What are the reasons for an elevated D-dimer (D-dimer) level?

Causes of Elevated D-dimer Levels

D-dimer is elevated in numerous clinical conditions involving both coagulation and fibrinolysis, with the most common causes being venous thromboembolism, sepsis, and malignancy. 1

What is D-dimer?

D-dimer is a biomarker representing both coagulation and fibrinolysis, specifically generated when crosslinked fibrin is digested by plasmin. It is the smallest fragment that is only generated when crosslinked fibrin is broken down 2. With a half-life of approximately 16 hours in circulation, D-dimer levels remain elevated for a considerable time after the initial thrombotic event 2.

Common Causes of Elevated D-dimer

Thrombotic Conditions

• Venous thromboembolism (VTE)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE) - most frequent thrombotic complication 2
  • Cerebral venous thrombosis 2
• Arterial thrombosis
  • Acute coronary syndromes
  • Ischemic stroke
  • Acute aortic dissection 2
• Disseminated intravascular coagulation (DIC) 2, 1

Inflammatory Conditions

• Infections
  • Sepsis 3
  • COVID-19 and other viral infections 2
• Acute respiratory distress syndrome (ARDS) 2
• Systemic inflammatory response syndrome

Malignancy

• Active cancer (29% of extremely elevated D-dimer cases) 3
• Metastatic disease

Other Medical Conditions

• Pregnancy (physiological increase, especially in third trimester) 1
• Advanced age (baseline levels increase with age) 1, 4
• Recent surgery or trauma (24% of extremely elevated cases) 3
• Liver disease (due to decreased clearance) 2
• Renal failure

Severity Correlation

The magnitude of D-dimer elevation often correlates with disease severity:

• Extremely elevated levels (>5000 μg/L or >10x normal cutoff) are highly specific for serious conditions:
  • 89% of cases with such elevations have VTE, sepsis, and/or cancer 3
  • 32% have pulmonary embolism
  • 29% have cancer
  • 24% have sepsis
  • 24% have recent trauma/surgery
  • 13% have deep vein thrombosis

Clinical Implications

1. Negative predictive value: A normal D-dimer has excellent negative predictive value for excluding VTE in low-risk patients 5

2. Prognostic value: Elevated D-dimer is independently associated with:

   • Increased mortality 6
   • Risk of incident VTE 6
   • Risk of recurrent VTE 6

3. Limitations in interpretation:

   • D-dimer assays lack standardization, with up to 10-fold differences between different testing methods 2
   • Single time-point measurements can be difficult to interpret due to the long half-life 2
   • Specificity decreases with age, pregnancy, and comorbidities 1, 4

Special Considerations

• Thrombosed vessels: D-dimer may be lower in patients with thoracic aortic dissection who have thrombosed false lumens 2

• Time from symptom onset: D-dimer levels may decrease with time from symptom onset, potentially leading to false negatives in subacute presentations 2

• Liver disease: Interpretation is complicated by baseline coagulation abnormalities 2

• COVID-19: Marked elevations are common and associated with disease severity and mortality 2

Clinical Approach

When encountering an elevated D-dimer, clinicians should:

1. Consider the clinical context and pretest probability
2. Recognize that extremely elevated levels (>5000 μg/L) warrant thorough investigation for serious underlying conditions
3. Use sequential measurements when monitoring disease progression
4. Interpret results in conjunction with other clinical and laboratory findings

Remember that D-dimer is not a diagnostic test but rather a sensitive marker that requires clinical correlation and often further diagnostic testing.