Chapter V

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THE  RECANALIZATION  OF  A  VENOUS  THROMBUS

The object of all forms of sclerotherapy should be the production of a permanent fibrous occlusion of a vein at a point which will control abnormal retrograde pressure and flow patterns. Such an occlusion develops over a period of time as a result of organization of a thrombus deliberately produced at the selected site. Three of the major pitfalls of this procedure are the production of uncontrolled thrombophlebitis and subsequent damage to normal valves; the formation of an occluding thrombus at a site which does not control the abnormal filling of the superficial system or the eventual recanalization of the thrombus which will result in the recurrence of symptoms.

In the introduction to this monograph it has been indicated that a form of sclerotherapy as successful as the best surgery has been developed. This has become possible because these three major pitfalls can be avoided. The method of diagnosing and occluding the appropriate segment of vein is described in Chapter VI. This chapter is concerned with a description of the processes of thrombus organization, and the way in which recanalization can be prevented.

Hojensgärd & Stürup (1952) concluded from their investigations of intravenous pressures in the leg that occlusion of incompetent perforating veins would restore the efficiency of the particular muscle pump involved. If this occlusion is to be effected by sclerotherapy, then thrombotic blockade must be able to withstand the pulsatile pressures of the order described in Chapter II.

John Hunter (1793) is credited with the first accurate description of thrombophlebitis. Virchow extended this to a description of the sequence of events leading to thrombosis, introducing the term phlebothrombosis. There is much confusion over the terms phlebothrombosis and thrombophlebitis. McLachlin & Paterson (1951) investigated the relationship of venous thrombosis and pulmonary embolism. They concluded that the separation of thrombosis into two separate entities on the grounds of different embolic potential was unwarranted. Thorbjarnarson (1961) concluded from his work that phlebothrombosis occurs as an extension of an area of thrombophlebitis. We believe that the distinction between phlebothrombosis and thrombophlebitis is academic, and of little clinical significance.

Since this chapter is concerned only with the results of thrombosis, a description of the clotting mechanisms will not be included.

The fate of a thrombus depends on several factors mentioned later in this section. It may be rapidly lysed and disappear completely. If the thrombus persists it becomes organized. It is, of course, possible for only part of the thrombus to become organized, the remainder having been lysed. An organized thrombus may become recanalized.

This is a process by which a thrombus is rapidly broken down. It is probably brought about by the fibrinolytic action of the blood. It has been shown in experimental animals the intravenous administration of plasmin or plasminogen activator will speed up the resorption of fresh coagulation thrombi (Sheery et al., 1959). Plasminogen is absorbed on to fibrin during clot formation and so subsequent lysis may be a local phenomenon occurring within the thrombus. It is also probable that the vein wall liberates highly lytic substances. Lysis may be further assisted by the ischaemia within the thrombus causing a release of tissue activator (Florey, 1962). Enzymes, released by degenerating leukocytes trapped within the thrombus, may also have a lytic effect.

The fate of a thrombus which does not undergo lysis depends upon the following factors:

1. The ratio of the diameter of the thrombus to the thickness of the surrounding vein wall. This ratio may vary at different regions of the same specimen.

2. The degree of cellular activity in the vein wall, and the rapidity with which it develops.

3. The degree of cellular and capillary invasion of the thrombus.

4. The intravenous pressure, and the degree of fluctuation of pressure in the vein above and below the area of phlebitis.

These factors are important because they determine the rate and completeness of organization, and the degree to which recanalization takes place.

This is a process by which the thrombus is invaded by cellular elements - leukocytes, fibroblasts and capillaries - from the vein wall. The thrombus becomes firmly attached to the vein wall where this occurs. Microscopic examination of sections of veins involved in thrombophlebitis shows that the vasa vasorum in the intima and media are considerably dilated  and that new capillaries derived from these vessels cross the vein wall, traverse the internal elastic lamina and invade the thrombus.

This cellular activity appears to be associated with trauma to the intima of the vein. The greater the area of intimal damage, the greater will be the area over which cellular activity develops. Cellular activity is more pronounced in a contracted thick wall than in one which is stretched and thin. This may be because the nutrition of a dilated vein is impaired.

The first essential step in the development of recanalization is the development of slit-like sinuses between the thrombus and the vein wall. These sinuses are infrequent and remain small in areas where invasion of the thrombus from the vein wall is taking place. If the thrombus is subjected to pressures from above, below and via the perforating veins, the sinuses enlarge and coalesce, and recanalization occurs.

Fibrosis ultimately occurs in those areas of the thrombus which have undergone organization. Vascularization promotes the development of collagen. As the collagen matures the capillary network regresses. The vein wall itself does not become completely fibrosed, but there is an increase in collagen separating the muscle fibres and this is in continuity with the collagen in the thrombus. Deposits of haemosiderin may be found in part of the vein wall, in the fibrosed thrombus and in the perivenous tissue.

In order to illustrate the sequelae of thrombophlebitis more clearly two extreme examples will now be described (Fegan & FitzGerald, 1965). (a) Phlebitis in which a large diameter thrombus develops with a thin distended vein wall encircling it. (b) Phlebitis in which a relatively small diameter thrombus develops within a contracted vein with a thick encircling vein wall, as a result of compression of the vein.

(a) This is the condition usually described as superficial thrombophlebitis. The lumen of the vein is fully occupied by clotted blood. The wall of the vein is stretched and painful. The wall-thrombus ratio is such that the diameter of the thrombus may be more than twenty times the thickness of the vein wall.

During the first 48 hours cellular activity occurs over most of the intima. One or two areas soon predominate, and invading cells stream into the thrombus from these points. The invasion is not very aggressive and takes place from a relatively small area of the intima. Because of the large diameter of the thrombus, the central part undergoes degeneration before the invading cellular elements can reach it. Recanalization commences with the appearance of peripheral sinuses between the thrombus and the vein wall. The thrombus is subjected to high pulsatile pressures and the slit-like sinuses gradually dilate and coalesce. The thrombus itself undergoes fibrosis and may ultimately be surrounded by several channels or it may be displaced to one side and included in the vein wall. The end result of this type of thrombosis is therefore recanalization. In addition, if the thrombosis takes place in the area in which there are normal valves these will be destroyed.

(b) Phlebitis in which a relatively small diameter thrombus develops within a contracted vein with a thick encircling vein wall. This type of lesion is produced when the technique of compression sclerotherapy is used successfully. The empty vein technique ensures the presence of only a minimal amount of blood in the vein. Isolation of the segment of vein prevents extension of the thrombosis beyond the area selected and as the sclerosant is undiluted by blood most of the intima within this area is severely damaged. The vein wall is thick and contracted and consequently profuse cellular activity takes place over a relatively wide area of intima.  Compression of the vein and ambulation of the patient protect the thrombus from pulsate pressures. The small diameter thrombus is therefore rapidly and widely invaded and there is little opportunity for recanalization to occur. The thrombus subsequently undergoes fibrosis and remains firmly attached around most of its periphery to the surrounding vein wall. This process is described in detail below.

Thirty seconds after injection. It is clear that the technique of emptying the vein and applying finger compression above and below the segment selected for injection does succeed in emptying the vein entirely. At 30 seconds after injection a varying amount of blood is left in the lumen. The following changes are observed. Over most of the circumference of the vessel the endothelial lining cells have either disappeared completely, been cast into the lumen or remain in position. In each case they are altered as follows. The cells have rounded up and are swollen; the nuclei are enlarged and the chromatin is coarsely granular or irregularly clumped, suggesting the early stages of karyorrhexis. Where a number of cells remain attached side by side to form a row, a jagged uneven 'saw-tooth' appearance is seen instead of the usual smooth lining common to endothelial surfaces. This is caused by the apparent disintegration of the cement lines between cells, which appear partly or completely detached one from the other, while remaining individually attached, at least for the present, at the base. All are swollen, and some project further into the lumen than others, while some are unusually tall and stand up in a peg-like fashion with the nucleus at the luminal border. The small quantity of blood remaining in the lumen (when compression is good) shows agglutinated masses of red blood cells alternating with paler pink areas of a fine fibrin network. Fibrin is clinging to the denuded endothelial surfaces and also to areas of surviving but altered endothelium. Some masses of agglutinated red cells lying in close proximity to these surfaces show the presence of large numbers of readily distinguishable platelets. It is not unreasonable to postulate a sequence of events in which, following chemical damage to the endothelium, platelets are attracted to these surfaces and adhere both to the surface and to each other, thus initiating the clotting process that involves any blood lying in the lumen of the vein segment.

One minute after injection. The number of endothelial cells still in position is further reduced: otherwise there is no change.

Five minutes. The appearance is similar to that already noted.

Twelve hours. The blood clot has the appearance of being formed in a standing column of blood and is a fibrin/red-cell complex. There is no evidence of 'layering' of the clot, such as is seen in naturally occurring deep vein thrombosis. The endothelium has disappeared at most areas about the circumference of the vessel and the resulting denuded areas are covered by a thin layer of fibrin.

Twenty-four hours. The blood clot shows numerous fissures irregularly distributed but found mainly towards the periphery. The endothelium has mostly disappeared about the entire circumference. The amount of surviving endothelium seen varies somewhat from vein to vein.

Thirty-six hours. This stage shows the commencement of organization of the clot. At a number of points, usually not more than two, and generally located in the same quadrant of the circumference, distinct finger-like processes consisting of proliferating fibroblasts can be seen advancing into the clot. The time at which organization begins seems to vary quite substantially. In some biopsies examined no attempt at organization was observed, even after a lapse of five days. No cause, clinical nor morphological, could be ascertained for this.

Six days. Organization continues but is still in the early stages. Some fibroblasts, however, have by now crossed the clot and reached the opposite side. Organization is still very limited in extent, being present at only one or two points of the circumference and not extending very far into the clot.

Eight days. In most cases organization shows little advance over that seen at six days. In general organization is quite slow.

Twelve days. The process now appears to have accelerated, and by the twelfth day the histological picture is as follows: only a small quantity of blood, apparently little altered, occupies the centre of the lumen of the vein. Outside this there is a thick layer of fibre extending about the entire circumference and organizing fibroblasts are moving in wide wedges from a number of points. Those coming from the same quadrant may join laterally with one another.

Fourteen days. Fibroblasts in proliferating wedges, spreading from opposite or near opposite points of the circumference, are by now meeting in the centre of the vessel. Any blood still remaining in the lumen is by now usually pushed to one side. A point to note is that now for the first time active new capillary formation is proceeding. Thus we can take it that up to two weeks elapse before the vascularization stage of organization begins in these cases. In all the cases observed up to this point compression of the vein had been good. If compression is playing a part in promoting eventual fibrous obliteration of a segment, then it is clear that it cannot be relaxed at this stage.

Three weeks. Organization is now well advanced and capillary formation is marked. The capillaries have a distinct lumen containing many red blood cells. The organizing clot shows all the classical features of a granulation tissue. Inflammatory cells are scanty, a small number of polymorphs, rather more lymphocytes, and a few plasma cells being present. Even at this stage, however, the centre of the original thrombus may still show apparently unaffected red blood cells. This may in fact represent a trickle of blood passing through the segment rather than surviving blood cells.

Four weeks. Biopsy at this stage was carried out on a number of cases where it was known that compression had been poorly maintained. The veins in these cases showed the presence of a much greater volume of blood clot than in the others. Early organization was evident at a few points on the periphery but was generally at an early stage. By way of contrast, vessels in which good compression had been maintained without interruption showed a picture of very good organization with bands of proliferating fibroblasts crossing the lumen in its entire width and advanced capillary formation.

Seven weeks. By this stage it is clear that the desired end-result is being achieved. The vascular granulation tissue described above is by now replaced by young cellular fibrous tissue, which fills most of the lumen of the vessel. It should be noted that in these vessels, where good compression has been maintained without interruption, the lumen is far smaller than where compression has been poor. The amount of space requiring to be filled by fibrous tissue is thus considerably less and it s not surprising that the majority of these veins show almost total obliteration by young fibrous tissue. At seven weeks most vessels show one or more re-established vascular channels lined by regenerated endothelium, through which blood is obviously flowing. These channels are small, however, and the clinical results obtained in these cases would suggest that they are not significant.

Ten weeks. The fibrous tissue is still a young cellular tissue containing numerous plump fibroblasts: capillaries are still evident but becoming less prominent. Small peripheral sinuses lined by endothelium are present at one or more points about the circumference. It is evident that these have formed at areas where the original blood clot has retracted from the wall of the vein between the areas of fibroblastic proliferation.

Sixteen weeks. Little change is seen from the previous picture: most of the vein is occupied by vascular fibrous tissue. Many veins do not show the peripheral sinuses described above but are filled with fibrous tissue about their entire circumference: however, these generally show a number of central fissures or sinuses lined by endothelium and presumably in continuity with the endothelial surfaces proximal and distal to the almost totally occluded segment.

Twenty weeks. This picture show little or no change from that seen at sixteen weeks.

Six to seven months. The appearance here is of a vessel containing mostly fibrous tissue with a number of fissure-like endothelium-lined channels, present either in the centre of the vessel or towards the periphery, where they are the end-result of initial clot reaction and subsequent endothelialization. It is noteworthy that the cases where the history of compression is good, tend to be those where the vascular channels remaining are located more centrally in the vessel. In other words successful compression leads to organization all round the circumference of the vessel. It is easy to accept that this will give a better clinical result than where organization is limited to portions of the circumference. The fibrous tissue at this stage is still quite cellular but some collagen fibre formation is evident.

One year. At this stage the fibrous tissue shows evidence of maturity, cellularity is diminished and the fibroblasts present are elongated cells in contrast to the plump cells seen previously; collagen formation is proceeding.

Five years. Five years after injection-compression therapy the vein in most cases shows firm fibrosis throughout its entire circumference except for a few small irregular fissure-like channels lined by endothelium. Some vessels show hyaline change of the collagenous tissue, but in general the picture is that of well organized fibrous tissue with gradually increasing collagen formation. The organized clot has by now become incorporated into the vein wall, forming an integral part of it.

Histological studies were carried out on varicose veins treated by compression sclerotherapy. The material consisted of biopsies performed on veins at intervals from 30 seconds to 5 years after injection. The chief purpose of the study was to observe the Histological changes in varicose veins and to determine the changes occurring in the vein subsequent to therapy and to correlate such changes with the clinical results obtained.

These findings can be summarized as follows:

(1) Injection sclerotherapy produces a fibrous occlusion of the selected vein segment which correlates well with the subsequent clinical course of the patient. The application of pressure is an essential part of the treatment and examination of the histological sequence of events in the thrombus indicates clearly that this must be maintained for at least six weeks, preferably eight weeks, to allow that organization to proceed to fibrous occlusion of the lumen.

(2) No marked increased in subendothelial connective tissue occurred in the injected veins, as might have been expected when intraluminal pressure diminished. The application of external pressure may be a factor preventing this. Varicose veins show such variation of change in the vessel wall itself, such as increased fibrosi of the media, muscle hypertrophy and atrophy, etc., that it is not easy to determine from a study of biopsies of injected veins whether changes in the wall are associated with therapy or in fact preceded it. Further study of the vein wall and perivenous tissues is required.

(3) In some biopsies of injected veins, no attempt at clot organization was evident even five days after injection. The cause of this delay did not emerge during this course of this study. In general organization of the clot produced is quite slow: it is clear that up to two weeks elapse before the vascularization stage of organization is produced. It is not surprising that most previous attempts at injection of varicose veins ended in failure, as any clots forming were rapidly recanalized or lysed completely. Compression, maintained without interruption, is essential to promote good organization of the clot. Furthermore, successful compression leads to organization all around the circumference of the vessel and this in turn produces the best and most enduring clinical results.

The sclerosant used in the form of treatment described in this book is sodium tetradecyl sulphate (sodium 1-isobutyl-4-ethyloctyl sulphate). It is the salt of an alkali metal and a long-chain fatty acid, and so has the properties of soap. In its solid state it is a white waxy substance, and is soluble in water, alcohol and ether. A 3% solution in 2% benzyl alcohol is prepared for clinical use.

1. Haemolysis. Varying concentrations of sodium tetradecyl sulphate in normal saline were added to heparinized blood, and fragility curves plotted, with the following results:

Red blood cells were lysed at concentrations of sodium tetradecyl sulphate of 0.125% or greater;

White blood cells were lysed at concentrations of sodium tetradecyl sulphate of 0.1% or greater;

Disruption of the membranes occurred at a concentration of 0.05%.

2. De-naturation of serum proteis. Addition of sodium tetradecyl sulphate to serum caused turbidity, and subsequent electrophoresis of the serum showed abnormal migration of the protein fractions. The reaction, which is very rapid, appears to be a combination of sodium tetradecyl sulphate and plasma protein. As a result there is complete inhibition of the detergent properties of the sclerosant.

In a study of ten patients, blood and urine samples were taken just before, and 45 minutes after, intravenous injections of sodium tetradecyl sulphate. Each patient received 1.5-3 ml. sodium tetradecyl sulphate as part of the treatment for varicose veins.

The bleeding time was measured, and the following investigations were performed on the blood samples:

Clotting time.

Prothrombin time.

Thromboplastin generation test.

Platelet count.

Serum direct van den Berg reaction.

Serum bilirubin estimation.

Serum glutamic oxalacetic transaminase (S.G.O.T.) estimation.

Serum glutamic pyruvic transminase (S.G.P.T.) estimation.

Lactic dehydrogenase L.DH.) estimation.

Spectroscopic examination for methaemoglobin and methalbumin was also performed.

The samples of urine were investigated for abnormal deposit, albumin and urobilinogen.

Apart from a slight increase in platelets in seven patients, the injection of sodium tetradecyl sulphate produced no changes in the results of these tests.

A solution of 0.05% sodium tetradecyl sulphate in normal saline was used to reconstitute dried fibrinogen, thromboplastin or thrombin. Thromboplastin generation tests were then performed. Sodium tetradecyl sulphate prevented the formation of a fibrous clot in each case, no matter to which constituent it had been added.

Since the solution of sodium tetradecyl sulphate used clinically contain 2% benzyl alcohol, it was important to know which was the active agent in producing local endosclerosis. A small series of intravenous injections of 2% benzyl alcohol solution, followed by compression and ambulation as in the technique described

in this book, failed to produce any clinical evidence of a sclerotic action at the site of injection.

Sodium tetradecyl sulphate:

(i) Combines rapidly with, and de-natures, protein.

(ii) Causes haemolysis, in vitro.

(iii) Inhibits blood coagulation.

These results suggest that the thrombus appearing at the injection site is not due to the action of sodium tetradecyl sulphate on blood. What probably happens is that the sodium tetradecyl sulphate combines with the protein of the endothelial lining, damaging the intima cells. Normal blood subsequently clots on the damaged intima. This explanation is supported by the clinical impression that an injection is more likely to be successful if the vein is empty of blood at the time of injection, since any blood present would tend to inactivate the sodium tetradecyl sulphate. It would also explain why involvement of the deep veins is so rare, since any sclerosant spilling into the deep system would be inactivated by the contained blood.

Fegan, w. g. & FitaGerald, D. E. (1965), Angiology, 16, 433.

Florey, H. (1962), Lectures on General Pathology. London: Lloyd-Luke.

Hojensgärd, i. c. & Stürup, H. (1952), Acta Physiol. Scand. 27, 49.

Hunter, J. (1793), Trans. Soc. Improv. Med. Chir. Knowledge, 1, 18.

McLachlin, J. & Paterson, J. C. (1951), Surg. Gynec. Obstet. 93, 1.

Sheery, S., Fletcher, A. P. & Alkjaersig, N. (1959), Physiol. Rev. 39, 343.

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