What are the other reasons besides blood clots (thrombosis) that can cause elevated D-dimer levels in a patient?

Non-Thrombotic Causes of Elevated D-Dimer

D-dimer elevation occurs in numerous conditions beyond thrombosis, including malignancy, sepsis, recent surgery or trauma, pregnancy, advanced age, acute aortic dissection, disseminated intravascular coagulation (DIC), massive bleeding, post-cardiac arrest status, and inflammatory states. 1

Major Non-Thrombotic Causes

Malignancy

• Cancer is present in 29% of patients with extremely elevated D-dimer (>5000 ng/mL) and should be considered if no other cause is identified. 1
• D-dimer levels >8000 ng/mL are associated with increased incidence of malignancy, with higher levels observed in breast, prostate, and bowel cancers. 2
• Elevated D-dimer in malignancy reflects the biology of the underlying tumor rather than solely indicating thrombosis. 2

Infection and Sepsis

• Sepsis causes significant D-dimer elevation through systemic activation of coagulation, with 94-100% sensitivity when measured within 24 hours. 3, 1
• Severe infection or inflammatory disease frequently elevates D-dimer, particularly in hospitalized patients. 1
• Pneumonia is one of the most common diagnoses associated with ultra-high D-dimer levels (>5000 ng/mL). 4

Disseminated Intravascular Coagulation (DIC)

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis. 3
• For suspected DIC, complete blood count, coagulation studies, and fibrinogen levels should be assessed. 1

Acute Aortic Dissection

• D-dimer >0.5 μg/mL has 94-100% sensitivity for acute aortic dissection, making it an excellent rule-out test. 1, 3
• D-dimer levels are typically immediately very high in aortic dissection, with highest diagnostic value in the first hour. 1
• Critical caveat: Intramural hematoma without intimal flap and thrombosed false lumen may produce negative D-dimer results. 3

Massive Bleeding and Trauma

• Massive gastrointestinal or other site bleeding causes very high D-dimer elevation (>50 mg/L FEU). 5
• Multiple traumatic injuries are associated with markedly elevated D-dimer levels. 5
• Recent surgery or fracture within the past month significantly elevates D-dimer. 1

Post-Cardiac Arrest

• Patients with cardiac arrest have very high D-dimer values when samples are taken immediately after recovery from cardiopulmonary resuscitation. 5

Pregnancy

• D-dimer levels increase progressively during pregnancy, peaking in the third trimester, with normal levels ranging from 0.11-0.40 μg/mL in the first trimester, 0.14-0.75 μg/mL in the second trimester, and 0.16-1.3 μg/mL in the third trimester (up to 2 μg/mL may still be normal). 1
• D-dimer rises two- to fourfold by delivery in normal pregnancy. 6

Advanced Age

• D-dimer specificity decreases steadily with age, reaching as low as 10% in patients over 80 years old. 1
• D-dimer rises with age, limiting its use in those >80 years old. 6
• Age-adjusted cutoffs (age × 10 ng/mL) should be used for patients over 50 years to improve specificity while maintaining sensitivity above 97%. 1

Acute Myocardial Infarction

• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis. 3

Following Fibrinolytic Therapy

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

COVID-19

• Elevated D-dimer is a predictor of mortality in COVID-19 patients, with non-survivors having median D-dimer of 2.12 μg/mL versus 0.61 μg/mL in survivors. 1
• In the largest COVID-19 study, 60% of patients with severe illness had D-dimer ≥0.5 mg/L. 1

Clinical Interpretation Algorithm

For Very High D-Dimer (>50 mg/L FEU)

• Although thromboembolism is the most frequently seen disorder (43% of cases), other conditions account for 57% of very high D-dimer values. 5
• Consider: massive bleeding, status post-CPR, sepsis with DIC, multiple traumatic injuries, hyperfibrinolysis, and HELLP syndrome. 5

For Ultra-High D-Dimer (>5000 ng/mL)

• VTE, cancer, and pneumonia are the most common diagnoses. 4
• Multiple clinical diagnoses are present in 61% of patients. 4
• No clear cause can be identified in 11.3% of patients. 4
• Mortality is particularly high when levels exceed 15,000 ng/mL (75% mortality in patients without identified diagnosis). 4

Important Limitations

• D-dimer has high sensitivity (≥95%) but very low specificity (35%) for thrombotic disease, meaning elevated levels occur commonly in patients without VTE. 3
• D-dimer testing has limited utility in hospitalized patients, post-surgical patients, pregnant women, and cancer patients due to high frequency of positive results regardless of VTE status. 1, 7
• A positive D-dimer alone cannot diagnose thrombosis and must always be followed by confirmatory imaging. 3, 7