Utility of D-dimer Testing in Special Populations

Authors: Lauren Willoughby, MD (Education Fellow, University of Wisconsin); Benjamin H. Schnapp, MD, MEd (Associate Program Director, University of Wisconsin) // Reviewed by: Joshua Lowe, MD (EM Attending Physician, USAF), Marina Boushra (EM-CCM, Cleveland Clinic Foundation); Brit Long, MD (@long_brit)

Case

A 36-year-old pregnant woman at 21 weeks gestation presents to the ED with chest pain. Her past medical history is notable for hypertension and hyperlipidemia. The chest pain started suddenly today while at rest, is located on the right side, and radiates to her back. She denies other symptoms, including leg pain or swelling. Vital signs include BP 130/75 mmHg, HR 115 bpm, RR 24 breaths per minute, oxygen saturation of 93% on room air, and an oral temperature of 98.8° F. Her lungs are clear to auscultation. There is no swelling, redness, or tenderness in her calves.

What are the next steps in the evaluation of this patient?

What is the utility of D-dimer testing in the evaluation of venous thromboembolism (VTE) for this patient?

How does her pregnancy affect the utility of D-dimer levels in the exclusion of VTE?

What is a D-dimer?

Intravascular activation of the coagulation cascade results in the production of a fibrin clot. The enzyme plasmin then degrades the fibrin clot into soluble D-dimer fragments. To maintain a state of homeostasis, any process that activates the coagulation cascade results in the production of both a fibrin clot and D-dimer fragments as that clot is degraded.¹ A D-dimer level can, therefore, be used as a non-specific and indirect biomarker for the presence of intravascular clotting, which may be useful in the diagnosis of VTE. However, D-dimer levels may be elevated for a variety of different physiologic and pathologic reasons. While diagnoses such as pulmonary embolism (PE) and deep vein thrombosis (DVT) are classically associated with D-dimer elevation, many other conditions such as surgery, cancer, inflammation, and infection will also cause activation of the coagulation cascade and production of clots, resulting in an elevation in D-dimer level (Table 1).

Clinical utility of D-dimer in the general population

The use of a D-dimer level in the evaluation of VTE in the general population has been extensively studied and validated. When assessing for VTE, the standard cut-off for a “positive” or elevated result is 500 ng/mL.^2,3  Sensitivity for VTE is high at this cut-off value, ranging between 75 and 96% depending on the assay used.^2,3 However, this high sensitivity comes at the expense of a low specificity, which can range between 45 and 83% depending on the assay used.² Since VTE can be a potentially life-threatening diagnosis, the cut-off value for a negative result must minimize the number of false negatives, or have a high sensitivity.³  If the cut-off value were raised, this would result in a larger number of false negatives and missed VTEs.

Because population incidence affects the negative predictive value (NPV) of D-dimer testing, it is important to determine the pre-test probability of a patient having a VTE prior to obtaining the D-dimer level. Physician gestalt and clinical decision-making tools such as the Wells’ (https://www.mdcalc.com/calc/115/wells-criteria-pulmonary-embolism) or Geneva (https://www.mdcalc.com/calc/1750/geneva-score-revised-pulmonary-embolism) scores are helpful when assessing a patient’s pre-test probability, which is categorized as low, moderate, or high risk.

D-dimer testing is most useful in low- to moderate-risk patients.^1-3 In this patient population, the NPV of a negative D-dimer level is high, such that a negative test makes further evaluation for VTE  unnecessary. Given the low specificity of D-dimer for VTE, if the D-dimer level is found to be elevated in this patient population, imaging tests with greater sensitivity are the recommended next step.^1-3  In patients with a high pre-test probability for VTE, advanced imaging without D-dimer testing is recommended. This is because even if the D-dimer is negative, the high prevalence of VTE in high-risk patients makes the NPV of the test low.²  The diagnostic utility of D-dimer testing in VTE in the general population is illustrated below in Figure 1, which outlines a diagnostic algorithm for the evaluation of PE based on D-dimer testing.

When VTE is suspected in a low- to moderate-risk patient, obtaining a D-dimer level can have numerous benefits. Results of blood work are usually available quicker than results of imaging studies, so the exclusion of VTE will typically be faster using a D-dimer level compared to imaging.^1-3  Since obtaining a D-dimer level may lead to a faster diagnosis, it can decrease the patient’s length of stay. Further, excluding VTE through D-dimer testing will reduce unnecessary radiation by decreasing the need for advanced studies such as CT.

D-dimer and special populations

While an elevated D-dimer level may indicate the presence of a pathologic process, higher levels may be normal in certain populations, particularly pregnant women and older patients. This presents diagnostic challenges for the emergency physician when evaluating these patients for VTE using D-dimer.

Pregnancy

D-dimer levels typically rise throughout pregnancy and reach the highest concentrations by the third trimester.² The physiologic rise in D-dimer levels makes the evaluation of PE in this patient population especially challenging because shortness of breath is common in pregnancy for reasons unrelated to VTE but pregnancy is a known risk factor for VTE.  To address this need, the pregnancy-adapted YEARS algorithm was developed and externally validated.⁴ This algorithm combines D-dimer level with the presence of three YEARS criteria (hemoptysis, clinical signs of DVT, and PE as the most likely diagnosis) to determine the next steps in the evaluation of PE in a pregnant patient (Figure 2).⁴ If the patient meets none of the YEARS criteria, the D-dimer cut-off for a positive test can be increased to 1,000 ng/mL.⁴

The pregnancy-adapted YEARS algorithm has been sho
wn to safely rule out pulmonary embolism in pregnant patients, with the incidence of VTE during a 3-month follow-up period being 0.42%.⁴ The pregnancy-adapted YEARS score has the highest efficacy during the first trimester.⁴ The ability to utilize a D-dimer level to rule out PE in pregnant patients is helpful in avoiding unnecessary radiation exposure to the patient and the fetus.

Older Adults

Elevated D-dimer levels are commonly found in older patients in the absence of pathology.⁵ Given the physiological rise in D-dimer levels with age, studies have investigated the use of an age-adjusted D-dimer cut-off when evaluating for a PE in patients greater than 50 years old. The optimal age-adjusted cut-off was determined to be the patient’s age multiplied by 10 as opposed to the traditionally used cut-off of 500 ng/mL.⁶ For example, a patient who is 70 years old would have an age-adjusted cut-off of 700 ng/mL. A follow-up study showed the age-adjusted D-dimer had a similar 3-month VTE risk as a D-dimer <500 ng/mL or a negative CT pulmonary angiogram.⁷   The American College of Emergency Physicians (ACEP) clinical policy supports the use of age-adjusted D-dimer testing when evaluating for VTE in older patients. ⁸

D-dimer testing beyond VTE  

While a D-dimer level is frequently obtained when evaluating for VTE, it may be useful in the workup of other disorders as well.

Acute Aortic Dissection (AAD)

A meta-analysis found that plasma D-dimer level <500 ng/mL is useful for identifying patients who are unlikely to have an AAD and do not require further aortic imaging. However, the authors do note that D-dimer testing is not applicable in high-risk patients (ie, those with a history Marfan syndrome or Ehlers-Danlos), and its use in specific types of aortic dissection (ascending vs descending) or in specific populations (ie, elderly), has not been extensively studied.⁹ Additionally, a D-dimer level in the evaluation of AAD is most useful within 24 hours of symptom onset.¹⁰ Therefore, though there is some evidence to support the use of obtaining a D-dimer level for evaluating for AAD as part of an overall clinical picture, the American College of Emergency Physicians (ACEP), recommends that physicians not rely on D-dimer results alone to exclude the diagnosis of AAD.¹¹

Disseminated Intravascular Coagulation (DIC)

D-dimer levels are also helpful when evaluating for DIC, a disease process of marked intravascular clot formation and degradation. The International Society of Thrombosis and Hemostasis recommends using a D-dimer level, in addition to other laboratory markers, as part of a scoring system to diagnose DIC.¹² It is important to note that the threshold for a positive result is different when evaluating for DIC, and the exact threshold remains unclear. However, based on prior studies, a D-dimer level of 3-7 mcg/mL has been suggested as a sensitive cut-off level for diagnosis of DIC.¹³

Pearls and Pitfalls

• Many conditions can cause an elevation in D-dimer levels. These conditions include VTE as well as infection, cancer, kidney or liver disease, and recent surgery
• D-dimer test has high sensitivity but low specificity for VTE.
• D-dimer testing is most useful in patients who are low-to-moderate-risk for VTE.
• D-dimer levels rise normally in older adult patients and throughout pregnancy, which requires modification to the typical algorithms used to evaluate for VTE
• D-dimer testing alone cannot rule out the presence of AAD

Case Resolution 

The patient’s D-dimer level was found to be 900 ng/mL. Given that she met no other YEARS criteria and was below the cutoff of 1000 ng/mL, she was deemed low-risk for PE and no additional work-up for PE was indicated.

References:

1. Linkins LA, Takach Lapner S. Review of D-dimer testing: Good, Bad, and Ugly. Int J Lab Hematol. 2017;39 Suppl 1:98-103. doi:10.1111/ijlh.12665
2. Weitz JI, Fredenburgh JC, Eikelboom JW. A Test in Context: D-Dimer. J Am Coll Cardiol. 2017;70(19):2411-2420. doi:10.1016/j.jacc.2017.09.024
3. Pulivarthi S, Gurram MK. Effectiveness of d-dimer as a screening test for venous thromboembolism: an update. N Am J Med Sci. 2014;6(10):491-499. doi:10.4103/1947-2714.143278
4. van der Pol LM, Tromeur C, Bistervels IM, et al. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. N Engl J Med. 2019;380(12):1139-1149. doi:10.1056/NEJMoa1813865
5. Harper PL, Theakston E, Ahmed J, Ockelford P. D-dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly. Intern Med J. 2007;37(9):607-613. doi:10.1111/j.1445-5994.2007.01388.x
6. Douma RA, le Gal G, Söhne M, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ. 2010;340:c1475. Published 2010 Mar 30. doi:10.1136/bmj.c1475
7. Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study [published correction appears in JAMA. 2014 Apr 23-30;311(16):1694]. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135
8. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Thromboembolic Disease:, Wolf SJ, Hahn SA, et al. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease. Ann Emerg Med. 2018;71(5):e59-e109. doi:10.1016/j.annemergmed.2018.03.006
9. Shimony A, Filion KB, Mottillo S, Dourian T, Eisenberg MJ. Meta-analysis of usefulness of d-dimer to diagnose acute aortic dissection. Am J Cardiol. 2011;107(8):1227-1234. doi:10.1016/j.amjcard.2010.12.027
10. Suzuki T, Distante A, Zizza A, et al. Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience. Circulation. 2009;119(20):2702-2707. doi:10.1161/CIRCULATIONAHA.108.833004
11.  American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Thoracic Aortic Dissection, Diercks DB, Promes SB, et al. Clinical policy: critical issues in the evaluation and management of adult patients with suspected acute nontraumatic thoracic aortic dissection [published correction appears in Ann Emerg Med. 2017 Nov;70(5):758]. Ann Emerg Med. 2015;65(1):32-42.e12. doi:10.1016/j.annemergmed.2014.11.002
12. Toh CH, Hoots WK; SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost. 2007;5(3):604-606. doi:10.1111/j.1538-7836.2007.02313.x
13. Suzuki K, Wada H, Imai H, et al. A re-evaluation of the D-dimer cut-off value for making a diagnosis according to the ISTH overt-DIC diagnostic criteria: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(7):1442-1444. doi:10.1111/jth.14134