What are the differential diagnoses for a raised D-dimer (D-dimer) level?

Differential Diagnoses for Elevated D-dimer

An elevated D-dimer indicates active fibrin formation and degradation, and while it has high sensitivity (96%) but very low specificity (35%) for thrombotic disease, the degree of elevation matters significantly—extremely elevated levels (>5000 μg/L) are 89% associated with serious illness including VTE, sepsis, and/or cancer. 1, 2

Thrombotic Causes

Venous Thromboembolism

• Pulmonary embolism is the most common diagnosis in patients with extremely elevated D-dimer (>5000 μg/L), accounting for 32% of cases 2
• Deep vein thrombosis accounts for 13% of cases with extremely elevated D-dimer 2
• D-dimer >0.5 μg/mL has 94-100% sensitivity for acute aortic dissection, making it an excellent rule-out test when measured within 24 hours of symptom onset 1, 3
• Cerebral venous thrombosis causes D-dimer elevation, though levels decline with time from symptom onset and may be falsely negative with lesser clot burden 1

Arterial Thrombosis

• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis 1

Critical Non-Thrombotic Causes

Acute Aortic Dissection

• Acute aortic dissection produces markedly elevated D-dimers with sensitivity of 94-100% when >0.5 μg/mL 1
• D-dimer levels are highest in the first hour and correlate with anatomical extension and early complications 1
• Critical caveat: Thrombosed false lumen or intramural hematoma without intimal flap may produce falsely negative results 1
• Time from symptom onset shows negative correlation with D-dimer levels—delayed presentations may have false-negative results 1

Infection and Inflammatory States

• Sepsis accounts for 24% of cases with extremely elevated D-dimer through systemic activation of coagulation 1, 2
• Pneumonia is frequently present when ultra-high D-dimer levels are encountered 4
• COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality; D-dimer >2.12 μg/mL is associated with mortality 1, 3
• Severe inflammatory states including acute respiratory distress syndrome (ARDS) are associated with elevated D-dimer 1

Disseminated Intravascular Coagulation (DIC)

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis 1
• The International Society on Thrombosis and Haemostasis defines moderate D-dimer elevation as 1000-5000 ng/mL and severe elevation as >5000 ng/mL when calculating DIC scores 3

Malignancy

• Active cancer accounts for 29% of cases with extremely elevated D-dimer (>5000 μg/L) 1, 2
• D-dimer is frequently elevated in active malignancy due to tumor-associated hypercoagulability 3
• Elevated D-dimer indicates increased thrombosis risk in active disease 5

Physiologic and Age-Related Causes

Pregnancy

• Normal pregnancy causes D-dimer elevation, rising two- to fourfold by delivery 5
• D-dimer levels increase progressively during pregnancy: 0.11-0.40 μg/mL in first trimester, 0.14-0.75 μg/mL in second trimester, and 0.16-1.3 μg/mL in third trimester (up to 2 μg/mL may still be normal) 3
• A normal D-dimer value still has exclusion value for PE in pregnancy 1

Advanced Age

• Advanced age is associated with naturally increasing D-dimer levels, necessitating age-adjusted cutoffs (age × 10 μg/L for patients >50 years) 1, 3
• D-dimer specificity decreases steadily with age, reaching as low as 10% in patients over 80 years old 3

Trauma and Surgery-Related Causes

Tissue Injury

• Recent trauma or surgery accounts for 24% of cases with extremely elevated D-dimer 2
• Tissue injury results in increased D-dimer levels that fail to normalize even after 14 days, eliminating the ability to use D-dimer testing to rule out DVT or PE in severely traumatized patients in the early post-trauma period 6
• Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis 1

Other Causes

Liver Disease

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

Recent Hospitalization

• Recent hospitalization and severe infection can impact D-dimer levels 1
• D-dimer testing has less usefulness in hospitalized and acutely ill patients due to high frequency of false-positive results 1

Clinical Approach Based on D-dimer Level

Moderately Elevated D-dimer (0.5-5.0 μg/mL)

• Use clinical probability assessment (Wells score or Geneva score) to guide further testing 1
• For low or intermediate clinical probability, proceed with imaging (compression ultrasonography for DVT, CT pulmonary angiography for PE) 1
• Consider age-adjusted cutoffs for patients >50 years (age × 10 μg/L) to improve specificity 1, 3

Extremely Elevated D-dimer (>5.0 μg/mL)

• 89% of patients with D-dimer >5000 μg/L have VTE, sepsis, and/or cancer 2
• D-dimer levels 3-4 times above normal warrant hospital admission even without severe symptoms, as this signifies increased thrombin generation and is associated with significantly increased mortality risk 3
• Proceed directly to CT pulmonary angiography when D-dimer exceeds 2000 ng/mL, even in patients with "unlikely" clinical probability scores 3
• If no clear source is identified with markedly elevated D-dimer, consider occult malignancy, sepsis, or disseminated intravascular coagulation 3

Ultra-High D-dimer (>15.0 μg/mL)

• Mortality was 75% in patients with D-dimer >15,000 ng/mL when no clear clinical diagnosis could be identified 4
• VTE, cancer, and pneumonia were frequently present when ultra-high D-dimer levels were encountered 4

Critical Pitfalls to Avoid

• Never use D-dimer to rule out aortic dissection in high-risk patients—the negative predictive value is inadequate in this population 1
• Never rely on a negative D-dimer alone in patients presenting >24 hours after symptom onset, as levels decline over time 1
• Never assume a negative D-dimer excludes intramural hematoma or dissection with thrombosed false lumen—these conditions frequently have false-negative results 1
• 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 1
• Do not forget age-adjusted cutoffs in elderly patients to improve specificity 1
• Do not assume that a positive D-dimer confirms VTE; further imaging is always required 1
• Consider heterophilic antibody interference when an elevated D-dimer value is not in conformity with clinical evidence 7
• Remember that D-dimer assays lack standardization across laboratories, and different reporting units (FEU vs DDU) complicate interpretation—FEU is approximately two-fold higher than DDU 1, 3