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

Causes of Elevated D-dimer Levels

Elevated D-dimer levels indicate active fibrin formation and degradation, and are associated with numerous thrombotic and non-thrombotic conditions including venous thromboembolism, sepsis, cancer, and inflammatory states. 1, 2

Thrombotic Causes

• Venous Thromboembolism (VTE)

  • Pulmonary embolism (PE) - a major cause of elevated D-dimer, with levels typically above 0.5 μg/mL 2
  • Deep vein thrombosis (DVT) - associated with significant D-dimer elevation 1
  • Cerebral venous thrombosis (CVT) - shows declining D-dimer levels over time from symptom onset 1

• Arterial Thrombosis

  • Myocardial infarction - associated with elevated D-dimer levels 1
  • Acute aortic dissection - D-dimer levels >0.5 μg/mL have a sensitivity of 94-100% 2

• Disseminated Intravascular Coagulation (DIC)

  • Characterized by markedly elevated D-dimer levels due to widespread clot formation and breakdown 1, 3

Non-Thrombotic Causes

• Infection and Inflammation

  • Severe infections and sepsis - associated with significant D-dimer elevation 2, 4
  • COVID-19 - elevated D-dimer predicts disease severity and mortality 1, 2
  • Acute respiratory distress syndrome (ARDS) - characterized by elevated D-dimer 1
  • COPD exacerbation - can present with elevated D-dimer even without PE 5

• Malignancy

  • Active cancer is associated with elevated D-dimer levels 4, 3
  • 29% of patients with extremely elevated D-dimer (>5000 μg/L) have cancer 4

• Physiological and Age-Related Factors

  • Advanced age - D-dimer levels naturally increase with age, necessitating age-adjusted cutoffs 1, 2
  • Pregnancy - D-dimer increases progressively during pregnancy, peaking in the third trimester 2

• Other Conditions

  • Recent surgery or trauma - causes significant D-dimer elevation for up to 48 hours 6
  • Liver disease - associated with altered D-dimer levels due to impaired clearance 1

Clinical Significance of D-dimer Elevation

• Extremely elevated D-dimer levels (>5000 μg/L or >10x normal) are highly specific for serious conditions - 89% of such cases are associated with VTE, sepsis, and/or cancer 4

• The distribution of diagnoses in patients with extremely elevated D-dimer includes:

  • Pulmonary embolism (32%)
  • Cancer (29%)
  • Sepsis (24%)
  • Trauma/surgery (24%)
  • Deep vein thrombosis (13%) 4

• D-dimer elevation is independently associated with increased mortality and subsequent VTE across various disease states 7

Important Considerations in D-dimer Interpretation

• D-dimer has high sensitivity but low specificity for thrombotic disorders 1, 2

• A normal D-dimer has high negative predictive value for excluding VTE in low-risk patients 1, 3

• D-dimer specificity decreases with age, reaching as low as 10% in patients over 80 years 2

• Age-adjusted D-dimer cutoffs (age × 10 μg/L) are recommended for patients over 50 years to improve specificity without compromising sensitivity 1, 2

• D-dimer assays lack standardization across laboratories, with different reporting units (FEU vs. DDU) complicating interpretation 2

• In trauma patients, D-dimer remains elevated for at least 48 hours after injury, limiting its utility for excluding thromboembolism during this period 6

• Persistent D-dimer elevation after anticoagulation therapy indicates increased risk of recurrent thrombosis 1, 3