What is the management approach for a patient with a raised D-dimer (D-dimer elevation) level?

Management of Raised D-dimer Levels

The management approach for a patient with a raised D-dimer level should follow a diagnostic algorithm based on clinical probability assessment, with further imaging studies indicated for patients with high clinical probability or positive D-dimer results.

Clinical Significance of D-dimer Elevation

• D-dimer is a fibrin degradation product resulting from plasmin-mediated proteolysis of crosslinked fibrin, indicating both coagulation activation and subsequent fibrinolysis 1
• D-dimer has high sensitivity but low specificity for thrombotic disorders, making it valuable as a rule-out test but not as a confirmatory test 1
• Elevated D-dimer is independently associated with increased mortality across various disease states and indicates increased risk of recurrent thrombosis 2
• Extremely elevated D-dimer levels (>10x normal) are highly specific for serious conditions including venous thromboembolism (VTE), sepsis, and/or cancer 3

Diagnostic Algorithm for Suspected Pulmonary Embolism

Step 1: Clinical Probability Assessment

• Assess clinical probability of pulmonary embolism (PE) using validated tools such as Wells score or Geneva score 4
• Categorize patients as having low, intermediate, or high clinical probability of PE, or alternatively as "PE likely" or "PE unlikely" 4

Step 2: D-dimer Testing

• For patients with low or intermediate clinical probability ("PE unlikely"), perform D-dimer testing 4
• D-dimer should NOT be measured in patients with high clinical probability ("PE likely") due to low negative predictive value in this population 4
• D-dimer is less useful in hospitalized patients due to high number needed to test to obtain clinically relevant negative results 4

Step 3: Imaging Studies

• If D-dimer is negative in low/intermediate probability patients, PE can be safely excluded (negative predictive value >99%) 5
• If D-dimer is positive or if clinical probability is high, proceed to multidetector computed tomographic pulmonary angiography (CTPA) 4
• CTPA is considered diagnostic of PE when it shows a clot at least at the segmental level of the pulmonary arterial tree 4

Special Considerations

Age-Adjusted D-dimer Cut-offs

• Consider age-adjusted D-dimer cut-offs for patients >50 years of age (age × 10 μg/L) to improve specificity without compromising sensitivity 4
• This approach has been validated in a multinational prospective management study 4

Pregnancy

• D-dimer levels increase physiologically throughout pregnancy, but a normal D-dimer value still has exclusion value for PE 4
• If D-dimer is elevated in pregnancy, lower limb compression ultrasonography (CUS) should be performed first, as a positive result warrants anticoagulation without further imaging 4
• If CUS is negative, further imaging with either perfusion lung scintigraphy or CTPA is needed 4

False Positives and Interferences

• Heterophilic antibodies can cause falsely elevated D-dimer levels 6, 7
• Consider this possibility when elevated D-dimer values do not match clinical presentation 6
• Other conditions associated with elevated D-dimer include:
  • Acute aortic dissection 1
  • Disseminated intravascular coagulation (DIC) 1
  • Arterial thrombosis including myocardial infarction 1
  • COVID-19 and severe inflammatory states 1
  • Liver disease with impaired clearance 1

Management Based on Diagnostic Results

• For confirmed VTE (PE or DVT), initiate anticoagulation therapy 4
• For patients with intermediate-risk PE (RV dysfunction on echocardiography or CTPA with positive troponin), hospitalize and monitor for early hemodynamic decompensation 4
• For high-risk PE with hemodynamic instability, consider reperfusion treatment (systemic thrombolysis, surgical pulmonary embolectomy, or catheter-directed treatment) 4
• If PE is excluded but D-dimer remains elevated, consider alternative diagnoses associated with D-dimer elevation 1, 3

Common Pitfalls to Avoid

• Do not measure D-dimer in patients with high clinical probability of PE, as a negative result does not reliably exclude PE in this population 4
• Do not rely solely on D-dimer for hospitalized patients, as many conditions can cause elevation 4
• Do not ignore extremely elevated D-dimer levels (>5000 μg/L), as they are highly specific for serious conditions including VTE, sepsis, and/or cancer 3
• Do not forget age-adjusted cut-offs in elderly patients to improve specificity 4
• Do not assume that a positive D-dimer confirms VTE; further imaging is always required 4