What are the common causes of an elevated D‑dimer?

Elevated D-Dimer: Common Causes

Elevated D-dimer levels most commonly indicate venous thromboembolism (VTE), sepsis, or malignancy, with extremely elevated levels (>5000 μg/L) being 89% specific for these serious conditions. 1, 2

Understanding D-Dimer Pathophysiology

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. 1 Critically, D-dimer specifically indicates breakdown of crosslinked fibrin, not fibrinogen, which distinguishes it from other fibrin degradation products. 1, 3

The test has high sensitivity (96%) but very low specificity (35%) for thrombotic disease, meaning elevated levels occur commonly in patients without VTE. 1 This poor specificity necessitates understanding the broad differential diagnosis.

Major Thrombotic Causes

Venous Thromboembolism

• Pulmonary embolism is the most common thrombotic cause, accounting for 32% of extremely elevated D-dimer cases. 2
• Deep venous thrombosis accounts for 13% of extremely elevated 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 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
• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis. 1

Major Non-Thrombotic Causes

Disseminated Intravascular Coagulation (DIC)

DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis. 1 All 43 patients with DIC in one study had elevated D-dimer levels. 4 DIC can complicate rhabdomyolysis, requiring assessment with complete blood count, coagulation studies, and fibrinogen levels alongside D-dimer. 5

Malignancy

• Cancer accounts for 29% of extremely elevated D-dimer cases. 2
• Elevated in 17 of 23 patients (74%) with malignant disease in one series. 4
• Variable rise in D-dimer indicates increased thrombosis risk in active disease. 3

Infection and Inflammation

• Sepsis accounts for 24% of extremely elevated D-dimer cases. 2
• COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality. 1
• Severe inflammatory states such as acute respiratory distress syndrome (ARDS) are associated with elevated levels. 1

Trauma and Surgery

Trauma/surgery accounts for 24% of extremely elevated D-dimer cases. 2 Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis. 1

Liver Disease

• Liver disease with impaired clearance is associated with altered D-dimer levels. 1
• Elevated in 48 of 59 patients (81%) with liver disease, though this may reflect both hypercoagulability and impaired clearance mechanisms. 4
• In post-liver transplant patients, impaired hepatic clearance, ascites-related complications, and compensatory coagulation activation all contribute to elevated levels. 6

Hematologic Disorders

Acute leukemia shows elevated D-dimer in 22 of 27 patients (81%) at presentation. 4

Physiologic Causes

Pregnancy

• D-dimer levels increase physiologically during pregnancy, rising two- to fourfold by delivery. 3
• Despite physiologic elevation, a normal D-dimer value still has exclusion value for PE in pregnancy. 1
• Elevated in 29 of 39 women (74%) in the third trimester of complicated pregnancy. 4

Advanced Age

Age-adjusted D-dimer cut-offs should be used for patients >50 years (age × 10 μg/L) to improve specificity without compromising sensitivity. 1 D-dimer rises with age, limiting its use in those >80 years old. 3

Physical Activity

Strenuous physical activity can cause physiologic D-dimer elevation. 7

Clinical Significance of Extremely Elevated Levels

When D-dimer exceeds 5000 μg/L (>10× the VTE exclusion cut-off), 89% of patients have VTE, sepsis, and/or cancer. 2 Even if sharply elevated D-dimers appear as a solitary finding, clinical suspicion of severe underlying disease should be maintained. 2

Critical Pitfalls to Avoid

• 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
• Never rely solely on D-dimer in hospitalized patients due to high frequency of false-positive results. 1
• Never use D-dimer to rule out aortic dissection in high-risk patients—the negative predictive value is inadequate in this population. 1
• Never assume a positive D-dimer confirms VTE; further imaging is always required. 1
• In post-liver transplant patients, standard VTE exclusion cutoffs do not apply due to expected physiological elevation; serial measurements are more valuable than isolated values. 6
• D-dimer levels decline over time from symptom onset, potentially causing false-negative results in delayed presentations. 1