Cascades, haemostasis and shock

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5.2 The complement cascade38
5.3 Haemostasis40
5.4 Shock41
Self-assessment: questions43
Self-assessment: answers44
Chapter overview
Shock is a complex series of changes which occur after severe and sudden diminution in the blood volume or cardiac output. The common feature of all causes of shock is insufficient circulating volume.

5.1. Principles of cascade systems

Learning objective
You should:

• describe the principles of cascade systems.
Enzyme cascades are involved in many processes in the body and are seen in immune, inflammatory and vascular events. They share the common underlying mechanism of cascade action in which the product of one reaction catalyses the subsequent reaction. For example, the blood plasma contains the components of four interlinked cascade systems that are involved in clotting and inflammation (see Table 5). Plasmin, a product of the fibrinolytic cascade, degrades the product of the clotting cascade and activates complement. Hageman factor, or factor XII, is a clotting factor which activates the complement, kinase and fibrinolytic systems (Figure 11). The caspase cascade has already been mentioned in Chapter 4.
Table 5 The plasma cascade systems
Activator(s) Important end product(s) Main functions
Kinin system Exposed collagen activates factor XII Bradykinin Vasodilatation/hypotension, increased vascular permeability, stimulates pain receptors
Complement system Antigen-antibody complexes (classical pathway); microbial endotoxin (alternative and MBL pathways) C3a/C5a
Membrane attack complex (C5-C9)
Chemotaxis, increased vascular permeability, releases histamine from mast cells
Cell lysis
Clotting system Exposed collagen activates factor XII (intrinsic pathway); thromboplastin from damaged tissues activates factor VII (extrinsic pathway) Thrombin Production of fibrin clot, proinflammatory actions on leucocytes and other cells
Fibrinolytic system Plasminogen activator from endothelium; activated factor XII Plasmin Lysis of fibrin clots by cleaving fibrin to form fibrin degradation products (FDPs), activation of complement cascade
At each step of the cascade, an inactive precursor is activated. Thus, the biologically inert components of the cascade can be present in the body ready to be activated, in contrast with systems where the component molecules have to be synthesised by cells when they are required for action. Therefore, cascades allow a rapid response to a stimulus. Also, one activated enzyme can catalyse the activation of a large number of its substrate molecules, so amplification of the response occurs at each step. Furthermore, the activated components can have more than one action, allowing for a large number of possible final effects. In this way, a few molecules of an initiating substance can have huge consequences, as when activation of a small amount of caspase 8 by Fas ligand binding starts a series of reactions that kill the cell (see Ch. 4).
Another characteristic of cascades is that each step of the process can be promoted or inhibited by other factors, allowing for tight control of the cascade. Typically, the active constituents have a short half life and are rapidly broken down or inactivated, so the cascade can be rapidly ‘switched off’ if required.
In summary, the advantages of cascade systems are:

• amplification of the original stimulus
• rapid reaction
• a variety of different actions resulting from one initial stimulus
• modulation and control by a wide range of other factors.

5.2. The complement cascade

Learning objectives
You should:

• discuss the three pathways by which the complement cascade is triggered
• describe the role of complement in host defence.
Complement is a system of soluble molecules that forms an important part of the body’s defence system against microbial infection. It is a cascade system and interacts with other components of the immune system (see Ch. 7).
Complement is activated via three pathways: the mannose-binding lectin (MBL, also known as mannan-binding lectin), classical and alternative pathways. The MBL and alternative pathways are triggered by microbial substances and do not require the participation of B cells or T cells. Therefore, these pathways represent part of innate immunity (see Ch. 7). The classical pathway is triggered by antigen–antibody binding. Figure 12 shows the main steps of the classical and alternative pathways leading to the formation of the membrane attack complex. The MBL pathway activates C4. Products of the fibrinolytic and kinin systems can also activate complement.
There are many functional consequences of complement activation (Box 4, Figure 12). Formation of the membrane attack complex is the final common pathway of the different limbs of the cascade; it makes a pore in the membrane of the target cell that leads to cell lysis. The anaphylatoxins are fragments of activated complement components that have cytokine-like effects, activating inflammatory cells and acting as chemoattractants for them. They can also degranulate mast cells. Fragments that remain attached to the target, such as C3b, promote phagocytosis, i.e. they are opsonins.
Box 4

Classical pathway

• Triggered by antigen–antibody complexes involving IgG or IgM

Alternative pathway

• Activated without IgG or IgM being present, e.g.:

• bacterial endotoxin (surface lipopolysaccharide of Gram-negative bacteria)
• snake venom
• aggregated IgA
Complement assists in defence in three ways:

Triggering acute inflammation: C3a, C5a, the anaphylatoxins, cause histamine-mediated vasodilatation and blood vessel leakage as well as acting as potent chemotaxins for neutrophils and monocytes
Helping phagocytosis by coating foreign substances, e.g. bacterial cell walls, with protein (opsonisation)
Direct killing of certain organisms: the membrane attack complex can kill some bacteria, e.g. Neisseria spp.
Complement activation can lead to extensive tissue damage and plays an important part in hypersensitivity reactions (see Ch. 8).

5.3. Haemostasis

Learning objectives
You should:

• distinguish the intrinsic from the extrinsic pathway
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