3 Thrombosis, embolism and infarction
Thrombosis (the formation of thrombus) is a well-ordered series of events involving the blood platelets and the clotting cascade. Platelets adhere to areas of endothelial damage and if the stimulus is strong enough will go on to platelet activation with shape change and release of a number of substances which enhance the process of thrombosis at the same time as aggregating together.
Thrombus may form in the heart, arteries, veins, or capillaries. The first stage involves platelets sticking to the damaged endothelium, and then a dense layer of fibrin and leucocytes adhere to the surface of the platelet. Blood clot (fibrin and red cells) develops on this layer of leucocytes and platelets, and then a secondary layer of platelets collects on the surface of the blood clot. The gradual extension of thrombosis leads to a propagated or consecutive thrombus. Organization then begins with adherence to the wall of the vessel as mural thrombus. A second stage develops with a further batch of platelets laid down over the initial aggregate and then a further layer of blood clot. In this way alternate layers of platelets and blood clot form a laminar arrangement. This causes a differential contraction of platelets and fibrin and gives a rippled appearance reminiscent of rippling of the sand on a beach. This has also been described as having a coralline appearance. The ridges on the surface of the thrombi are known as the lines of Zahn after the pathologist who first described them. Further development depends on whether the endothelium is healthy and on the rate of blood flow. Thus in an artery with thrombosis secondary to atherosclerosis, thrombosis may extend to the next branch after the endothelium becomes healthy again, assuming that there are collaterals with a reasonable blood flow. In veins, where the process tends to start in the pocket just above the valve, a number of things may happen: the process may end and the thrombus become covered with new endothelial cells; alternatively it may continue until a segment of vein is occluded. There is then a stagnant column of blood until the next tributary, and this stagnant column tends to coagulate, forming propagated thrombus. If the blood flow is reduced, the propagation may continue extensively. It may adhere to the sidewall of the veins in places or it may be largely free, simply attached to the site of origin. This latter type of thrombus can become dislodged relatively easily, forming a pulmonary embolism.
Not all these factors need to be present at the same time; some will be dominant in one clinical situation, whilst others will predominate in another. For example, venous thrombosis is commonly due to alterations in blood flow, while arterial thrombosis is more commonly due to vessel wall changes of atheroma, which does not occur in veins.
Atheroma of the arterial wall presents a good example of how vessel damage can lead to thrombosis and it is also a very common and important clinical situation. Atheroma is discussed in greater detail elsewhere (Chapter 9), but some points will be discussed here because they are relevant to the process of thrombosis.
Vascular endothelial cells have intrinsic fibrinolytic activity in which plasminogen, an inactive plasma protein synthesised in the liver, is converted to the active fibrinolytic enzyme plasmin. Whether thrombosis occurs or proceeds depends on the balance between the processes of thrombosis and fibrinolysis.
As fatty streaks progress they present more obstruction to normal flow, and endothelial cells may be lost. Fibrin and platelets may become deposited on the surface and protrude into the lumen, causing more turbulence, and a complicated atheromatous plaque develops. In addition to the risk of thrombosis on a complicated plaque there is also a risk from haemorrhage within it, and when it occurs it causes the plaque to protrude even further into the lumen.
Mechanical damage and vascular inflammation are the commonest causes of damage to venous walls, with subsequent thrombus formation. Inflammation of vessel walls, either arteries or veins, can cause thrombus formation, but the converse is also true. Thrombus initiates an inflammatory response, and in any given instance it can be difficult to say whether the process represents phlebothrombosis (thrombus due to inflammation) or thrombophlebitis (inflammation due to thrombosis). However, the commonest cause of venous thrombosis is alteration to blood flow.
Alterations in blood flow are critical in the venous system since pressure is much lower and the normal rate of flow is much slower than in the arteries. As pressure is so much lower in the venous system and the vein walls are so much thinner than the walls of arteries of the same calibre, use is made of the pumping action of the surrounding muscle groups to aid return of blood to the heart. Consequently any decrease in muscle activity deprives venous blood of this added action and relative stasis occurs. Thus venous thrombosis becomes more likely in the veins of immobile subjects. The elderly are particularly at risk since they often have a degree of venous impairment or relative cardiac failure. One of the commonest deficiencies of the elderly venous system is impairment of the function of venous valves, and thrombosis is often seen to begin at the site of valves where, even under normal circumstances, some degree of turbulence is to be expected. For this reason it is particularly important to promote muscle contraction in the legs of the elderly in the postsurgical period. Another cause of relative immobility is long aeroplane journeys where immobility is combined with some degree of dehydration often aggravated by alcohol consumption.
The factor V Leiden mutation affects approximately 5% of the population and approximately 20% of those with thrombosis. Hyperhomocysteinaemia affects approximately 10% of the population and also about 20% of those with thrombosis. The others are less common.
The situation is complicated in that many patients with abnormal tests for thrombophilia never have any clinical problem and many with thrombosis have normal blood tests. The tests are expensive and patients with venous thromboembolism require anticoagulants and if this is recurrent they will require them long term. The clinical picture is, therefore, more important than the results of blood tests although these may be helpful in the long-term management of patients.
It is not clear what factors determine which of these fates a thrombus will suffer, although size may be a factor. Small thrombi are being formed and resolved constantly, and some degree of disturbance of blood flow is probably required to tip the scales and cause a thrombus to organise. Certainly a larger thrombus will cause turbulence and/or inflammation and make it likely that further thrombosis will occur on its surface, causing the thrombus to lengthen, a process known as propagation. Resolution means that the clot is completely dissolved by processes of thrombolysis. In the clinical setting this is achieved by the use of thrombolytic enzymes, e.g. plasminogen activator or urokinase, but these have to be delivered onto the clot more or less directly, otherwise they diffuse through the blood stream and may become so dilute that they are ineffectual. Current therapies involve substances that act directly or indirectly on plasminogen activators. Compounds such as aspirin and heparin help prevent further thrombus formation but do not help in lysis of an established thrombus. If the thrombus is not completely removed then the residue undergoes organisation.
Organisation is the process by which the thrombus is converted to a scar and eventually covered by endothelial cells. Intravascular scarring is essentially similar to those processes involved in the production of scars from thrombi in wound healing generally (Chapter 1). The main difference between intravascular granulation tissue and a thrombus is that with a thrombus the vascular phase of granulation tissue is prolonged and, if the thrombus does not resolve completely, the capillaries fuse together, resulting in one or several new vessels passing through the scar. This process is called recanalisation and in some cases may result in one or more functional vascular channels.
Thromboembolism is embolisation of a thrombus and should be distinguished from emboli of other materials since the clinical setting is different, as is the treatment. The effects of thromboemboli depend upon where the embolus settles, which in turn depends upon where the thrombus forms and what size the embolus is. Emboli arising from thrombi in veins will all go to the lungs (unless there is an abnormal connection between right and left heart). They will generally not arrest early in the circulation since the veins increase in diameter with the direction of blood flow as they approach the lungs, and only then do they start to turn into progressively smaller vessels of the lung bed. Arterial emboli will arrest in the artery with the smallest calibre which they can enter, and this will always be more peripheral than their origin because arterial size decreases in the direction of blood flow.
An embolus is an abnormal mass of undissolved material which passes in the blood stream from one part of the circulation to another, impacting in vessels too small to allow it to pass. The actual material which passes along the blood stream is termed an embolus. When it impacts and obstructs the flow of blood, this is known as an embolism. Thus when a thrombus in the leg breaks off, this is an embolus, and when it impacts in the pulmonary artery it is a pulmonary embolism. Emboli may consist of: