What causes elevated D-dimer (D-dimer is a protein fragment produced when a blood clot dissolves) 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 D-dimer values. 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 2
• It has a half-life of approximately 16 hours in circulation and specifically indicates the breakdown of crosslinked fibrin, not fibrinogen 2
• D-dimer assays lack standardization across laboratories, with different reporting units complicating interpretation 3, 2

Major Causes of Elevated D-dimer

Thrombotic Conditions

• Pulmonary embolism (PE) - accounts for approximately 32% of extremely elevated D-dimer cases 1
• Deep vein thrombosis (DVT) - accounts for approximately 13% of extremely elevated D-dimer cases 1
• Acute aortic dissection - associated with significantly elevated D-dimer levels 2, 3
• Arterial thrombosis, including myocardial infarction 2, 4

Inflammatory and Infectious Conditions

• Sepsis - accounts for approximately 24% of extremely elevated D-dimer cases 1
• COVID-19 - associated with markedly elevated D-dimer levels that predict disease severity and mortality 2, 3
• Disseminated intravascular coagulation (DIC) - characterized by elevated D-dimer levels due to widespread coagulation activation 2, 5
• Severe inflammatory states such as acute respiratory distress syndrome (ARDS) 2

Malignancy

• Cancer - accounts for approximately 29% of extremely elevated D-dimer cases 1
• Active malignancy causes variable rises in D-dimer and indicates increased thrombosis risk 5
• Higher D-dimer levels independently predict cancer incidence and mortality 4

Other Causes

• Trauma or recent surgery - accounts for approximately 24% of extremely elevated D-dimer cases 1
• Pregnancy - D-dimer rises physiologically, increasing two- to fourfold by delivery 5
• Advanced age - D-dimer naturally increases with age, limiting its diagnostic utility in those >80 years old 5
• Liver disease - altered D-dimer levels due to impaired clearance 2

Clinical Significance of Elevated D-dimer

• D-dimer has high sensitivity but low specificity for thrombotic disorders 2
• An extremely elevated D-dimer (>5000 μg/L or >10x the normal cut-off) is highly specific for serious illness, primarily VTE, sepsis, and/or cancer 1
• Elevated D-dimer is independently associated with increased risk for:
  • Incident VTE 6
  • Recurrent VTE 6
  • All-cause mortality 4
  • Cardiovascular mortality 4
  • Cancer mortality 4
  • Non-cardiovascular, non-cancer mortality 4

Important Considerations in D-dimer Interpretation

• D-dimer elevation can persist after anticoagulation therapy, indicating increased risk of recurrent thrombosis 2, 5
• Age-adjusted D-dimer cut-offs should be considered in elderly patients (age × 10 μg/L) to improve specificity 2
• D-dimer levels can be affected by various factors, including:
  • Inflammatory cytokines, especially in COVID-19 patients 3
  • Thrombosed false lumens or intramural hematomas 3
  • Time from symptom onset (levels decrease with time) 3
  • Chronicity of the condition 3

Clinical Pitfalls in D-dimer Assessment

• D-dimer elevations are not specific for any single condition and can be elevated in numerous pathologies 3, 7
• False-negative D-dimer results can occur in:
  • Younger patients 3
  • Short dissection lengths 3
  • Thrombosed false lumens 3
  • Localized intramural hematomas without intimal flaps 3
• 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 2