What are the possible causes of an elevated D-dimer (D-dimer test) in a patient, especially in those with a history of clotting disorders, such as factor V Leiden or antithrombin deficiency, or those who are older, immobile, or have recently undergone surgery?

Reasons for Elevated D-Dimer

D-dimer elevation occurs in numerous thrombotic and non-thrombotic conditions, making it highly sensitive but poorly specific for venous thromboembolism. While D-dimer is excellent for excluding VTE when negative in low-risk patients, elevated levels require clinical context and further investigation rather than confirming any specific diagnosis 1.

Major Thrombotic Causes

Venous Thromboembolism

• Pulmonary embolism is the most common thrombotic cause, present in 32% of patients with extremely elevated D-dimer (>5000 μg/L) 2
• Deep vein thrombosis accounts for 13% of cases with markedly elevated D-dimer 2
• Cerebral venous thrombosis causes D-dimer elevation, though levels decline over time from symptom onset and may correlate with clot burden 1, 3

Arterial Thrombosis

• Acute myocardial infarction produces D-dimer elevation through arterial thrombosis and secondary fibrinolysis 3
• Acute aortic dissection demonstrates 94-100% sensitivity for D-dimer >0.5 μg/mL when measured within 24 hours of symptom onset 3, 4
• Two previously undiagnosed aortic dissections were identified among 85 patients with markedly elevated D-dimer who did not have PE 4

Major Non-Thrombotic Causes

Malignancy

• Active cancer is present in 29% of patients with extremely elevated D-dimer (>5000 μg/L) 2, 4
• Six new cancer diagnoses were identified among 85 patients with very high D-dimer without PE 4
• Cancer is particularly common in hepatoma, colon cancer, lung cancer, and uterine cancer 5
• D-dimer elevation in malignancy results from tumor-associated hypercoagulability 3

Infection and Inflammation

• Sepsis accounts for 24% of cases with extremely elevated D-dimer through systemic activation of coagulation 2
• Severe infection was the most common cause (41.2%) among patients with markedly elevated D-dimer without PE 4
• COVID-19 produces elevated D-dimer that predicts disease severity, with levels >2.12 μg/mL associated with mortality 3, 6
• Acute respiratory distress syndrome (ARDS) and other severe inflammatory states elevate D-dimer 3

Disseminated Intravascular Coagulation

• DIC produces markedly elevated D-dimer through widespread activation of coagulation and fibrinolysis 3
• DIC is frequently observed in patients with hepatoma 5

Cardiovascular Disease

• Congestive cardiac failure causes D-dimer elevation 1
• Cardiovascular disease accounted for 14.1% of cases with very high D-dimer without PE 4

Surgery and Trauma

• Recent surgery or trauma within the past month significantly elevates D-dimer 3, 6
• Surgery/trauma accounted for 24% of cases with extremely elevated D-dimer and 14.1% of cases without PE 2, 4

Hospitalization and Acute Illness

• Hospitalized patients commonly have elevated D-dimer regardless of VTE status 1
• D-dimer has limited diagnostic utility in acutely ill hospitalized patients due to high false-positive rates 3, 7

Pregnancy and Obstetrics

• Pregnancy causes physiologic D-dimer elevation that increases progressively, peaking in the third trimester (up to 2.0 μg/mL may be normal) 3, 6
• Despite physiologic elevation, normal D-dimer still has exclusion value for PE in pregnancy 3

Advanced Age

• Elderly patients have naturally increasing D-dimer levels with age, with specificity decreasing to only 10% in patients >80 years using standard cutoffs 3, 6, 7
• Age-adjusted cutoffs (age × 10 μg/L) should be used for patients >50 years to improve specificity while maintaining >97% sensitivity 3, 6

Liver Disease

• Impaired hepatic clearance in liver disease alters D-dimer levels 3

Following Fibrinolytic Therapy

• Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis 3

Clinical Significance of Extremely Elevated D-Dimer

D-dimer levels 3-4 times above normal (>1.5-2.0 mg/L) warrant hospital admission consideration even without severe symptoms, as this signifies substantial thrombin generation and increased mortality risk 3, 6.

• Among 581 patients with D-dimer >5000 μg/L (>10× normal), 89% had VTE, sepsis, and/or cancer 2
• Mortality over 2-year follow-up was 43.5% in patients with markedly elevated D-dimer without PE, with poorest outcomes in those with new or active cancer 4
• In COVID-19, D-dimer >2.12 μg/mL was associated with mortality (non-survivors: 2.12 μg/mL vs survivors: 0.61 μg/mL) 6

Critical Diagnostic Pitfalls to Avoid

• Never use elevated D-dimer alone to diagnose VTE—confirmation with imaging is always required, as specificity is only 35% 3, 7
• Never measure D-dimer in high clinical probability patients—proceed directly to imaging, as negative results do not reliably exclude PE in this population 3
• Never dismiss extremely elevated D-dimer (>5000 μg/L) as a non-specific finding—it is uniquely associated with severe disease including VTE, sepsis, cancer, or aortic dissection 2, 4
• Never forget time-dependent decline—D-dimer levels decrease over time from symptom onset, potentially causing false-negative results in delayed presentations 1, 3
• Never ignore age in interpretation—use age-adjusted cutoffs (age × 10 μg/L) for patients >50 years 3, 6, 7

Diagnostic Approach Algorithm

For Low-to-Intermediate Clinical Probability of VTE:

• D-dimer <0.5 μg/mL (or age-adjusted cutoff) safely excludes VTE without further testing 3, 7
• D-dimer ≥0.5 μg/mL requires imaging: compression ultrasound for DVT or CT pulmonary angiography for PE 3, 7

For High Clinical Probability of VTE:

• Proceed directly to imaging without D-dimer testing 3, 7

For Markedly Elevated D-Dimer (>5000 μg/L) Without VTE:

• Investigate for sepsis, active malignancy, and aortic dissection 2, 4
• Consider occult cancer workup if no clear source identified, as 29% have malignancy 2, 4
• Hospital admission should be considered given 43.5% two-year mortality 4