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 together account for approximately 89% of cases with extremely elevated D-dimer levels. 1

Thrombotic Causes

• Venous thromboembolism (VTE) is a major cause of D-dimer elevation:

  • Pulmonary embolism (PE) - present in approximately 32% of patients with extremely elevated D-dimer levels 1
  • Deep vein thrombosis (DVT) - present in approximately 13% of patients with extremely elevated D-dimer levels 1
  • Cerebral venous thrombosis (CVT) - D-dimer levels decline with time from symptom onset and may correlate with clot burden 2

• Arterial thrombosis including:

  • Acute aortic dissection - D-dimer levels >0.5 μg/mL have a sensitivity of 94-100% 3, 4
  • Myocardial infarction and other arterial thrombotic events 4

Non-thrombotic Causes

• Infectious and inflammatory conditions:

  • Sepsis - present in approximately 24% of patients with extremely elevated D-dimer levels 1
  • Severe COVID-19 infection - elevated D-dimer predicts disease severity and mortality 4
  • Severe inflammatory states such as acute respiratory distress syndrome (ARDS) 4
  • Disseminated intravascular coagulation (DIC) 4

• Malignancy - present in approximately 29% of patients with extremely elevated D-dimer levels 1

• Trauma and surgery - present in approximately 24% of patients with extremely elevated D-dimer levels 1

  • Tissue injury from trauma causes persistent D-dimer elevation that may not normalize even after 14 days 5

• Physiological conditions:

  • Pregnancy - D-dimer levels increase progressively during pregnancy:
    • First trimester: 0.11-0.40 μg/mL
    • Second trimester: 0.14-0.75 μg/mL
    • Third trimester: 0.16-1.3 μg/mL (up to 2 μg/mL may still be normal) 3
  • Advanced age - D-dimer levels naturally increase with age, necessitating age-adjusted cutoffs 2, 4

• Other conditions:

  • Liver disease with impaired clearance 4
  • Recent hospitalization 2
  • Severe infection or inflammatory disease 2

Clinical Significance of D-dimer Testing

• D-dimer has high sensitivity but low specificity for thrombotic disorders 3, 6
• A normal D-dimer has high negative predictive value for excluding VTE in low-risk patients 6, 7
• The negative predictive value for VTE is approximately 100% with D-dimer levels below established thresholds 7
• D-dimer testing is less useful in hospitalized and acutely ill patients due to high frequency of false-positive results 4

Special Considerations

• Age-adjusted D-dimer cutoffs (age × 10 μg/L) should be used for patients >50 years to improve specificity without compromising sensitivity 2, 4
• In patients with previous VTE, D-dimer testing still has a high negative predictive value, but the proportion of negative results is lower, reducing its clinical usefulness in this population 8
• Extremely elevated D-dimer levels (>5000 μg/L or >10x normal cutoff) are highly specific for serious illness, primarily VTE, sepsis, and/or cancer 1

Common Pitfalls in D-dimer Interpretation

• D-dimer assays lack standardization across laboratories, complicating interpretation 4
• D-dimer should not be measured in patients with high clinical probability of PE, as a negative result does not reliably exclude PE in this population 4
• A positive D-dimer does not confirm VTE; further imaging is always required 4
• D-dimer has limited specificity in elderly patients, pregnant women, and those with recent surgery, trauma, or active inflammation 2, 3

Understanding these various causes of D-dimer elevation is crucial for appropriate clinical interpretation and subsequent management decisions.