (and fibrinogen) into the fragments D and E. Due to cross-linkage between D-domains in the fibrin clot, the action of plasmin releases fibrin degradation products with cross-linked D-domains. The smallest unit is D-dimer. Detection of D-dimers, which specifies cross-linked fibrin degradation products generated by reactive fibrinolysis, is an indicator of coagulation activity. Fibrin degradation products are not consistently "D-dimer" but are a mixture of fragments and complexes of different molecular weight. The presence of D-dimer confirms that both thrombin and plasmin have been generated since it can only be produced as the result of the plasmin degradation of cross-linked fibrin. The in vivo half-life of D-dimer is approximately eight hours.11Elevated D-dimer levels are observed in all diseases and conditions with increased coagulation activation, eg, thromboembolic disease, DIC, acute aortic dissection, myocardial infarction, malignant diseases, obstetrical complications, third trimester of pregnancy, surgery, or polytrauma.12-17However, in the context of venous thromboembolism, symptoms being present since a certain period of time, eg, longer than a week, may produce normal D-dimer values.18For the diagnosis of DIC a scoring system has been suggested, in which elevated D-dimer levels represent the major indicator of DIC.12While increased levels of D-dimer are not specific for DVT or PE, low D-dimer levels may be used to rule out these conditions. The negative predictive values for DVT and PE are approaching 100% for the Innovance D-dimer assay employing a cutoff of <0.5 mg/L FEU. The negative predictive value is further enhanced through the use of a clinical probability model along with D-dimer in the decision process.12-15Values less than 0.5 mg/L FEU in an individual with a low clinical risk of venous thrombosis can serve as the basis for not performing more expensive diagnostic tests for DVT and PE. Patients with results greater than this cutoff require further diagnostic testing to establish the diagnosis.D-dimer levels are known to increase with age; eg, median D-dimer levels in apparently healthy men aged 75 to 79 are about twice as high as in men aged 60 to 64.19This increase in the basal D-dimer concentration is responsible for the decrease in the specificity of D-dimer measurements for exclusion of VTE in the elderly. Several studies on D-dimer for exclusion of venous thromboembolism (VTE) have been reëvaluated using an age-specific cutoff.20-23The aim was to improve the effectiveness of D-dimer testing in ruling out VTE.20-23The cutoff provided with the patient result is the manufacturer-determined value for exclusion of VTE; however, it has been determined that D-dimer values increase with age, and this can make VTE exclusion of an older population difficult. To address this, the American College of Physicians, based on best available evidence and recent guidelines, recommends that clinicians use age-adjusted D-dimer thresholds in patients greater than 50 years of age with:(a)a low probability of PE who do not meet all "pulmonary-embolism-rule-out criteria," or(b)in those with intermediate probability of PE.21The formula for an age-adjusted D-dimer cutoff is "age/100." For example, a 60-year-old patient would have an age-adjusted cutoff of 0.6 mg/L FEU, and an 80-year-old patient would have an age-adjusted cutoff of 0.8 mg/L FEU.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

This is the most common Lipid Panel. Components include those useful in the detection, classification, and monitoring of patients with hyperlipidemia.

Heart Health & Cardiovascular, Genetic Testing

Elevated concentrations of Lp(a) are associated with increased risk of coronary artery disease.

Heart Health & Cardiovascular, Blood Disorders

Thrombin time will be extended when functional fibrinogen levels are <100 mg/dL.6,7This can occur due to congenital conditions including afibrinogenemia (complete lack of fibrinogen), hypofibrinogenemia, and in dysfibrinogenemia, a condition characterized by the presence of dysfunctional fibrinogen. Acquired conditions can lead to diminished fibrinogen levels and extended thrombin times include liver disease, renal disease, disseminated intravascular coagulation (DIC), amyloidosis, malignancy, and thrombolytic therapy.6Thrombin inhibitors including heparin, argatroban, and hirudin will cause an extended thrombin time.7

Heart Health & Cardiovascular, Fitness & Performance

Creatine kinase (CK) is an enzyme, found primarily in muscle and brain tissue, which exists as three dimeric isoenzymes: CK-MM (CK-3), CK-MB (CK-2), and CK-BB (CK-1) − built from subunits designated M and B. The CK-MB isoenzyme, which has a molecular mass of approximately 87 kilodaltons, accounts for 5% to 50% of total CK activity in myocardium. In skeletal muscle, by contrast, it normally accounts for ≤1%, CK-MM being the dominant form, though the percentage can be as high as 10% in conditions reflecting skeletal muscle injury and regeneration (eg, severe exercise, muscular dystrophy, polymyositis).1CK-MB is one of the most important myocardial markers (in spite of not being altogether cardiac-specific), with well-established roles in confirming acute myocardial infarction (AMI) and in monitoring reperfusion during thrombolytic therapy following AMI.1In AMI, plasma CK-MB typically rises some four to six hours after the onset of chest pains, peaks within 12 to 24 hours, and returns to baseline levels within 24 to 48 hours. The pattern of serial CK-MB determinations is more informative than a single determination: one CK-MB measurement, even when taken at an appropriate time, cannot definitively confirm or rule out the occurrence of AMI. High levels might reflect skeletal injury rather than myocardial damage. A value within the reference range might be significant if it represents an increase from the patient's baseline level. (Low baseline levels are sometimes encountered in the elderly.) Accordingly, it has been recommended that CK-MB be measured on admission to the emergency room and at intervals thereafter (eg, at three-hour intervals over a six-hour to nine-hour period in patients with nonspecific electrocardiogram changes;1,2or at six-hour to eight-hour intervals over a 24-hour period and more frequently if thrombolytic therapy has been instituted).1

Heart Health & Cardiovascular, Fitness & Performance

CK-MB isusually not elevated inexercise (total CK elevated); myxedema (total CK elevated in about half of cases); injections into muscle (total CK elevated); strokes, CVA, and other brain disorders in which total CK may be increased; pericarditis; pneumonias or other lung diseases; pulmonary embolus; seizures (CK may be very high but no great MB increase, if any). Although CK-MB is not usually increased in angina, some CK-MB elevations are recognized in angina patients, depending partly on laboratory methodology.

Heart Health & Cardiovascular

Total cholesterol and triglycerides are required as well for determination of lipid risk factors for coronary artery disease. These tests with HDL-C and LDL-C are the usual lipid profile. HDL-C is especially apt to be low in male subjects who are obese and sedentary, in those who smoke cigarettes, and in those who have diabetes mellitus. Uremia is also associated with lower HDL-C. Exercise, appropriate diet and moderate ethanol intake increase HDL-C.HDL-C is useful with cholesterol in forecasting protection against coronary artery disease in the industrialized countries, possible because of ingestion of high fat diets.Those at least risk for development of coronary arterial disease have low cholesterol, low triglycerides, and high HDL-C.Factors contributing to decreased HDL-C include:• Genetic factors: primary hypoalphalipoproteinemia6• Cigarette smoking7• Obesity7• Hypertriglyceridemia7• Lack of exercise• Steroids − androgens, progestogens, anabolic• Thiazides• Beta-adrenergic blockers• Probucol• Neomycin

Heart Health & Cardiovascular

Apolipoprotein B (APO B) has been reported to be a powerful indicator of CAD. In some patients with CAD, APO B is elevated even in the presence of normal LDL cholesterol.

Heart Health & Cardiovascular

There is a correlation between increased risk of premature heart disease with decreasing size of LDL particles. Ion mobility offers the only direct measurement of lipoprotein particle size and concentration for each lipoprotein from HDL3 to large VLDL.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommend matching the intensity of statin treatment with the absolute risk of cardiovascular events. However, the standard lipid panel alone does not provide a complete assessment of absolute risk of CVD. Adding advanced CVD markers (ion mobility, apob, lp(a), hs crp and lppla2) in addition to the lipid panel will improve assessment of the CVD risk.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The Lipid Panel with Reflex to Direct LDL panel includes evaluation of total cholesterol, HDL-cholesterol, triglyceride (TG), LDL-cholesterol (calculated), cholesterol/HDL ratio (calculated), and non-HDL cholesterol; direct LDL-C measurement will be performed at additional cost if the TG level is >400 mg/dL. This panel is useful in the detection, classification, and monitoring of hyperlipidemia, especially those expected to have highly elevated TG levels.LDL-C is widely accepted as a key factor for assessing the risk of coronary artery disease (CAD) [1]. The American Heart Association recommends lipid testing for adults over the age of 20 every 4 to 6 years [2]. Direct LDL-C measurement is more accurate than calculated LDL-C for patients with TG levels >400 mg/dL, and patients with hyperlipoproteinemia type III (dysbetalipoproteinemia). Thus, as indicated above, this panel is especially useful for individuals likely to have highly elevated TG and provides a basis for more realistic assessment of CAD risk in this group. It may also help track treatment progress by allowing healthcare practitioners to evaluate overall lipid levels, as well as direct LDL-C [3].In addition to genetic causes that lead to highly elevated TG levels, certain medical conditions can also increase TG, including diabetes, thyroid disease, liver and kidney diseases, and obesity [4].Calculated LDL values have a variance of 11% to 26%, whereas direct LDL-C values have a variance of less than 4% [5].In rare cases, gammopathy, especially monoclonal IgM (Waldenstrom’s macroglobulinemia), may cause unreliable results.References1. Grundy SM, et al.Circulation. 2019;139:e1082-e1143.2. Stone NJ, et al.Circulation. 2014;129 (suppl 2):S1-S45.3. Armbruster DA, Lambert PA.Lab Med. 1996;9:613-617.4. NHLBI. High blood triglycerides.https://www.nhlbi.nih.gov/health-topics/high-blood-triglycerides.5. Schectman G, et al.Clin Chem. 1994;39:1495-1503.

Heart Health & Cardiovascular

The sdLDL test is used in conjunction with other lipid measurements and clinical evaluations to aid in the risk management of lipoprotein disorders associated with cardiovascular disease.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

This is the most common Lipid Panel. Components include those useful in the detection, classification, and monitoring of patients with hyperlipidemia.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The advanced lipid profile provides a more comprehensive assessment of dyslipidemia and cardiovascular risk than standard lipid panel measurements.

Heart Health & Cardiovascular, Nutrition & Vitamins

An elevated concentration of Homocysteine is an independent risk factor for cardiovascular disease.

Heart Health & Cardiovascular

The oxidized LDL test may be ordered for individuals at low or intermediate risk of metabolic syndrome or cardiovascular disease. In addition, this test is useful in individuals who have cardiovascular disease and are at risk for an adverse cardiac event.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The NMR LipoProfile® test is a blood test that directly measures the amount of LDL circulating in the body. “LDL” is low-density lipoprotein and has long been recognized as a major causal factor in the development of heart disease. Although the relationship of increased LDL particle number and plaque buildup in the artery wall has been known since the 1950s, a diagnostic test did not exist to measure LDL particle number (LDL-P). Historically, LDL cholesterol, or LDL-C, has been used to estimate LDL levels to assess a patient’s LDL-related cardiovascular risk and judge an individual’s response to LDL-lowering therapy. The NMR LipoProfile® test reports results for LDL-P, a more reliable measure of LDL that directly counts the number of LDL particles a patient has using NMR technology.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The NMR LipoProfile® test is a blood test that directly measures the amount of LDL circulating in the body. “LDL” is low-density lipoprotein and has long been recognized as a major causal factor in the development of heart disease. Although the relationship of increased LDL particle number and plaque buildup in the artery wall has been known since the 1950s, a diagnostic test did not exist to measure LDL particle number (LDL-P). Historically, LDL cholesterol, or LDL-C, has been used to estimate LDL levels to assess a patient’s LDL-related cardiovascular risk and judge an individual’s response to LDL-lowering therapy. The NMR LipoProfile® test reports results for LDL-P, a more reliable measure of LDL that directly counts the number of LDL particles a patient has using NMR technology.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

The NMR LipoProfile® test is a blood test that directly measures the amount of LDL circulating in the body. “LDL” is low-density lipoprotein and has long been recognized as a major causal factor in the development of heart disease. Although the relationship of increased LDL particle number and plaque buildup in the artery wall has been known since the 1950s, a diagnostic test did not exist to measure LDL particle number (LDL-P). Historically, LDL cholesterol, or LDL-C, has been used to estimate LDL levels to assess a patient’s LDL-related cardiovascular risk and judge an individual’s response to LDL-lowering therapy. The NMR LipoProfile® test reports results for LDL-P, a more reliable measure of LDL that directly counts the number of LDL particles a patient has using NMR technology.

Heart Health & Cardiovascular

TMAO is a dietary metabolite produced by a pathway involving gut microbiota. TMAO concentrations increase in the blood after ingestion of dietary choline and L-carnitine, which are abundant in meat, eggs, liver, and wheat germ and energy drinks. Choline and L-carnitine are metabolized in the gut by microbiota to form trimethylamine (TMA), which is subsequently oxidized in the liver into TMAO by flavin monooxygenases (FMOs). TMAO concentrations have been shown to be reduced in animals and humans treated with broad-spectrum oral antibiotics confirming the requirement for gut bacteria in the formation of TMA and TMAO.2-6TMAO has been hypothesized to promote atherosclerosis by upregulating macro-phage scavenger receptor activity and downregulating bile acid synthesis which together reduce reverse cholesterol transport.2-6

Heart Health & Cardiovascular

The oxidative conversion of low density lipoproteins (LDL) to oxidized low density lipoproteins (oxidized LDL) is now considered to be a key event in the biological process that initiates and accelerates the development of the early atherosclerotic lesion, the fatty streak.1-5Experimental studies have shown that native LDL becomes atherogenic when it is converted to oxidized LDL, and that oxidized LDL is more atherogenic than native LDL.1-5Oxidized LDL is found in monocyte-derived macrophages in atherosclerotic lesions, but not in normal arteries.6The uptake of LDL into macrophages does not occur by way of the classic Brown/Goldstein LDL receptor.7Numerous studies1-5,8have established that LDL, the major carrier of blood cholesterol, must first be converted to oxidized LDL so that it can be recognized by "scavenger" or "oxidized LDL receptors" on monocyte-derived macrophages. The binding of oxidized LDL to macrophages is a necessary step by which oxidized LDL induces cholesterol accumulation in macrophages, thus transforming the macrophages into lipid-laden foam cells.8

Heart Health & Cardiovascular

The Clinical Guidelines Subcommittee of the Endocrine Society has produced a practice guideline for the detection, diagnosis, and treatment of patients with primary aldosteronism (PA).1Primary aldosteronism (PA) is defined as a group of disorders in which aldosterone production is inappropriately high, relatively autonomous, and nonsuppressible by sodium loading.1This inappropriate production of aldosterone can result in cardiovascular damage, suppression of plasma renin, hypertension, sodium retention, and potassium excretion that can lead to hypokalemia. PA is commonly caused by an adrenal adenoma, by unilateral or bilateral adrenal hyperplasia, or, in rare cases, by the inherited condition of glucocorticoid-remediable aldosteronism (GRA).In the past, clinical guidelines indicated that hypokalemia was required for the diagnosis of PA. As a result, PA was considered to be a relatively uncommon cause of hypertension, accounting for <1% of cases;2,3however, more recent studies have challenged these assumptions. Cross-sectional and prospective studies report PA in >10% of hypertensive patients, both in general and in specialty settings.4-12Only a small subset of these patients with PA (9% to 37%) had hypokalemia.13These studies indicate that normokalemic hypertension constitutes the most common presentation of the disease, with hypokalemia probably present in only the more severe cases. In fact, the presence of hypokalemia has low sensitivity and specificity, and a low positive predictive value for the diagnosis of PA.1The new consensus guideline1recommends that case detection of primary aldosteronism (PA) should be undertaken in patient groups with relatively high prevalence of PA. These include patients with:• Joint National Commission (JNC) stage 2 (>160−179/100−109 mmHg), or stage 3 (>180/110 mmHg) hypertension• Drug-resistant hypertension• Hypertension and spontaneous or diuretic-induced hypokalemia• Hypertension with adrenal incidentaloma• Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years).The new consensus guideline1also recommends case detection for all hypertensive first-degree relatives of patients with PA. The consensus group went on to recommend the use of the plasma aldosterone:renin ratio (ARR) to detect cases of PA in these patient groups.14-20The ARR is calculated as the ratio of the serum aldosterone (in ng/dL) divided by serum plasma renin activity (in ng/mL/hour). The guideline indicates that the diagnosis of PA provides the opportunity for health benefits provided by curative approaches including surgery or improved control of hypertension through specific medical treatment.The consensus guideline recommended that patients with a positive ARR should proceed to confirmatory testing by any of four confirmatory tests described within the document and listed below to definitively confirm or exclude the diagnosis.11. Oral sodium loading2. Saline infusion3. Fludrocortisone suppression4. Captopril challengeRefer to the consensus document for a more detailed description of the confirmatory test.1

Heart Health & Cardiovascular, Nutrition & Vitamins

An elevated concentration of homocysteine is an independent risk factor for cardiovascular disease. When used in conjunction with methylmalonic acid (MMA), these tests are useful to diagnose and monitor vitamin B12 (cobalamin) and folic acid deficiency and are often useful in evaluating macrocytosis (an elevated MCV, an erythrocytic index).

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

The GlycA test quantifies an NMR signal that appears in a region of theNMR LipoProfile®test spectrum separate from that used for lipoprotein particle analysis. Data indicate that this signal is a marker of systemic inflammation, suggesting it may have clinical utility similar or complementary to high sensitivity C-reactive protein (hsCRP), fibrinogen, and other biomarkers of inflammation.1,2The NMR signal, named "GlycA," originates from the N-acetyl methyl groups of the N-acetylglucosamine moieties on the carbohydrate portions of circulating glycoproteins.1,3The measured amplitude of this signal reflects the extent of plasma protein glycosylation (not to be confused with nonenzymatic glycation reflecting glucose levels). Most acute phase proteins, released from the liver during an inflammatory response, are glycosylated, and some are glycosylated differentially as a function of inflammation. Acute-phase proteins, such as α1-acid glycoprotein (also known as orosomucoid), haptoglobin, α1-antitrypsin, α1-antichymotrypsin, and transferrin circulate at high enough concentrations to make major contributions to the GlycA signal.1Therefore, GlycA is hypothesized to be a nonspecific measure of global inflammation status.Unlike existing biomarkers of inflammation that are discrete molecular species, such as CRP or inflammatory cytokines, GlycA is a composite biomarker that integrates the protein levels and glycosylation states of several of the most abundant acute-phase proteins in serum. This allows for a more stable measure of systemic inflammation with lower intra-individual variability for GlycA than hsCRP.1While guidelines recommend two serial measurements be taken at least two weeks apart when using hsCRP for CV disease risk assessment, only one measurement is necessary for evaluation of a patient's CV risk using the GlycA test.

Heart Health & Cardiovascular

Apolipoprotein A1 is the primary protein associated with HDL cholesterol. Like HDL cholesterol, increased concentrations are associated with reduced risk of cardiovascular disease.

Heart Health & Cardiovascular

This test measures creatine kinase (CK) isoenzymes and may be useful in assessing disorders associated with muscle damage. Fractions of CK isoenzymes relative to total CK levels are reported.Creatine kinase (CK) is a dimeric enzyme composed of either 2 B subunits (CK-BB), 2 M subunits (CK-MM), or an M and a B subunit (CK-MB). CK-MM is the primary isoenzyme found in the skeletal muscle and heart tissue. CK-BB is mainly found in the brain and smooth muscle of gastrointestinal tract and urinary bladder. CK-MB is mainly found in the heart with a small amount in skeletal muscle [1].An increase in the CK level is often observed in inflammatory myopathy (eg, viral myositis, polymyositis, and immune-mediated myopathies), muscular dystrophy (eg, Duchenne sex-linked muscular dystrophy), rhabdomyolysis, or malignant hyperthermia [1]. In patients with neuromuscular disorders, an increased CK level may be the only initial manifestation [1]. Other causes of elevated CK levels include hypothyroidism, direct muscle trauma (eg, surgery and intramuscular injection), excessive exercise, and certain medications (eg, statins, fibrates, antiretrovirals, and angiotensin II receptor antagonists) [1].The quantitation of CK-MB levels in serum was widely used to diagnose acute myocardial infarction but has been replaced by troponin I and T levels, which are more cardiac-specific [2,3]. CK-MB measurement, preferably expressed as CK-MB relative to the total CK level, is only indicated in patients with suspected acute coronary syndrome or reinfarction when troponin T and I testing are not available [2]. In individuals with chronic muscle damage/disease or chronic renal failure, CK-MB may account for the elevation of CK levels owing to the phenomenon of "fetal reversion" [1].CK-BB levels may be increased in newborns with brain damage or very low birth weight, although healthy newborns can also have increased CK-BB levels as a result of birth related muscle trauma [1].The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.References1. Panteghini M, et al. Serum enzymes. In: Rifai N, et al. eds.Tietz Textbook of Laboratory Medicine. 7th ed. Elservier Inc; 2022:4149-4299.2. CKMB: optimal testing recommendations. AACC. Accessed October 11, 2022.https://www.aacc.org/advocacy-and-outreach/optimal-testing-guide-to-lab-test-utilization/a-f/ckmb

Heart Health & Cardiovascular

Lactic acid is the endproduct of the anaerobic metabolism of glucose. The blood lactic acid concentration is affected by its production in muscle cells and erythrocytes and its rate of metabolism in the liver. During exercise, blood lactate can increase up to ten times of normal levels.

Heart Health & Cardiovascular, Diabetes & Blood Sugar

Offered as part of multiple lab tests

Hormone Testing, Heart Health & Cardiovascular

Approximately 1-2% of individuals with primary hypertension have primary hyperaldosteronism characterized by hypokalemia (low potassium) and low direct renin. Because serum aldosterone concentrations vary due to dietary sodium intake and body positions, some physicians prefer measurement of 24-hour urine concentrations for aldosterone.

Heart Health & Cardiovascular

Patterns of LD isoenzymes in acute pulmonary edema include the isomorphic pattern and LD5increases.8Serum LD increases also in patients with bacterial pneumonia, in whom LD isoenzyme patterns are described.9Macroenzymes, high molecular weight complexes, occur with LD as well as with CK and other enzymes. LD isoenzymes may complex to IgA or IgG. Such LD macroenzymes are characterized by abnormal position of isoenzyme bands, broadening or abnormal motility of a band and otherwise unexplained increase of total serum LD. Some of these patients have abnormal ANA results and IgG complexes.10Some have abnormalities of light chains.11Treatment with streptokinase was found to produce a LD-streptokinase complex which was seen as a band at the origin in electrophoresis.12An isoenzyme band cathodal to LD5has been calledLD6. It is not an immunoglobulin complex. It has occurred in subjects with liver disease and is said to indicate a grave prognosis.10,13,14The association between LD1and testicular seminoma has been widely recognized. Its relationship to nonseminomatous testicular tumors as well is described.15The ovarian equivalent of seminoma is dysgerminoma, which also may relate to LD1increases.16,17A variety of malignant tumors are characterized by total LD increases, sometimes with isomorphic patterns7or with LD5increases.18Increased LD5:LD1ratio is suggestive of prostatic carcinoma or other cancers.19Increases in LD1:LD4ratio was found to be a good indicator of MI.20In a series of 220 patients with carcinoma of breast, LD was the most common enzyme elevated. The nonspecificity of single enzyme elevation was discussed, but enzymes provide an inexpensive baseline for postoperative follow-up. Enzyme elevation defines a subgroup of patients deserving further evaluation.21In malignancy of various types, there is reported an abnormal isoenzyme of LD migrating between albumin and LD1on agarose gel electrophoresis.22An inverted LD5:LD4ratio is not to be confused with LD1:LD2ratio, used to evaluate acute MI. There is evidence that when LD5sufficiently exceeds LD4, liver disease might exist. Such liver disease might be primary or secondary (eg, congestive heart failure). Additional tests which may be useful, if clinically indicated, to work up such possible liver disease or injury might include ALT (SGPT), GGT, serum protein electrophoresis, and prothrombin time. LD5is the striated muscle as well as the liver fraction. Although striated muscle problems are usually clinically obvious, occasionally the physician does not get a clinical history of the postictal state or of various withdrawal syndromes. In such situations, a CK may be helpful.

Heart Health & Cardiovascular

Lactate dehydrogenase (LD) is present in many different organs and tissues such as liver, heart, muscles, kidney, lungs and blood. The usual designation of isoenzymes is LD-I, LD-II, LD-III, LD-IV and LD-V. LD isoenzymes tissue specificity is derived from the fact that LD subunits are synthesized in well-defined ratios and could be used in investigating unexplained causes of Total LD elevations and detection of macro-LD. Do not use LD isoenzymes to detect myocardial injury.

Heart Health & Cardiovascular

SeeProtein C Deficiency Profile [283655]for more clinical information.

Heart Health & Cardiovascular, General Health & Wellness

Troponin T (TnT) is a component of the contractile apparatus of the striated musculature. Although the function of TnT is the same in all striated muscles, the cardiac isoform of TnT originating exclusively from the myocardium clearly differs from skeletal muscle TnT. As a result of its high tissue‐specificity, cardiac troponin T (cTnT) is a cardio‐specific, highly sensitive marker for myocardial damage. Cardiac troponin T increases rapidly10after acute myocardial infarction (AMI) and may persist up to 2 weeks thereafter.11,12In contrast to ST‐elevation myocardial infarction (STEMI), the diagnosis of non‐ST elevation myocardial infarction (NSTEMI) relies heavily upon elevated cardiac troponin (cTn) concentrations in the appropriate clinical context. The Third Universal Definition of Myocardial Infarction (MI) has confirmed cTn as the biomarker of choice.13Diagnosis of MI is made with acute changes in cTn concentrations with at least one serial sample above the 99th percentile upper reference limit (URL), taken together with evidence of myocardial ischemia (symptoms, electrocardiogram (ECG) changes or imaging results). Various guidelines and publications recommend the optimal imprecision (coefficient of variation) of cTn assays at the 99th percentile upper reference limit be less than or equal to 10%.10,13-17Several guidelines and research activities recognize that improved analytical sensitivity of cTn assays during the last several years has allowed for detection of other etiologies. Chronic cTn elevations can be detected in clinically stable patients such as patients with ischemic or non‐ischemic heart failure,18,19patients with different forms of cardiomyopathy,20renal failure,21-27sepsis,28and diabetes.29Elevated concentrations of cTn can also occur in other clinical conditions such as myocarditis,30heart contusion,31pulmonary embolism,32and drug‐induced cardiotoxicity.33To distinguish between acute and chronic cTn elevations, the Universal Definition of MI stresses the need for serial sampling to observe a rise and/or fall of cTn above the 99th percentile upper reference limit consistent with the clinical assessment, including ischemic symptoms and electrocardiographic changes.13Troponin elevations may persist for up to 14 days or occasionally longer.13Other diagnostic tests such asNT‐proBNP and CRP can complement the diagnostic and prognostic information of cTnT in different indications.By current universal definition of the disease (AMI), the 99th percentile URL should be used as a diagnostic cutoff of AMI,13and is endorsed by major local guidelines.10,16,34Higher cutoffs produce higher estimates of clinical specificity and positive predictive value (PPV), but tend to underestimate clinical sensitivity and negative predictive value (NPV).35When switching to the Elecsys Troponin T Gen 5 STAT assay, users should be aware that the guideline compliant test using the 99th percentile URL as a diagnostic cutoff, can lead to a relative increase in the diagnosis of acute MIs compared to contemporary assays using other, often higher cutoffs.10,36-38

Heart Health & Cardiovascular, Diabetes & Blood Sugar

Offered as part of multiple lab tests

Diabetes & Blood Sugar, Heart Health & Cardiovascular

The MVX test produces a multimarker score (MVX values 1-100) that is proportional to a patient's relative risk of all-cause death occurring in the approximate near term (within about 10 years), independent of age and other mortality risk factors. The MVX score is calculated from measured concentrations of six serum metabolites that are combined into two "sub-index" scores considered to reflect mainly the inflammatory and malnutrition elements of the intertwined metabolic malnutrition-inflammation syndrome. These "sub-index scores" are the Inflammation Vulnerability Index (IVX), derived from levels of GlycA and small HDL particles, and Metabolic Malnutrition Index (MMX), derived from levels of the three branched-chain amino acids (valine, leucine, isoleucine) and citrate.MVX scores were associated with one-year and five-year mortality.1,2MVX scores are related to mortality risk irrespective of cause (e.g., CV death and non-CV death). Associations of MVX with all-cause mortality were similar in men and women and are independent of risk factors (e.g., BMI or age) that may affect five-year survival rates.1Clinical utility in high CVD-risk patients could be stratification of those who have the highest likelihood of survival vs. those who may need aggressive intervention.1Varying levels of IVX and MMX scores in different patients may help physicians choose personalized treatments (e.g., treatment of a patient with high IVX with an anti-inflammatory agent).Extending lifespan is among the overarching objectives of modern healthcare, which is organized around therapeutic areas that target the diseases and chronic conditions (including old age) that are the primary causes of death. Mitigating disease risk will unquestionably lower mortality risk, but a new concept is emerging that near-term survival, independent of disease status, is strongly influenced by previously unrecognized metabolic factors that make individual patients either relatively resilient or vulnerable. Described initially in the context of chronic kidney disease, and later in heart failure, liver disease, rheumatoid arthritis and cancer, excess mortality risk was attributed to a syndrome of combined muscle wasting, metabolic malnutrition and inflammation.3,4The reason there is so little awareness of the impact this malnutrition-inflammation syndrome has on mortality risk, and the therapeutic opportunities it offers to extend survival in those at high risk, is a lack of simple quantitative clinical assessment tools.5The new MVX biomarker is intended to meet this need, both for prognostic purposes and to aid investigation of the efficacy and safety of potential therapeutic interventions. MVX is related to metabolic determinants of survival that are "downstream" of risk factors for the development of various diseases.1

Heart Health & Cardiovascular

Lp-PLA2is a calcium-independent phospholipase A2 enzyme that is associated with both low-density lipoprotein (LDL) and, to a lesser extent, high-density lipoprotein (HDL) in human plasma and serum1and is distinct from other such phospholipases such as cPLA2and sPLA2.2,3Lp-PLA2is produced by macrophages and other inflammatory cells and is expressed in greater concentrations in advanced atherosclerotic lesions than early-stage lesions.4,5Several lines of evidence suggest that oxidation of LDL plays a critical step in the development and progression of atherosclerosis.6,7Lp-PLA2participates in the breakdown of oxidized LDL in the vascular wall by hydrolyzing the oxidized phospholipid, producing lysophosphatidylcholine and oxidized free fatty acids, both of which are potent pro-inflammatory products that contribute to the formation of atherosclerotic plaques.8-10Lp-PLA2has demonstrated modest intra- and inter-individual variation, commensurate with other cardiovascular lipid markers and substantially less variability than high sensitivity C-reactive protein (hs-CRP). In addition, Lp-PLA2is not elevated in systemic inflammatory conditions, and may be a more specific marker of vascular inflammation. The relatively small biological variation of Lp-PLA2and its vascular specificity are of value in the detection and monitoring of cardiovascular risk.11-13

Heart Health & Cardiovascular

Apolipoprotein A1 is the primary protein associated with HDL cholesterol. Like HDL cholesterol, increased concentrations are associated with reduced risk of cardiovascular disease. Apolipoprotein B-100 is the primary protein associated with LDL cholesterol and other lipid particles. Like LDL cholesterol, increased concentrations are associated with increased risk of cardiovascular disease. The ratio of these two apolipoproteins correlates with risk of cardiovascular disease.

Heart Health & Cardiovascular

B-type natriuretic peptide (BNP), also referred to as brain natriuretic peptide, is a member of a family of structurally similar peptide hormones that includes atrial natriuretic peptide.1BNP is a 32-amino-acid peptide that contains a 17-amino-acid ring structure that is formed as the result of an internal disulfide bond. BNP is predominantly secreted by the ventricles of the heart in response to increased pressure. BNP acts as a vasodilator and has diuretic and natriuretic properties. BNP suppresses both sympathetic tone and the renin-angiotensin system. These physiologic effects serve to reduce intraventricular pressure and improve the symptoms of congestive heart failure (CHF).BNP levels increase with age and can be transiently increased by vigorous exercise.1,2BNP levels correlate with end-diastolic pressure and tend to be increased in patients with diminished left ventricular ejection fraction.1,3BNP levels have been shown to be useful in the diagnosis of patients with symptoms that are consistent with CHF. Maisel and coworkers4found that a BNP cutoff of 75 pg/mL could be used to predict systolic and/or diastolic abnormalities accurately in symptomatic patients referred to echocardiology for left ventricular function studies. They found that this cutoff identified patients with abnormal function from a population of 200 patients with a sensitivity of 95.9%, specificity of 86%, positive predictive value of 98%, and a negative predictive value of 89%. The overall accuracy of the diagnosis with a cutoff of 75 pg/mL was 93%. These results were similar to those found by Dao and coworkers.5They found that BNP levels could be used to accurately identify patients with CHF from a population of patients presenting at the emergency room with shortness of breath (dyspnea). They found that a BNP value >80 pg/mL could be used to identify patients with CHF from this population with a sensitivity of 97%, specificity of 98%, positive predictive value of 92%, and a negative predictive value of 98%.6

Heart Health & Cardiovascular

Assessment of skeletal muscle breakdown (rhabdomyolysis).

Hormone Testing, Heart Health & Cardiovascular

Measurement of the Plasma Renin activity is useful in evaluating hypertension.

Heart Health & Cardiovascular

Fibrinogen, also referred to as factor I, is a 340 kilodalton glycoprotein that is produced by the liver.1Fibrinogen has a plasma half-life of about four days. Proteolytic conversion of fibrinogen to fibrin occurs through both the extrinsic and intrinsic pathways.1Fibrinogen deficiency should be considered when a patient with bleeding history has both extended protime (PT) and activated partial thromboplastin time (aPTT).2,3Fibrinogen activity should be measured when a patient has a history of bleeding and the PT and aPTT are normal, as these assays are generally insensitive to fibrinogen deficiency unless levels drop to <100 mg/dL.Congenital afibrinogenemia, a condition associated with the complete absence of fibrinogen, is rare with only about 150 cases reported in the literature.1,2Fibrinogen deficiency is inherited as an autosomal recessive trait.2,3Afibrinogenemia occurs in individuals who are homozygous or doubly heterozygous for mutations. These individuals have infinite protime and aPTT results due to the inability to produce fibrin. Approximately 25% of patients with afibrinogenemia have mild thrombocytopenia.2Individuals who are heterozygous for congenital fibrinogen deficiency are usually asymptomatic unless their fibrinogen levels fall to <50 mg/dL.2Both functional (activity) and antigenic levels are diminished in these individuals.2Fibrinogen deficiency affects both males and females with a prevalence that is equal in all ethnic groups.2Acquired deficiencies occur in individuals with significant hepatic dysfunction, renal disease, and after L-asparaginase therapy.1Diminished levels can also be seen in patients with disseminated intravascular coagulation (DIC) or who are undergoing thrombolytic therapy.1Fibrinogen is one of the major determinants of the erythrocyte sedimentation rate and individuals with afibrinogenemia typically have greatly extended sedimentation rates.2Individuals with dysfibrinogenemia have fibrinogen that is qualitatively defective with low functional fibrinogen levels (activity) and normal or decreased antigenic levels.1Congenital dysfibrinogenemia is inherited as an autosomal dominant mutation.1A number of disfibrinogenemic defects have been identified with a variety of manifestations including abnormal fibrin polymerization, impaired fibrinopeptide release, abnormal fibrin stabilization, and abnormal fibrin clot lysis.1,2Fibrinogen activity and antigen levels are useful in the diagnosis of dysfibrinogenemia since these individuals often have diminished activity relative to antigen levels.3Reptilase time is generally greatly prolonged, to a greater degree than prolongation of the thrombin time.Individuals with afibrinogenemia have bleeding tendencies of varying severity.2Symptoms often start in early infancy with umbilical cord bleeding, intracerebral hemorrhage, or bleeding at circumcision.1-3Individuals with afibrinogenemia also suffer from deep muscle and joint bleeding and other mucous membrane bleeding throughout life.1Women with afibrinogenemia typically do not experience menorrhagia.3Patients with heterozygous hypofibrinogenemia usually have a minimal history of bleeding with symptoms only observed after major surgery or trauma.1,2Approximately 50% of individuals with dysfibrinogenemia are asymptomatic.1,2These individuals are usually detected when prolonged clotting times are discovered as a result of routine laboratory testing; however, about one in four will suffer prolonged bleeding after surgery and approximately 20% will have an increased tendency toward thrombosis.1A number of clinical and epidemiological studies have revealed a consistent association between elevated fibrinogen levels and increased risk for atherosclerotic vascular disease;5however, it remains to be determined whether increased fibrinogen acts as a mediator of arterial thrombosis or simply reflects the inflammation associated with atherosclerosis.5

Genetic Testing, Heart Health & Cardiovascular

Offered as part of multiple lab tests

Drug & Alcohol Testing, Heart Health & Cardiovascular

Digoxin is a cardiac glycoside derived from the digitalis plant. It is used to treat congestive heart failure and atrial dysrhythmias. Digoxin levels are monitored to assure adequate therapeutic levels are achieved and to avoid toxicity.

Heart Health & Cardiovascular

Tacrolimus, previously known as FK506, is an immunosuppressive drug derived fromStreptomyces tsulenbaensis. It has been shown to be effective for the treatment of rejection following liver and kidney transplantations. Clinical trials are continuing for a variety of indications. Tacrolimus inhibits T-lymphocyte activation by inhibition of the phosphatase activity of calcineurin, although the exact mechanism of action is not known. Tacrolimus is bound to plasma proteins and is highly bound to erythrocytes (ratio of whole blood:plasma ranging from 12 to 67). Tacrolimus may be administered IV or orally. Absorption from the GI tract is variable and irregular. Peak blood concentrations are achieved at 1.5 to 3.5 hours. The elimination half-life from whole blood is 11.7 hours in liver transplant patients. Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Care must be taken if tacrolimus is used in combination with other immunosuppressive drugs, particularly cyclosporine. Drugs found to increase tacrolimus levels include diltiazem, verapamil, clotrimazole, fluconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, nelfinavir, ritonavir, as well as grapefruit juice. Decreased tacrolimus levels have been found with coadministration of rifampicin, phenytoin, carbamazepine, phenobarbital, octreotide, and St John's wort.1

Hormone Testing, Heart Health & Cardiovascular

Metanephrine and normetanephrine (together referred to as metanephrines) are the 3-methoxy metabolites of the catecholamines, epinephrine and norepinephrine, respectively. The methylation of catecholamines is accomplished by catecholamine O-methyltransferase, a membrane-bound enzyme of chromaffin cells.1,5,13-18Levels of these metabolites can be increased in both plasma and urine in patients with catecholamine-producing tumors such as pheochromocytomas, paragangliomas and neuroblastomas. Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and para-sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest progenitor cells, including adrenal chromaffin cells and similar cells in extra-adrenal sympathetic and para-sympathetic paraganglia. Approximately 10% of pheochromocytomas and 35% of paragangliomas are malignant. About a third of these tumors are associated with three specific syndromes: von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1. A number of germline mutations responsible for PPGLs have been identified.19,20Neuroblastomas are derived from immature embryonic neuroblast cells that also form tumors at adrenal and extra-adrenal locations, but present almost exclusively in childhood.21Patients with PPGLs can present with episodic hypertension related to excessive catecholamine synthesis and variety of other symptoms that can include tachycardia, headache, palpitations, profuse diaphoresis, and pallor.5,22Less frequently, these tumors can manifest as nausea, vomiting, flushing, and weight loss. In young patients with normal body weight, hypertension with diabetes mellitus may suggest PPGL.23Many patients present with an unidentified mass lesion and no specific clinical symptoms associated with PPGL. Given the relative non-specificity of symptoms and the low prevalence of the condition (less than one per 100,000 individuals in the general population),24it is not unusualfor the diagnosis of PPGL to be delayed. The critical first step for diagnosis is to recognize the possibility of the tumor.2,25,26The consequences of delayed detection can be severe as excessive catecholamine secretion can precipitate life-threatening hypertension, intracerebral hemorrhage, and cardiac arrhythmias.27,28When detected early, these tumors are potentially curable.29Diagnosis of pheochromocytoma and paraganglioma relies on biochemical evidence of catecholamine production by the tumor. Guidelines suggest that measurement of plasma-free metanephrines or urinary fractionated metanephrines should be performed in symptomatic patients,2,30patients with an adrenal incidentaloma,31and in individuals who have a hereditary risk for developing a pheochromocytoma or paraganglioma.20Metanephrines are produced continuously by the normal adrenal and by tumors via a process that is independent of catecholamine release, which for some tumors occurs at low rates or is episodic in nature.2,16-18While non-chromaffin cells of the sympathetic nervous system are the major sites of norepinephrine metabolism, they do not convert catecholamines to metanephrines because they lack the catecholamine O-methyltransferase enzyme. Consequently, plasma levels of free metanephrines reflect functional chromaffin cell quantity and become elevated in patients with catecholamine-producing chromaffin tumors.13,16Since many PPGLs produce and metabolize catecholamines but do not secrete the amines continuously or in amounts sufficient to produce a diagnostic signal, the metanephrines are superior to the parent catecholamines as diagnostic biomarkers.32,33The high diagnostic accuracy of measurements of urine fractionated metanephrines and plasma-free metanephrines has been confirmed by a large number of studies.2,10-12,16-18,34To ensure optimal diagnostic accuracy, samples for plasma metanephrine testing should be collected with the patient in a fully recumbent, supine position (for at least 30 minutes before sampling) and reference intervals established in the same position should be used.2Numerous studies have confirmed that lying supine at rest prior to blood collection prevents false-positive results due to postural-related stimulus of norepinephrine secretion.2,3,10,32,33,35,36Applying reference ranges established from samples collected in a supine position, the sensitivity of plasma metanephrines approaches 100%, such that a finding of normal levels has a very high negative predictive value for ruling out catecholamine secreting tumor.2,36Normetanephrine or metanephrine elevated three-fold or more above upper cutoffs are rarely false positives and should be followed up in most cases by imaging to locate the tumor.2,6,33In cases of borderline elevation (less than three-fold the upper limit of the reference interval) repeat testing with sampling in a supine position and/or second-line tests such as the measurement of fractionated 24-hour urinary metanephrines and performance of a clonidine suppression test with measurements of plasma normetanephrine can be performed prior to proceeding to imaging studies.2,37Chromogranin A levels are elevated in most patients with PPGLs and have been associated with risk of malignancy.37-39However, the test is not specific and is seen in other disorders such as carcinoid.

Heart Health & Cardiovascular

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet activating factor Acetylhydrolase, is an inflammatory enzyme that circulates bound mainly to low density lipoproteins and has been found to be localized and enriched in atherosclerotic plaques. In multiple clinical trials, Lp-PLA2 activity has been shown to be an independent predictor of coronary heart disease and stroke in the general population. Measurement of Lp-PLA2 may be used along with traditional cardiovascular risk factor measures for identifying individuals at higher risk of cardiovascular disease events. Clinical management may include beginning or intensifying risk reduction strategies. The activity assay is an enzyme assay run on an automated chemistry platform.

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

BNP is increased in congestive heart failure, left ventricular hypertrophy, acute myocardial infarction, coronary angioplasty, and hypertension. Elevations are also observed in pulmonary hypertension (indicating right ventricular dysfunction), acute lung injury, hypervolemic states, chronic renal failure and cirrhosis. Decreasing levels indicate therapeutic response to anti-hypertensive therapy.

Hormone Testing, Heart Health & Cardiovascular

Aldosterone is a hormone produced by the adrenal glands. Patients with primary hyperaldosteronism exhibit hypokalemia, hypertension, and low direct renin concentrations.

Heart Health & Cardiovascular

MPO plays an important role in the innate host-defense mechanism of human and animals.Myeloperoxidate (MPO) is a hemoprotein present in leukocytes and catalyzes the hydrogen peroxide mediated peroxidation of halide ions to produce strong reactive oxidant species such as hypochlorous acid that are of potent antimicrobial activities against a broad range of invading parasites and pathogens. However, MPO-derived reactive oxidants also promote host tissue injury through lipid and protein peroxidations that lead to systemic inflammation.

Heart Health & Cardiovascular

Offered as part of multiple lab tests

Heart Health & Cardiovascular

Serum carnitine analysis is useful in the diagnosis and monitoring of patients with carnitine deficiency (either primary or secondary). Primary carnitine deficiency is an autosomal recessively inherited genetic condition that affects carnitine uptake by cells and tissues through a defect in the plasma membrane carnitine transporter. Secondary carnitine deficiency can be seen in some disease states or in patients on carnitine-poor diets, but is also seen in a number of metabolic disorders. In these disorders, carnitine complexes with the accumulated substrate of the blocked metabolic step, and the resulting acylcarnitine ester is excreted in the urine, leading to a depletion of carnitine in the patient.

Blood Disorders, Heart Health & Cardiovascular

High serum viscosity may be most commonly observed in patients with Waldenström's macroglobulinemia and multiple myeloma. Patients with high viscosity may have capillary occlusion, stasis hypoxia, and acidosis.

Blood Disorders, Heart Health & Cardiovascular

Factor VII is a 48 kilodalton single-chain nonenzymatic cofactor that is synthesized in the liver.6Factor VII is a vitamin K-dependent protein with a plasma concentration of 0.5 mg/mL.6The plasma half-life of factor VII is short at about four to six hours.6Factor VII deficiency should be considered when a patient with excessive bleeding has an extended protime (PT) and a normal activated partial thromboplastin time (aPTT). Congenital factor VII deficiency is rare (less than one case per 500,000 individuals) and is inherited as an autosomal recessive trait.6,7This condition affects both males and females and the prevalence of factor VII deficiency is equal in all ethnic groups.6,7A few cases of combined congenital factor II, VII, IX, and X factor deficiencies have been reported.6Symptoms (homozygotes and double heterozygotes) can include mucosal bleeding, epistaxis, postsurgical and postpartum hemorrhage, menorrhagia, gastrointestinal bleeding, and umbilical cord hemorrhage.6-8Heterozygotes are usually asymptomatic.8Factor VII plasma activity <30% may result in excessive bleeding following a traumatic event.6Spontaneous bleeding similar to that observed in severe hemophilia may occur when the activity is <1%;6,7however, symptomatology does not always correlate with the degree of factor VII deficiency and some patients with low levels may have no bleeding symptoms at all.6,7Diminished factor VII levels can be seen in patients with significant hepatic dysfunction, with oral anticoagulant (coumarin) therapy, and in individuals with vitamin K deficiency.6,7Low levels can also be observed in patients with specific factor VII inhibitors and in association with homocystinuria and aplastic anemia.7High levels of factor VII activity were found to be associated with increased risk for ischemic heart disease events by the Northwick Park Heart Study in 1986;9however, more recent studies have failed to identify factor VII levels as an independent risk factor for thrombosis.10A recent consensus conference of the College of American Pathologists on diagnostic issues in thrombophilia did not recommend measurement of factor VII levels for the assessment of thrombotic risk.10

Blood Disorders, Heart Health & Cardiovascular

Factor VIII is a large glycoprotein cofactor (320 kilodaltons) that is produced mainly in hepatocytes, but also to some extent by liver macrophages, megakaryocytes, and endothelial cells.6,10Factor VIII circulates in the plasma bound to von Willebrand factor (vWF) at a concentration of approximately 0.1 mg/mL.10The plasma half-life of factor VIII is short at about 8 to 10 hours.10Factor VIII deficiency should be suspected when a patient with excessive bleeding has a normal protime (PT) and an extended activated partial thromboplastin time (aPTT).Hemophilia A, or classic hemophilia, occurs as the result of congenital deficiency of factor VIII.6,11Clinical features of hemophilia A are the same as for hemophilia B which is caused by factor IX deficiency (seeFactor IX Activity [086298]). Hemophilia A is the second most common inherited bleeding abnormality (second only to von Willebrand disease), occurring in approximately 1 of every 5000 live male births.6,11Hemophilia A accounts for approximately 85% of all hemophilia cases.11This condition is transmitted as an X chromosome-linked hereditary disorder.11The majority of cases occur in men whose mothers are carriers of the genetic defect. About 30% of factor VIII deficiencies arise in men as spontaneous mutations.6,11The prevalence of hemophilia A is equal in all ethnic groups.6,11Female carriers of hemophilia A may rarely present with excessive bleeding.6Hemophilia symptoms can also occur in female carriers who have a high degree of lyonization of the factor VIII alleles.11Females with Turner syndrome karyotype XO, can also be symptomatic.11The severity of hemophilia A can be defined by the level of factor VIII activity.7,11Severe hemophilia, which represents approximately half the cases, is associated with a factor VIII level <1%. About 10% of cases are moderate with factor VIII levels of 1% to 5% and the remaining 30% to 40% of hemophiliacs have the mild condition with factor VIII levels above >5%.Approximately 45% of cases of severe hemophilia A occur as the result of a genetic inversion of intron 22 of the factor VIII gene locus.7,11,12This genetic mutation results in the production of a protein that has no functional or immunologic factor VIII activity.11Numerous deletions, point mutations, and missense mutations have also been implicated in hemophilia A.7,11Family studies combined with genetic testing can determine if at-risk women are carriers for a hemophilia A mutation.11Factor VIII activity levels should not be used as the method of determining carrier status because a number of clinical conditions including pregnancy, infection, or inflammation can affect activity levels.11Patients with hemophilia A can present with any number of bleeding manifestations.6,11Often, infants with severe hemophilia are first diagnosed during the neonatal period because of excessive bleeding after circumcision or due to cord necrosis.11Hemophilic infants also frequently suffer from intracranial hemorrhage or scalp hematomas. Spontaneous hemarthroses, a common symptom of hemophilias, typically do not occur until the child starts walking.7,11Hematomas can often be observed at the sites of intramuscular injections for vaccination or medication. The most common sites of spontaneous bleeding in patients with severe hemophilia involve the joints and muscles. Recurrent bleeding leads to chronic muscle injury and degeneration of the joint tissue.6,11Gastrointestinal bleeding can occur in approximately 10% of hemophiliacs.11Males with mild-to-moderate hemophilia and female carries may have an increased bleeding tendency, especially following surgery or trauma.7Most individuals with von Willebrand disease will have decreased factor VIII levels because the von Willebrand factor (vWF) is the carrier protein for factor VIII in plasma.6,11Individuals with von Willebrand disease type 2 Normandy will have normal to slightly low vWF ristocetin cofactor activity and von Willebrand factor antigen and low factor VIII levels due to defective binding of factor VIII to the variant vWF molecule.11Factor VIII levels are elevated at birth and increase during pregnancy.6Factor VIII is an acute phase reactant with levels that rise during periods of acute stress, following surgery, and in inflammatory conditions.6Levels can also increase as the result of strenuous exercise or the administration of several drugs including epinephrine, DDAVP, or estrogen (for birth control or hormone replacement therapy). Factor VIII levels can be elevated in a number of clinical conditions including carcinoma, leukemia, liver disease, renal disease, hemolytic anemia, diabetes mellitus, deep vein thrombosis, and myocardial infarction.6Persistent elevation of factor VIII above 150% is associated with an increased risk for venous thrombosis of more than fivefold.10,13Elevated factor VIII is also associated with an increased risk for recurrence of venous thromboembolism. Risk is graded such that the higher the factor VIII activity, the higher the risk.14The basis for this increased risk is not well understood as genetic studies of the factor VIII and von Willebrand factor genes failed to identify a genetic basis for this increased risk.10Values >150% are observed in 20% to 25% of individuals with venous thrombosis or thromboembolism in the absence of other known causes of factor VIII elevation.13A syndrome of combined factor VIII and V deficiencies has been described in over 60 families in and around the Mediterranean basin.15Hemophilia A patients receiving replacement products can develop inhibitors to factor VIII due to the production of alloantibodies.6,8Acquired hemophilia caused by the development of autoantibodies to factor VIII can also occur.9This rare condition (1 in 1,000,000 individuals) can following pregnancy and in elderly individual with autoimmune disorders. In this life-threatening condition, patients have bleeding symptoms similar to those seen in severe congenital hemophilia A.

Heart Health & Cardiovascular

Low levels of fibrinogen are associated with bleeding most commonly secondary to liver disease or disseminated intravascular coagulation (DIC). Fibrinogen is an acute phase reactant and thus elevated levels may be associated with inflammation. Increased concentrations are also associated with increased risk of atherosclerosis.

Heart Health & Cardiovascular

The NMR LipoProfile® test is a blood test that directly measures the amount of LDL circulating in the body. “LDL” is low-density lipoprotein and has long been recognized as a major causal factor in the development of heart disease. Although the relationship of increased LDL particle number and plaque buildup in the artery wall has been known since the 1950s, a diagnostic test did not exist to measure LDL particle number (LDL-P). Historically, LDL cholesterol, or LDL-C, has been used to estimate LDL levels to assess a patient’s LDL-related cardiovascular risk and judge an individual’s response to LDL-lowering therapy. The NMR LipoProfile® test reports results for LDL-P, a more reliable measure of LDL that directly counts the number of LDL particles a patient has using NMR technology.

Heart Health & Cardiovascular

The NMR LipoProfile® test is a blood test that directly measures the amount of LDL circulating in the body. “LDL” is low-density lipoprotein and has long been recognized as a major causal factor in the development of heart disease. Although the relationship of increased LDL particle number and plaque buildup in the artery wall has been known since the 1950s, a diagnostic test did not exist to measure LDL particle number (LDL-P). Historically, LDL cholesterol, or LDL-C, has been used to estimate LDL levels to assess a patient’s LDL-related cardiovascular risk and judge an individual’s response to LDL-lowering therapy. The NMR LipoProfile® test reports results for LDL-P, a more reliable measure of LDL that directly counts the number of LDL particles a patient has using NMR technology.

Heart Health & Cardiovascular

ADMA and SDMA may be measured in individuals with multiple risk factors for the development of cardiovascular disease.

Heart Health & Cardiovascular

Gut microbes live symbiotically within the human digestive tract and play important roles in host defense, immunity, and nutrient processing and absorption. The diverse community is unique to each person and influenced by both acute and chronic dietary exposures to various food sources. Nutrients such as phosphatidylcholine (also known as lecithin), choline, and L-carnitine are abundant in animal-derived products such as red meat, egg yolk and full-fat dairy products. When consumed, these nutrients are processed by gut bacteria resulting in the release of various metabolites including TMA (trimethylamine) into the blood. TMA is then transported to the liver where it is converted into TMAO (trimethylamine N-oxide) which has been shown to regulate various physiological processes involved in the development of atherosclerosis.

Autoimmune & Inflammation, Heart Health & Cardiovascular

Autoimmune vasculitis diseases are characterized by abnormal immune responses that result in inflammation and necrosis of blood vessels. The immune dysfunction may be triggered by infection, autoimmune disease, or exposure to a drug; often the cause is unknown. ANCA-associated vasculitis diseases are often characterized by the size of the blood vessels involved. The diseases present with diverse clinical features and are often rapidly progressive, causing irreversible injury to the vessels of the organs affected, such as the kidneys and lungs.

Heart Health & Cardiovascular

Myeloperoxidase testing may be used for individuals with multiple risk factors for cardiovascular disease, or those with established disease.

Heart Health & Cardiovascular

D-Dimer is one of the measurable by-products of activation of the fibrinolytic system. Quantitation of D-Dimer assesses fibrinolytic activation and intravascular thrombosis. D-Dimer is of particular value in excluding the diagnosis of venous thromboembolism among patients at high risk.

Heart Health & Cardiovascular

The expression “free” in free catecholamine fractionation means unconjugated. This assay is of most value for pheochromocytoma when specimen is collected during a hypertensive episode. Since a 24-hour urine collection represents a longer sampling time than a random, or symptom-directed serum sample, and because catecholamine secretion by pheochromocytomas is intermittent, the urine test may detect some cases missed by a blood level.

Hormone Testing, Heart Health & Cardiovascular

The three catecholamines (norepinephrine, epinephrine and dopamine) are the principal secretory products of neural tissue. Clinically, the measurement of circulating catecholamines is valuable in the diagnosis of catecholamine secreting tumors associated chiefly with hypertension (pheochromocytomas, neuroblastomas and gangliomas) and with the evaluation of orthostatic hypotension.

Heart Health & Cardiovascular

This assay aids in the diagnosis of individuals suspected of congestive heart failure; is indicated for risk stratification of patients with acute coronary syndrome and congestive heart failure. Also aids in the assessment of increased risk of cardiovascular events and mortality for patients at risk of heart failure who have stable coronary artery disease.

Blood Disorders, Heart Health & Cardiovascular

To evaluate an isolated prolonged PT or to evaluate prolongation of both the APTT and PT and to document factor X deficiency.6-8Factor X is a 54.8 kilodalton vitamin K-dependent glycoprotein coagulation factor that is produced by the liver.6Normal factor X's plasma concentration is approximately 10 mg/mL and half-life is about 40 hours.6Factor X activation occurs by both the extrinsic and intrinsic pathways. Factor X deficiency should be considered when a patient with bleeding history has both extended protime (PT) and activated partial thromboplastin time (aPTT). The dilute Russell viper venom (dRVVT) measures the activation of factor X and will be prolonged in patients with deficiency.7,8Congenital factor X deficiency is rare and is inherited as an autosomal recessive trait.6This condition affects both males and females.6A few cases of combined congenital factor II, VII, IX, and X factor deficiencies have been reported.6Acquired deficiencies occur with significant hepatic dysfunction, with vitamin K antagonist (warfarin) therapy, and in individuals with vitamin K deficiency.6,7Factor X deficiency may be associated with primary systemic amyloidosis.6,8Isolated factor X deficiency may also occur in patients with respiratory infections, acute myeloid leukemia, amyloidosis, and with other malignancies.7Acquired specific factor X inhibitors are rare in patients without congenital deficiency.6,7Symptoms (homozygotes) include hematoma formation, postsurgical hemorrhage, menorrhagia, hematuria, and umbilical cord hemorrhage.6,7Factor X plasma activity <30% may result in excessive bleeding following a traumatic event.6Spontaneous bleeding similar to that observed in severe hemophilia may occur when the activity is <1%.6,7

Autoimmune & Inflammation, Heart Health & Cardiovascular

Cardiolipin antibodies (CA) are detected in a subgroup of patients with autoimmune disorders, particularly Systemic Lupus Erythematosus (SLE), who are at risk for vascular thrombosis, thrombocytopenia, cerebral infarct and/or recurrent spontaneous abortion. Elevations of CA associated with increased risk have also been seen in idiopathic thrombocytopenic purpura, rheumatoid and psoriatic arthritis, and primary Sjögren's syndrome.

Hormone Testing, Heart Health & Cardiovascular

The Aldosterone-renin ratio is used to screen for primary aldosteronism.

Heart Health & Cardiovascular

Left ventricular dysfunction can occur as a part of coronary heart disease, arterial hypertension, valvular disease, and primary myocardial disease. If the left ventricular dysfunction remains untreated and is progressive, the potential for mortality is high ,e.g. due to sudden cardiac death. Chronic cardiac insufficiency is a clinical syndrome caused by impairment of the cardiac pumping function. Based on the symptoms, the severity of cardiac insufficiency is classified in stages (New York Heart Association classification [NYHA] I‑IV).3,4Clinical information and imaging procedures are used to diagnose left ventricular dysfunction.5The significance of natriuretic peptides in the control of cardiovascular system function has been demonstrated. Studies reveal that natriuretic peptides can be used for diagnostic clinical problems associated with left ventricular dysfunction.6The following natriuretic peptides have been described: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).7,8ANP and BNP, as antagonists of the renin‑angiotensin‑aldosterone system, influence by means of their natriuretic and diuretic properties, the electrolyte and fluid balance in an organism.9,10In subjects with left ventricular dysfunction, serum and plasma concentrations of BNP increase, as do the concentrations of the biologically inactive prohormone, proBNP. ProBNP, comprising 108 amino acids, is secreted mainly by the ventricle and, in this process, is cleaved into physiologically active BNP (77‑108) and the N‑terminal fragment NT‑proBNP (1‑76).8Studies indicate that NT‑proBNP can be used in diagnostic and prognostic applications.11-13The concentration of NT‑proBNP in serum or plasma correlates with the prognosis of the left ventricular dysfunction. Fisher et al found that congestive heart failure patients with NT‑proBNP values above median had a 1-year mortality rate of 53% compared to 11% in patients below median.14In the GUSTO IV study, which involved more than 6800 patients, it was shown that NT‑proBNP was the strongest independent predictor of 1-year mortality in patients with acute coronary syndrome.15The following cut-points have been suggested for the use of proBNP for the diagnostic evaluation of heart failure (HF) in patients with acute dyspnea16,17:ModalityAge(years)Optimal CutPointDiagnosis (rule in HF)<50450 pg/mL50 - 75900 pg/mL>751800 pg/mLExclusion (rule out HF)Age independent300 pg/mL

Heart Health & Cardiovascular

Galectin-3 is member of the protein family known as galectins. Galectins bind to certain carbohydrates via specific carbohydrate recognition domains (CRDs). Galectin-3 is a 29 to 35 kDa chimera-type galectin − the only member of the galectin family with an extended N-terminal domain constituted of tandem repeats of short amino acid segments (a total of 110-130 amino acids) linked to a single C-terminal CRD of about 130 amino acids.Galectin-3 interacts with carbohydrates, such as N-acetyllactosamine (LacNac), certain cell surface receptors (such as macrophage CD11b/CD18) and extracellular receptors (such as collagen). Galectins play an important and complex role in intracellular pathways and disease mechanisms. Under certain circumstances, galectin-3 is secreted in the extracellular matrix and galectin-3 can be measured in plasma or serum of healthy individuals. Galectin-3 has been implicated in a variety of biological processes important in heart failure including myofibroblast proliferation, fibrogenesis, tissue repair, cardiac remodeling and inflammation. Experimental data implicate galectin-3 in heart failure development and progression and administration of galectin-3 can induce cardiac fibrosis and reduced ejection fraction in animals. Blockade of galectin-3 prevents organ fibrosis following inflammation and organ damage.The experimental data are corroborated by several independent clinical studies that indicated that elevated levels of galectin-3 (>17.8 ng/mL) are associated with an increased near-term or long-term risk for hospitalization or death (p<0.05 after adjusting for pertinent covariates). Galectin-3 levels reflect the presence of specific underlying disease processes and are not affected by the degree of decompensation. Hence galectin-3 levels, once elevated, remain generally constant and do not fluctuate with signs and symptoms of heart failure. Although certain medical and device treatments appear to be effective in patients with elevated galectin-3, galectin-3 plasma levels are generally not affected by these treatments.Galectin-3 and natriuretic peptides are measures of separate and distinct biological processes. Each marker provides independent and complementary information on the status and prognosis of patients with chronic heart failure.

Heart Health & Cardiovascular

SeeProtein C Deficiency Profile [283655]for more clinical information.

Heart Health & Cardiovascular

Protein C (PC) deficiency may be congenital or acquired and is associated with venous thrombosis. Acquired PC deficiency may occur with vitamin K antagonists/deficiency, liver disease, malignancy, consumptive DIC, surgery, trauma, and hepatic immaturity of the newborn.Anticoagulant interference: Expected impact by therapeutic levels (potential interference depends upon drug concentration): Vitamin K antagonists (eg warfarin): decrease; Heparin (UFH or LMWH): no effect to falsely increased activity levels at higher levels; Dabigatran or Argatroban (Thrombin Inhibitors): may falsely increase activity; Rivaroxaban, Apixaban, Edoxaban (Factor Xa Inhibitors): may falsely increase activity.

Heart Health & Cardiovascular

A galectin-3 test may be ordered for the identification of individuals with chronic heart failure at elevated risk of disease progression.

Blood Disorders, Heart Health & Cardiovascular

Protein C (PC) is a vitamin K-dependent plasma protein that is synthesized by the liver as an inactive precursor.7-9This protein is then further transformed into activated PC by a complex of thrombin and the endothelial factor, thrombomodulin, that is bound to phospholipid membrane in a calcium-dependent manner. aPC regulates the coagulation process by inactivating factors Va and VIIIa. Protein S, another vitamin K-dependent protein, serves as an essential cofactor of aPC for the inactivation of factors Va and VIIIa. In inhibiting these factors, PC serves to limit thrombus extension, and thus acts as a major regulator of the coagulation process.Congenital protein C deficiency:Congenital PC deficiency has been estimated to occur in approximately 3 out of 1000 individuals.7,8Between 2% and 5% of cases of recurrent venous thrombosis are related to congenital PC deficiency.7Nearly 50% of individuals with heterozygous PC deficiency and 10% of their relatives experience thrombotic episodes by age 45. Initial thrombotic events frequently occur between 20 and 30 years of age. The probabilities of thrombosis or pulmonary emboli increase dramatically when PC activity levels fall to <50%.7Thrombosis can sometime occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.7In the majority of cases, thrombosis can be linked to trauma, surgery, pregnancy oral contraceptive usage, or other risk factors. However, thrombosis can occur spontaneously with no precipitating events or other known risk factors in about 33% of cases.7Congenital PC deficiency can be classified as either type I or type II.9Type I deficiency results from a quantitative reduction in PC production, resulting in a simultaneous decrease of both the functional and antigenic levels of PC. In type II deficiency, PC antigen concentration is normal but its activity is diminished because the PC is dysfunctional due to genetic defect. This is reflected by a diminished PC activity in the context of normal PC antigen levels. Neonates born with homozygous or doubly heterozygous PC deficiency suffer from DIC or purpura fulminans of the newborn, devastating conditions requiring immediate treatment.8Acquired protein C deficiency:Acquired PC deficiency occurs more frequently than congenital deficiency.7PC levels can be transiently diminished after a thrombotic event or surgery. Oral anticoagulant therapy with warfarin will lower PC levels. Vitamin K deficiency, due to dietary insufficiency or malabsorption, will also lead to reduced PC levels. Acquired deficiency can be found in individuals with disseminated intravascular coagulation (DIC) and sepsis. Severe hepatic disorders (hepatitis, cirrhosis, etc), renal failure, malignancy, and inflammatory bowel disease can lead to diminished PC levels.7Drug therapy with L-asparaginase or fluorouracil can also reduce PC levels.In some cases, warfarin anticoagulation of thrombotic patients with heterozygous PC deficiency will induce skin necrosis due to the rapid drop in already low PC activity.7,9

Blood Disorders, Heart Health & Cardiovascular

Factor IX is a 72 kilodalton vitamin K-dependent glycoprotein proenzyme that is produced by the liver.6Factor IX's plasma concentration is 3-5 mg/mL and half-life is about 24 hours.6Factor IX deficiency should be suspected when a patient with excessive bleeding has a normal protime (PT) and an extended activated partial thromboplastin time (aPTT).Hemophilia B, or Christmas disease, occurs as the result of congenital deficiency of factor IX.6,7Clinical features of hemophilia B are the same as for hemophilia A which is caused by factor VIII deficiency (seeFactor VIII Activity [086264]). Hemophilia B is less common than hemophilia A, occurring in approximately 1 of every 30,000 live male births.7The prevalence is significantly higher in Amish and East Indian populations.8This condition is transmitted as an X chromosome-linked hereditary disorder.7The majority of cases occur in men whose mothers are carriers of the genetic defect. A subtype of hemophilia B, hemophilia B Leiden, is characterized by altered developmental expression of factor IX such that plasma factor IX levels may be <1% of normal during childhood, but after puberty may gradually rise to a maximum of 70% of normal.12Hemophilia B can also occur as the result of spontaneous mutations of the factor IX gene locus.7Female carriers of hemophilia B may rarely present with excessive bleeding.7Hemophilia symptoms can also occur in female carriers that have a high degree of lyonization of the factor X alleles.7Females with Turner syndrome, karyotype XO, can also be symptomatic.7The severity of hemophilia B can be defined by the level of factor IX activity.7,8Severe hemophilia is associated with a factor IX level of <1%. Moderate hemophilia B occurs with factor IX levels of 1% to 5% and mild hemophilia has factor IX levels >5%.Patients with hemophilia B can present with any of a number of bleeding manifestations.6,7Often, infants with severe hemophilia are first diagnosed during the neonatal period because of excessive bleeding after circumcision or due to cord necrosis.7Hemophilic infants also frequently suffer from intracranial hemorrhage or scalp hematomas. Spontaneous hemarthroses, a common symptom of hemophilias, typically do not occur until the child starts walking.7,8Hematomas can often be observed at the sites of intramuscular injections for vaccination or medication. The most common sites of spontaneous bleeding in patients with severe hemophilia are involve the joints and muscles. Recurrent bleeding leads to chronic muscle injury and degeneration of the joint tissue.6,7Gastrointestinal bleeding can occur in approximately 10% of hemophiliacs.7Males with mild to moderate hemophilia and female carriers may have an increased bleeding tendency, especially following surgery or trauma.8Acquired factor IX deficiency can occur as the result of oral anticoagulant therapy or with vitamin K deficiency.6,8Individuals with advance liver disease can have a generalized decrease in coagulation factors, including factor IX.Elevation of factor IX, if persistent, has been associated with approximately a twofold increased risk for venous thrombosis.9The basis for this increased risk is not well understood and the clinical cutoff for risk assessment has yet to be established.9Hemophilia B patients receiving replacement products can develop inhibitors to factor IX in approximately 3% of cases, due to the production of alloantibodies.6,10Acquired hemophilia caused by the development of autoantibodies to factor IX can also occur.11This rare condition can occurs most often in individuals with autoimmune disorders. These patients have bleeding symptoms similar to those seen in congenital hemophilia B.

Blood Disorders, Heart Health & Cardiovascular

Factor V is a large (330 kilodalton) single-chain nonenzymatic cofactor that is synthesized in hepatocytes, megakaryocytes, and endothelial cells.6,7,9Approximately 20% of the total factor V is carried in the α granules of platelets and is released when platelets are activated.6The structure of factor V is similar to that of factor VIII.9Factor V's plasma concentration is 7 mg/mL and half-life is about 15 to 36 hours. Factor V activation occurs by both the extrinsic and intrinsic pathways. Factor V deficiency should be considered when a patient with bleeding history has both extended protime (PT) and activated partial thromboplastin time (aPTT).Congenital factor V deficiency, sometimes referred to as parahemophilia, is rare (less than one case per million individuals) and is inherited as an autosomal recessive trait.6,7,9This condition affects both males and females and the prevalence of inherited factor V deficiency is equal in all ethnic groups.9Factor V levels are decreased both in plasma and platelets.6A syndrome of combined factor V and VIII deficiencies has been described in over 60 families in and around the Mediterranean basin.8Symptoms (homozygotes) can include hematoma formation, postsurgical and postpartum hemorrhage, menorrhagia, hematuria, and umbilical cord hemorrhage.6,9Factor V plasma activity <30% may result in excessive bleeding following a traumatic event.9Unlike individuals with severe hemophilia, patients with factor V levels <1% do not typically develop spontaneous joint hemarthroses.6Diminished factor V levels can be seen in liver disease, disseminated intravascular coagulation (DIC) syndromes, and in other consumption coagulopathies.9,10Specific factor V inhibitors can occur, especially after surgical procedures that involve multiple exposures to bovine topical thrombin.9Postoperative treatment with aminoglycosides and penicillin has also been associated with development of factor V inhibitors.6,7Inhibitors do not typically develop in individuals with factor V deficiency.6One study found that elevated factor V activity may be associated with increased risk for myocardial infarction;11however, a recent consensus conference of the College of American Pathologists on diagnostic issues in thrombophilia did not recommend measurement of factor V levels for the assessment of thrombotic risk.10

Blood Disorders, Heart Health & Cardiovascular

Factor II is a 72-kilodalton vitamin K-dependent glycoprotein coagulation factor that is produced by the liver.6Normal factor II plasma concentration is approximately 100 mg/mL and half-life is about 60 hours.6Factor II activation occurs by both the extrinsic and intrinsic pathways. Factor II deficiency should be considered when a patient with bleeding history has both extended protime (PT) and activated partial thromboplastin time (aPTT). Inhibitors to factor II may develop in select patients with lupus anticoagulants and tends to occur more frequently in a pediatric population. These inhibitors bind factor II in plasma and clear the antibody-antigen complex resulting in a factor II deficiency and enhanced bleeding potential. A factor II Bethesda (inhibitor) assay is negative in this instance. The dilute Russell's viper venom time (dRVVT) will be prolonged in patients with factor II deficiency.7,8Congenital factor II deficiency is rare (fewer than 100 cases have been reported) and is inherited as an autosomal recessive trait.6,7This condition affects both males and females, and the prevalence of factor II deficiency is equal in all ethnic groups.6A few cases of combined congenital factor II, VII, IX, and X deficiencies have been reported.6Acquired deficiencies occur with significant hepatic dysfunction, with oral anticoagulant (coumarin) therapy, and in individuals with vitamin K deficiency.7,8Diminished levels that can be associated with bleeding can be observed in some patients with lupus anticoagulants due to enhanced clearance of prothrombin/antibody complexes.6,7Symptoms of factor II deficiency include easy bruising, hematoma formation, postsurgical hemorrhage, menorrhagia, epistaxis, and umbilical cord hemorrhage.6,7Heterozygous individuals typically have factor II activities near 50% and are asymptomatic or have minor bleeding complications associated with trauma or surgery.7Factor II plasma activity <30%, as can be observed in individuals with homozygous deficiency, may result in excessive bleeding following a traumatic event.6,8Spontaneous bleeding or hemarthroses are rare but may occur in homozygotes with very low activity.6-8Factor II activity in excess of 115% has been associated with an increased risk of thrombosis.6TheG20210Amutation in the prothrombin gene can be associated with increased plasma prothrombin levels.6,9This polymorphism can be identified in 1% to 2% of the US population, but is highly race-dependent. This mutation is relatively uncommon in African Americans, Asians, and native Americans.9A recent consensus conference of the College of American Pathologists on diagnostic issues in thrombophilia concluded that the prothrombinG20210Amutation is a significant risk factor of venous thromboembolism and should be considered in the initial evaluation of potential inherited thrombophilia.9

Blood Disorders, Heart Health & Cardiovascular

Factor XI is a 160 kilodalton glycoprotein proenzyme that is produced by the liver and megakaryocytes.6-8Factor XI's plasma concentration is 4-6 mg/mL and half-life is about 60 hours.6Hereditary factor XI deficiency, referred to as hemophilia C, is transmitted as an autosomal recessive mutation.6-8This condition affects both males and females and the majority of reported cases have been diagnosed in Ashkenazi Jews.6,7As many as 11% of Ashkenazi Jews will be heterozygous for factor XI deficiency and up to 0.3% will be homozygous.8Individuals who are heterozygous for factor XI deficiency mutation typically have levels between 30% to 60% and homozygotes have levels <20%.8The bleeding associated with factor XI deficiency is generally not as severe as that found with hemophilia A or B.7Severity of bleeding does not always correlate with the plasma level of factor XI.6,7Individuals with factor XI deficiency can suffer from easy bruising, epistaxis, hematuria, and menorrhagia.6,7Excessive bleeding postpartum and after oral cavity surgery can occur.7Acquired inhibitors of factor XI are very rare.6Spontaneous autoantibodies are more common and generally occur in patients with underlying autoimmune disorders or in patients treated with chlorpromazine.6

Blood Disorders, Heart Health & Cardiovascular

Factor XII along with prekallikrein and high molecular weight kininogen make up the contact activation system. These factors are necessary for clot formation in the activated partial thromboplastin (aPTT). In the test tube, factor XII is activated by contact with negatively-charged surfaces;8however, deficiencies of these factors have no hemorrhagic consequence because physiologic clotting is activated by alternate paths that bypass the contact system.6,7Factor XII is an 80 kilodalton single-chain proenzyme that is synthesized in the liver. Factor XII's plasma concentration is 30 mg/mL and half-life is about 50 hours. Factor XII deficiency is usually inherited in an autosomal recessive manner and heterozygous deficiency is relatively common, affecting somewhere between 1.5% and 3% of the population.6In fact, mild factor XII deficiency is the most common cause of extended aPTT in the nonbleeding patient in the absence of lupus anticoagulant.6Factor XII deficiency should be suspected whenever a patient has a normal protime (PT) and an extended aPTT and no history of bleeding. Factor XII levels are moderately diminished in heterozygous individuals with levels ranging between 20% and 60% of normal.7Homozygous individuals typically have levels <1%.6Severe factor XII deficiency is characterized by aPTT that can be longer than 100 seconds.7Typically, there is correction with a normal plasma mixing study.Factor XII can be affected, either increased and decreased in a number of conditions including septicemia, coronary artery disease, pharmacological thrombolysis, inflammatory bowel disease, pregnancy, lactic acidosis, hemodialysis, and angioedema.6,8Decreased factor XII levels can be seen in liver disease and renal disease.6A number of investigators have reported that congenital factor XII deficiency may be associated with an increased incidence of venous thrombosis;8however, a recent consensus conference of the College of American Pathologists on diagnostic issues in thrombophilia found no evidence to support hypercoagulability in patients homozygously deficient for factor XII or any of the other contact factors.8

Heart Health & Cardiovascular

Aids in characterization of congenital protein C deficiency. Type I deficiency is characterized by reduction in activity (functional) and antigen levels. With type II deficiency (dysfunctional protein), antigen levels may be normal and activity levels are decreased. Acquired deficiencies may occur with vitamin K antagonists/deficiency, liver disease, malignancy, consumptive DIC, surgery, trauma, and hepatic immaturity of the newborn. Drug therapy with L-asparaginase or fluorouracil can also reduce Protein C antigen levels.Anticoagulant interference: vitamin K antagonists (eg. warfarin) will decrease PC antigen levels. PC antigen testing is not impacted by other anticoagulants (heparins, and target specific anticoagulants such as Dabigatran, Argatroban, Rivaroxaban, Apixaban, Edoxaban).

Blood Disorders, Heart Health & Cardiovascular

Protein S (PS) is produced by the liver, megakaryocytes, and endothelial cells.6-8PS is synthesized as an inactive precursor that is activated by carboxylation of several glutamic acid residues by a vitamin K-dependent carboxylase. PS serves as an essential cofactor of activated protein C (aPC). In the presence of calcium, PS binds tightly to the phospholipid surfaces of endothelial cells and activated platelets. This serves to concentrate the PS/aPC complex at the site of thrombus formation where it regulates the coagulation process by enzymatically neutralizing activated factors Va and VIIIa. PS greatly potentiates the anticoagulant function of aPC. PS is enzymatically neutralized by thrombin. After thrombin proteolysis, PS retains its affinity for phospholipids, but loses its anticoagulant function as the cofactor for aPC.A portion of the PS in blood is bound to the protein, which binds the C4b region of complement (ie, the C4b-binding protein [C4b-BP]).7This C4b-BP forms a 1:1 complex with PS. In plasma, a dynamic equilibrium is reached between C4b-BP-bound and free PS. The free PS form represents about 40% of total PS in normal individuals. Only the free form can act as the cofactor for aPC and accelerate its anticoagulant activity. The PS that is bound to C4b-BP does not possess any anticoagulant activity because in cannot interact with aPC.A deficiency in PS, either congenital or acquired, increases the risk of thromboembolism because of a decrease in the anticoagulant capacity of the blood. Thrombotic episodes can occur when PS activity drops to <50% of normal.6Congenital protein S deficiency:The prevalence of congenital PS deficiency in the general population experiencing their first venous thrombosis is approximately 1%.7In patients with a family history of thrombophilia, the likelihood of congenital PS deficiency being the cause reaches as high as 10%.7This autosomal dominant defect occurs in the general population in approximately 1 in 700 individuals.6Nearly 50% of individuals with congenital PS deficiency will experience a thrombotic event before the age of 45.6Thrombosis can sometimes occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.6Congenital PS deficiency can be further classified based on the measured levels of total and free PS antigen along with functional PS activity.7• Type I PS deficiency is the most common type, representing approximately 90% of cases.6This condition is characterized by a reduction in overall PS antigen levels. Levels of total PS in patients with type I deficiency are typically around 50% of normal while free PS and PS activity are often even lower.• Type II PS deficiency is characterized by a reduced PS activity but with normal antigen levels of both total and free PS.• Type III PS deficiency is characterized by a disproportionately reduced PS activity and free antigen levels in individuals with normal total PS levels.Acquired protein S deficiency:Acquired PS deficiency occurs more frequently than congenital deficiency.6-8Acquired deficiency can occur as the result of decreased PS synthesis or increased consumption. PS synthesis can be diminished in a number of conditions including oral anticoagulant therapy, vitamin K deficiency, liver disease, chemotherapy, and L-asparaginase therapy. PS consumption can occur during disseminated intravascular coagulation (DIC), acute thrombosis, polycythemia vera, sickle cell disease, and essential thrombocythemia. Protein S levels are also dependent, in part, on age, sex, and hormonal status, tending to be lower in the young and lower in women than in men. Levels may be further decreased in premenopausal women on oral contraceptive agents. Protein S values decrease with increasing gestational age. Free PS antigen and PS activities are also often diminished in nephrotic syndrome.7Warfarin-induced skin necrosis has been reported in some cases of PS deficiency.8Infants born with homozygous or doubly heterozygous PS deficiency are usually born with purpura fulminans of the newborn, a devastating condition requiring immediate treatment.8

Heart Health & Cardiovascular

The F2-isoprostane/creatinine ratio is the "gold standard" for measuring oxidative stress and has utility in individuals who have lifestyle risks due to poor diet or smoking, a family history of cardiovascular disease, or hyperlipidemia. High levels are seen in conditions associated with increased risk of atherosclerosis and certain cancers.

Heart Health & Cardiovascular

von Willebrand Disease is the most common hereditary bleeding disorder and it may also be acquired. Von Willebrand Factor (VWF) is critical for normal hemostasis; mediating platelet adhesion to the damaged endothelium and protecting Factor VIII from proteolytic degradation in circulation. VWF Multimeric Analysis is used to assist in categorizing disease subtype.

Genetic Testing, Heart Health & Cardiovascular

Venous thromboembolism is a multifactorial disease influenced by genetic, environmental, and circumstantial risk factors. The c.1601G>A (p. Arg534Gln) variant in the F5 gene, commonly referred to as Factor V Leiden, is a genetic risk factor for venous thromboembolism. Heterozygous carriers of this variant have a 6- to 8-fold increased risk for venous thromboembolism. Individuals homozygous for this variant (ie, they have a copy of the variant on each chromosome) have an approximately 80-fold increased risk for venous thromboembolism. Individuals who carry both a *97G>A variant in the F2 gene and Factor V Leiden have an approximately 20-fold increased risk for venous thromboembolism. Risks are likely to be even higher in more complex genotype combinations involving theF2c.*97G>A variant and Factor V Leiden.1Additional risk factors include but are not limited to: deficiency of protein C, protein S, or antithrombin III, age, male sex, personal or family history of deep vein thromboembolism, smoking, surgery, prolonged immobilization, malignant neoplasm, tamoxifen treatment, raloxifene treatment, oral contraceptive use, hormone replacement therapy, and pregnancy. Management of thrombotic risk and thrombotic events should follow established guidelines and fit the clinical circumstance. This result cannot predict the occurrence or recurrence of a thrombotic event.Genetic coordinators are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Heart Health & Cardiovascular

This test is useful to evaluate a prolonged aPTT. Deficiency of Factor IX can be seen with congenital deficiency (Hemophilia B, X-linked disorder) which affects approximately 1 in 25,000 males. As a vitamin K-dependent clotting factor, decreased levels are also observed with vitamin K antagonists (eg. warfarin therapy) and vitamin K deficiency. Deficiencies may be seen with liver disease, disseminated intravascular coagulation (DIC) and in other consumptive coagulopathies.Anticoagulant interference: Expected impact by therapeutic levels (potential interference depends upon drug concentration): Warfarin: decrease; Heparin (UFH or LMWH): no effect to inhibitor pattern; Dabigatran or Argatroban (Thrombin Inhibitors): no effect to inhibitor pattern; Rivaroxaban, Apixaban, Edoxaban (Factor Xa Inhibitors): no effect to inhibitor pattern. Other limitations: Lupus anticoagulant may cause falsely low to inhibitor pattern. Factor specific inhibitors (autoantibodies or in response to replacement therapies) may cause falsely low or inhibitor patterns.

Diabetes & Blood Sugar, Heart Health & Cardiovascular

The determination of insulin in serum is primarily used for the diagnosis of glycemic disorders in diabetic and pre-diabetic patients in the assessment of insulin resistant syndromes. Insulin is synthesized by the pancreatic beta cell as a precursor, proinsulin. Proinsulin is processed to insulin and C-peptide, a contiguous peptide between the insulin A and B chains, as it passes through the cell. The C-peptide in the proinsulin ensures correct folding and processing of proinsulin as it passes through the cell. Both insulin and C-peptide are released together from the beta cells in response to increased glucose levels. Because of differences in half-life and hepatic clearance, peripheral blood levels of C-peptide and insulin are no longer equimolar but remain highly correlated. A steady-state plasma glucose test in individuals undergoing an insulin suppression test to assess insulin resistance found that the combination of insulin and C-peptide was a better indicator of insulin resistance than either one individually.

Blood Disorders, Heart Health & Cardiovascular

This test is useful to evaluate a prolonged aPTT. The most common form of hemophilia is caused by a deficiency of Factor VIII. Hemophilia A is an X-linked disorder affecting between 1 in 5,000 to 10,000 males. Borderline low Factor VIII activity can be seen in female carriers of the defective Factor VIII gene. Typically this test is combined with other screening tests (eg. von Willebrand factor, Ristocetin Cofactor Activity) to evaluate for the presence von Willebrand disease.Anticoagulant interference: Expected impact by therapeutic levels (potential interference depends upon drug concentration): Warfarin: no effect; Heparin (UFH or LMWH): no effect to inhibitor pattern; Dabigatran or Argatroban (Thrombin Inhibitors): no effect to inhibitor pattern; Rivaroxaban, Apixaban, Edoxaban (Factor Xa Inhibitors): no effect to inhibitor pattern. Other limitations: Factor VIII levels may be falsely low due to Lupus anticoagulant. A chromogenic Factor VIII activity is suggested. The presence of factor VIII antibodies (autoantibodies or antibodies resulting from replacement therapy) can result in low factor VIII levels. This test is NOT recommended for patients receiving emicizumab (ie. Hemilbra) as this therapy will yield falsely elevated values. Factor VIII is a positive acute phase reactant and levels will increase in a variety of clinical scenerios.

Heart Health & Cardiovascular

Tacrolimus is an immunosuppressant drug which has been shown to be effective for the treatment of rejection following transplantation.

Heart Health & Cardiovascular

Thromboxane B2 (TxB2) is the stable, inactive product of prostaglandin metabolism of thromboxane A2, which is renally cleared and, therefore, can be measured in the urine. Studies have shown that thromboxane B2 is a sensitive indicator of platelet activation. Since platelets participate in atherogenesis and contribute to acute, ischemic complications, elevated TxB2 levels may reflect ongoing cardiovascular, peripheral vascular, and cerebrovascular disease processes. TxB levels may also be of interest in conditions with increased platelet turnover, such as disseminated intravascular coagulation or immune thrombocytopenia. Studies of patients with diffuse atherosclerotic disease show that TxB2 may be a more sensitive measure of platelet activation than other platelet-specific proteins. Serum or plasma TxB2 assays are typically limited to a research setting because of the significant in vitro platelet instability.Urinary TxB2 is of interest in monitoring the anticoagulant response to aspirin therapy since aspirin inhibits the formation of TxB2 in platelets. In patients responsive to aspirin therapy and taking an adequate dose, urinary 11-dehydro TxB2 levels should be reduced below a predetermined cutoff when compared to control values.

Heart Health & Cardiovascular

Aspirin (which inhibits platelet cyclooxygenase) reduces the risk of thrombosis in cardiovascular disease by impairing platelet function. Patients who do not respond to the platelet inhibitory effects of aspirin are designated as "aspirin resistant". The measurement of 11-dhTXB2 in urine (the principal metabolite of platelet cyclooxygenase derived thromboxane B2) may be used in individuals with cardiovascular disease prior to initiation of aspirin therapy, or in individuals non-responsive to aspirin therapy.

Genetic Testing, Heart Health & Cardiovascular

Hyperhomocysteinemia is multifactorial, involving genetic, clinical, and environmental risk factors. Reduced enzyme activity of methylenetetrahydrofolate reductase (MTHFR) is a genetic risk factor for hyperhomocysteinemia, particularly when serum folate levels are low. There are two common variants in the MTHFR gene that can decrease enzyme activity: c.665C>T (p. Ala222Val), legacy name C677T, and c.1286A>C (p. Glu429Ala), legacy name A1298C. These variants do not independently increase risk of conditions related to hyperhomocysteinemia in the absence of elevated homocysteine levels. Measurement of total plasma homocysteine is recommended. Patients should share their MTHFR genotype with physicians who are making decisions regarding chemotherapy treatments that depend on folate, such as methotrexate. Guidelines do not recommend genotyping of these two MTHFR variants in the evaluation of venous thromboembolism or obstetric risk due to limited evidence of clinical utility. Genetic coordinators are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Genetic Testing, Heart Health & Cardiovascular

Hyperhomocysteinemia is multifactorial, involving genetic, clinical, and environmental risk factors. Reduced enzyme activity of methylenetetrahydrofolate reductase (MTHFR) is a genetic risk factor for hyperhomocysteinemia, particularly when serum folate levels are low. There are two common variants in the MTHFR gene that can decrease enzyme activity: c.665C>T (p. Ala222Val), legacy name C677T, and c.1286A>C (p. Glu429Ala), legacy name A1298C. These variants do not independently increase risk of conditions related to hyperhomocysteinemia in the absence of elevated homocysteine levels. Measurement of total plasma homocysteine is recommended. Patients should share their MTHFR genotype with physicians who are making decisions regarding chemotherapy treatments that depend on folate, such as methotrexate. Guidelines do not recommend genotyping of these two MTHFR variants in the evaluation of venous thromboembolism or obstetric risk due to limited evidence of clinical utility. Genetic coordinators are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Genetic Testing, Heart Health & Cardiovascular

Hyperhomocysteinemia is multifactorial, involving genetic, clinical, and environmental risk factors. Reduced enzyme activity of methylenetetrahydrofolate reductase (MTHFR) is a genetic risk factor for hyperhomocysteinemia, particularly when serum folate levels are low. There are two common variants in the MTHFR gene that can decrease enzyme activity: c.665C>T (p. Ala222Val), legacy name C677T, and c.1286A>C (p. Glu429Ala), legacy name A1298C. These variants do not independently increase risk of conditions related to hyperhomocysteinemia in the absence of elevated homocysteine levels. Measurement of total plasma homocysteine is recommended. Patients should share their MTHFR genotype with physicians who are making decisions regarding chemotherapy treatments that depend on folate, such as methotrexate. Guidelines do not recommend genotyping of these two MTHFR variants in the evaluation of venous thromboembolism or obstetric risk due to limited evidence of clinical utility. Genetic coordinators are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Blood Disorders, Heart Health & Cardiovascular

Aids in characterization of Antithrombin deficiency (AT, previously referred to as Antithrombin III) which is associated with increased thrombotic risk. Type I deficiency is characterized by reduction in activity and antigen levels simultaneously. With type II deficiency, activity levels are lower in comparison to the antigen levels (dysfunctional protein). Acquired deficiency, more common than inherited defects, can occur due to: liver disease, nephrotic syndrome, heparin therapy, disseminated intravascular coagulation (DIC), sepsis, and L-asparaginase chemotherapy.Anticoagulant interference: heparin therapy may lower AT levels. Other anticoagulants do not impact testing (warfarin, target specific anticoagulants such as Dabigatran, Argatroban, Rivaroxaban, Apixaban, Edoxaban).

Heart Health & Cardiovascular, Genetic Testing

This test determines the subtypes of APOE which will aid in the risk assessment of Coronary Heart Disease (CHD) and Hyperlipoproteinemia.

Genetic Testing, Heart Health & Cardiovascular

Type III hyperlipoproteinemia (broad β disease) is a familial dyslipidemia characterized by the combination of elevated serum cholesterol and triglycerides and the presence of the apolipoprotein E (Apo E) genotype E2/E2. Type III hyperlipoproteinemia has an incidence of 1/2,000−1/10,000. This lipid disorder is associated with a high risk of coronary heart disease and peripheral vascular disease. Onset of type III hyperlipoproteinemia is generally in adulthood but varies from late teens to old age. Before vascular disease develops there are usually no symptoms, and most patients with type III hyperlipoproteinemia are identified only from elevated serum cholesterol and triglycerides discovered during a routine screen. Symptoms include angina, heart attack, claudication, and leg pain. In untreated patients, xanthomas (fat deposits) are occasionally seen (flat in palmar creases or tuberous in joints).The E2 variant of apolipoprotein E is defective in binding to receptors that normally clear harmful lipid particles called B-VLDL from the circulation. One percent of the general population has the E2/E2 genotype, and development of the frank lipid disorder occurs in 1% to 5% of these predisposed individuals, triggered by secondary genetic, hormonal or environmental factors. Ninety-five percent of patients with type III hyperlipoproteinemia are homozygous for E2. Demonstration of the E2/E2 genotype is essential for diagnosis of type III hyperlipoproteinemia.Distinguishing this disorder from other causes of elevated cholesterol is important because effective treatment of type III hyperlipoproteinemia to prevent atherosclerosis often requires a different approach than treatment of other dyslipidemias.

Autoimmune & Inflammation, Heart Health & Cardiovascular

Lupus anticoagulants are nonspecific antibodies that extend the clotting time of phospholipid-dependent clotting assays such as the aPTT.6,7Unlike specific factor antibodies, LA are usually associated with venous thrombosis, pulmonary embolism, arterial thrombosis, and recurrent fetal loss.8LA do not specifically inhibit individual coagulation factors; rather they neutralize anionic phospholipid-protein complexes that are involved in the coagulation process. Prolongation of clot-based assays is highly dependent on the sensitivity of the reagent employed. Reagents with reduced amounts of phospholipid, such as the aPTT-LA and dilute Russell viper venom time (dRVVT), have enhanced sensitivity for LA.6Due to the heterogeneity of LA antibodies, no single assay will identify all cases.8The International Society on Thrombosis and Haemostasis (ISTH) has established criteria for the diagnosis of lupus anticoagulants.6-8Testing for lupus anticoagulant (LA) and the antiphospholipid syndrome that is associated with these antibodies is described in more detail in the online Coagulation Appendices: Lupus Anticoagulants and Antiphospholipid Syndrome.

Genetic Testing, Heart Health & Cardiovascular

Type III hyperlipoproteinemia (broad β disease) is a familial dyslipidemia characterized by the combination of elevated serum cholesterol and triglycerides and the presence of the apolipoprotein E (Apo E) genotype E2/E2. Type III hyperlipoproteinemia has an incidence of 1/2,000−1/10,000. This lipid disorder is associated with a high risk of coronary heart disease and peripheral vascular disease. Onset of type III hyperlipoproteinemia is generally in adulthood but varies from late teens to old age. Before vascular disease develops there are usually no symptoms, and most patients with type III hyperlipoproteinemia are identified only from elevated serum cholesterol and triglycerides discovered during a routine screen. Symptoms include angina, heart attack, claudication, and leg pain. In untreated patients, xanthomas (fat deposits) are occasionally seen (flat in palmar creases or tuberous in joints).The E2 variant of apolipoprotein E is defective in binding to receptors that normally clear harmful lipid particles called B-VLDL from the circulation. One percent of the general population has the E2/E2 genotype, and development of the frank lipid disorder occurs in 1% to 5% of these predisposed individuals, triggered by secondary genetic, hormonal or environmental factors. Ninety-five percent of patients with type III hyperlipoproteinemia are homozygous for E2. Demonstration of the E2/E2 genotype is essential for diagnosis of type III hyperlipoproteinemia.Distinguishing this disorder from other causes of elevated cholesterol is important because effective treatment of type III hyperlipoproteinemia to prevent atherosclerosis often requires a different approach than treatment of other dyslipidemias.

Cancer Screening, Heart Health & Cardiovascular

Vascular endothelial growth factor (VEGF) is a homodimeric 34 to 45 kilodalton, heparin-binding glycoprotein. VEGF has potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells.1,2VEGF expression is regulated by hypoxia, with levels increasing when cells detect an environment low in oxygen. Physiologically, VEGF induces new blood vessel formation during embryonic development, after tissue injury and in response to blocked vessels. VEGF is thought to play an important role in several physiologic processes, including wound healing, ovulation, menstruation, maintenance of blood pressure and pregnancy.1VEGF has also been associated with a number of pathologic processes that involve angiogenesis, including arthritis, psoriasis, macular degeneration and diabetic retinopathy.1,3POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is a rare paraneoplastic syndrome, caused by a plasma cell proliferative disorder, which is most commonly lambda restricted.4The neurological hallmark, which forms one of the mandatory criteria for diagnosis, is a subacute onset demyelinating neuropathy, which can be rapidly disabling and painful. Elevated VEGF is highly specific for POEMS syndrome (though not pathognomonic) and thought to be involved in the pathophysiology of systemic features including organomegaly and volume overload. VEGF levels reflect disease activity, falling with treatment and rising with disease progression or relapse. Monitoring VEGF levels may be useful as a disease prognostic marker.5In general, the growth and spread of tumors has been shown to be dependent on the development of increased vascularization in the tumor vicinity in order to maintain sufficient oxygenation.1,6Tumor expression of proangiogenic factors, including VEGF, has been associated with advanced tumor progression in a number of human cancers.7,8Increased expression of VEGF has been associated with poorer prognosis in patients with cancer of the colon,9-11stomach,12-14pancreas,15,16breast,17-20ovary,21,22prostate,23,24liver,25oral squamous cell,26bone27and in melanoma.28Serum VEGF levels are significantly higher than plasma levels. This is thought to reflect the fact that VEGF is released into the serum from platelets as part of the clotting process.29It has been hypothesized that VEGF released from activated platelets may have a role in angiogenesis during wound healing and may also be associated with pathological conditions, such as atherosclerosis, tumor growth and metastasis formation.29In different studies, serum VEGF12,21,22,25,26and plasma VEGF11,17,23,24levels have been found to correlate with the clinical status of patients with cancer.

Heart Health & Cardiovascular, Autoimmune & Inflammation

Useful in predicting risk of cardiovascular disease.

Heart Health & Cardiovascular

UFH and LMWH are anticoagulants commonly used to decrease the risk of venous or arterial thrombosis.6-9Overdosing with these medications can increase the risk of hemorrhage and inadequate dosing decreases the efficacy of anticoagulation. These drugs work as anticoagulants by enhancing the ability of plasma antithrombin to bind and inactivate the serine proteases XIIa, XIa, IXa, Xa, and thrombin. Therapeutic monitoring is commonly performed because of the wide interindividual variation in response to this therapy.Historically, many laboratories have monitored heparin levels using the activated partial thromboplastin time (aPTT) test. A large number of conditions can complicate the use of the aPTT in monitoring UFH therapy.6The College of American Pathologists (CAP) divided these factors into three groups.6The first group of complicating factors encompasses those that affect the bioavailability of heparin. Aging, obesity, changes in heparin binding proteins, hepatic disease, renal disease, and heparin resistance fall under this heading. The second group of complicating factors includes those that alter the aPTT dose response to heparin. Increased factor VIII or fibrinogen levels, decreased antithrombin levels, or a mild reduction in multiple factors (as might be seen in the early stages of a consumptive coagulopathy or in oral anticoagulant therapy) are examples of this type of complicating factor. Lastly, those factors that tend to cause a prolonged aPTT in the absence of heparin therapy should be considered. Lupus anticoagulants or deficiency in contact factors can produce an extended baseline aPTT. In all of these cases, the heparin anti-Xa assay may be more appropriate for monitoring heparin therapy.The aPTT should not be used for therapeutic monitoring of low molecular weight heparin because this drug typically does not affect the aPTT significantly.6,7

Genetic Testing, Heart Health & Cardiovascular

Deep vein thrombosis (DVT) and coronary artery disease (CAD) are associated with increased PAI-1 levels. Elevated PAI-1 levels may help predict risk of reinfarction in survivors of myocardial infarction, particularly in young individuals. PAI-1 levels tend to be lower in individuals with 4G/5G or 5G/5G genotype compared to a 4G/4G genotype.

Genetic Testing, Heart Health & Cardiovascular

Deep vein thrombosis (DVT) and coronary artery disease (CAD) are associated with increased PAI-1 levels. Elevated PAI-1 levels may help predict risk of reinfarction in survivors of myocardial infarction, particularly in young individuals. PAI-1 levels tend to be lower in individuals with 4G/5G or 5G/5G genotype compared to a 4G/4G genotype.