D-dimer utilization for the diagnosis of venous thromboembolism

The value of the D-dimer assay as a tool in the management of patients suspected of venous thromboembolism (VTE) continues to grow. The D-dimer assay is commonly used to rule out VTE in conjunction with pretest probability (PTP) clinical scoring algorithms. VTE, or pathological blood clots, form in the body as a result of blood coagulation activation. Though activation of the coagulation system is essential in the case of injury, several acquired or temporary clinical risk factors, including obesity, autoimmune antiphospholipid antibodies, prolonged immobility, cancer, cardiac failure, major surgery or trauma, increasing age, or pregnancy can lead to VTE.¹ Inherited genetic risk factors, such as factor V Leiden (FVL) or prothrombin gene mutation (PGM), give rise to increased familial VTE risk. According to the U.S. Centers for Disease Control and Prevention (CDC), between five percent and eight percent of the U.S. population carries an inherited genetic defect producing VTE risk, with FVL being the most common.²

The burden of VTE

VTE can present as a deep vein thrombosis (DVT), commonly appearing in smaller diameter distal veins of the lower extremities where blood flow is slower. If a DVT occurrence is not detected early, the thrombus (or a portion of the thrombus) can travel to the lungs, where it becomes a pulmonary embolism with a high risk of morbidity and mortality. The CDC estimates that 900,000 people are affected by VTE annually, with up to 100,000 likely deaths due to the disorder. The estimated incidence is based on analyses of clinical administrative databases and hospital- and community-based studies. The incidence ranges from one per 100,000 in the young and increases to about one per 100 in people 80 years and older. Because of the difficulty in documenting DVT and PE separately from concomitant disease states, along with the inherent limitations of administrative databases and community-based studies, VTE may be vastly underreported.²

Rapid and accurate exclusion of VTE is critical to maintain patient health when patients are suspected of the pathology, as many patients who are at risk may not be aware and clinicians may not recognize the disorder among other potential comorbidities. Again, according to the CDC, 10 percent to 30 percent of patients diagnosed with DVT/PE will die within one month of being diagnosed. Worse, death is the first symptom in about 25 percent of patients. In those who survive VTE, one in three patients will experience a recurrence within 10 years, making ongoing testing and treatment with anticoagulation necessary for those affected.² Even if a DVT is resolved, the thrombus can cause post-thrombotic syndrome (PTS), a significant clinical issue bringing long-term damage including chronic leg pain, swelling, redness, and ulcers.

Monetary costs associated with VTE diagnosis present a significant burden on the healthcare system, with a total burden on the U.S. healthcare system of approximately $2 billion. Imaging techniques requiring capital equipment and dedicated staff contribute to the documented burden, making clear the advantage of appropriate use of laboratory testing and PTP to significantly reduce the monetary burden.

Diagnosing DVT and PE

The Wells Score is one of the more common PTP algorithms in use, recommended by the 2015 guideline on PE diagnosis from the American College of Physicians.³ According to the Wells score for PE risk stratification, points are assigned when patients present with history of DVT/PE, elevated heart rate, recent surgery/immobilization, outward signs, less likely alternative diagnosis, hemoptysis (blood-stained sputum), and cancer. If the score is 0-1, a low classification is assigned. If 2-6, the patient is classified at intermediate risk. If the score is 7 or greater, the patient has a high risk of PE. The scoring criteria are different, but structured similarly for DVT risk stratification. Best practices, including those reported by the Clinical Laboratory Standards Institute (CLSI), dictate that a screening D-dimer assay be performed when the Wells score is low or moderate probability.⁴

D-dimer plasma levels are commonly measured by automated laboratory immunoassay methods, but the assay can also be performed using less sensitive near-patient or point-of-care methods. D-dimers, fragments of crosslinked fibrin, are present in high levels when fibrinolysis (clot digestion) processes have recently occurred, and they indicate a “smoking gun” for active clotting (and concomitant clot digestion) processes in the patient. Not only is D-dimer useful for VTE diagnosis, but it is also a mainstay of the clinical scoring algorithm to assist with diagnosis of disseminated intravascular coagulation (DIC).⁵

If a positive D-dimer result is reported, confirmatory imaging techniques, including compression ultrasound or contrast venography (for DVT) and pulmonary angiography or perfusion scanning (for PE) are performed. If the Wells score indicates high risk for DVT or PE, the patient goes directly to imaging. Importantly, when the D-dimer assay is performed appropriately in the manner described, there is potential to avoid unnecessary and expensive imaging techniques. Significant radiation exposure is experienced by the patient especially in the case of PE imaging procedures, much more compared to standard chest X-rays. In addition, these imaging procedures are not available in all healthcare facilities (especially after normal business hours) due to a requirement for specialized equipment along with trained technicians and clinicians to interpret results. Thus, use of the D-dimer assay in concert with PTP, as described, has significant potential to save time in preventing morbidity and mortality by treating the patient earlier and preventing unnecessary radiation exposure. At the same time, precious healthcare dollars are utilized more efficiently, with emergency department length of stay reduced by more than 50 percent and with greater than $2,000 cost-of-care reduction per patient.^6-8

Evaluating D-dimer assays

D-dimer assays are most useful when demonstrated to have high clinical sensitivity to detect all patients with DVT and/or PE. In addition, the assay must have a high clinical specificity to rule out those patients who do not have DVT or PE. Specificity saves healthcare dollars by preventing false positives, resulting in fewer unneeded imaging procedures. Last, D-dimer assays with high negative predictive value (NPV) demonstrate the ability of the test to identify disease-free individuals among a total population of patients with true negative test results. Specificity, sensitivity, and NPV can be accurately determined by use of appropriately designed, multicenter management trials such as one published recently.⁹

Though not a new tool in the clinicians’ toolbox, the D-dimer assay continues to be a mainstay of the clinical laboratory and is also featured in many multicenter clinical trials to extend the utility and applicability of the assay. For example, several recent studies have focused on adjusting the cutoff of the D-dimer assay for the age of the patient to correct for the trend of increasing D-dimer values as patients age.^10,11 In addition, randomized controlled trials such as MAGELLAN have demonstrated the utility of elevated baseline D-dimer levels for prospectively evaluating risk of VTE for inpatients.¹² Interested observers should expect to see additional clinical trials reported to further demonstrate the role of D-dimer testing in thrombotic disease pathologies.

BIBLIOGRAPHY

1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495-501.
2. Centers for Disease Control and Prevention. Venous thromboembolism (blood clots). https://www.cdc.gov/ncbddd/dvt/data.html.
3. Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;163(9):701-711.
4. Clinical and Laboratory Standards Institute (CLSI). Quantitative D-dimer for the exclusion of venous thromboembolic disease; approved guideline. CLSI document H59-A. 2011.
5. Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037.
6. Crichlow A, Cuker A, Mills AM. Overuse of computed tomography pulmonary angiography in the evaluation of patients with suspected pulmonary embolism in the Emergency Department. Acad Emerg Med. 2012; 19(11):1220-1226.
7. Soo Hoo GW, Wu CC, Vazirani S, Ziaoping L, Brack BM. Does a clinical decision rule using D-dimer level improve the yield of pulmonary CT angiography? Am J Roentgenol. 2011;196(5):1059-1064.
8. Huisman MV, Klok FA. How I diagnose acute pulmonary embolism. Blood. 2013;121: 4443-4438.
9. Pernod G, Wu H, de Maistre E, et al. Validation of STA-Liatest D-Di assay for exclusion of pulmonary embolism according to the latest Clinical and Laboratory Standard Institute/Food and Drug Administration guideline. Results of a multicenter management study. Blood Coagul Fibrinolysis. 2017;28(3):254-260.
10. Mullier F, Vanpee D, Jamart J, et al. Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department. Blood Coagul Fibrinolysis. 2014; 25(4):309-315.
11. van Es J, Mos I, Douma R, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost. 2012; 107(1):167-171.
12. Cohen AT, Spiro TE, Spyropoulos AC, et al. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost. 2014; 12(4):479-487.

Paul Riley, PhD, MBA, serves as Scientific Business Development Manager for Diagnostica Stago Inc, North America. He is responsible for customer education and scientific support for the company, covering the United States and Canada. He has great interest in working with thought leaders to assist with performing studies and contributing to advancement of hemostasis science.