What are the causes of elevated d-dimer (D-dimer) levels?

Causes of Elevated D-dimer Levels

Elevated D-dimer levels are primarily caused by conditions that activate both coagulation (clot formation) and fibrinolysis (clot breakdown), with the most common causes being venous thromboembolism, sepsis, and cancer, which together account for approximately 89% of extremely elevated D-dimer cases. 1

Pathophysiology of D-dimer

• D-dimer is a fibrin degradation product that results from plasmin-mediated proteolysis of crosslinked fibrin, representing both coagulation activation and subsequent fibrinolysis 2
• It has a relatively long half-life in circulation (approximately 16 hours), which affects interpretation of single measurements 2
• D-dimer specifically indicates the breakdown of crosslinked fibrin, not fibrinogen 2

Common Causes of Elevated D-dimer

Thrombotic Conditions

• Pulmonary embolism (32% of extremely elevated cases) 1
• Deep vein thrombosis (13% of extremely elevated cases) 1
• Acute aortic dissection 2
• Disseminated intravascular coagulation (DIC) 2
• Arterial thrombosis including myocardial infarction 2

Infectious and Inflammatory Conditions

• Sepsis (24% of extremely elevated cases) 1
• COVID-19 (associated with disease severity and mortality) 2
• Severe inflammatory states 2
• Acute respiratory distress syndrome (ARDS) 2

Malignancy

• Active cancer (29% of extremely elevated cases) 1
• Cancer patients have higher baseline D-dimer levels, indicating increased thrombotic risk 3

Other Common Causes

• Recent trauma or surgery (24% of extremely elevated cases) 1, 4
• Advanced age (D-dimer naturally increases with age) 2, 3
• Pregnancy (levels increase 2-4 fold by delivery) 3, 5
• Liver disease with impaired clearance 2

Clinical Significance of Elevated D-dimer

Diagnostic Value

• D-dimer has high sensitivity but low specificity for thrombotic disorders 2
• A normal D-dimer has high negative predictive value for excluding venous thromboembolism in low-risk patients 2, 3
• Extremely elevated levels (>5000 μg/L or >10x normal) are highly specific for serious illness 1

Prognostic Implications

• Elevated D-dimer is independently associated with increased mortality across various disease states 6
• In COVID-19, elevated D-dimer predicts disease severity and mortality 2
• Persistent elevation after anticoagulation therapy indicates increased risk of recurrent thrombosis 5

Important Caveats and Pitfalls

Timing Considerations

• In trauma patients, D-dimer remains elevated for at least 48 hours after injury, limiting its diagnostic utility during this period 4
• Sequential measurements are required to confirm active fibrinolysis 2

Measurement Limitations

• D-dimer assays lack standardization and harmonization across laboratories 2
• Different reporting units (D-dimer units vs. fibrinogen equivalent units) complicate interpretation 2
• False-negative results can occur in:
  • Chronic rather than acute thrombosis 2
  • Thrombosed false lumens or intramural hematomas 2
  • Short dissection lengths 2
  • Delayed presentation after symptom onset 2

Special Populations

• Age-adjusted cut-offs should be considered in elderly patients due to naturally increasing levels with age 2, 3
• Pregnancy is associated with progressively increasing D-dimer levels 3
• Patients with liver disease may have altered D-dimer levels due to impaired clearance 2