Biologic Properties

We’ve talked about how the complement system gets activated (the pathways), but now let’s focus on what it actually does once those protein dominos start falling. These actions are the reason complement is so critical in both protecting us and, unfortunately, sometimes causing problems in transfusion medicine!

Think of the activated complement components as having several distinct “job functions” in the body:

Cell Lysis: The “Punching Holes” Function (via MAC)

• Key Player: The Membrane Attack Complex (MAC), specifically C5b-9
• What it Does: This is the most dramatic outcome. The fully assembled MAC inserts itself into the target cell’s membrane (like a red blood cell, bacterium, or even some virus-infected cells), forming a transmembrane channel or pore
• Biological Consequence: This pore disrupts the cell’s osmotic integrity. Water and ions flood into the cell, causing it to swell and burst (lyse). For red blood cells, this is intravascular hemolysis – destruction within the blood vessels, releasing free hemoglobin into the plasma
• Blood Bank Relevance
  • Acute Hemolytic Transfusion Reactions (AHTRs): Especially in ABO incompatibility where potent IgM antibodies rapidly activate complement to completion, leading to massive intravascular hemolysis. This is a medical emergency!
  • Paroxysmal Nocturnal Hemoglobinuria (PNH): Patients’ red cells lack complement regulatory proteins (CD55, CD59), making them highly susceptible to spontaneous complement-mediated lysis
  • Visible Hemolysis in Testing: Seeing hemolysis in a test tube (e.g., during crossmatching or antibody ID) is often a sign of complement activation to the terminal pathway and is considered a positive reaction indicating potential in vivo hemolysis

Opsonization: The “Eat Me” Signal

• Key Player: Primarily C3b (and its breakdown product iC3b). C4b plays a minor role
• What it Does: When C3 is cleaved, C3b fragments covalently bind (“stick”) to the surface of the target particle (e.g., a red cell coated with antibody, or a bacterium). This coating process is called opsonization
• Biological Consequence: Phagocytic cells, particularly macrophages (found abundantly in the spleen and liver) and neutrophils, have specific complement receptors (like CR1 which binds C3b, and CR3/CR4 which bind iC3b). When these receptors encounter a C3b-coated particle, it triggers phagocytosis – the engulfment and destruction of the particle
• Blood Bank Relevance
  • Extravascular Hemolysis: This is the primary mechanism for removing red cells coated with complement (often triggered by IgG antibodies that activate complement only partially, or when MAC formation is inhibited). Macrophages in the spleen and liver recognize the C3b-coated cells and remove them from circulation. This is typically slower and less dramatic than intravascular hemolysis but is a common cause of Delayed Hemolytic Transfusion Reactions (DHTRs) and is seen in Warm Autoimmune Hemolytic Anemia (WAIHA)
  • DAT Positivity: The stable breakdown product C3d often remains on the red cell surface after C3b has been cleaved further by regulatory factors. The presence of C3d is detected by anti-C3d in the AHG reagent during a Direct Antiglobulin Test (DAT), indicating complement activation occurred in vivo

Inflammation: Sounding the Alarm

• Key Players: The small fragments released during cleavage: C5a, C3a, and C4a. These are collectively called anaphylatoxins
• What they Do: These peptides diffuse away from the site of activation and interact with receptors on various cells, particularly mast cells and basophils
• Biological Consequences
  • Mast Cell Degranulation: Causes release of histamine and other inflammatory mediators. This leads to increased vascular permeability (leaky blood vessels -> swelling/edema) and vasodilation (widening of blood vessels -> redness, drop in blood pressure)
  • Smooth Muscle Contraction: Can affect airways and blood vessels
  • Chemotaxis: C5a is a powerful chemoattractant, meaning it recruits inflammatory cells like neutrophils and macrophages to the site of complement activation, amplifying the inflammatory response
• Blood Bank Relevance
  • Symptoms of Transfusion Reactions: Many systemic symptoms associated with hemolytic transfusion reactions (fever, chills, flushing, hypotension, back pain, shortness of breath) are mediated by the release of these anaphylatoxins and subsequent inflammatory responses
  • C5a-mediated neutrophil activation is also implicated in the pathophysiology of Transfusion-Related Acute Lung Injury (TRALI), although the primary trigger there involves antibodies against HLA or neutrophil antigens

Immune Complex Clearance: Housekeeping Duty

• Key Players: C3b and Red Blood Cell CR1 receptors
• What it Does: Antibodies binding to soluble antigens form circulating immune complexes. Complement activation (specifically C3b deposition) coats these complexes. Red blood cells have CR1 receptors that bind these C3b-coated complexes
• Biological Consequence: Red blood cells act like a transport system, shuttling these potentially harmful immune complexes from the circulation to the liver and spleen. There, resident macrophages efficiently remove the complexes from the RBC surface (usually without destroying the RBC itself) for disposal
• Blood Bank Relevance: This is more of a general immune function, but it highlights the role of RBCs beyond oxygen transport. Defects in this clearance mechanism can contribute to autoimmune diseases where immune complexes deposit in tissues (like lupus)

Summary of Biologic Properties

Property	Key Mediator(s)	Primary Outcome	Blood Bank Relevance Example
Lysis (Intravascular)	MAC (C5b-9)	Pore formation -> Cell bursting	Acute HTR (e.g., ABO incompatibility), PNH
Opsonization (Phagocytosis)	C3b, iC3b	Coating cells -> Recognition by phagocyte CR1/CR3 -> Engulfment	Extravascular HTR, AIHA, DAT positive for C3d
Inflammation	C5a, C3a, C4a	Mast cell degranulation (histamine), Chemotaxis (esp. C5a recruits neutrophils)	Systemic symptoms in HTRs (fever, hypotension), Role in TRALI
Immune Complex Clearance	C3b, RBC CR1	Binding complexes -> Transport to liver/spleen -> Removal by macrophages	General mechanism preventing tissue deposition

Key Terms

• Biologic Properties: The functions or effects that a substance (like complement components) has within a living system
• Lysis: The disintegration or rupture of a cell membrane
• Membrane Attack Complex (MAC): The terminal complement complex (C5b-9) responsible for forming pores in cell membranes and causing lysis
• Intravascular Hemolysis: Destruction of red blood cells within the blood vessels, typically mediated by MAC formation
• Opsonization: The process of coating a particle (e.g., cell, bacterium) with molecules (opsonins like C3b or IgG) that enhance its uptake by phagocytic cells
• C3b: A major fragment of C3 activation that acts as an opsonin and is a component of the C5 convertase
• Complement Receptors (CR): Cell surface proteins (e.g., CR1 on macrophages and RBCs) that bind specific complement fragments like C3b
• Extravascular Hemolysis: Destruction of red blood cells outside the blood vessels, primarily by macrophages in the spleen and liver recognizing opsonized (C3b/IgG coated) cells
• Anaphylatoxins: Small complement fragments (C5a, C3a, C4a) that mediate local and systemic inflammatory responses, including mast cell degranulation and chemotaxis
• Chemotaxis: The directed movement of cells (like neutrophils) towards a chemical signal (like C5a)
• Immune Complex: A cluster formed by the binding of antibodies to soluble antigens. Complement aids in their clearance