Role of platelets

The mechanism for closing small gaps in vessel walls brought about by trauma involves the platelets. Platelets are smaller than red blood cells, rather angular in appearance, and have no nucleus. They are derived from large, multinucleated cells in the bone marrow called megakaryocytes. Although platelets have no nucleus, they are highly structured internally and contain a variety of organelles, some of which are specific to them. As well as mitochondria and the various cytoskeletal elements found in most cells, platelets also contain alpha granules and dense granules. The alpha granules contain several substances involved in the process of platelet adhesion to damaged vessel walls (fibrinogen, fibronectin, platelet growth factor and an antiheparin as well as less well defined substances), and the dense granules contain substances such as adenosine diphosphate (ADP) that cause platelets to aggregate.

Platelets are activated and the contents of their granules are released when the platelets come into contact with collagen, as may be found in damaged vessel walls, or with polymerising fibrin. The platelets change shape and extend pseudopodia; their granules release their contents and the platelets form a mass that covers the vessel wall defect until the endothelial cells have regenerated and repaired the vessel permanently. However, if this process is activated within an intact vessel, it results in a thrombus.

Thrombus formation

There are three predisposing situations that may result in thrombus formation. These were described originally by Virchow and are known as Virchow’s triad. The three factors are:

Not all three are needed for thrombosis to occur, but any one of them may result in thrombosis in a particular case.

If we consider the sequence of events involved in the formation of thrombus on the basis of an atheromatous plaque (Ch. 13), this will serve as a very good example of the factors listed by Virchow.

Arterial thrombosis

In its earliest phase the atheromatous plaque may consist of a slightly raised fatty streak on the intimal surface of any artery, such as the aorta (Fig. 8.2). With time, the plaque enlarges and becomes sufficiently raised to protrude into the lumen and cause a degree of turbulence in the blood flow. This turbulence eventually causes loss of intimal cells, and the denuded plaque surface is presented to the blood cells, including the platelets. The turbulence itself will predispose to fibrin deposition and to platelet clumping; the bare luminal surface of the vessel will have collagen exposed and platelets will settle on this surface. Thus we have two of the factors described in Virchow’s triad operating in an atheromatous plaque. If this plaque exists in the aorta of a smoker or someone with a high cholesterol level and a high level of low density lipoprotein—common risk factors for atheroma—then the third of Virchow’s factors is introduced, since these changes in blood constituents are well known to predispose to thrombus formation. This process, once begun, may be self-perpetuating, as it has been shown that platelet-derived growth factor, which is contained in the alpha granules, causes proliferation of arterial smooth muscle cells, which are an important constituent of the atheromatous plaque.

Fig. 8.2 Thrombosis. Thrombosis is exemplified by its occurrence on an atheromatous plaque, a particularly common event. Important steps in this sequence include: loss of endothelial cells and exposure of the underlying collagen; platelet adherence and activation; partial or complete arterial occlusion by the multilayered thrombus.

Thus, the first layer of the thrombus is a platelet layer. Formation of this layer in turn causes the precipitation of a fibrin meshwork, in which red cells are trapped, and a layer of this meshwork is developed on top of the platelet layer. The alternating bands of white platelets and red blood cells in thrombi were first described by Zahn and are called the lines of Zahn. This complex structure now protrudes even further into the lumen, causing more turbulence and forming the basis for further platelet deposition. The normal flow of blood within the vessels is laminar; the cells move in the swifter central lane and the plasma runs along the walls. Therefore, the greatest degree of turbulence occurs at the downstream side of arterial thrombi, as the blood passes over the thrombus, and on the upstream side of venous thrombi for the same reason. Thrombi will therefore grow in the direction of blood flow; this process is known as propagation.

Venous thrombosis

In veins, however, the blood pressure is lower than in arteries and atheroma does not occur; so what initiates venous thrombus formation? Most venous thrombi seem to begin at valves. Valves naturally produce a degree of turbulence because they protrude into the vessel lumen and they may be damaged by trauma, stasis and occlusion. However, thrombi can also form in veins of young, active individuals with no predisposing factors that can be identified. Once they begin, the thrombi grow by successive deposition in the manner described previously and this process may produce a highly patterned, coralline growth (Fig. 8.3). Since normal flow within the vessels is laminar, most of the blood cells are kept away from diseased walls or from damaged vein valves. However, if the blood pressure is allowed to fall during surgery or following a myocardial infarction, then flow is slower through the vessels and thrombosis becomes a likely event. Similarly, the venous return from the legs is very reliant upon calf muscle contraction and relaxation, which massages the veins and, because of the valves, tends to return the blood heartwards. So, if elderly subjects are immobilised for any reason, they are at great risk from the formation of deep leg vein thromboses. The frequency with which deep vein thrombosis is found to occur following surgery is directly related to the enthusiasm with which it is sought (e.g. by the pathologist at postmortem examination) and the sensitivity of the methods used to demonstrate it. Postmortem studies on unselected medical and surgical patients show significant deep vein thrombosis in 34% of the former and 60% of the latter, regardless of the cause of death.

Fig. 8.3 Venous thrombus. Femoral vein opened at autopsy to reveal a thrombus. Histological section showing the characteristic laminated or coralline structure of a thrombus.

When a vein becomes thrombosed it evokes an inflam-matory reaction, a phenomenon known as thrombophlebitis; the opposite process also occurs—a vein that is inflamed will often thrombose and this is known as phlebothrombosis. The end effect is the same, a thrombosed and inflamed vein, but clearly if there is a predisposing cause then the cause needs to be recognised and treated.

Clinical effects

The effects of thrombosis are apparent only if the thrombus is sufficiently large to affect the flow of blood significantly. Arterial thrombosis results in loss of pulses distal to the thrombus and all the signs of impaired blood supply: the area becomes cold, pale and painful, and eventually the tissue dies and gangrene results. In venous thromboses, 95% of which occur in leg veins, the area becomes tender, swollen and reddened, as blood is still carried to the site by the arteries but cannot be drained away by the veins. The tenderness is due to developing ischaemia in the vein wall initially, but there is also general ischaemic pain as the circulation worsens. The more specific clinical effects of thrombosis depend on the tissue that is affected.

Myocardial infarction is often associated with thrombus formation in coronary arteries and is responsible for numerous sudden deaths (Ch. 13).

Strokes may be due to the formation of thrombus in a cerebral vessel, although they may be also the result of haemorrhage or embolism (Ch. 26).

Thrombophlebitis migrans occurs in previously healthy veins in any area of the body. The thromboses appear and disappear, changing site all the time, and the condition may persist for months or even years. It is extremely ominous and usually indicates the presence of visceral cancer, commonly of the pancreas. The mechanism remains obscure.

Fate of thrombi

Various fates await the newly formed thrombus (Fig. 8.4). In the best scenario it may resolve; the various degradative processes available to the body may dissolve it and clear it away completely. It is not known what proportion of thrombi follow this course, but the total number is likely to be large. A second possibility is that the thrombus may become organised into a scar by the invasion of macrophages, which clear away the thrombus, and fibroblasts, which replace it with collagen, occasionally leaving a mural nodule or web that narrows the vessel lumen. A third possibility is that the intimal cells of the vessel in which the thrombus lies may proliferate, and small sprouts of capillaries may grow into the thrombus and later fuse to form larger vessels. In this way the original occlusion may become recanalisedand the vessel patent again. Another common result is that the thrombus affects some vital centre and causes death before either the body or the clinicians can make an effective response; this event is very common. Finally, fragments of the thrombus may break off into the circulation, a process known as embolism.

Fig. 8.4 Consequences of thrombosis. Lysis of the thrombus and complete restitution of normal structure usually can occur only when the thrombus is relatively small and is dependent upon fibrinolytic activity (e.g. plasmin). The thrombus may be replaced by scar tissue which contracts and obliterates the lumen; the blood bypasses the occluded vessel through collateral channels. Recanalisation occurs by the ingrowth of new vessels which eventually join up to restore blood flow, at least partially. Embolism caused by fragmentation of the thrombus and resulting in infarction at a distant site.

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