What causes hyperfibrinogenemia and how is it managed?

Causes and Management of Hyperfibrinogenemia

Hyperfibrinogenemia (elevated fibrinogen levels) is primarily caused by inflammatory conditions, malignancies, and certain genetic disorders, and should be managed based on the underlying cause with careful monitoring for thrombotic complications.

Causes of Hyperfibrinogenemia

Inflammatory Conditions

• Hyperfibrinogenemia commonly occurs as part of the acute phase response during inflammation, with fibrinogen acting as an acute phase protein 1
• Inflammatory mediators, particularly interleukin-6, stimulate increased fibrinogen production in the liver 2
• Chronic inflammatory states can lead to persistently elevated fibrinogen levels 1

Malignancies

• Various cancers, particularly hepatocellular carcinoma and gastric cancer, can produce significant hyperfibrinogenemia 2, 3
• Tumor cells may directly produce fibrinogen, as demonstrated by immunohistochemical detection of fibrinogen in tumor tissues 2
• Cancer-associated hyperfibrinogenemia correlates with tumor progression and poor prognosis 3

Other Causes

• Certain dysfibrinogenemias (qualitative fibrinogen disorders) can present with elevated fibrinogen levels 4
• Stress response with elevated cortisone levels can contribute to hyperfibrinogenemia 2
• Pregnancy is associated with physiologically increased fibrinogen levels 5

Clinical Significance and Risks

Thrombotic Risk

• Epidemiologic studies demonstrate a strong association between long-term hyperfibrinogenemia and both arterial and venous thrombosis 5
• Experimental models show that elevated fibrinogen (up to 4 g/L) directly promotes thrombosis after vascular injury, with a dose-dependent effect 5
• Hyperfibrinogenemia may be both a biomarker of cardiovascular risk and a causative mechanism of thrombosis 5, 6

Laboratory Abnormalities

• Paradoxically, very high fibrinogen levels can prolong coagulation tests (activated partial thromboplastin time, prothrombin time, and thrombin time) 2
• This prolongation is likely due to the effect of excess fibrin on thrombin (antithrombin I) and restricted fibrin polymerization 2

Management Approach

Diagnosis and Assessment

• Measure plasma fibrinogen concentration using both functional (Clauss method) and antigenic (immunoturbidimetry) assays 2, 4
• Evaluate for underlying causes with inflammatory markers (C-reactive protein, white blood cell count), liver function tests, and screening for malignancy when appropriate 3
• Consider genetic testing in cases of familial hyperfibrinogenemia or when congenital fibrinogen disorders are suspected 4

Treatment Principles

• The primary approach is to treat the underlying cause of hyperfibrinogenemia 2, 3
• For cancer-associated hyperfibrinogenemia, tumor resection can normalize fibrinogen levels 2
• For inflammatory conditions, treating the underlying inflammation should reduce fibrinogen levels 1

Thrombosis Prevention and Management

• Consider thromboprophylaxis in patients with hyperfibrinogenemia and additional risk factors for thrombosis 5
• In patients with dysfibrinogenemia type 3B (thrombotic-related variants), thromboprophylaxis should be initiated early, especially during high-risk periods like pregnancy 5
• Monitor fibrinogen levels regularly in patients receiving fibrinogen replacement therapy to avoid excessive elevation 5

Special Considerations in Pregnancy

• Pregnancy in women with congenital fibrinogen disorders requires multidisciplinary management 5
• For women with dysfibrinogenemia and hyperfibrinogenemia with thrombotic phenotype, thromboprophylaxis should be considered throughout pregnancy 5
• Target fibrinogen levels should not exceed necessary therapeutic levels to avoid thrombotic complications 5

Clinical Pitfalls and Caveats

• Do not assume all elevated fibrinogen levels require treatment - physiologic increases occur in pregnancy and mild inflammatory states 5, 1
• Avoid excessive fibrinogen replacement in patients with congenital fibrinogen disorders, as this may increase thrombotic risk 5
• Remember that some patients with hyperfibrinogenemia may paradoxically have prolonged clotting times, which could be misinterpreted as a bleeding disorder 2
• Be aware that patients with certain congenital fibrinogen disorders may have both bleeding and thrombotic risks, making management particularly challenging 6