Stroke and the pharmaceutical industry

The biology of stroke

In order to appreciate the relationship between stroke and the medicines in use or under development, some aspects of blood clotting and arterial disease need to be described.

The blood clotting process: Blood has a natural tendency to clot and does so rapidly if removed from the body. This is normally prevented by natural anti-coagulants, the most powerful of which is heparin, stored mostly in the liver and lungs. However, there are times when clotting is essential, for example to stem the loss of blood in cases of tissue injury. There are three phases of clotting following injury:

• the vasoconstriction phase
• the platelet phase (divided into adhesion, activation and aggregation stages)
• the coagulation phase

The vasoconstriction phase refers to blood vessels clamping shut following damage by contraction of their muscle walls. It is brought about by chemicals released at the site of injury and by nerve impulses arising from the pain response. This is followed by the platelet phase in which platelets clump together and form a platelet plug. If this fails to control blood loss, then the coagulation phase is triggered in which a complex cascade of reactions leads to the formation of an insoluble blood clot. If clotting happens abnormally inside a blood vessel, then the resulting thrombus can restrict or block blood flow, resulting in a heart attack, a stroke or another problem.

The platelet phase is central to thrombus formation inside blood vessels. Important triggers of platelet aggregation are found in the wall of blood vessels, especially a substance called collagen, a main constituent of many body tissues. Normally, collagen is separated from the platelets by the inner lining of cells, rather like the teflon coating in a frying pan, which prevents platelet triggering.

Damage to the cell lining by plaque often exposes collagen, to which platelets stick, using specialised receptors (the adhesion stage). This activates the platelets and they change shape, putting out extensions which cover the exposed or damaged collagen areas. In the process, they come into close contact with each other and chemicals called adenosine diphosphate (ADP) and thromboxane A2 (TXA2) are released (the activation stage). These substances attract other platelets and cause them to bind fibrin from the blood to their so-called GPIIb/IIIa receptors, to stick together and add to the growing blood clot (the aggregation stage).

The coagulation phase is very complex, but ends with the conversion of a protein dissolved in the blood called fibrinogen into insoluble hair-like strands of fibrin. This is brought about by the enzyme thrombin. The fibrin entangles platelets and red blood cells into a solid mass.

How blood clots are naturally dispersed: It is believed that hundreds of small clots form within the blood vessels of healthy people every day. These are quickly removed to restore normal blood flow through a series of chemical events that ‘digest’ the unwanted clots. A key substance in this process is called plasminogen which becomes trapped within the platelet-fibrin tangles during clot formation. Plasminogen can be activated within the clot by a natural tissue plasminogen activator (t-PA) to form plasmin, which is able to digest the fibrin threads and disperse the clot.

top of page

Plaque formation: The blood vessels of young healthy people have elastic walls and a smooth inner surface. However, quite early in life, damage to the cell lining of the blood vessels and the layers below it attract fatty deposits (called fatty streaks). Adverse lifestyle factors such as cigarette smoking and high animal fat diet, clinical factors such as diabetes and high blood pressure, or high cholesterol levels as a result of genetic or other factors, all add to the damage. The smooth muscles begin to divide, calcium deposits start to form, leading to loss of elasticity and the blood vessel begins to bulge on the inside. Further deposition of calcium, fat, cholesterol, fibrin and cellular debris narrow the width of the blood vessel, which may ulcerate. This creates turbulence in the blood flow, damaging platelets, which start to build up as a blood clot or thrombus. This process can go on until the vessel is largely blocked, causing conditions such as angina, heart failure and peripheral vascular disease in the limbs. Plaque is especially hazardous, because fragments which break off circulate in the blood and lodge in the brain, where they can cause a stroke.

top of page

Blood clots and brain cell death: Blood clots do not in themselves cause the death of brain cells, but the damage is a consequence of the interruption that the clot causes in the supply of oxygen and glucose (for energy). The speed at which cells die is variable – those close to the site of a stroke will often die quickly but further away, in an area called the penumbra, cell function declines over several hours.

The chemical events leading to the death of brain cells have been the subject of intensive research and can be broadly divided into five steps or phases.

• In Step 1, the blood clot or bleeding causes a fall in oxygen and glucose supply. If blood flow is less than 20 millilitres per 100 grammes of brain tissue per minute, cells begin to suffer from energy shortage. At below 10 millilitres per 100 grammes per minute, oxygen and energy depletion begin to have a serious impact.
• At this stage, Step 2 is triggered. Cells generate acids such as lactic acid, which in turn leads to cellular swelling and a disturbance in the movement of ions such as sodium and potassium. The cells then depolarise (i.e. lose the electrical charge on their membranes).
• Step 3 is where, as a result of depolarisation, calcium floods in and causes the release of excessive amounts of the neurotransmitter, glutamate, which binds to glutamate receptors on neighbouring cells.
• This excess glutamate leads to Step 4 – over-excitation in the nerve cells and further rounds of ion movement and functional loss.
• Finally, in Step 5, internal structures begin to fail, fatty acids are converted into inflammatory molecules, and highly reactive free radicals are formed – all of which culminate in the death of the nerve cell. In effect, the injured cells self-destruct.

This entire process is complete in many patients in just a few hours, after which the cells are irreversibly damaged. This short ‘window of opportunity’ is vital, because it provides doctors with a brief chance to save cells in the penumbra, either by restoring blood flow or by giving ‘neuroprotective’ medicines designed to interrupt the process.

top of page

< Previous Page | Contents | Next Page >