What is Fibrinogen?
Fibrinogen (Factor I) is a soluble glycoprotein synthesized by the liver that serves as the substrate for fibrin clot formation. It is the final and essential step in the coagulation cascade, converting from soluble fibrinogen to insoluble fibrin mesh that stabilizes blood clots.
Structure and Function
Fibrinogen is a large, complex protein with critical hemostatic functions:
- Molecular structure: 340 kDa glycoprotein composed of three pairs of polypeptide chains (Aα, Bβ, γ)
- Synthesis: Produced exclusively by hepatocytes in the liver
- Plasma concentration: Normally 200-400 mg/dL (highest concentration of any coagulation factor)
- Half-life: 3-5 days (relatively long for a clotting factor)
How Fibrinogen Works in Coagulation
Fibrinogen is the final common pathway substrate converted to fibrin clot:
- Step 1: Coagulation cascade activates prothrombin → thrombin (Factor IIa)
- Step 2: Thrombin cleaves fibrinogen → releases fibrinopeptides A and B → forms fibrin monomers
- Step 3: Fibrin monomers spontaneously polymerize → soluble fibrin polymer
- Step 4: Factor XIIIa (activated by thrombin) cross-links fibrin polymers → stable, insoluble fibrin clot
- Result: Mesh network of fibrin strands traps platelets and RBCs → hemostatic plug
Fibrinogen as an Acute Phase Reactant
Unlike most clotting factors, fibrinogen INCREASES during inflammation and acute illness:
- Inflammatory response: IL-6 and other cytokines stimulate hepatic fibrinogen synthesis
- Timeline: Levels rise within 24-48 hours of inflammatory stimulus
- Magnitude: Can increase 2-3 fold (up to 600-800 mg/dL) during acute inflammation
- Clinical uses: Nonspecific marker of inflammation (like ESR, CRP); elevated in infection, malignancy, pregnancy, MI, trauma
Dual Nature of Fibrinogen: This creates an important clinical paradox. In most inflammatory conditions (infection, trauma, surgery), fibrinogen RISES as an acute phase reactant. Therefore, a NORMAL or LOW fibrinogen in a critically ill patient is concerning and suggests consumption (DIC), severe liver dysfunction, or massive hemorrhage depleting fibrinogen faster than it can be synthesized.
Low Fibrinogen (Hypofibrinogenemia)
Decreased fibrinogen impairs clot formation and increases bleeding risk. Determine whether this is acquired (most common) or congenital.
Disseminated Intravascular Coagulation (DIC) - Most Common Cause
- Mechanism: Widespread activation of coagulation → consumes fibrinogen faster than liver can synthesize
- Classic DIC laboratory triad:
- Low fibrinogen (<100 mg/dL)
- Low platelets (<100,000/μL)
- Prolonged PT/aPTT
- Elevated D-dimer (>4000 ng/mL)
- Common causes of DIC: Sepsis (most common), trauma, obstetric complications (abruption, amniotic fluid embolism, retained dead fetus), malignancy (especially AML-M3), massive transfusion
- Clinical presentation: Bleeding from venipuncture sites, GI bleeding, oozing from wounds, petechiae, purpura; may have concurrent thrombosis
Liver Disease - Decreased Synthesis
- Mechanism: Liver synthesizes all clotting factors including fibrinogen; hepatic failure → decreased production
- Pattern: Low fibrinogen + prolonged PT/INR (all factors low) + low albumin
- Severity correlation: Fibrinogen drops in advanced cirrhosis or acute liver failure
- Differentiate from DIC: Platelets may be low (hypersplenism) but D-dimer typically not markedly elevated unless concurrent DIC
Massive Hemorrhage and Transfusion
- Dilutional coagulopathy: Massive blood loss → resuscitation with crystalloid/RBCs → dilutes remaining fibrinogen
- Consumptive coagulopathy: Ongoing bleeding consumes clotting factors including fibrinogen
- Massive Transfusion Protocol (MTP): Fibrinogen <150 mg/dL triggers cryoprecipitate administration
- Trauma coagulopathy: Fibrinogen often first factor to drop critically low (before other factors)
Obstetric Emergencies
- Placental abruption: Tissue factor release → DIC → rapid fibrinogen consumption
- Amniotic fluid embolism: Fetal material in maternal circulation → severe DIC
- Postpartum hemorrhage: Fibrinogen drops precipitously with massive bleeding; target >200 mg/dL
- HELLP syndrome: Hemolysis, elevated liver enzymes, low platelets → may have low fibrinogen
Fibrinolytic Disorders - Excessive Breakdown
- Primary fibrinolysis: Excessive plasmin activity degrades fibrinogen (rare; seen with tPA overdose, prostate surgery)
- Thrombolytic therapy: tPA, streptokinase, urokinase → systemic fibrinogen degradation
- Differentiate from DIC: Primary fibrinolysis has normal platelets, normal/slightly prolonged PT/aPTT, very high D-dimer
Congenital Fibrinogen Disorders (Rare)
- Afibrinogenemia: Absent fibrinogen (<10 mg/dL); autosomal recessive; severe bleeding from birth
- Hypofibrinogenemia: Low fibrinogen (20-100 mg/dL); mild-moderate bleeding
- Dysfibrinogenemia: Qualitative defect; normal fibrinogen level but abnormal function; variable bleeding or thrombosis
Elevated Fibrinogen (Hyperfibrinogenemia)
Elevated fibrinogen is NOT a clotting disorder but an inflammatory marker. May increase thrombosis risk.
Acute Phase Reaction
- Infection/sepsis: Bacterial, viral, fungal infections
- Inflammation: Rheumatoid arthritis, inflammatory bowel disease, vasculitis
- Tissue damage: Myocardial infarction, stroke, trauma, surgery
- Malignancy: Many cancers elevate fibrinogen as acute phase reactant
Pregnancy
- Physiologic increase: Fibrinogen rises progressively during pregnancy (400-600 mg/dL by 3rd trimester)
- Hypercoagulable state: Contributes to increased VTE risk in pregnancy
Smoking and Cardiovascular Disease
- Chronic elevation: Smokers have chronically elevated fibrinogen
- Cardiovascular risk factor: High fibrinogen associated with increased MI, stroke, and peripheral vascular disease risk
Diagnosing DIC with Fibrinogen
DIC diagnosis requires multiple laboratory abnormalities; fibrinogen is one key component.
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| Test | DIC Pattern | Diagnostic Points |
|---|---|---|
| Fibrinogen | <100 mg/dL | Consumption exceeds production (2 points if <100) |
| Platelets | <100,000/μL | Consumption and adhesion to fibrin (1 point if <100k) |
| PT/aPTT | Prolonged | Factor consumption (1 point if prolonged) |
| D-dimer | >4000 ng/mL | Fibrin degradation products (3 points if >4000) |
ISTH DIC Score (International Society on Thrombosis and Haemostasis):
- Platelet count: >100k = 0 points; <100k = 1 point; <50k = 2 points
- D-dimer: Normal = 0 points; moderate increase = 2 points; strong increase = 3 points
- PT prolongation: <3 sec = 0 points; 3-6 sec = 1 point; >6 sec = 2 points
- Fibrinogen: >100 mg/dL = 0 points; <100 mg/dL = 1 point
- Score ≥5: Compatible with overt DIC
Fibrinogen Replacement Guidelines
Indications for Fibrinogen Replacement:
- Fibrinogen <100 mg/dL AND active bleeding
- Fibrinogen <150 mg/dL in massive transfusion protocol
- Fibrinogen <200 mg/dL before major surgery or obstetric hemorrhage
- Congenital afibrinogenemia or severe hypofibrinogenemia
Replacement Products:
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| Product | Fibrinogen Content | Dosing | Advantages/Disadvantages |
|---|---|---|---|
| Cryoprecipitate | 150-250 mg per unit | 10 units (1 "pool") raises ~70-100 mg/dL; 1 unit raises ~10 mg/dL | Readily available, inexpensive; risk of viral transmission, volume load, ABO incompatibility |
| Fibrinogen Concentrate | 1 gram per vial | 3-4 grams (50-70 mg/kg) raises ~100 mg/dL | Virally inactivated, small volume, precise dosing; expensive, limited availability |
| Fresh Frozen Plasma | 200-400 mg per unit | NOT recommended for isolated fibrinogen replacement | Large volume required (10-15 units), slow, inefficient; use only if other products unavailable |
Cryoprecipitate Dosing for Critical Fibrinogen Replacement:
- Standard dose: 10 units (1 pool) for average adult
- Expected rise: 1 unit raises fibrinogen ~10 mg/dL; 10 units → ~70-100 mg/dL increase
- Goal: Target fibrinogen >100 mg/dL (active bleeding) or >150-200 mg/dL (surgery, massive transfusion)
- Recheck: Measure fibrinogen 30-60 minutes after transfusion
- Repeat dosing: If still <100 mg/dL, give additional cryoprecipitate
- Ongoing consumption: In DIC or massive hemorrhage, may need repeated dosing every 4-6 hours
Approach to Low Fibrinogen
Step 1: Assess clinical context
- Is patient bleeding? (active hemorrhage, oozing from IV sites, petechiae)
- High-risk scenario? (trauma, postpartum, sepsis, major surgery)
Step 2: Check coagulation panel
- PT/aPTT (prolonged in DIC, liver disease)
- Platelet count (low in DIC, high in reactive thrombocytosis)
- D-dimer (markedly elevated in DIC, >4000 ng/mL)
Step 3: Differentiate DIC from other causes
DIC vs Liver Disease vs Dilutional Coagulopathy:
- DIC: Low fibrinogen, low platelets, prolonged PT/aPTT, HIGH D-dimer (>4000), clinical scenario (sepsis, trauma, abruption)
- Liver disease: Variable fibrinogen (normal to low), low platelets (hypersplenism), prolonged PT/INR, D-dimer normal/mild elevation, chronic liver disease history
- Dilutional coagulopathy: Low fibrinogen, variable platelets, prolonged PT/aPTT, D-dimer variable, massive transfusion/resuscitation
Step 4: Treat underlying cause + replace fibrinogen if indicated
- DIC: Treat sepsis, remove dead fetus, control bleeding source; supportive transfusion
- Liver disease: Vitamin K trial, treat hepatic decompensation; FFP for procedure coverage
- Massive hemorrhage: Activate MTP, balanced resuscitation, cryoprecipitate for fibrinogen <150 mg/dL
Physiologic Factors That Increase Fibrinogen
- Pregnancy: Physiologic increase to 400-600 mg/dL by third trimester
- Acute phase response: Any inflammatory stimulus (infection, trauma, MI, surgery) raises fibrinogen within 24-48 hours
- Smoking: Chronic tobacco use elevates baseline fibrinogen
- Oral contraceptives: Estrogen increases fibrinogen synthesis
- Age: Fibrinogen increases slightly with age
Medications That Affect Fibrinogen
- Decrease fibrinogen: Thrombolytics (tPA, streptokinase), L-asparaginase (chemotherapy agent), androgens, anabolic steroids
- Increase fibrinogen: Oral contraceptives, estrogen therapy, growth hormone
Pre-analytical Errors
- Underfilled tube: Excess citrate causes falsely low fibrinogen
- Clotted sample: Falsely low (fibrinogen consumed in clot); reject and redraw
- Hemolyzed sample: May interfere with optical assays
- Lipemia: Turbid sample interferes with clot detection
- Delayed processing: Fibrinogen stable for 4 hours at room temperature
Assay Considerations
- Clauss method (most common): Functional assay; measures clotting time after excess thrombin added
- Immunologic assay: Measures fibrinogen antigen (not function); may be elevated in dysfibrinogenemia
- Heparin interference: High-dose heparin may falsely lower fibrinogen on some assays
Clinical Pearl
"First to drop in trauma, last to recover": In massive hemorrhage and trauma, fibrinogen is often the FIRST clotting factor to fall to critically low levels (<100 mg/dL), even before PT/aPTT prolong significantly. Check fibrinogen early in massive transfusion protocol and replace aggressively (target >150-200 mg/dL).
Clinical Pearl
DIC triad - remember "Low, Low, Prolonged": Low fibrinogen (<100), Low platelets (<100k), Prolonged PT/aPTT + sky-high D-dimer (>4000). If all four abnormal in appropriate clinical context (sepsis, trauma, abruption), DIC diagnosis is almost certain.
Clinical Pearl
Fibrinogen is an acute phase reactant: Unlike other clotting factors that drop in liver disease, fibrinogen can be NORMAL or even ELEVATED in early cirrhosis because it rises with inflammation. Therefore, a LOW or even normal-low fibrinogen in a critically ill patient is concerning - should be elevated from acute phase response.
Don't use FFP to replace fibrinogen: FFP contains only 200-400 mg fibrinogen per unit. You would need 10-15 units to meaningfully raise fibrinogen (massive volume load, hours to infuse). Use cryoprecipitate (10 units raises fibrinogen ~70-100 mg/dL with only 200-300 mL volume) or fibrinogen concentrate (3-4 grams in 200 mL raises ~100 mg/dL).
Cryoprecipitate contains more than fibrinogen: Each unit of cryoprecipitate contains ~150-250 mg fibrinogen PLUS Factor VIII (80-100 units), Factor XIII, vWF, and fibronectin. This makes it useful for hemophilia A emergencies when Factor VIII concentrate unavailable, though specific factor concentrates preferred.
Clinical Pearl
Postpartum hemorrhage and fibrinogen: Fibrinogen drops rapidly during obstetric hemorrhage (faster than other factors). Target fibrinogen >200 mg/dL in PPH. Some guidelines recommend empiric cryoprecipitate in massive PPH even before lab results available. Early fibrinogen replacement improves outcomes.
Clinical Pearl
Fibrinogen as cardiovascular risk marker: Chronically elevated fibrinogen (>400 mg/dL) is an independent risk factor for MI, stroke, and PAD. Elevated fibrinogen increases blood viscosity and promotes thrombosis. Smoking cessation lowers fibrinogen levels.
Congenital afibrinogenemia is life-threatening: Patients with absent fibrinogen (<10 mg/dL) have severe spontaneous bleeding (umbilical stump bleeding, intracranial hemorrhage, hemarthrosis). Requires lifelong prophylactic fibrinogen concentrate or cryoprecipitate 1-2×/week. Unlike hemophilia, cannot delay treatment.
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