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

Causes of 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 thrombotic cause of elevated D-dimer, with 32% prevalence among patients with extremely elevated levels (>5000 μg/L). 2
• Deep vein thrombosis accounts for 13% of cases with extremely elevated D-dimer. 2
• D-dimer demonstrates high sensitivity (≥95%) for VTE but low specificity (35%), making it excellent for exclusion but poor for confirmation. 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 measured within 24 hours of symptom onset, though levels may be lower with thrombosed false lumens or intramural hematomas. 1
• Cerebral venous thrombosis causes D-dimer elevation, though levels decline with time from symptom onset. 1

Non-Thrombotic Causes

Infection and Inflammation

• Sepsis is present in 24% of patients with extremely elevated D-dimer (>5000 μg/L) and causes significant elevation through systemic activation of coagulation. 2, 1
• Severe inflammatory states, including acute respiratory distress syndrome (ARDS), are associated with elevated D-dimer levels. 1
• 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), and 60% of patients with severe illness had D-dimer ≥0.5 mg/L. 3, 1

Malignancy

• Cancer is present in 29% of patients with extremely elevated D-dimer (>5000 μg/L) and should be considered if no other cause is identified. 2, 1
• Active malignancy causes variable D-dimer elevation due to tumor-associated hypercoagulability and indicates increased thrombosis risk. 4, 1

Disseminated Intravascular Coagulation

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis, with 71.4% of non-survivors meeting DIC criteria during hospital stay. 3, 1
• D-dimer is very sensitive to DIC and may be markedly elevated alongside prolonged prothrombin time and decreased fibrinogen and platelets. 4, 3

Surgery and Trauma

• Recent surgery or trauma within the past month significantly elevates D-dimer and accounts for 24% of cases with extremely elevated levels. 2, 1
• Recent fracture causes significant D-dimer elevation. 1

Cardiovascular Conditions

• Cardiovascular disease accounts for 14.1% of patients with extremely elevated D-dimer who don't have PE. 5
• Following fibrinolytic therapy causes D-dimer elevation through therapeutic fibrinolysis. 1

Physiologic States

• Advanced age is associated with naturally increasing D-dimer levels, with specificity decreasing to approximately 10% in patients >80 years, necessitating age-adjusted cutoffs (age × 10 μg/L for patients >50 years). 1
• Pregnancy causes physiologic D-dimer elevation, rising two- to fourfold by delivery, with normal ranges of 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). 4, 1
• Recent hospitalization can impact D-dimer levels. 1

Liver Disease

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

Clinical Significance by Degree of Elevation

Moderate Elevation (500-5000 μg/L)

• Requires clinical probability assessment and further diagnostic workup based on presentation. 1
• D-dimer >0.5 μg/mL requires further evaluation for PE or DVT in patients with low-to-intermediate clinical probability. 1

Marked Elevation (>5000 μg/L)

• 89% of patients with extremely elevated D-dimer (>5000 μg/L) have a diagnosis of 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
• In COVID-19 patients, D-dimer >5000 ng/mL is associated with 50% positive predictive value for thrombotic complications, and therapeutic anticoagulation should be initiated in hospitalized patients with this level or rapid doubling from baseline >2000 ng/mL within 24-48 hours. 1

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, and imaging should proceed directly. 1
• Do not rely on a negative D-dimer alone in patients presenting >24 hours after symptom onset, as levels decline over time. 1
• Do not assume that a positive D-dimer confirms VTE; further imaging is always required. 1
• D-dimer testing has less usefulness in hospitalized and acutely ill patients due to high frequency of false-positive results. 1
• Even if sharply elevated D-dimers are a seemingly solitary finding, clinical suspicion of severe underlying disease (VTE, sepsis, cancer, aortic dissection) should be maintained. 2