What are the common causes of an elevated D-dimer level?

What Causes Elevated D-Dimer?

D-dimer elevation occurs through two primary mechanisms: thrombotic conditions that activate coagulation and fibrinolysis (VTE, PE, aortic dissection, DIC), and non-thrombotic conditions that trigger systemic coagulation activation (sepsis, malignancy, liver disease, pregnancy, advanced age, recent surgery/trauma, and inflammatory states). 1

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 venous thrombosis accounts for 13% of cases with extremely elevated D-dimer 2
• D-dimer is elevated in 17 of 18 patients with confirmed DVT 3
• Cerebral venous thrombosis causes D-dimer elevation, though levels decline with time from symptom onset 4

Arterial Thrombotic Events

• Acute aortic dissection produces markedly elevated D-dimers with 94-100% sensitivity when >0.5 μg/mL 4
• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis, though only 4 of 27 patients with acute MI had elevated levels in one study 4, 3

Disseminated Intravascular Coagulation

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis 4
• D-dimer was elevated in all 43 patients with DIC in one cohort 3
• In COVID-19 patients, 71.4% of non-survivors met DIC criteria during hospitalization 5

Non-Thrombotic Causes

Infection and Sepsis

• Sepsis accounts for 24% of cases with extremely elevated D-dimer and causes significant elevation through systemic activation of coagulation 4, 2
• In COVID-19 patients, D-dimer >2.12 μg/mL was associated with mortality (non-survivors: 2.12 μg/mL vs survivors: 0.61 μg/mL) 5, 1
• VTE occurred in 27% of COVID-19 patients, with acute pulmonary embolism being the most frequent thrombotic complication (81%) 5

Malignancy

• Active cancer is present in 29% of patients with extremely elevated D-dimer (>5000 μg/L) 2
• D-dimer was elevated in 17 of 23 patients with malignant disease 3
• Variable rise in D-dimer indicates increased thrombosis risk in active disease 6

Liver Disease

• Hepatic dysfunction raises D-dimer levels by impairing clearance of fibrin-degradation products and producing a coagulopathic state 1
• D-dimer was elevated in 48 of 59 patients with liver disease 3
• Chronic alcohol-induced hepatic dysfunction specifically impairs clearance mechanisms 1

Pregnancy

• Normal pregnancy causes D-dimer to rise progressively, increasing two- to fourfold by delivery 6
• Third trimester levels range from 0.16-1.3 μg/mL, with levels up to 2.0 μg/mL potentially normal 5, 1
• D-dimer was elevated in 29 of 39 women in the third trimester of complicated pregnancy 3

Trauma and Surgery

• Recent surgery or trauma accounts for 24% of cases with extremely elevated D-dimer 2
• Recent surgery or fracture within the past month significantly elevates D-dimer 1

Advanced Age

• Aging causes naturally increasing D-dimer levels, with specificity decreasing to approximately 10% in patients >80 years 1, 6
• Age-adjusted cutoffs (age × 10 ng/mL) should be used for patients over 50 years 1

Hematologic Malignancies

• Acute leukemia at presentation showed elevated D-dimer in 22 of 27 patients 3
• There was a significant correlation (r = 0.84) between plasma D-dimer and serum FDP levels in acute leukemia 3

Other Inflammatory States

• Severe inflammatory disease frequently elevates D-dimer, particularly in hospitalized patients 1
• Alcohol withdrawal can provoke systemic inflammation that further elevates D-dimer independent of any thrombotic process 1

Clinical Significance by D-Dimer Level

Mild Elevation (500-2000 ng/mL)

• May be attributable to physiologic causes (age, pregnancy) or mild inflammatory states 7
• Requires clinical probability assessment using Wells score or Geneva score 1

Moderate Elevation (2000-5000 ng/mL)

• The European Society of Cardiology recommends proceeding directly to CT pulmonary angiography when D-dimer exceeds 2000 ng/mL, even in patients with "unlikely" clinical probability scores 1
• In COVID-19 patients, therapeutic anticoagulation should be initiated with D-dimer >5000 ng/mL or rapid doubling from baseline >2000 ng/mL within 24-48 hours 1

Extreme Elevation (>5000 ng/mL)

• 89% of patients with extremely elevated D-dimer have VTE, sepsis, and/or cancer 2
• 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 1
• Extremely elevated levels are highly specific for serious illness and should never be dismissed as a "solitary finding" 2

Important Clinical Pitfalls

• Never order D-dimer without first assessing clinical probability—this is the most common error 1
• D-dimer has high sensitivity (≥95%) but low specificity (35%) for VTE, making it excellent for exclusion but poor for confirmation 1, 4
• Do not measure D-dimer in high clinical probability patients—proceed directly to imaging 4
• D-dimer levels decline over time from symptom onset, potentially causing false-negative results in delayed presentations 4
• Hospitalized patients, cancer patients, post-surgical patients, and elderly patients >80 years have dramatically reduced D-dimer specificity—proceed directly to imaging based on clinical probability alone 1