by Donna Castellone, MS, MT (ASCP) SH •
June 12, 2019
CASE 1: A critically ill 76-year-old male patient has been admitted into the ICU for an infection; possibly septic.
He has a history of DVT. The clinician orders a D-dimer. It is positive (0.860 ug/ml FEU).
Does the patient have a blood clot?
CASE 2: A 40-year-old male comes into the ED complaining of sudden onset of shortness of breath. He has had a cold for 2 days, but now feels a heaviness in his chest. He does have a history of asthma. Performs a D-dimer, which is negative.
Doesn't order a VQ scan, treats the patient, gives him medication with orders to follow up with his family physician next week.
Is that the right thing to do?
How do we use the results of the D-dimer? D-dimer results are used as part of the clinical decision process in the evaluation and assessment of disorders that result in the breakdown of fibrinogen and fibrin during fibrinolysis. This includes deep vein thrombosis (DVT), pulmonary embolism (PE) and disseminated intravascular coagulation (DIC.)1 The d-dimer is a specific indication of fibrin formation but also as a laboratory marker for in vivo coagulation activation.2 Elevated levels are found in thrombosis, PE, venous thrombosis (VTE), DIC, myocardial infarction, stroke, liver disease, malignancy and pregnancy.1
D-dimers form from this breakdown of clots, and consists of several fragments which include X, Y, D and E. There are two covalently bound fibrin D domains cross linked as a result of the action of FXIII during clot formation.3
The d-dimer fragment contains two D domains and an E domain. This is the target epitope that is unique for fibrin specific degradation and is recognized by monoclonal antibodies that are now used for testing the d-dimer.4 However, there is no international standard for the D-dimer, it is up to the manufacturer to use internal standardization. It is important to have good lot to lot standardization for consistency of results.2 It is also important to know that there are two different reporting units: D-dimer units (DDU) and Fibrinogen Equivalent Units (FEU). Quantitative D-dimer assay result can be reported as either concentration of D-dimer or as FEUs, depending on the calibration method. The two numerical values are easily convertible to each other, since the mass of one unit of fibrinogen-equivalent units (FEU) equals approximately half of one D-dimer unit (DDU): 1 FEU = 2 X DDU
For example, 0.5 µg/mL FEU = 0.25 µg/mL DDU. Clinicians must understand (in particular if they work at different institutions, how patient results are reported as well as cutoff values.
The next unknown for the test could be the cutoff value and the type of test performed.
A cut off value for a d-dimer test is the value in which the test can rule out the presence of a clot. Any level below the cut-off value, means the patient doesn’t have a clot while anything above the cut-off value may mean the patient has a clot, but it must be confirmed with additional radiographic testing. Based on the type of study the manufacturer conducts to determine the cut-off value, the d-dimer can be used as an aid in diagnosis or to exclude a VTE. The clinical study conducted by the manufacturer will score patients for the likelihood of a VTE and classify them as having a low, moderate or high PTP. The result of the d-dimer is compared to the result of an ultrasound and the absence or presence of a clot. If 99% of the patients enrolled have a negative d-dimer along with a negative ultrasound, the test can be used to exclude the presence of a clot. This exclusionary claim allows clinicians to use the results of a negative d-dimer to exclude the presence of a DVT or PE5.
Additionally, laboratories need to provide a reference range for the d-dimer. D-dimers are detectable in low levels in healthy individuals due to the process in which small amounts of fibrinogen are converted to fibrin physiologically.5 The normal range of the d-dimer test may exceed the value of the cutoff which can add to the confusion of interpreting the d-dimer result.
So what does a positive or a negative result mean, and does one size fit all?
Knowing what has been reviewed, lets look at case 1. We have a positive D-dimer result on a patient with a positive history of thrombosis. What are the issues? First we are testing on an inpatient. Based on the manufacturer’s claim in the package insert, have their clinical studies included inpatient populations or outpatients? Can they have a history of DVT? Is it specific for thrombosis? What does that positive mean? A positive D-dimer is not specific for anything. It detects the generation of both thrombin and plasmin. When determining if a patient has a blood clot, the validity of the D-dimer lies in the negative predictive value, that is, the ability to rule out a clot. This determination can be made if the assay has been FDA cleared with an exclusionary claim. So can our patient have a clot? They may, but they may also have DIC, or something else that causes activation of coagulation. The other issue to consider is the patient’s age. It has been established that baseline D-dimer values increase with age, so the next issue is if there should be age adjusted D-dimers.
A study using a healthy population revealed that in the upper 95th percentile the d-dimer level was 2.5 times greater in people >70 years of age compared to those < 50 years of age. 6 As a result of this, several studies have looked at having an age adjusted d-dimer cutoff when ruling out VTE in patients over the age of 50. This age adjusted d-dimer cutoff is calculated by using the patients' age and multiplying by 10 when using FEUs and multiplying by 5 when using DDU. For example, if the patient is 70 years old, the upper limit of the normal for that age is then 700 FEU and if the units are DDU, the upper limit is then 350 ng/mL.
Conversely, the concentrations of the d-dimer are lower in young healthy subjects. A study demonstrated that using a fixed threshold of 0.250 mg/L FEU resulted in improved sensitivity for both proximal and isolated distal DVT in patients with a low to moderate PTP. This decreased the rate of false negatives.7
Using an age adjusted d-dimer can increase the specificity of the d-dimer for each age group reducing the amount of false positive tests, and prevents unnecessary testing while still being safe for the patient.
Let's look at case 2. This is an otherwise healthy male, with no comorbidities, and a strong possibility of an alternative diagnosis. He is an outpatient with a negative D-dimer. The laboratory used an automated immunoturbidimetric D-dimer assay which had been FDA cleared for exclusion for PE. A prospectively collected clinic trial looking at over 1000 patients suspected of DVT and or PE were tested and imaged and their imaging results were compared to the D-dimer. A negative predictive value of >99% was determined. This results in the ability to rule out a PE patients with a low-moderate pre-test probability and a negative D-dimer without being imaged. This patient's diagnosis was asthmatic bronchitis. D-dimer was able to effectively rule out a PE.
The negative predictive value of the D-dimer has been established, and the limited specificity of the test also has been demonstrated. But what about people who have persistently elevated levels of D-dimer? Is that a significant finding that can impact patient outcomes? It has been shown that D-dimer levels may be elevated in pregnancy, inflammation, malignancy, trauma, post surgically and in both liver and heart disease8. In a review of cases of elevated D-dimer results, the most common diagnosis has been PE, followed by cancer, sepsis, trauma and DVT.9 Tumor cells can release toxins and cause vascular endothelial injury, as well as the fibrinolytic activator on the surface of tumor cells they present with a higher D-dimer if these patients present with a higher d-dimer. In this cohort of patients, the established cut off to rule out DVT is unsuitable due to the elevated baseline.10
Studies have also shown that elevated D-dimer is associated with an increased risk of mortality, independent of age and sex. In instances of ischemic stroke, poorer survival is seen when the D-dimer is elevated.11 This is also seen in patients with cardiovascular disease and an increased risk of mortality. This was also demonstrated in the setting of acquired pneumonia and sepsis.12 Even when 17,359 subjects who were free of cardiovascular disease and cancer had an elevated D-dimer result, it was associated with increased mortality over a 4 year period.13
The D-dimer results need to be looked at in the context of the patient, their diagnoses and possible factors that may impact the results. A negative value provides insight to ruling out disorders as opposed to a positive result which requires further investigation.
Even though the test is non-specific, an independent elevation of a D-dimer should not be ignored as it may be an indication of an underlying disease.
Hui, S., Mast, A. E., A non-invasive Triage Test for patients with suspected DVT, Clinical Laboratory News, April 2009, 35. #4.
Dempfle CE. D-dimer: standardization versus harmonization.Thromb Haemost 2006;95:399–400.
Linkins, A.,Takach-Lapner, S., Review of D-dimer testing: Good, Bad, and Ugly, International Journal of Laboratory Hematology. February 2017.
Riley, RS., Gilbert, AR., Dalton, JB., Pai, S., McPherson, RA., Widely Used Types and Clinical Applications of D-Diimer, Laboratory Medicine, Volume 47, Issue 2, 1 May 2016, Pages 90–102.
CLSI. Quantitative D-Dimer with Emphasis on the Evaluation of Venous Thromboembolic Disease; Proposed Guideline. CLSI document H59-P. Wayne, PA: Clinical and Laboratory Standards Institute; 2009
Haase C, Joergensen M, Ellervik C, Joergensen MK, Bathum L. Age-and sex-dependent reference intervals for D-dimer:evidence for a marked increase by age. Thromb Res. 2013;132:676-680
Prochaska, JH., , Frank, B., Nagler.,M.,, Lamparter., H, Gerhard et al. Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis, Scientific Reports, July 2017. www.nature.com\scientificreports
Cervellin G, Bonfanti L, Picanza A, Lippi G. Relation of d-Dimer and Troponin I in Patients With New-Onset Atrial Fibrillation. Am J Cardiol. 2014 Oct 1. 114(7):1129-30.
Schutte T1, Thijs A, Smulders YM., Never ignore extremely elevated D-dimer levels: they are specific for serious illness. Neth J Med. 2016 Dec;74(10):443-448
Aishima K, Yoshimoto Y. Screening strategy using sequential serum D-dimer assay for the detection and prevention of venous thromboembolism after elective brain tumor surgery. Br J Neurosurg. 2013;27: 348–354.
Feinberg WM, Erickson LP, Bruck D, Kittelson J. Hemostatic markers in acute ischemic stroke. Association with stroke type, severity, and outcome. Stroke. 1996;27(8):1296–1300
Querol-Ribelles JM, Tenias JM, Grau E, Querol-Borras JM, Climent JL, Gomez E, et al. Plasma D-dimer levels correlate with outcomes in patients with community-acquired pneumonia. Chest. 2004;126(4):1087–1092
Di Castelnuovo A, de Curtis A, Costanzo S, Persichillo M, Olivieri M, Zito F, et al. Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SAstudy. Haematologica. 2013;98(9):1476–1480.