What is D-dimer?
D-dimer is a specific fibrin degradation product that results from plasmin-mediated breakdown of cross-linked fibrin, serving as a biomarker of both coagulation activation and fibrinolysis. 1
Biochemical Structure and Formation
D-dimer refers to the covalently bound D-domains of adjacent fibrin monomers along with an E-domain of the opposite and staggered strand. 1 This molecular structure is created when plasmin degrades cross-linked fibrin during fibrinolysis, producing complex fragments containing D and E domains. 1
The key distinguishing feature is that D-dimer is specific to cross-linked fibrin breakdown and is absent from fibrinogen and non-cross-linked fibrin fragments. 1 This specificity makes it an indicator of actual thrombus formation and subsequent degradation, rather than simply reflecting fibrinogen levels. 2, 3
D-dimer has a half-life of approximately 16 hours in circulation, which allows detection even after the initial thrombotic event. 2, 4
Clinical Measurement and Testing
Since the development of monoclonal antibody-based assays in the 1980s, D-dimer measurements have proven to be a reliable diagnostic tool. 1 These assays use monoclonal antibodies specific for epitopes on D-D fragments. 1
Critical Testing Limitations
A major pitfall is the lack of standardization across D-dimer assays—different manufacturers produce results that can vary by as much as 20-fold. 5 The intra-method coefficients of variation range from 6.4% to 17.7%. 5
D-dimer can be reported in two fundamentally different unit types: 4
- Fibrinogen Equivalent Units (FEU)
- D-dimer Units (DDU)
FEU values are approximately two-fold higher than DDU values, creating significant confusion if the unit type is not clearly specified. 4 Additionally, reporting may use mg/L, μg/mL, or ng/mL, further complicating interpretation. 1
Cutoff values are NOT transferable between different assay methods or institutions—each laboratory's specific reference range must be known. 4
Diagnostic Performance Characteristics
D-dimer testing has high sensitivity but low specificity for thrombotic disorders. 1, 2 This means:
- A negative D-dimer result effectively excludes venous thromboembolism (VTE) in low-risk patients 1, 2
- A positive result does NOT confirm VTE and requires further imaging 2
For suspected deep vein thrombosis, a meta-analysis of 97 studies reported overall sensitivity of 90.5% and specificity of only 54.7%, with significant heterogeneity between studies. 1
Standard Reference Values
The normal range for D-dimer is typically less than 0.5 μg/mL (or 500 ng/mL), with values above this threshold considered elevated. 4
For patients over 50 years of age, age-adjusted cutoffs (age × 10 ng/mL) should be used to improve specificity while maintaining sensitivity above 97%. 2, 4 This adjustment is necessary because D-dimer specificity decreases steadily with age, reaching as low as 10% in patients over 80 years old. 4
Clinical Applications
D-dimer is most commonly used to exclude VTE in patients with low or intermediate clinical probability. 1, 2 It should NOT be measured in patients with high clinical probability of pulmonary embolism, as the negative predictive value is too low in this population. 2
D-dimer has been consistently shown to be the most significant marker for illness severity and death risk prediction in conditions like COVID-19. 1
Conditions Causing Elevated D-dimer
D-dimer levels are elevated in numerous non-thrombotic conditions, limiting specificity: 1
- Malignancy 1, 4
- Sepsis and disseminated intravascular coagulation 1, 4
- Recent surgery or trauma 1, 4
- Pregnancy (physiologically increases, peaking in third trimester) 2, 4
- Advanced age 1, 4
- Inflammatory conditions 1
- Acute aortic dissection 2, 4
- Atrial fibrillation and stroke 1
In hospitalized and acutely ill patients, D-dimer testing has less usefulness due to the high frequency of false-positive results from these confounding conditions. 1, 2
Extremely Elevated Values
Extremely elevated D-dimer levels (>5000 μg/L, or >10 times the cutoff) are highly specific for serious illness. 4, 6 In one study, 89% of patients with extremely elevated D-dimer had VTE, sepsis, and/or cancer. 6 D-dimer levels 3-4 times above normal warrant hospital admission even without severe symptoms, as this signifies increased thrombin generation and significantly increased mortality risk. 4
Common Clinical Pitfalls
Never rely solely on D-dimer for hospitalized patients—the high rate of false positives from concurrent illness makes interpretation unreliable. 1, 2
Do not forget to apply age-adjusted cutoffs in elderly patients—using standard cutoffs leads to unnecessary imaging and overdiagnosis. 2, 4
Always specify which assay method and units are being used when reporting D-dimer results, as values are not comparable across different testing platforms. 1, 4
Fragments from proteolysis of fibrinogen and fibrin by elastase and other enzymes can interfere with testing, especially in sepsis or inflammation. 1