• Fibrinogen, or Factor I, is converted to fibrin by thrombin and is a critical component of the coagulation system.
• Perioperatively, hypofibrinogenemia may be treated with purified human fibrinogen, cryoprecipitate, or fresh frozen plasma.

• Normal plasma fibrinogen in adults is 1.5–3.5 g/L (150–350 mg/dL). Synthesis occurs in the liver and is increased during an inflammatory state (infection, pregnancy, etc.).
• Physiological function: Fibrinogen is captured in the wound by activated platelets via glycoprotein IIb/IIIa receptors. A fibrin monomer is formed after thrombin cleaves peptides from fibrinogen. Thrombin also activates factor XIII, which cross-links fibrin monomers into a mesh. Fibrin can catalyze plasmin activation by serving as binding sites (lysine residues) for plasminogen and tissue plasminogen activator.
• Purified human fibrinogen (lyophilized) is currently indicated for acute bleeding episodes in patients with congenital fibrinogen deficiency (e.g., afibrinogenemia, hypofibrinogenemia).
  • Derived from pooled human plasma
  • The concentrate is pasteurized (heat treated) at 60°C for 20 hours for virus inactivation.
  • Can be stored between +2 to +8°C for 30 months
  • Therapeutic target level is 1.0–1.5 g/L (or 100–150 mg/dL).
  • In patients with congenital hypofibrinogenemia, the half-life is reported to be 78.7 ± 18.1 hours.

• Factor I deficiency: Presents as a combined bleeding disorder; it affects both platelets and clotting
  • Qualitative:
    • Dysfibrinogenemia results from defects to the factor I molecule. Patients rarely present with bleeding; in fact, some are predisposed to forming clots. Typically does not require any treatment such as cryoprecipitate, fresh frozen plasma, or purified fibrinogen. Occasionally, patients may be on anticoagulants.
  • Quantitative: Both conditions are inherited in an autosomal-dominant fashion and can affect both males and females.
    • Afibrinogenemia is the complete absence of fibrinogen and is typically diagnosed in newborns. It often presents as bleeding from the umbilical cord, genitourinary tract, or CNS.
    • Hypofibrinogenemia is a low level of fibrinogen (<100 mg/dL). Symptoms can range from mild, moderate, to severe bleeding.
• Increased fibrinogen levels:
  • Stroke: Associated with an increased risk of fatal and non-fatal, first-time, and hemorrhagic and ischemic strokes.
  • Coronary artery disease: Patients have increased levels, particularly those with a history of myocardial infarction.
  • Independent risk factor. Some studies have suggested that increased levels of fibrinogen exceed the effects of homocysteine, cholesterol, and other lipids in the pathogenesis of myocardial and cerebral infarction.
  • Mortality. A significant independent predictor of death from all causes in both men and women. This is believed to be due to its ability to promote thromboses, the underlying mechanisms for ischemia of myocardial infarction and stroke.
  • Cancer, diabetes, hypertension: Increased levels have been associated with these disease states.
  • Inflammatory process: Fibrin may play a role in inflammatory processes such as the development of rheumatoid arthritis.
  • Modification of levels. Smoking cessation, exercise, and medications have been shown to decrease levels.
• Complications of fibrinogen replacement:
  • Purified fibrinogen:
    • In disseminated intravascular coagulation (DIC), it can potentially worsen coagulopathy and organ dysfunction by forming fibrin in microcirculations.
    • Allergic reactions
    • The risks of pathogen transmission are considered to be low but possible for non-enveloped virus including parvovirus B19 and hepatitis A.
    • Venous and arterial thromboembolic complications should be cautioned.
    • The safety of purified human fibrinogen concentrate during pregnancy or breastfeeding has not been established in controlled clinical trials.
• Complications of cryoprecipitate and fresh frozen plasma replacement:
  • Volume overload and decreased hematocrit
  • Transfusion-related acute lung injury
  • Thromboembolic risks with cryoprecipitate
  • Infectious transmission
  • Acute hemolytic transfusion reaction, nonhemolytic febrile, and allergic reactions
  • Hypocalcemia

• Measuring fibrinogen:
  • The Clauss method is used to measure the fibrinogen concentration (30–60 minutes turn-around time). It may be falsely elevated after large amounts of hydroxyethyl starch infusion.
  • Thromboelastometry can be used to measure fibrin(ogen)-specific clot firmness using cytochalasin D (FIBTEM value below 7 and 10 mm suggests plasma fibrinogen <150 mg/dL).
• "Acquired" hypofibrinogenemia:
  • Major bleeding can be accompanied by decreased levels during trauma and surgery. Assuming normal fibrinogen level at baseline, critical levels (1 g/L or 100 mg/dL) of fibrinogen are reached after a loss of about 1.4 times the blood volume.
  • Cell saver: Large amounts of shed blood processed in the cell salvage system can deplete plasma coagulation factors, including fibrinogen.
  • Disseminated DIC that is associated with severe sepsis and eclampsia.
• Purified fibrinogen replacement:
  • No blood typing or thawing is necessary.
  • Less likely to induce hemodilution and thrombocytopenia after infusion compared to fresh frozen plasma (FFR).
• Following major obstetric hemorrhage, a work up should include an assessment of fibrinogen levels.
• Fibrin sealant: Human plasma-derived fibrinogen is clinically used as a fibrin sealant (Tisseel, Crosseal, Evicyl) for topical hemostasis.

• Dose (mg/kg body wt) = [target level (mg/dL) – measured level (mg/L)]/1.7 (mg/dL per mg/kg body weight).
• To raise plasma fibrinogen from 99 to 150 mg/dL, the required dose is (150 – 99)/1.7 = 30 mg/kg.
• In case of bleeding and fibrinogen level is unknown, the recommended initial dose is 70 mg/kg.

• Fresh Frozen Plasma
• Cryoprecipitate
• Coronary Artery Disease
• D-Dimer
• Transfusion Related Lung Injury

Kenichi A. Tanaka , MD, MSc

Satoru Ogawa , MD