HOME       SELECTED ARTICLES  . . .     FEEDBACK     SEARCH

Angiology, Vol. 16, No. 8, August 1965

W. G. FEGAN, M.Ch., F.R.C.S.I.

D. E. FITZGERALD, M.Sc., L.R.C.P., S.I.

Venous thrombosis and its complications have been widely discussed for over a century. So much has been written about it that the casual observer might feel there is little to be added to the volume of literature on this subject. However, a large quantity of the literature is confined to clinical appraisal of the condition, and many of the histologic descriptions are based on conclusions reached from investigations performed on arterial thrombosis.^{1, 2, 19} Intimal thickenings in veins and their relationship to neighbouring arteries were described by Short in 1954,¹⁸ and similar investigations were carried out on rats by Mehrotra in 1953.¹⁷

The purpose of this work has been to determine how a thrombus, produced in the lumen of a vein by injection of a sclerosant, can develop into a permanent occlusion.

One hundred and forty specimens of postinjection veins were obtained by biopsy. These were taken from volunteer patients attending the Varicose Veins Clinics. The specimens were fixed in formol saline and mounted in paraffin wax.

Vital or basic factors influencing a venous occlusion are: (1) The mural to thrombus ratio. The transverse measurement of the thrombus is compared to the thickness of the surrounding vein wall. This ratio may vary. In thrombophlebitis there is usually a large thrombus formed in a dilated thin-walled vessel, and the proportions are approximately 20:1. However, in the post-injection type, when the empty vein technique is used, this ration is altered. The thrombus is formed in a narrowed lumen and surrounded by a thick vein wall, giving the proportion of approximately 2:1.

(2) The degree of cellular activity in the subendothelial layer, and the rapidity with which this develops. (3) The degree of capillary invasion of the thrombus. (4) The intravenous pressure, and the degree of fluctuation of pressure in the vein above and below the thrombus.

The balance between these factors decides the final outcome of a venous thrombosis, that is, if it is to be recanalized or developed into a total occlusion. For the purpose of description thrombophlebitis may be divided into two extremes of the one condition: (1) phlebitis with a large thrombus, and (2) phlebitis with minimal thrombus formation.

Phlebitis with a large thrombus. In this condition the transverse section shows the relationship of thrombus to vein wall. The lumen of the vessel is full of blood, and the vessel is usually dilated. The mural to thrombus ration is altered, presenting a large diameter thrombus surrounded by distended and thin vein wall.

In all of the specimens examined, the thrombus is attached to a part of the vein wall. The endothelium is disrupted at this point, and maximal cellular activity develops at this point. While this is developing, the thrombus is also retracting. Two types of shrinkage can be described in an organizing thrombus. Contraction is caused by the network of strands, developed in the thrombus, which draw the surface of the thrombus inwards. If a firm anchorage occurs at the attachment area, then the thrombus retracts towards it. This shrinkage produced spaces between the original endothelium and the surface of the thrombus, and these peripheral spaces or sinuses rapidly develop endothelial linings. As contraction and retraction continue, these peripheral sinuses fuse with one another, forming large peripheral sinuses. The rate at which shrinkage occurs depends on the size of the thrombus.

This area is clearly demonstrated by the proliferation of subendothelial cells. During the first 48 hours this activity is visible around most of the intima. However, one or two areas soon predominate, and invading cells can be observed streaming into the thrombus from these points. As the attachment area becomes established, it will have the effect on shrinkage mentioned above.

The attachment area develop more rapidly and with more certainty when these has been damage to the intima by chemical irritants. When, however, the effect is produced primarily by the presence of the thrombus, the subendothelial reaction is slower to develop. The factors responsible for deciding the point of attachment are not clear. Serial sections show that the area changes its position around the circumference of the lumen along the length of vein involved. Therefore, the point of attachment would not appear to be caused by the site of needle puncture. However, the precise position of flow of the sclerosant within the isolated segment of vein is not known, and this may be an important factor in provoking some areas of intima more than others.

The blood cells enmeshed in the reticular network of the thrombus start to disintegrate gradually. This occurs mainly in regions which the cellular invasion fails to reach and is only found when the thrombus is large. Clinically these areas demonstrate fluctuation on palpation, but this usually develops approximately 2 to 3 weeks after onset. The area can be aspirated with a needle, and black tarry altered blood will be removed.

The distance to be traversed by the invading cells is of great importance to the final state of the occlusion. As the invasion lines are developing, the thrombus is retracting and contracting. The mechanical effect of this is to reduce the size of the thrombus and thus reduce the distance to be traversed by these invading cells. But peripheral sinuses will develop as a result of the shrinkage. If the thrombus is large and there are areas which invasion has failed to reach, then disintegration occurs, which causes the production of sinuses within the thrombus. These may be termed central sinuses.

While the fate of the thrombus is in the delicate state of development, irregular fluctuations of intravenous pressure force against it both proximally and distally with every contraction of the leg muscles.^{12, 13} This pressure varies greatly with muscle activity and changes of posture; thus the strain on the occlusion is seldom steady, but varies from such levels as 10 mm Hg to perhaps 150 mm Hg or greater. These variations are irregular and may be quite sudden. Areas of peripheral sinus formation, in the presence of this ram effect at either end of the occlusion, will soon dilate and spread. The thinned out vein wall, and delicate occlusion can offer little resistance and will be easily separated by the chiselling effect of the hemostatic ram in much the same way as Roux's third stage of hemodynamic factors. Dible² quotes Roux's theory of vascular development as follows.

1. The stage of genetic factors: here capillary development begins and proceeds for a limited time without the presence of a circulation as in capillaries of the yolk sac.
2. A stage of adaptation: in which the circulation is established and the primitive axial system of the limb becomes adapted to the special features of the species by the development or suppression of vessels.
3. A stage of hemodynamic factors: in which the full development of the vascular system is associated with hemodynamic influences.

The development of peripheral sinuses follows a pattern similar to that referred to in Roux's stage of hemodynamic factors. Unless the occluding thrombus is protected from the intravenous pressure until collagenization is complete, then it will open up and form a new channel.

The balances between these vital processes must be altered in the following way if sclerotherapy is to be successful. (1) The thrombus must be small, and the vein contracted around it, forming a thick protecting wall; (2) the reduced diameter of the thrombus allows complete cellular invasion to occur rapidly; (3) the effect of the hemostatic ram must be neutralized or drastically reduced by external compression; (4) sinus formation is reduced to a minimum.

Several authors have suggested that endothelial cells could develop into macrophages, myeloid cells or hemocytoblasts. Mehrotra¹⁷ supported this view following his experiments with rats. The response of the cell depends upon its environment.

The point of attachment has been defined above as the area of maximal cellular invasion of the thrombus. At this point there is destruction of the endothelium. The effect of the sclerosant is probably on the cement substance between and covering the endothelial cells.¹⁵ This is followed by disruption of the cell itself and exposure of the subendothelial layer. As the thrombus is formed, the fluid elements of the blood tend to "insudate" the wall of the vessel. (The term insudation is used to describe the passage of plasmatic substances into the vessel wall, due to the reduction of endothelial integrity, such as may occur in torsion of a section of bowel producing local vascular congestion¹⁵). In response to this, considerable proliferation of subendothelial cells occurs, and these enter the thrombus.

In the early stages a reticulin network develops in the thrombus and along these fibres the subendothelial cells advance. In this position the cells have the appearance of fibroblasts. In front of these there is considerable leukocytic infiltration.

At the same time that this develops, marked dilation of the vasa vasorum occurs in the adventitia and the media. The original reticulin network is replaced by collagen; this occurs first at the attachment area but spreads into the thrombus as the fibroblasts follow the leukocytes. With the development of collagen new capillaries grow into the thrombus from the vasa vasorum. This vascularization of the thrombus does not produce recanalization. The more pronounced the arteriovenous capillary network that has developed, the more rapidly collagenization of the thrombus occurs. Wall-to-wall production of collagen prevents the expansion of peripheral sinuses. The shrinkage associated with fibrous tissue involves both the wall and the thrombus, leaving no true demarcation between the wall and the occlusion.

As phagocytosis nears completion and the deposited collagen matures, the capillary invasion regresses. The thrombus should now be termed occlusion for this is what it has now become. A collagen block produced in the vein serves as an organic ligature produced from the patient's own cells, thus rendering the block invulnerable to the destructive action of the patient's various protective mechanisms. The sinuses that may have started to develop in the early stages with endothelial lining have been bound around by maturing fibrous tissue. The few remaining capillaries develop thick walls, with the appearance of endarteritis. The wall of the vein itself retains its original structure with an increase in collagen separating the muscle fibres. This collagen may be the pseudocollagen described by Lendrum^{14, 15.}

The production of a permanent occlusion in a vein following the injection of a sclerosant has been described. The importance of the relationship of the size of the thrombus and the thickness of the vein wall has been shown, and the bearing that this has on successful cellularization or organization has been demonstrated. The formation of peripheral sinuses and the development of an arteriovenous capillary network in the thrombus has been discussed, together with the significance of the effect of fluctuating intravenous pressure and external compression on the production of a permanent intravenous occlusion.

HOME       SELECTED ARTICLES  . . .     FEEDBACK     SEARCH