Lecture 5

Definition of Plasma:

• Fluid left after red blood cells (RBCs) and immune cells are removed.

• Will clot unless inhibited.

Importance of Plasma Proteins:

• Crucial to inflammation and blood clotting!

Definition of Serum:

• The fluid left after the blood clot and cells are removed.

Definition of Plasma Proteins:

• Major Types of Plasma Proteins:

  • Albumin (60%): Major component of osmotic pressure of plasma.

  • Globulins (35%): Includes antibodies (immunoglobulins) and transport proteins.

  • Fibrinogens (4%): Functions in blood clotting.

Plasma Protein Functions:

• Albumin: Creates osmotic pressure to draw H2O from interstitial fluid into capillaries, maintaining blood volume and pressure.

• Fibrinogen: Essential component of coagulation (blood clotting).

• Globulins Types:

  • α and β globulins: Enzymes and proteins that transport compounds (e.g., transferrin, lipid and cholesterol transport).

  • β globulins: Includes C-reactive protein and complement proteins, important in host defense.

  • ϒ globulins: Immunoglobulins (Ig) produced by B cells for host defense against pathogens (e.g., IgG, IgE, IgM, IgA, IgD).

Plasma Protein Use in Disease:

• Albumin (25 grams):

  • Indications: Shock, Burns, Adult Respiratory Distress Syndrome, Cardiopulmonary Bypass Surgery.

• IVIG (Intravenous Immunoglobulin) (4 grams):

  • Indications: Primary Immunodeficiency Diseases, Autoimmune Diseases, Chronic Inflammatory Demyelinating Polyneuropathy, Idiopathic Thrombocytopenic Purpura.

• Alpha-I Antitrypsin (0.15 to 0.30 grams):

  • Indications: Alpha-I Antitrypsin Deficiency (Genetic COPD).

• Coagulation Factors:

  • Factor VIII: 300 to 450 IUs; Factor IX: 180 to 200 IUs

  • Indications: Hemophilia A & B, von Willebrand Disease, Bleeding Disorders.

Importance of Plasma Proteins:

• Encouragement for plasma donation due to its necessity for treating patients.

• Required plasma donations per condition:

  • Hemophilia: More than 1200 donations

  • Alpha-1 Patient: More than 900 donations

  • Primary Immune Deficiency: More than 130 donations

Four Major Functions of Plasma Proteins:

• Transport essential minerals and nutrients in the bloodstream.

• Maintain osmotic pressure of the blood by displacing water molecules in plasma.

• Defend against disseminating pathogens (via antibodies, complement).

• Plug holes in injured blood vessels by forming blood clots.

Clotting Factors and Blood Clotting Cascade:

• Key components: Prothrombin, Thrombin, Fibrinogen (soluble), Fibrin (insoluble).

• Process Overview:

  • Injury to vessel lining triggers clotting factor release.

  • Formation of a sticky platelet plug.

  • Fibrin strands adhere to the plug, forming an insoluble clot.

Hemophilia:

• Condition caused by a deficiency of clotting factors (VIII, IX), crucial in converting prothrombin to thrombin.

C-reactive Protein (CRP):

• Synthesized in the liver.

• Levels can increase up to 1000-fold during inflammation (an acute phase protein).

• Initiates binding of complement proteins by binding to phospholipids on dead or dying cells.

• CRP levels are used as a lab test to measure inflammation (not specific to any one disease).

The Complement System: Overview

• Classical Pathway: Involves C1 complex interaction with antibodies.

• Complement proteins: Need activation through cleavage; central in immune response and inflammation.

Complement System Functions:

• Limit pathogen spread.

• Activate cellular innate immunity.

• Create holes in pathogen cell membranes (via membrane attack complex).

Pathways of Complement Activation:

• Initiated by C1 or MBL/MASP molecules cleaving C4 and C2 to form C3 convertase.

• Switching between classical and alternative pathways results in a powerful amplification loop for C3 cleavage.

C3 and C5 Convertase Structures:

• Classical pathway: C3 Convertase = C4bC2b; C5 Convertase = C4bC2bC3b.

• Alternative pathway: C3 Convertase = C3bBb; C5 Convertase = C3bBbC3b.

Ren reiterated pathways: Repeat on initiation of pathways leading to C5b and MAC formation.

Membrane Attack Complex Formation:

• Sequential assembly of complement proteins C5b through C9 to form a pore in the pathogen membrane.

Alternative Pathway's Initiation:

• Spontaneous cleavage of C3 by microbial enzymes or free C3 convertase to activate the immune response.

Effects of Complement Activation:

• Increase in vascular permeability, cell adhesion, chemotaxis, inflammation, macrophage activity, and other immune responses.

Complement-mediated Phagocytosis:

• Bacteria coated with complement facilitates phagocytosis.

• CR1 interaction with C3b needed for effective macrophage phagocytosis.

Complement Deficiencies in Health:

• Genetic deficiencies of complement components lead to increased infection susceptibility, particularly with encapsulated bacteria.

• Deficiencies in C1q lead to autoimmune diseases like Systemic Lupus Erythematosus.

Regulation of Complement Proteins:

• Mechanisms to prevent damage to host cells, including factors like C1 inhibitor, CD59, and Decay Accelerating Factor (DAF).

C1 Inhibitor's Role:

• Functions to inhibit multiple plasma cascade pathways including classical complement pathway and lectin complement pathway.

Hereditary Angioedema:

• Caused by C1 Inhibitor deficiency, leading to spontaneous inflammation-like symptoms.

Regulation of Membrane Attack Complex Activity:

• CD59 prevents complement pore formation in host cells, protecting against lysis.

Human CD59 Deficiency and PNH:

• Low levels of CD59 increase susceptibility to MAC formation, leading to red blood cell destruction in conditions like Paroxysmal Nocturnal Hemoglobinuria (PNH).

PNH Mechanism:

• C3b accumulation on RBCs leads to complement activation and cell lysis, causing significant health issues.