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

Causes of False Elevated D-Dimer

D-dimer elevation is not "false" in most clinical scenarios—it reflects genuine activation of coagulation and fibrinolysis, but the elevation is frequently non-specific and occurs in numerous conditions beyond venous thromboembolism.

Understanding D-Dimer Specificity

D-dimer has high sensitivity (96%) but very low specificity (35%) for thrombotic disease, meaning elevated levels occur commonly in patients without VTE 1. The term "false positive" is somewhat misleading because the D-dimer elevation represents real fibrin formation and degradation—just not necessarily from the condition being investigated 1.

Major Non-Thrombotic Causes of D-Dimer Elevation

Cardiovascular Conditions

• Acute myocardial infarction causes D-dimer elevation through arterial thrombosis and secondary fibrinolysis 1
• Acute aortic dissection produces markedly elevated D-dimers (sensitivity 94-100% when >0.5 μg/mL), though levels may be lower with thrombosed false lumens or intramural hematomas 1
• Atrial fibrillation and other arrhythmias are associated with elevated D-dimers 2

Infection and Inflammation

• Sepsis causes significant D-dimer elevation through systemic activation of coagulation 1
• Severe inflammatory states including acute respiratory distress syndrome (ARDS) elevate D-dimers 3
• COVID-19 produces markedly elevated D-dimers that predict disease severity and mortality 3
• General infections were the most common cause (41.2%) of extremely elevated D-dimers (>5000 μg/L) in patients without PE 4

Malignancy

• Active cancer is present in approximately 29% of patients with extremely elevated D-dimers (>5000 μg/L) who don't have VTE 5
• D-dimer levels >8000 ng FEU/mL are independently associated with increased incidence of malignancy and reduced survival 2
• Occult malignancy should be considered when D-dimers are inexplicably elevated without other clear causes 6, 4
• Higher D-dimer levels are observed in breast, prostate, and bowel cancers 2

Trauma and Surgery

• Recent trauma or surgery causes D-dimer elevation that fails to normalize even after 14 days, contrary to the previously held belief that levels return to normal within 3 days 7
• In severely traumatized patients (mean ISS score 20), tissue injury resulted in D-dimer levels persistently above 500 ng/mL throughout the entire observation period 7
• This persistent elevation eliminates the ability to use D-dimer testing to rule out DVT or PE in severely traumatized patients in the early post-trauma period 7

Disseminated Intravascular Coagulation (DIC)

• DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis 1, 3

Pregnancy

• Physiologic pregnancy causes progressive D-dimer elevation, 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 (up to 2 μg/mL may be normal) in third trimester 8
• Despite physiologic elevation, a normal D-dimer still has exclusion value for PE in pregnancy 3

Age-Related Elevation

• Advanced age causes naturally increasing D-dimer levels, with specificity decreasing to as low as 10% in patients over 80 years 3, 8
• Age-adjusted cutoffs (age × 10 μg/L) should be used for patients >50 years to improve specificity while maintaining sensitivity >97% 3, 9, 8

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 1

Conditions Causing False-Negative D-Dimers

While the question asks about false elevations, it's critical to recognize conditions causing false-negative results in actual thrombotic disease:

• Thrombosed false lumen in aortic dissection produces lower D-dimer levels 1
• Intramural hematoma without intimal flap may have negative D-dimers 1
• Short dissection length and young patient age are associated with false-negative results 1
• Time from symptom onset shows negative correlation with D-dimer levels in aortic dissection 1
• Chronic versus acute dissection—D-dimer levels are higher in acute presentations 1

Clinical Implications and Pitfalls

When D-Dimer Has Limited Utility

• Hospitalized patients have high frequency of false-positive results, with the number needed to test to exclude one PE increasing from 3 to >10 9, 8
• Post-surgical patients routinely have elevated D-dimers regardless of VTE status 9, 7
• Cancer patients frequently have elevated D-dimers independent of thrombosis 9, 5, 2

Extremely Elevated D-Dimers (>5000 μg/L)

When D-dimers are extremely elevated (>10 times the VTE exclusion cutoff), 89% of patients have VTE, sepsis, and/or cancer 5. The differential diagnosis includes:

• Pulmonary embolism (32% of cases) 5
• Cancer (29% of cases) 5
• Sepsis (24% of cases) 5
• Trauma/surgery (24% of cases) 5
• Deep vein thrombosis (13% of cases) 5

Critical Caveat

D-dimer specificity ranges from only 40% to 100% in various studies, meaning positive results require imaging confirmation and cannot diagnose thrombotic disease alone 1, 9.