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 venous thromboembolism (VTE), sepsis, and cancer, which collectively account for approximately 89% of cases with extremely elevated levels (>5000 μg/L). 1

Common Causes of Elevated D-dimer

D-dimer is a biomarker that represents both coagulation (fibrin clot formation) and fibrinolysis (fibrin clot degradation). It is generated when crosslinked fibrin is digested by plasmin 2. The following conditions commonly cause D-dimer elevation:

Thrombotic Conditions

• Pulmonary embolism (PE) - present in 32% of patients with extremely elevated D-dimer 1
• Deep vein thrombosis (DVT) - present in 13% of patients with extremely elevated D-dimer 1
• Cerebral venous thrombosis (CVT) 3
• Disseminated intravascular coagulation (DIC) 2

Inflammatory and Infectious Conditions

• Sepsis - present in 24% of patients with extremely elevated D-dimer 1
• COVID-19 - associated with disease severity and mortality 2
• Acute respiratory distress syndrome (ARDS) 2
• Other inflammatory conditions 3

Malignancy

• Active cancer - present in 29% of patients with extremely elevated D-dimer 1
• New or previously diagnosed active cancer 4

Trauma and Surgical Conditions

• Recent surgery or trauma - present in 24% of patients with extremely elevated D-dimer 1
• Post-operative states 3

Cardiovascular Conditions

• Myocardial infarction 2
• Aortic dissection - can present with markedly elevated D-dimer 4

Physiological States

• Advanced age - requires age-adjusted cutoffs (age × 10 μg/L) for patients over 50 years 3
• Pregnancy - normal ranges vary by trimester:
  • First trimester: 0.11-0.40 μg/mL
  • Second trimester: 0.14-0.75 μg/mL
  • Third trimester: 0.16-1.3 μg/mL 3

Clinical Significance of D-dimer Elevation

Diagnostic Value

• Normal D-dimer (<500 μg/L) has high negative predictive value for VTE in low and intermediate pretest probability patients 3
• D-dimer has a long half-life (~16 hours), which makes single time-point measurements difficult to interpret 2
• Sequential measurements may be needed to confirm active fibrinolysis 2

Prognostic Significance

• Extremely elevated D-dimer (>5000 μg/L) is highly specific for serious illness 1
• Elevated D-dimer is independently associated with increased risk for:
  • Incident VTE
  • Recurrent VTE
  • Mortality 5

Special Considerations

• D-dimer testing methods vary significantly between laboratories 3
• Standard cutoff is 500 μg/L FEU (Fibrinogen Equivalent Units) 3
• Age-adjusted cutoff (age × 10 μg/L) improves specificity while maintaining sensitivity in patients over 50 years 3
• Critically elevated D-dimer levels (≥5 mg/mL) require therapeutic anticoagulation and thorough investigation for underlying thrombosis 3

Clinical Pitfalls and Caveats

• D-dimer assays are neither standardized nor harmonized, making comparison between studies and laboratories difficult 2
• Up to 10-fold differences have been observed between different ELISA kits measuring the same samples 2
• A second rise in D-dimer values after initial normalization may indicate development of pathologic thrombosis, particularly in trauma patients 6
• In patients with markedly elevated D-dimer and negative CTPA for PE, consider other serious conditions including:
  • Occult malignancy
  • Aortic dissection
  • Severe infection 4
• For patients with high pretest probability of VTE, proceed directly to appropriate imaging regardless of D-dimer result 3

D-dimer elevation should never be dismissed as non-specific, especially when levels are markedly elevated, as these almost always indicate serious underlying pathology requiring prompt evaluation and management.