What can cause elevated D-dimers (D-dimer test) besides thrombosis in a patient with a history of cardiovascular disease?

Elevated D-Dimer: Non-Thrombotic Causes

D-dimer elevation occurs in numerous serious conditions beyond thrombosis, with the most common being sepsis/infection (41%), cardiovascular disease including acute aortic dissection (14%), recent surgery or trauma (14%), and active malignancy (11%), particularly when levels are markedly elevated. 1

Major Non-Thrombotic Causes

Infection and Sepsis

• Sepsis is the leading non-thrombotic cause of elevated D-dimer, accounting for 24-41% of cases with markedly elevated levels through systemic activation of coagulation. 2, 3, 1
• Severe inflammatory states including acute respiratory distress syndrome (ARDS) cause significant D-dimer elevation. 2
• In empyema and severe infections, D-dimer levels 3-4 times above normal create a hypercoagulable state and warrant hospital admission consideration. 4

Cardiovascular Conditions

• Acute aortic dissection produces markedly elevated D-dimers with 94-100% sensitivity when >0.5 μg/mL, making it a critical diagnosis not to miss. 2, 5
• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis. 2
• Important caveat: Thrombosed false lumen in aortic dissection or intramural hematoma without intimal flap may produce falsely low or negative D-dimer results. 2

Malignancy

• Active 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. 5
• Cancer accounts for 10.6-29% of markedly elevated D-dimer cases, with higher levels observed in breast, prostate, and bowel cancers reflecting tumor biology rather than thrombosis alone. 3, 1, 6
• D-dimer levels >8000 ng FEU/mL are associated with increased incidence of malignancy and reduced overall survival. 6

Disseminated Intravascular Coagulation (DIC)

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis. 2
• Assessment should include complete blood count, coagulation studies, and fibrinogen levels when DIC is suspected. 5

Trauma and Surgery

• Tissue injury from trauma causes D-dimer elevation that fails to normalize even after 14 days, eliminating the ability to use D-dimer testing to rule out VTE in severely traumatized patients. 7
• Recent surgery or trauma accounts for 14% of markedly elevated D-dimer cases. 1

COVID-19

• COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality. 2
• D-dimer >2.12 μg/mL was associated with mortality in COVID-19 patients (non-survivors: 2.12 μg/mL vs survivors: 0.61 μg/mL). 5
• In severe COVID-19,60% of patients had D-dimer ≥0.5 mg/L. 5

Recent Fibrinolytic Therapy

• Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis. 2

Age-Related Considerations

• Advanced age is associated with naturally increasing D-dimer levels, necessitating age-adjusted cutoffs (age × 10 μg/L for patients >50 years). 2
• D-dimer specificity decreases steadily with age, reaching as low as 10% in patients over 80 years old. 5

Physiologic States

• Pregnancy causes physiologic D-dimer elevation, peaking in the third trimester with normal levels up to 2 μg/mL, though a normal D-dimer still has exclusion value for PE. 2, 5
• Liver disease with impaired clearance is associated with altered D-dimer levels. 2

Clinical Significance of Extremely Elevated D-Dimer

• 89% of patients with extremely elevated D-dimer (>5000 μg/L) have VTE, sepsis, and/or cancer, with pulmonary embolism being most common (32%), followed by cancer (29%) and sepsis (24%). 3
• D-dimer levels 3-4 times above normal warrant hospital admission consideration due to increased mortality risk from thrombotic complications. 5, 4
• Mortality at 2-year follow-up was 43.5% in patients with markedly elevated D-dimer without PE, with particularly poor outcomes in those with new or active cancer. 1

Critical Pitfalls to Avoid

• Never assume elevated D-dimer equals thrombosis—D-dimer has high sensitivity (96%) but very low specificity (35%) for thrombotic disease. 2
• Do not rely solely on D-dimer for hospitalized patients, as acutely ill patients have high frequency of false-positive results. 2
• Do not forget that D-dimer levels decline over time from symptom onset, potentially causing false-negative results in delayed presentations of aortic dissection or cerebral venous thrombosis. 2
• Even if sharply elevated D-dimers are a seemingly solitary finding, clinical suspicion of severe underlying disease (VTE, sepsis, cancer, aortic dissection) should be maintained. 3