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

Causes of Elevated D-dimer Levels

Understanding D-dimer Physiology

D-dimer is a fibrin degradation product resulting from plasmin-mediated proteolysis of crosslinked fibrin, indicating both coagulation activation and subsequent fibrinolysis, with a half-life of approximately 16 hours in circulation. 1 This biomarker specifically indicates the breakdown of crosslinked fibrin present in blood clots, not fibrinogen, making it a marker of active thrombus formation and degradation. 1

The key limitation is that D-dimer has high sensitivity (96%) but very low specificity (35%) for thrombotic disease, meaning elevated levels occur commonly in patients without venous thromboembolism. 1

Major Thrombotic Causes

Venous Thromboembolism

• Pulmonary embolism is the most common thrombotic cause, accounting for 32% of extremely elevated D-dimer cases (>5000 μg/L). 2
• Deep vein thrombosis accounts for 13% of extremely elevated D-dimer cases. 2
• Cerebral venous thrombosis causes D-dimer elevation, though levels decline with time from symptom onset and may be falsely negative with lesser clot burden or delayed presentation. 1

Arterial Thrombosis

• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis. 1
• Acute aortic dissection produces markedly elevated D-dimers with sensitivity of 94-100% when >0.5 μg/mL, though levels may be lower with thrombosed false lumens or intramural hematomas. 1

Major Non-Thrombotic Causes

Infection and Inflammation

• Sepsis causes significant D-dimer elevation through systemic activation of coagulation, accounting for 24% of extremely elevated cases. 1, 2
• COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality, with levels >2.12 μg/mL associated with death. 1, 3
• Severe inflammatory states, including acute respiratory distress syndrome (ARDS), are associated with elevated D-dimer levels. 1

Disseminated Intravascular Coagulation (DIC)

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis. 1
• DIC can complicate severe rhabdomyolysis, requiring assessment of complete blood count, coagulation studies, and fibrinogen levels alongside D-dimer. 4

Malignancy

• Cancer is present in 29% of patients with extremely elevated D-dimer (>5000 ng/mL) and should be considered if no other cause is identified. 3, 2
• Active malignancy causes tumor-associated hypercoagulability leading to D-dimer elevation. 3

Trauma and Surgery

• Recent surgery or trauma accounts for 14.1% of markedly elevated D-dimer cases. 5
• Recent surgery or fracture within the past month significantly elevates D-dimer. 3

Cardiovascular Disease

• Cardiovascular disease (excluding aortic dissection and MI) accounts for 14.1% of markedly elevated cases. 5

Physiologic and Age-Related Causes

• Advanced age is associated with naturally increasing D-dimer levels, with specificity decreasing to approximately 10% in patients >80 years. 1, 3
• Pregnancy causes physiologic D-dimer elevation, peaking in the third trimester with normal levels up to 2 μg/mL. 3

Hepatic Disease

• Liver disease with impaired clearance is associated with altered D-dimer levels. 1

Following Therapeutic Interventions

• Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis. 1

Clinical Significance by D-dimer Level

Standard Elevation (>0.5 μg/mL)

• Requires clinical probability assessment for venous thromboembolism using Wells score or Geneva score. 1
• In low-to-intermediate probability patients, proceed to imaging if elevated. 3

Marked Elevation (3-4 times normal)

• D-dimer levels 3-4 times above normal warrant hospital admission consideration even without severe symptoms, as this signifies substantial thrombin generation and increased mortality risk. 3

Extreme Elevation (>5000 μg/L or >10x normal)

• 89% of patients with extremely elevated D-dimer have VTE, sepsis, and/or cancer. 2
• In COVID-19 patients, D-dimer >5000 ng/mL is associated with 50% positive predictive value for thrombotic complications. 3
• Even if sharply elevated D-dimers are a seemingly solitary finding, clinical suspicion of severe underlying disease should be maintained. 2

Critical Diagnostic Pitfalls

• Never measure D-dimer in patients with high clinical probability of PE, as a negative result does not reliably exclude PE in this population. 1
• D-dimer levels decline over time from symptom onset, potentially causing false-negative results in delayed presentations. 1
• Thrombosed false lumen in aortic dissection and intramural hematoma without intimal flap may produce falsely negative D-dimer results. 1
• D-dimer testing has less usefulness in hospitalized and acutely ill patients due to high frequency of false-positive results. 1
• Use age-adjusted D-dimer cutoffs (age × 10 μg/L) for patients >50 years to improve specificity without compromising sensitivity. 1