Causes of Elevated D-dimer Levels
D-dimer levels can be elevated in numerous conditions beyond venous thromboembolism, including malignancy, disseminated intravascular coagulation, increasing age, infection, pregnancy, following surgery or trauma, inflammatory conditions, atrial fibrillation, and stroke. 1
Pathophysiology of D-dimer
- D-dimer is a fibrin degradation product resulting from plasmin-mediated proteolysis of crosslinked fibrin, indicating both coagulation activation and subsequent fibrinolysis 1
- It has a half-life of approximately 16 hours in circulation, making it detectable even after the initial thrombotic event 1
- D-dimer specifically indicates the breakdown of crosslinked fibrin, not fibrinogen 1
Thrombotic Causes of Elevated D-dimer
- Venous thromboembolism (VTE): Deep vein thrombosis (DVT) and pulmonary embolism (PE) are classic causes of elevated D-dimer 1, 2
- Acute aortic dissection: D-dimer levels >0.5 μg/mL have a sensitivity of 94-100% for this condition 2
- Arterial thrombosis: Including myocardial infarction 1
- Disseminated intravascular coagulation (DIC): Characterized by markedly elevated D-dimer levels 1, 3
Non-thrombotic Causes of Elevated D-dimer
- Malignancy: Active cancer is associated with elevated D-dimer levels 1, 4
- Infection and sepsis: Particularly severe infections and septic states 1, 2, 4
- Pregnancy: D-dimer levels increase progressively during pregnancy, peaking in the third trimester 2
- Normal ranges: 0.11-0.40 μg/mL (first trimester), 0.14-0.75 μg/mL (second trimester), 0.16-1.3 μg/mL (third trimester) 2
- Advanced age: D-dimer naturally increases with age, limiting its diagnostic utility in elderly patients 1, 5
- Recent surgery or trauma: Injury can elevate D-dimer independent of thromboembolism 1, 6
- In severely injured trauma patients, D-dimer remains elevated for at least 48 hours after injury 6
- Inflammatory conditions: Including acute respiratory distress syndrome (ARDS) 1
- COVID-19: Associated with elevated D-dimer levels that predict disease severity and mortality 1, 2
- Atrial fibrillation: Can cause elevated D-dimer levels 1
- Stroke: Associated with increased D-dimer 1
- Liver disease: Impaired clearance can alter D-dimer levels 1
Clinical Significance of Extremely Elevated D-dimer
- Extremely elevated D-dimer levels (>5000 μg/L or >10x normal upper limit) are highly specific for serious illness 4
- In one study, 89% of patients with extremely elevated D-dimer had a diagnosis of VTE, sepsis and/or cancer 4
- The prevalence was highest for pulmonary embolism (32%), followed by cancer (29%), sepsis (24%), trauma/surgery (24%), and deep vein thrombosis (13%) 4
Prognostic Implications
- An elevated D-dimer is independently associated with increased risk for incident VTE, recurrent VTE, and mortality across various disease states 5
- Persistent elevation after anticoagulation therapy indicates increased risk of recurrent thrombosis 1
Clinical Application and Limitations
- D-dimer has high sensitivity but low specificity for thrombotic disorders 1, 7
- A normal D-dimer has high negative predictive value for excluding VTE in low-risk patients 1, 7
- D-dimer testing has less usefulness in hospitalized and acutely ill patients due to high frequency of false-positive results 8
- Age-adjusted D-dimer cut-offs (age × 10 μg/L) should be considered for patients >50 years to improve specificity 1
- D-dimer assays lack standardization across laboratories, complicating interpretation 1