Haemostasis

Introduction

Haemostasis is the normal spontaneous arrest of bleeding from ruptured blood vessels. Normal haemostasis depends on a combination of events: the vascular response, which occurs mainly at capillary and small vessel level, the platelet (or thrombocyte) response, which also occurs in capillaries and small vessels, and the blood coagulation response which takes place in the arteries and veins.

Vascular responses

• There are several possible vascular responses, of which one or more may be recruited in normal haemostasis.
  • Vascular contraction.
    • This is usually a temporary effect.
    • Gives a partial arrest of blood flow.
    • Is important in larger vessels.
  • Vascular shunting.
    • Blood is redistributed using alternative pathways to by-pass the injured area.
  • Increased blood viscosity.
    • The "sludging" effect.
      • RBCs become more packed.
    • Is due to plasma loss through vascular walls and leaky plugs.
  • Plasma loss
    • Loss of plasma to the surrounding tissue spaces results in pressure on the vessel walls.

Platelet Responses

• Platelet responses are very important in maintaining haemostasis.
• When platelets are activated, the haemostatic plug is formed.
  • The influence of thrombosthenin gives clot organisation and fibrin formation.
    • The clot continues to be organised and to contract over the 3-5 days following formation.

The Platelet Release Reaction

• A series of events activates platelets to allow them to form the haemostatic plug.

1. Adhesion
   • The first stage in platelet activation is an increase in the adhesiveness of platelets.
   • Adhesion may be initiated by several scenarios:
     • The release of ADP from damaged endothelial cells.
     • Platelet contact with collagen or basement membrane.
     • Platelet contact with some denatured proteins and antibody-antigen complexes.
   • A friable and leaking plug is formed within 1 minute by this adhesion stage.
2. Agglutination.
   • More ADP is released, bringing and linking more platelets into the clot.
   • A chain reaction.
3. Aggregation.
   • "Viscous metamorphosis".
   • Platelets aggregate to form a tightly packed mosaic.
   • Results in compaction of the plug.
     • Gives a good temporary seal to the injured vessel in about 5-30 minutes.
4. Disruption.
   • Further aggregation of platelets is stimulated by prostaglandin endoperoxide (PGG2) release.
   • Platelet breakdown produces phospholipids (platelet factors 3 and 4).

Blood Coagulation

• Blood coagulation is a cascade system.
  • There is a series of conversions of proenzymes to active forms.
    • The amount and speed increases at each level.
  • The major trigger for the system is contact activation.
• There are both intrinsic and extrinsic systems within the clotting cascade.
  • The intrinsic system
    • This refers to the clotting factors.
      • Are derived from plasma.
      • Can operate in the absence of tissue damage.
    • It takes some minutes for the body to activate the intrinsic system.
  • The extrinsic system
    • This refers to the tissue thromboplastin.
    • Depends on vascular damage as a trigger.
      • Involves platelet activity.
    • Operates in a matter of seconds.
• The plasma and tissue (intrinsic and extrinsic) components combine to produce:
  • Thrombin.
    • Releases ADP from platelets in order to recruit more platelets to the plug.
  • Platelet factors.
    • Catalyse the conversion of soluble fibrinogen to insoluble fibrin.
      • There is progessive infiltration of the initial thrombocyte plug by strands of fibrin, leading to the formation of a composite plug.
      • The fibrin also polymerises, causing coagulation of the blood and clot formation.
• After the clot has formed, the platelets actively contract.
  • The contractile protein is thrombosthenin.
  • Fibrin strands shorten, increasing the strength of the clot and bringing vessel walls closer together.
• The clot is broken down by fibrinolysis.
  • Infiltration by new fibroblasts and capillaries occurs.
    • Granulation tissue is formed within 3 days, and permanent repair, either functional or non-functional, occurs in around 1 week.

Factors Affecting Coagulation

• The blood coagulation process is beneficial, as it is designed to minimise blood loss.
  • However, if the mechanism is prematurely or inadvertently triggered, or fibrin deposition becomes excessive, the blood vessels may be obstructed.
• There is an inhibitor system to guard against the cascade being inappropriately triggered, and a mechanism to remove clots once their purpose is achieved (fibrinolysis).
  • Normally there is a dynamic equilibrium between clotting and fibrinolysis.
    • The vascular system is guarded from the two principal hazards - haemorrhage and excessive clotting.

Natural Inhibitors

• A number of factors act on the clot within a few minutes to give a natural limiting mechanism.
  • Antithrombins
    • Reduce the level of free thrombin.
    • Absorb thrombin from fibrin strands.
    • The most important one is antithrombin III.
  • Factors interfering with fibrin polymerisation.
  • Free thrombin negative feed-back
    • High levels of free thrombin destroys activated Factor VIII.

Enhancement of Coagulation

• Coagulants enhance clotting.
• The most commonly encountered coagulants are toxins such as snake venoms.
  • Some venoms have a thrombin-like activity.
  • Other venoms have a plasma thromboplastin-like effect.

Defective Coagulation

See section in pathology

Fibrinolysis

• The mechanism of fibrinolysis is designed to prevent the danger of over-production or persistence of fibrin.
• Plasminogen, and inactive proenzyme in plasma, can be activated by a variety of factors to give plasmin, an active protease.
  • Plasmin breaks down fibrin.
• In normal haemostasis, small blood clots are usually remodelled or dispersed by fibrinolysis by 1-2 weeks post-damage.
  • Where clots are larger, fibrosis followed by recanalisation may occur.
• Occasionally, there may be enhancement of fibrin destruction through this system, e.g.
  • In severe bacterial infections, for example haemolytic streptococci.
  • Following violent stress or injury with severe pain.
    • A general hyperfibrinolytic state is produced after widespread or severe clotting where all the circulating fibrinogen is used up.
  • On inactivation of endogenous plasminogen inhibitors, for example salicylates.
  • Snake venoms.
    • Venoms of some snakes (Russell's viper, Malayan Pit viper) produce a haemorrhagic shock syndrome as a result of the defibrination action of the venom.

Other Systems Involved in Haemostasis

Activation of the blood coagulation cascade often activates, or is accompanied by the activation of other systems. This appears to be largely the result of activating Factor XII (the Hageman factor) - i.e. the initiation of plasma thromboplastin.

Kinin system

Usually this system is associated with inflammatory reactions.

• Inactive kininogen (a 2-globulin fraction of plasma) is activated by plasmin and kallikreins.
• Increases vascular permeability
• Increases leucocyte migration
• May give the pain sensation

The Complement System

The complement system is another cascade system where inactive precursors in plasma are triggered by:

• Bacterial enzymes
• Antigen-antibody complexes
• Thrombin

Pathology

• Defective coagulation
• Haemorrhagic diseases