Causes of Elevated D-Dimer
Understanding D-Dimer Physiology
D-dimer is a fibrin degradation product resulting from plasmin-mediated proteolysis of crosslinked fibrin, indicating both coagulation activation and subsequent fibrinolysis. 1 It has a half-life of approximately 16 hours in circulation and specifically indicates the breakdown of crosslinked fibrin, not fibrinogen. 1
The critical concept is that D-dimer has high sensitivity (96%) but very low specificity (35%) for thrombotic disease, meaning elevated levels occur commonly in patients without venous thromboembolism. 1
Major Thrombotic Causes
Venous Thromboembolism
- Pulmonary embolism is the most common thrombotic cause, accounting for 32% of extremely elevated D-dimer cases (>5000 μg/L). 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. 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 sensitivity of 94-100% when measured within 24 hours of symptom onset. 1, 3 However, thrombosed false lumen or intramural hematoma may produce lower or negative D-dimer results. 1
Major Non-Thrombotic Causes
Infection and Inflammation
- Sepsis causes significant D-dimer elevation through systemic activation of coagulation, accounting for 24% of extremely elevated D-dimer cases. 1, 2
- COVID-19 is associated with elevated D-dimer levels that predict disease severity and mortality, with D-dimer >2.12 μg/mL associated with death. 1, 3
- Severe inflammatory states such as acute respiratory distress syndrome (ARDS) cause D-dimer elevation. 1
Malignancy
- Active cancer accounts for 29% of extremely elevated D-dimer cases (>5000 μg/L). 2, 4 Cancer causes D-dimer elevation through tumor-associated hypercoagulability. 3
- The prevalence of new or active cancer is 10.6% among patients with markedly elevated D-dimer who do not have pulmonary embolism. 4
Disseminated Intravascular Coagulation (DIC)
- DIC is characterized by markedly elevated D-dimer levels due to widespread activation of coagulation and fibrinolysis. 1
Trauma and Surgery
- Recent trauma or surgery accounts for 24% of extremely elevated D-dimer cases. 2
- After severe injury, the vast majority of patients without thromboembolism have positive D-dimer assays before 48 hours post-injury, with only 37% having true-negative results at 48 hours. 5
- D-dimer levels remain elevated for at least 6 days after severe trauma, with only 30% having true-negative results at day 6. 5
Cardiovascular Conditions
- Cardiovascular disease (excluding acute MI and dissection) accounts for 14.1% of markedly elevated D-dimer cases. 4
Physiologic and Age-Related
- Advanced age is associated with naturally increasing D-dimer levels, necessitating age-adjusted cutoffs (age × 10 μg/L for patients >50 years). 1
- Pregnancy causes physiologically elevated D-dimer levels, peaking in the third trimester (up to 2 μg/mL may be normal). 3
Liver Disease
- Liver disease with impaired clearance is associated with altered D-dimer levels. 1
Recent Fibrinolytic Therapy
- Recent thrombolytic therapy causes D-dimer elevation through therapeutic fibrinolysis. 1
Clinical Significance of Extremely Elevated D-Dimer
When D-dimer is extremely elevated (>5000 μg/L or >10× the cutoff to exclude VTE), 89% of patients have a diagnosis of VTE, sepsis, and/or cancer. 2 This represents a uniquely specific finding for serious illness despite D-dimer's general reputation for poor specificity. 2
D-dimer levels 3-4 times above normal warrant hospital admission consideration even without severe symptoms, as this signifies substantial thrombin generation and is associated with significantly increased mortality risk. 3
Important Clinical Considerations
Populations with Frequently Elevated D-Dimer
- Hospitalized and acutely ill patients have high frequency of false-positive results, limiting D-dimer usefulness in this population. 1
- Post-surgical patients frequently have elevated D-dimer regardless of thrombosis status. 1
- Patients with severe infection or inflammatory disease commonly have elevated D-dimer. 1
Prognostic Implications
- Elevated D-dimer is independently associated with increased mortality across various disease states. 1
- In COVID-19, D-dimer >2.12 μg/mL distinguishes non-survivors (median 2.12 μg/mL) from survivors (median 0.61 μg/mL). 3
- Persistent elevation after anticoagulation therapy indicates increased risk of recurrent thrombosis. 1
Critical Pitfall
A positive D-dimer cannot diagnose thrombosis and must always be followed by confirmatory imaging, as the specificity is only 35%. 1, 6 The test is valuable for ruling out disease when negative in low-risk patients, not for ruling in disease when positive. 1