American Society for Clinical Laboratory Science

Ten Things Physicians and Patients Should Question

Items 1–5 Released June 10, 2020; Items 6–10 Released September 13, 2021

  1. 1

    Don’t order a factor V Leiden (FVL) mutation assay as the initial test to identify a congenital cause for a thrombotic event. First, order a phenotypic activated protein C resistance (APCR) ratio assay.

    There exist several acquired APCR conditions such as elevated factor VIII and antibody-mediated APCR that can lead to thrombotic events such as deep venous thrombosis or pulmonary embolism. Further, several factor V Leiden-independent mutations may be associated with thrombosis. Best practice guidelines recommend testing for APCR using one of several phenotypic clot-based APCR ratio assays as an initial assay and following up positive APCR ratio results with the molecular factor V Leiden assay. Most currently available phenotypic tests are economical, have a greater than 95% concordance with molecular testing and up to 99% clinical sensitivity. Based on Medicare reimbursement rates, switching to initial-phase phenotypic testing and relying on its negative predictive value with follow-up genotypic testing on APCR-positive samples could result in a 75% reduction in costs. Although the FVL mutation assay is often ordered to determine the cause of venous thromboembolic disease, the APCR ratio assay provides greater clinical sensitivity at a lower cost. In instances when clot-based thrombosis risk testing is indicated during acute thrombosis, line-associated thrombosis, or anticoagulant therapy, the APCR is compromised and the FVL mutation assay is used as a primary assay.

  2. 2

    Do not use herpes simplex virus (HSV) polymerase chain reaction (PCR) testing for genital HSV infection screening in adults and adolescents. Real-time HSV PCR testing should only be used to confirm herpes diagnosis in patients with suspected herpes.

    HSV shedding is intermittent. Therefore, testing swabs from asymptomatic patients is not recommended for routine diagnosis since it is unlikely to yield confirmation of carrier status. However, laboratory confirmation in all patients with suspected herpes is recommended. HSV DNA detection by real-time PCR is considered the gold standard for diagnosis. Swabs for testing are taken from the base of the lesion (vesicles should be unroofed with a needle or scalpel blade). HSV typing into HSV-1 and HSV-2 is recommended in all patients with first-episode genital herpes to guide counselling and management.

  3. 3

    Do not transfuse red blood cells as the sole intervention for expansion of circulatory volume unless deemed necessary for patients experiencing severe hemorrhage.

    The Canadian Transfusion Requirements in Critical Care (TRICC) trial was the first to investigate a liberal versus restrictive approach to red blood cell (RBC) transfusions. The trial included a total of 838 hemodynamically stable, critically ill patients who had a hemoglobin (Hgb) concentration less than 9 g/dL (adult transfusion trigger 7–8 g/dL). The trial defined two categories for the study, a “liberal” approach that required allogeneic RBC transfusions for patients with Hgb less than 10 g/dL and a “restrictive” approach for patients with a Hgb concentration less than 7 g/dL. Patients were randomly divided between both study groups and were evaluated at 30 days. There was no significant mortality difference. The trial also noted a significantly better survival rate among patients less than 55 years old within the restrictive group; including in particular less acutely ill patients. Subsequent studies have shown that clinically stable patients may benefit more from a restrictive approach by reducing the percentage of patients exposed to allogeneic RBCs. It is not recommended to transfuse RBCs as the sole intervention for volume expansion. The World Health Organization recommends volume-expanding solutions such as crystalloids or colloids to expand fluid volume. These promote blood circulation through vital organs and tissues. RBC transfusions should be used to treat conditions such as severe hemorrhage that otherwise lead to significant mortality. Recent evidence for blood transfusions suggests that a restrictive transfusion approach is safer and as effective as a liberal approach for post-operative stable patients, normovolemic critically ill-patients with a hemoglobin transfusion trigger of 7–8 g/dL and patients with clinical symptoms of anemia. The exception to the restrictive approach is comprised of patients with clinically significant cardiovascular conditions. Blood products carry the risk of transmitted infectious diseases and adverse effects of blood transfusion (e.g. immunosuppressive complications).

  4. 4

    Avoid using hemoglobin to evaluate patients for iron deficiency in susceptible populations. Instead, use ferritin.

    Iron depletion is a progressive process with anemia as the final phase. Thus, screening for iron deficiency using hemoglobin (Hgb) will only identify the most severe cases. Moreover, Hgb is not specific for iron deficiency or iron deficiency anemia. Iron deficiency is one of the most common nutritional deficiencies worldwide. Prevalence of iron deficiency in USA women ages 12–49 years rose from 11% in 2003 to 14.8% in 2010. Pregnant women and young children are also high-risk groups and must be evaluated. Iron deficiency in U.S. toddlers, without anemia, is estimated at 6.6%–15.2%.

    Serum ferritin is a measure of iron stores and is the most sensitive biomarker to test for early stages of iron deficiency as well as iron deficiency anemia. Sensitivity of ferritin test is 89% for diagnosis of iron depletion compared to hemoglobin, which is only 26%. Moreover, a ferritin cut off of ≤30 ng/mL provides 92% sensitivity and 98% specificity for iron deficiency anemia and is the best screening test for this disorder.

    Evaluating patients for iron deficiency with ferritin will identify early stage iron deficiency and will potentially result in iron therapy, preventing iron deficiency anemia. Iron deficiency anemia has been long associated with psychomotor and cognitive abnormalities but even iron deficiency without anemia has been related to negative  eurodevelopmental outcomes in children.

    Ferritin is an acute phase reactant, and occasionally in inflammatory conditions, ferritin levels may be normal or elevated even in the presence of iron deficiency. Additional laboratory tests such as reticulocyte hemoglobin content (CHR or Ret-He), mean corpuscular volume (MCV), red cell distribution width (RDW), and additional iron studies such as percent transferrin saturation and total iron binding capacity, accompanying clinical correlation are also helpful to determine iron deficiency.

  5. 5

    Do not order a comprehensive stool ova and parasite (O&P) microscopic exam on patients presenting with diarrhea less than seven days’ duration who have no immunodeficiency or no history of living in or traveling to endemic areas where gastrointestinal parasitic infections are prevalent. If symptoms of infectious diarrhea persist for seven days or longer, start with molecular or antigen testing and next consider a full O&P microscopic exam if other testing is negative.

    The comprehensive O&P microscopic exam often requires submission of multiple stool samples, it is labor intensive, requires significant expertise to perform, and typically has lower sensitivity when compared to many other tests now available. Instead, consider ordering antigen detection tests (i.e. direct fluorescent antibody, enzyme immunoassay, indirect immunofluorescence assay, rapid immunochromatographic tests), modified acid-fast stain, or molecular tests that detect specific gastrointestinal parasites most commonly acquired in the U.S. When investigating cases of gastrointestinal disease, it is important to take a comprehensive clinical history that considers the patient’s exposure risk, mechanism(s) of transmission, and immune status. Patients lacking international travel history or residence in areas where parasites are endemic are most likely to be exposed to intestinal parasites associated with outbreaks from exposure to contaminated food or water. In the U.S. these pathogens include Giardia duoedenalis (G. lamblia, G. intestinalis), Entamoeba histolytica, Cryptosporidium, and Cyclospora. For most individuals with healthy immune systems, symptoms self-resolve without treatment. In individuals with prolonged symptoms, risk for development of severe infection, or when pathogen identification is necessary for public health reasons, testing is recommended. Numerous antigen detection assays and molecular tests, including multiplex panels, have been developed for targeted detection of the most common gastrointestinal parasites acquired in the U.S.

  6. 6

    Avoid routine prothrombin time (PT) and partial thromboplastin time (PTT, APTT) pre-operative screens on asymptomatic patients, use instead a history-based bleeding assessment test.

    The 1989 Medical Necessity Project of the Blue Cross and Blue Shield Association endorsed by the American College of Physicians found that at least 70% of PT and PTT tests were not clinically indicated. Subsequently, nine observational studies, including three prospective trials, reported that PT and PTT positive predictive values for bleeding complications ranged from 0.03 to 0.22, whereas computed 95% confidence intervals for each assay generates a 2.5% false positive rate. A review of 27,737 PT and PTT results over two decades showed that only 8% of PTs and PTTs were clinically indicated based on current or prior patient history of bleeding. A study of general hospital unregulated coagulation screening requests produced few abnormal results with no evidence that they were associated with an increased bleeding risk. In this study, all bleeding cases could be attributed to an underlying condition. The risk of intraoperative bleeding is best predicted from a careful history that includes a questionnaire-based bleeding assessment test (BAT).

  7. 7

    Do not order a homocysteine assay as part of the thrombophilia work up.

    For long it was thought that elevated homocysteine was associated with cardiovascular diseases. That in turn could lead to coronary artery disease, heart attacks, strokes, clots in veins causing deep vein thrombosis (DVT) and pulmonary embolism (PE), and pregnancy complications among others. But in 2010 the American Heart Association declared that elevated homocysteine levels were not considered to be a major risk factor for cardiovascular disease. Subsequently, in 2013, the American College of Obstetricians and Gynecologists recommended that fasting homocysteine levels should not be ordered as part of work up for venous thromboembolism. Homocysteine is a breakdown product of methionine that can be recycled by the human body with the help of the enzyme methylene tetrahydrofolate reductase (MTHFR) to reuse in building proteins. A mutation of the MTHFR gene (C677T) impairs its ability to process folate that may lead to elevated homocysteine levels. An elevated homocysteine level is not a clotting disorder and should not be included in thrombophilia testing panels.

  8. 8

    Do not order a protein S activity assay for measuring protein S function. Instead, order free protein S antigen.

    Thrombophilia has numerous causes, including protein S deficiency, of which there are 3 recognized types. Type I and type III are quantitative defects while type II is a qualitative defect.

    Types of Heterozygous Protein S Deficiency

    Type Free Protein S Antigen  Total Protein S Antigen  Functional Protein S Activity
     I Decreased  Decreased Decreased
    II Normal  Normal Decreased
    III Decreased Normal Decreased

    Type II is extremely rare and is not considered a risk factor for thrombophilia. While functional protein S activity is commonly measured to detect
    protein S deficiency, there are problems with this test. It is a clot-based assay and has a large coefficient of variation; the test is affected by patients
    who have factor V Leiden mutation or lupus anticoagulant. On the contrary, free protein S antigen assay is more specific for detecting true deficiencies
    and only free protein S has anticoagulant activity. Measuring free protein S antigen provides more reliable results, when testing for protein S deficiency
    is clinically warranted.

  9. 9

    Do not use viscoelastic testing to determine blood product transfusions in trauma patient resuscitation without an established, institutional treatment algorithm in place.

    Currently, many trauma patients presenting to emergency departments are resuscitated through blood product transfusions guided by conventional coagulation tests (CCTs) only. Acute care organizations that utilize viscoelastic testing (VET) in conjunction with CCTs do not commonly have treatment algorithms in place to guide blood transfusions in trauma patients, which can result in the overuse of blood products. When assessing the number of hospitals that have institutional massive transfusion protocols (MTP), one study documented that only 9% of surveyed facilities utilize VET in their MTPs.

    Several recent studies compared patient outcomes in facilities that incorporate viscoelastic methodologies into their MTPs against those that did not. Mortality and blood product transfusion rates were measured and positive correlations between CCTs in conjunction with VET versus CCTs-only were found. Not only did viscoelastic-guided resuscitation result in higher survival rates and fewer transfused blood products, but also identified those at risk for hyperfibrinolysis, which is a limitation of CCTs. Apart from positive patient outcomes with VET+CCT, another study found that MTP trauma patients guided by VET-only versus CCT-only had no difference in patient outcomes.

    When observing the opportunity of replacing CCTs with VET for trauma activations in the Emergency Department, the reviewed literature seems to be inconclusive. A study of 1,974 major trauma activations argues that rapid thromboelastography methods, a form of VET, are better predictors for massive transfusions; however, another study argued that, because VET testing takes longer to perform than CCTs, VET should not be the sole tool to assess coagulopathies in these patients. Ultimately, the inconsistencies in evidence to date do not support one testing approach over the other, but some data does suggest that a combined approach may be beneficial towards patient outcomes – when properly followed.

  10. 10

    Do not use serum cortisol levels as initial screening for adrenal hyperfunction [Cushing syndrome], instead consider superior strategies provided in the justification.

    Serum cortisol levels do not provide high-end diagnostic accuracy or sensitivity when used as an initial diagnostic test. Late night salivary cortisol samples employing an approved collection device, 24-hour urine free cortisol [UFC], or a 1 mg overnight dexamethasone suppression test [DST] should be used as an initial test. These tests have a high diagnostic accuracy for Cushing syndrome [CS]. Multiple screening tests may need to be performed based on the variability of hypercortisolism in CS. Two measurements of abnormal cortisol levels with these tests are recommended for an initial diagnosis, further workup should be referred to an endocrinologist to make the final diagnosis. Each of these tests has different limitations and should be chosen based on the lifestyle and medical history of the patient. Patients with erratic sleep schedules or shift workers would not obtain accurate results from a late-night salivary cortisol test. Women taking oral estrogen, those taking antiepileptic drugs [phenytoin and phenobarbitone], and pregnant women could have falsely elevated cortisol levels as CYP3A4 metabolizes dexamethasone with the DST. UFC tests require rigorous collection management and should not be used on patients experiencing renal failure, or those suspected to have mild CS. Exogenous glucocorticoid use must be excluded before performing these biochemical tests.

These items are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their physician.

The American Society for Clinical Laboratory Science (ASCLS) and its 9,000 clinical laboratory professional, student, and educator members in more than 50 state and regional constituent societies work to advance the expertise of clinical laboratory professionals who, as integral members of interprofessional healthcare teams, deliver quality, consumer-focused, outcomes-oriented clinical laboratory services through all phases of the testing process to prevent, diagnose, monitor and treat disease. The Society promotes high standards of practice by holding the profession accountable to a Code of Ethics, through dissemination of knowledge at educational programs and through publications; maintains a supportive community to advocate on behalf of current and future laboratory professionals; and provides laboratory professionals a voice to legislators and regulators through collective, grassroots efforts.

How This List Was Created

(1-5)
George Fritsma, MS, MLS (ASCP), and the late Cindy Johns, MS, MLS (ASCP) hosted a plenary presentation “Enhancing Laboratory Communication to Reduce Extra-analytical Errors” at the ASCLS Clinical Laboratory Educators’ Conference in Boston in February 2017. Their talk referenced the ABIMF Choosing Wisely initiative. Subsequent discussions resulted in the ASCLS Board of Directors appointing a Choosing Wisely task force that evolved to a standing committee. The committee is composed of ASCLS members representing all medical laboratory science disciplines.

The committee collaborated with respective ASCLS Scientific Assemblies in developing and reviewing recommendations, which the Board of Directors reviewed and accepted for publication. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.

 

(6-10)

American Society for Clinical Laboratory Science (ASCLS) recommendations were developed under the leadership of ASCLS’s Choosing Wisely Committee and the ASCLS president and executive vice president. The Committee examined numerous options based on evidence available through an extensive review of  the literature and member proposals. Subject matter experts from the ASCLS Scientific Assemblies reviewed and recommended approval of their respective recommendations, which are subsequently approved by the ASCLS Board of Directors. The recommendations were subsequently reviewed in collaboration with the ASCP Test Utilization Steering Committee prior to submission.

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