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Functions of All Plasma Proteins

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Overview: Classification by Electrophoresis

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1. Albumin

• Site of synthesis: Liver exclusively
• Plasma concentration: ~3.5-5.0 g/dL (55-60% of total plasma protein)
• Half-life: ~20 days

1. Colloid osmotic (oncotic) pressure - the single most important function; maintains ~25 mmHg oncotic pressure across capillary walls, preventing fluid loss into tissues. Loss of albumin (e.g., nephrotic syndrome, cirrhosis) leads to edema.
2. Transport / carrier protein - binds and transports fatty acids, bilirubin, bile salts, hormones (steroids, thyroid hormones), hydrophobic amino acids, vitamins (B12, D), calcium, and numerous drugs (warfarin, aspirin, penicillin).
3. Labile protein reserve - macrophages phagocytose plasma proteins via pinocytosis; amino acids are released and redistributed to tissues in starvation or severe illness.
4. Buffering - weak acid-base buffer contributing ~15% of blood's total buffering capacity (alongside hemoglobin) via ionizable -COOH and -NH2 groups.
5. Nutritional marker - serum albumin correlates with mortality risk across many diseases; falls in malnutrition (though slowly, given its 20-day half-life).

• Guyton and Hall Textbook of Medical Physiology, p. 856; Ganong's Review of Medical Physiology, 26th Ed

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2. Fibrinogen

• Synthesis: Liver
• Concentration: 200-450 mg/dL
• MW: 340,000 Da; the largest plasma protein

1. Hemostasis - polymerizes into fibrin threads (under thrombin action) to form the blood clot scaffold; essential for sealing vascular damage.
2. Wound healing - fibrin matrix serves as substrate for fibroblast migration.
3. Acute-phase reactant - levels rise during inflammation, infection, and trauma.

• Junqueira's Basic Histology; Sleisenger & Fordtran's GI and Liver Disease

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3. Alpha Globulins

Alpha-1 Fraction

• The major serine protease inhibitor (serpin) of plasma
• Function: Inhibits trypsin, elastase, and other serine proteases released by neutrophils during inflammation, protecting tissues (especially lung alveoli) from proteolytic damage
• Deficiency causes emphysema and liver disease
• Concentration rises during acute-phase response

• Function: Inhibits the proliferating response of peripheral lymphocytes to mitogens; possible role in modulating inflammation. Binds certain drugs (e.g., lidocaine, propranolol).
• Rises sharply during acute-phase response

• Function: Inhibits chymotrypsin-like serine proteinases
• Increases during acute-phase response

• Function: Fetal equivalent of albumin - osmotic regulation and binding/carrier protein in fetal blood; normally very low in adults
• Clinical marker: elevated in hepatocellular carcinoma (HCC) and neural tube defects; mild elevation indicates hepatocellular regeneration

Alpha-2 Fraction

• Concentration: 40-180 mg/dL
• Function: Binds free hemoglobin released during intravascular hemolysis in a 1:1 complex, preventing:
  • Renal loss of iron
  • Oxidative damage to kidneys from free hemoglobin
  • The complex is taken up by the reticuloendothelial system for iron recycling
• Antioxidant role
• Acute-phase protein (rises in inflammation)

• Concentration: 15-60 mg/dL
• Function:
  • Transports copper (carries 6 atoms of copper per molecule; transports ~95% of serum copper)
  • Has ferroxidase activity - oxidizes Fe2+ to Fe3+, enabling iron loading onto transferrin
  • Antioxidant (scavenges free radicals)
• Decreased in Wilson disease; increased in inflammation, cholestasis, pregnancy

• Concentration: 150-420 mg/dL
• Function: Broad-spectrum inhibitor of serum endoproteases (trypsin, chymotrypsin, plasmin, thrombin). Acts as a protease "trap." Important in regulating coagulation and fibrinolysis.

• Function: Precursor to angiotensin I; substrate for renin. The starting point of the renin-angiotensin-aldosterone axis controlling blood pressure and volume.

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4. Beta Globulins

• Concentration: 3.0-6.5 mg/dL
• Half-life: ~8-10 days
• Function:
  • Transports iron in plasma (binds 2 atoms of Fe3+ per molecule)
  • Delivers iron to tissues (especially erythroid precursors for hemoglobin synthesis) via transferrin receptors
  • Bacteriostatic effect by sequestering iron away from bacteria
• Increases in iron deficiency, pregnancy; decreases with inflammation (negative acute-phase reactant), liver disease

• Concentration: 50-100 mg/dL
• Function: Binds free heme (porphyrins, especially heme) in a 1:1 complex after haptoglobin is saturated; transports heme to liver for recycling. Prevents heme-mediated oxidative damage.

• Function: Transport cholesterol and triglycerides from liver to peripheral tissues. Apolipoprotein B is their structural scaffold.

• Function: Components of the complement cascade
  • C3: central complement component; opsonization, lysis, inflammation
  • C4: part of the classical and lectin pathways; contributes to membrane attack complex formation
• Both are acute-phase proteins (increase in inflammation)

• Function: Extracellular matrix adhesion glycoprotein; promotes cell adhesion, wound healing, opsonization of pathogens

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5. Gamma Globulins (Immunoglobulins)

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6. Coagulation Factors (Special Plasma Proteins)

• Antithrombin III - inhibits thrombin and factor Xa; heparin cofactor
• Protein C + Protein S (vitamin K-dependent) - activated protein C inactivates factors Va and VIIIa, limiting clot propagation
• Plasminogen - precursor to plasmin; fibrinolysis

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7. Acute-Phase Proteins (Summary)

• Albumin, transferrin, transthyretin (prealbumin), retinol-binding protein

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8. Other Notable Plasma Proteins

• Function: Carrier for thyroid hormones (T3/T4) and retinol-binding protein (RBP); also a transport vehicle for retinol
• Short half-life (~2 days); sensitive early marker of hepatic synthetic function and nutritional status

• Function: Carries vitamin A (retinol) from liver to target tissues; circulates bound to transthyretin

• Function: Primary carrier of thyroid hormones (T4 > T3) in blood (~75%)

• Function: Binds and transports testosterone and estradiol; regulates their bioavailability

• Function: Transports cortisol (~75%) and progesterone in plasma

• Function: Mediator of the anabolic effects of growth hormone; promotes cell growth and differentiation

• Function: Antiprotease; inhibits complement activation (C1r, C1s), kallikrein, factor XIIa, and factor XIa. Deficiency causes hereditary angioedema.

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Key Points for Exam

1. Albumin = #1 by concentration; #1 for oncotic pressure; most versatile carrier
2. All plasma proteins except immunoglobulins are synthesized in the liver
3. Immunoglobulins are made by plasma cells (derived from B lymphocytes)
4. Fibrinogen is the largest plasma protein; absent in serum (consumed in clotting)
5. Vitamin K-dependent clotting factors: II, VII, IX, X (and protein C, S)
6. Haptoglobin falls in hemolysis (used up); transferrin rises in iron deficiency
7. CRP and SAA are the two major acute-phase proteins in humans
8. Negative acute-phase reactants: albumin, transferrin, transthyretin, RBP