What are the possible causes of elevated D-dimer (D-dimer) levels?

Reasons for Elevated D-Dimer

D-dimer elevation occurs through two primary mechanisms: thrombotic conditions that activate coagulation and fibrinolysis, and non-thrombotic conditions that trigger systemic coagulation activation, with the degree of elevation providing critical diagnostic information about disease severity. 1

Thrombotic Causes

Venous Thromboembolism

• Pulmonary embolism is the most common cause of extremely elevated D-dimer (>5000 μg/L), accounting for 32% of cases with markedly elevated levels 2
• Deep vein thrombosis accounts for 13% of extremely elevated D-dimer 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 myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis 1
• Acute aortic dissection produces markedly elevated D-dimers with 94-100% sensitivity when >0.5 μg/mL, though levels may be lower with thrombosed false lumens or intramural hematomas 1, 3

Non-Thrombotic Causes

Infection and Inflammation

• Sepsis causes significant D-dimer elevation through systemic activation of coagulation, accounting for 24% of extremely elevated cases 1, 2
• COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality, with levels >2.12 μg/mL associated with death 1, 3
• Severe inflammatory states including acute respiratory distress syndrome (ARDS) are associated with elevated D-dimer 1
• Acute exacerbation of COPD can cause very high D-dimer levels even without pulmonary embolism, particularly in end-stage disease with hypercapnia 4

Malignancy

• Active cancer accounts for 29% of patients with extremely elevated D-dimer (>5000 ng/mL) and should be considered if no other cause is identified 3, 2
• D-dimer elevation in malignancy indicates increased thrombosis risk in active disease 5

Disseminated Intravascular Coagulation

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis 1, 5

Trauma and Surgery

• Recent trauma or surgery accounts for 24% of extremely elevated D-dimer cases 2
• Recent fracture within the past month significantly elevates D-dimer 3

Physiologic Conditions

• Advanced age is associated with naturally increasing D-dimer levels, with specificity decreasing to approximately 10% in patients >80 years 1, 3
• Pregnancy causes physiologic D-dimer elevation, with normal levels ranging from 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, 5

Other Conditions

• Liver disease with impaired clearance is associated with altered D-dimer levels 1
• Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis 1
• Cigarette smoking can elevate D-dimer levels 4

Clinical Significance by D-Dimer Level

Moderate Elevation (500-5000 μg/L)

• Requires clinical probability assessment and further diagnostic workup based on presentation 3
• D-dimer >0.5 μg/mL requires further evaluation for pulmonary embolism or deep vein thrombosis in patients with low-to-intermediate clinical probability 3

Marked Elevation (>5000 μg/L)

• 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 3
• In COVID-19 patients, D-dimer >5000 ng/mL is associated with 50% positive predictive value for thrombotic complications 3

Critical Diagnostic Pitfalls

• Never use D-dimer to rule out disease in high-risk patients for pulmonary embolism or aortic dissection—the negative predictive value is inadequate in this population 1
• D-dimer levels decline over time from symptom onset, potentially causing false-negative results in delayed presentations 1
• Thrombosed false lumen in aortic dissection and intramural hematoma without intimal flap may produce negative D-dimer results 1
• D-dimer has high sensitivity (≥95%) but low specificity (35-40%) for thrombotic disease, meaning elevated levels occur commonly in patients without VTE 1, 3
• D-dimer testing has less usefulness in hospitalized and acutely ill patients due to high frequency of false-positive results 1