Why Fibrinogen is Elevated
Fibrinogen is elevated primarily as an acute phase reactant in response to inflammation, infection, tissue injury, or physiological states like pregnancy. 1
Primary Causes of Elevated Fibrinogen
Inflammatory and Infectious Processes
- Acute and chronic inflammatory diseases trigger fibrinogen elevation as part of the acute phase response, with fibrinogen rising alongside C-reactive protein (CRP) during inflammatory states 1
- COVID-19 infection commonly causes elevated fibrinogen (67.2% of patients), particularly in severe disease, where it reflects excessive inflammation rather than coagulopathy 2
- Tissue injury and trauma lead to increased fibrinogen production as part of the body's healing response 1
Cardiovascular Disease
- Acute coronary syndromes are strongly associated with elevated fibrinogen levels, which serve as an independent risk marker for both short-term and long-term mortality and subsequent myocardial infarction 1, 3
- Elevated fibrinogen contributes to cardiovascular events through multiple mechanisms: infiltration of vessel walls, increased blood viscosity, enhanced platelet aggregation, and accelerated thrombus formation 3
- The predictive value of elevated fibrinogen for cardiovascular events is comparable to elevated cholesterol levels 3
Physiological States
- Pregnancy causes a normal, progressive increase in fibrinogen levels, reaching 3.7 to 6.2 g/L during the third trimester, with median levels of 3.86 g/L at 36 weeks 4
- This physiological elevation is so pronounced that D-dimer levels up to 2 μg/mL can still be within normal range for pregnant women 4
Pathophysiological Mechanisms
How Elevated Fibrinogen Causes Disease
- Rheological effects: Increased blood viscosity from elevated fibrinogen impairs blood flow 3
- Prothrombotic state: Enhanced platelet aggregation and thrombus formation increase clotting risk 3, 5
- Atherogenesis: Fibrinogen infiltrates vessel walls, promoting atherosclerotic plaque formation 3
- Inflammatory amplification: Elevated fibrinogen perpetuates inflammatory responses 5
Clinical Significance by Level
- Normal range: 2.0-4.0 g/L 1
- Mild elevation (400-700 mg/dL): Associated with 20% incidence of prolonged reptilase times 6
- Moderate elevation (700-1,000 mg/dL): Associated with 34% incidence of prolonged reptilase times 6
- Severe elevation (>1,000 mg/dL): Associated with 47% incidence of prolonged reptilase times and increased disease severity 6
Disease-Specific Associations
Venous Thromboembolism
- Elevated fibrinogen is associated with pulmonary embolism (PE), particularly PE combined with deep venous thrombosis (DVT), with a 2.1-fold increased risk in the highest quintile (≥4.6 g/L) 7
- Notably, elevated fibrinogen is NOT associated with DVT alone after multivariable adjustment, suggesting fibrinogen elevation may be a marker rather than a direct cause of thrombosis 7
COVID-19 Severity
- Fibrinogen at 528.0 mg/dL is the optimal cutoff to predict severe COVID-19 disease, with 66.7% sensitivity and 70.3% specificity 2
- Patients with severe COVID-19 have significantly higher fibrinogen levels on admission compared to non-severe disease 2
- In deteriorating COVID-19 patients developing coagulopathy, fibrinogen levels paradoxically decrease, signaling consumption and poor prognosis 4
Important Clinical Caveats
Not Always Pathological
- Elevated fibrinogen in pregnancy is physiological and expected, not pathological 4
- Fibrinogen elevation may be a marker of underlying disease rather than a direct cause of thrombosis, as genetic variants that increase fibrinogen are not associated with increased PE or DVT risk 7
Laboratory Considerations
- Artificial colloids like hydroxyethyl starch can cause overestimation of fibrinogen levels when measured by the Clauss method 1
- Elevated fibrinogen prolongs reptilase time but typically not thrombin time, which can mimic dysfibrinogenemia 6
- Before diagnosing dysfibrinogenemia in patients with prolonged reptilase times, always measure fibrinogen levels to exclude reactive elevation 6