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Chapter
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6
Use of Compression Therapy
154
162. Batch AJ, Wickremesinghe SS, Gannon
ME, Dormandy JA. Randomized trial
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163. Rodrigus I, Bleyn J. For how long do
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165. Shepard JT. Reflex control of the
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167. Ninia JG. Treatment of vulvar
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173. Bodian EL. Techniques of
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178 Harridge H. The treatment of primary
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180. Scurr JH, Coleridge-Smith P, Cutting P.
Varicose veins: optimum compression
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181. Menezes A. Compression élastique
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primitives: réflexions auprès de 67
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editors. Phlébologie ’92. Paris: John
Libbey Eurotext; 1992.
182. Rastel D, Perrin M, Guidicelli H.
Résultats d’une enquête sur les
techniques compressives et
contensives utilisées dans le traitement
chirurgical des varices.
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183. Partsch H, editor: Evidence based
compression therapy. An initiative of
the International Union of
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?ezm=VAS&la=d&ShowIssue=1469.
184. Lugli M, Cogo A, Guerzoni S, et al.
Effects of eccentric compression by a
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saphenous vein: a randomized study.
Phlebology 2009;24:151.
185. Thaler E, Huch A, Zimmermann R.
Compression stockings prophylaxis of
emergent varicose veins in pregnancy:
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186. Austrell C, Thulin I, Norgren L. The
effects of long-term graduated
compression treatment on venous
function during pregnancy.
Phlebology 1995;10:165.
187. Weber S, Schneider KT, Bung P, et al.
Effects of compression stockings on
blood circulation in late pregnancy.
Geburtshilfe Frauenheilkd 1987;47:
396.
188. Norgren L, Austrell C, Nilsson L. The
effect of graduated compression hosiery
on femoral blood flow during late
pregnancy. Presented at the Sixth
Annual Meeting of the American
Venous Forum, Maui, February 23–25,
1994.
189. Austrell C, Nilsson L, Norgren L.
Maternal and fetal haemodynamics
during late pregnancy: effect of
compression hosiery treatment.
Phlebology 1993;8:155.
190. Krijnen RM, de Boer EM, Ader HJ,
Bruynzeel DP. Venous insufficiency in
male workers with a standing
profession. Part 2: Diurnal volume
changes of the lower legs.
Dermatology 1997;194:121.
191. Jonker MJ, deBoer EM, Adèr HJ,
Bezemer PD. The oedema-protective
effect of Lycra support stockings.
Dermatology 2001;203:294.
192. Jungbeck C, Peterson K, Danielsson G,
Norgren L. Effects of compression
hosiery in female workers with a
standing profession. Phlebology
2002;16:117.
193. Landgraf H, Vanselow B, SchulteHuermann D, et al. Economy class
syndrome: rheology, fluid balance,
and lower leg edema during a
simulated 12-hour long distance
flight. Aviat Space Environ Med
1994;65:930.
194. Schobersberger W, Mittermayer M,
Innerhofer P, et al. Coagulation
changes and edema formation during
long-distance bus travel. Blood Coagul
Fibrinolysis 2004;15:419.
195. Mittermayr M, Fries D, Innerhofer P,
et al. Formation of edema and fluid
shifts during a long-haul flight. J
Travel Med 2003;10:334.
196. Iwama H, Furuta S, Ohmizo H.
Graduated compression stocking
manages to prevent economy class
syndrome. Am J Emerg Med 2002;20:
378.
197. Scurr JH, Machin SJ, Bailey-King S,
et al. Frequency and prevention of
symptomless deep-vein thrombosis in
long-haul flights: a randomised trial.
Lancet 2001;357:1485.
198 Partsch H. Intermittent pneumatic
compression in immobile patients.
Int Wound J 2008;5:389.
199. Amaragiri SV, Lees TA. Elastic
compression stockings for prevention
of deep vein thrombosis (Cochrane
Review). Cochrane Database Syst Rev
2000;(3):CD001484.
200. Kakkos SK, Caprini JA, Geroulakos G,
et al. Combined intermittent
pneumatic leg compression and
pharmacological prophylaxis of
venous thromboembolism in high
risk patients. Cochrane Database Syst
Rev 2008 Oct 8;(4):CD005258.
201. Morris RJ, Woodcock JP. Evidencebased compression: prevention of
stasis and deep vein thrombosis. Ann
Surg 2004;239:162.
202. Kearon C, Kahn SR, Agnelli G, et al.
Antithrombotic therapy for venous
thromboembolic disease. American
College of Chest Physicians evidencebased clinical practice guidelines, 8th
edn. Chest 2008;133:454S.
203. Brandjes DPM, Büller H, Hejboer H,
et al. Incidence of the postthrombotic
syndrome and the effects of
compression stockings in patients
with proximal venous thrombosis.
Lancet 1997;349:759.
204. Prandoni P, Lensing AW, Prins MH,
et al. Below-knee elastic compression
stockings to prevent the postthrombotic syndrome: a randomized,
controlled trial. Ann Intern Med
2004;141:249.
205. Ginsberg JS, Hirsh J, Julian J, et al.
Prevention and treatment of
postphlebitic syndrome: results of a
3-part study. Arch Intern Med
2001;161:2105.
206. Kolbach DN, Sandbrink MWC,
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Hamulyak K, et al. Nonpharmaceutical measures for
prevention of post-thrombotic
syndrome (Cochrane Review). In: The
Cochrane Library. Issue 2. Chichester,
UK: John Wiley; 2004.
207. Kahn SR, Azoulay L, Hirsch A, et al.
Effect of graduated elastic compression
stockings on leg symptoms and signs
during exercise in patients with deep
venous thrombosis: a randomized
cross-over trial. J Thromb Haemost
2003;1:494.
208. Partsch H, Blättler W. Compression
and walking versus bed rest in the
treatment of proximal deep venous
thrombosis with low molecular weight
heparin. J Vasc Surg 2000;32:861.
209. Blättler W, Partsch H. Leg compression
and ambulation is better than bed rest
for treatment of acute deep venous
thrombosis. Int Angiol 2003;22:393.
210. Partsch H. Therapy of deep vein
thrombosis with low molecular weight
heparin, leg compression and
immediate ambulation. Vasa
2001;30:195.
211. Kolbach DN, Sandbrink MWC,
Neumann HAM, Prins MH.
Compression therapy for treating stage
I and II (Widmer) post-thrombotic
syndrome (Cochrane Review). In: The
Cochrane Library. Issue 2. Chichester,
UK: John Wiley; 2004.
212. Mani R, Vowden K, Nelson EA.
Intermittent pneumatic compression
for treating venous leg ulcers
(Cochrane Review). In: The Cochrane
Library. Issue 3. Chichester, UK: John
Wiley; 2004.
213. Phillips TJ, Machado F, Trout R, et al.
Prognostic indicators in venous ulcers.
J Am Acad Dermatol 2000;43:627.
214. Hendricks WM, Swallow RT, Asheboro
BA. Management of stasis leg ulcers
with Unna’s boots versus elastic
support stockings. J Am Acad
Dermatol 1985;12:90.
215. Koksal C, Bozkurt AK. Combination
of hydrocolloid dressings and medical
compression stockings versus Unna’s
boot for the treatment of venous leg
ulcers. Swiss Med Weekly 2003;133:
364.
216. Jünger M, Wollina U, Kohnen R, Rabe
E. Efficacy and tolerability of an ulcer
compression stocking for therapy of
chronic venous ulcer compared with a
below-knee compression bandage:
results from a prospective,
randomized, multicentre trial. Curr
Med Res Opin 2004;20:1613.
217. Jünger M, Hafner HM. Interface
pressure under a ready made
compression stocking developed for
the treatment of venous ulcers over a
period of six weeks. Vasa 2003;
32:87.
218 Amsler F, Willenberg T, Blättler W. In
search of optimal compression
therapy for venous leg ulcers: a
meta-analysis of studies comparing
divers bandages with specifically
designed stockings. J Vasc Surg
2009;50:668.
219. Jünger M, Partsch H, Ramelet AA,
Zuccarelli F. Efficacy of a ready made
tubular compression device versus
short-stretch compression bandages in
the treatment of venous leg ulcers.
Wounds 2004;16:313.
220 Milic DJ, Zivic SS, Bogdanovic DC,
Perisic ZD, et al. A randomized trial of
the Tubulcus multilayer bandaging
system in the treatment of extensive
venous ulcers. J Vasc Surg 2007;46:
750.
221. Nelson EA, Bell-Syer SE, Cullum NA.
Compression for preventing
recurrence of venous ulcers (Cochrane
Review). Cochrane Database Syst Rev
2000;(4):CD002303.
222 Nelson EA, Harper DR, Prescott RJ,
et al. Prevention of recurrence of
venous ulceration: randomized
controlled trial of class 2 and class 3
elastic compression. J Vasc Surg
2006;44:803.
223. Korn P, Patel ST, Heller JA, et al. Why
insurers should reimburse for
compression stockings in patients
with chronic venous stasis. J Vasc Surg
2002;35:950.
224. Badger CM, Peacock JL, Mortimer PS.
A randomized, controlled, parallelgroup clinical trial comparing
multilayer bandaging followed by
hosiery versus hosiery alone in the
treatment of patients with
lymphedema of the limb. Cancer
2000;88:2832.
225. Mason M. Bandaging and subsequent
elastic hosiery is more effective than
elastic hosiery alone in reducing
lymphoedema. Aust J Physiother
2001;47:153.
References
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7
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C H A P T E R
Mechanism of Action of Sclerotherapy
General Mechanism for Producing
Endothelial Damage
Sclerotherapy refers to the introduction of a foreign substance
into the lumen of a vessel, aiming to create venous wall
damage leading to occlusion of the vessel (Fig. 7.1). This procedure, when performed on telangiectasias, is referred to as
microsclerotherapy.
The mechanism of action for sclerosing solutions is that of
producing endothelial damage (endosclerosis) that causes
endofibrosis. The extent of damage to the blood vessel wall
determines the effectiveness of the solution. Endothelial cells
are highly complex and represent the largest cell type in the
human body. In addition to their function as a conduit for
blood, these cells react to mechanical forces and multiple
substances produced locally or circulating in the blood. They
have a broad range of metabolic activities, including, but not
limited to:
• uptake and degradation of circulating norepinephrine
(adrenaline), epinephrine (adrenaline), bradykinin, and
serotonin
• the conversion of angiotensin I to the vasoconstrictor
angiotensin II
• production of plasminogen activator inhibitor
• production of heparin and/or heparin-like substances
• production of prostacyclin, which acts both on vascular
smooth muscle and on platelet aggregation
• production of endothelium-derived relaxing factor
• storage and secretion of histamine
• synthesis of basic fibroblast growth factor (FGF)
• modulation of inflammation through interactions with
tumor necrosis factor (TNF) and interferon-γ.
In addition, endothelial cells in one organ and in one location may act differently than endothelial cells elsewhere. They
appear to be specialized to their area. Thus it is paradoxical
that sclerotherapy treatment is not without significant adverse
sequelae (see Chapter 8).
Endothelial destruction by sclerosing solutions is both dose
and time dependent.
cells demonstrated activation of calcium signaling and nitric
oxide pathways followed by cell death after exposure to sclerosing solutions. Cell death occurred within 15 minutes with
0.3% polidocanol (POL) or 0.1% sodium tetradecyl sulfate
(STS). At less than 0.003% POL or 0.005% STS cells remained
alive after 60 minutes. Combined with protein-binding of
detergent sclerosing solutions and a 10,000-fold dilution after
release into the circulation, these studies demonstrate the
safety of sclerotherapy, since sclerosing solutions are rapidly
diluted to ‘safe’ concentrations distal to the point of
injection.
Total endothelial destruction results in the exposure of
subendothelial collagen fibers, causing platelet aggregation,
1
2–5
6
In vitro studies of cultured endothelial
adherence, and release of platelet-related factors. This series of
events initiates the intrinsic pathway of blood coagulation by
activating factor XII. Ideally, sclerosing solutions otherwise
should not cause activation or release of thromboplastic activity because this would initiate the extrinsic pathway of blood
coagulation. Excessive thrombosis is detrimental to the production of endofibrosis because it may lead to recanalization
of the vessel as well as excessive intravascular and perivascular inflammation and its resulting sequelae (see Chapter 8).
This is thought to be prevented or at least minimized with
postsclerotherapy compression (see Chapter 6). However,
thrombosis usually occurs to some degree as a result of
sclerotherapy.
If a thrombus is formed, it should be well anchored to the
venous wall to prevent embolization. Wolf
lished that effective sclerosis causes thrombosis that penetrates
the full thickness of the adventitia of the vessel wall. Schnei-
8
der
has shown in histologic examinations of sclerosed varices
that the strongest fixation of a thrombus occurs in areas where
the entire endothelium is destroyed. Therefore, endothelial
damage must be complete and should result in minimal
thrombus formation with subsequent organization and fibrosis (Fig. 7.2). In addition, after sclerotherapy, maximum fullthickness fibrosis of the treated segment occurs after 6 weeks
of compression.
of thrombosis, compression may facilitate endofibrosis (see
Chapter 6). Chleir and Vin
between a clot observed during a spontaneous thrombosis
‘thrombus’ and during the sclerosing process, for which they
suggested the neologism ‘sclerus’ (Table 7.1).
In a pilot study, analysis of the content of sclerosed veins
has shown that an important number of fibroblasts are often
detected at the 6th week. Evidence of correlation with durable
occlusion of the vein is still lacking.
The fate of vasa vasorum during the process is not clear
either. Secondary recanalization after lysis of the clots
which cause obstruction early in the reaction, and the subsequent bleeding after several weeks, could explain why foamsclerosed veins fill up again with blood around the
6th week.
Endothelial damage can be provoked by a number of
mechanisms, such as a change in the surface tension of the
plasma membrane or modification of the physical–chemical
milieu of the endothelial cell through a change of intravascular pH or osmolality. The endothelium can be destroyed
directly by caustic chemicals or by other physical factors such
as heat and cold. For sclerotherapy to be effective without
recanalization of the thrombotic vessel, the endothelial
damage and resulting vascular necrosis must be extensive
enough to destroy the entire blood vessel wall.
Destruction of the entire vessel wall and not just the
endothelium is necessary, as demonstrated in animal studies
described later in this chapter. The reason may relate to the
multifunctional nature of vascular smooth muscle cells. These
9
Therefore, in addition to limiting the extent
10
have described the differences
7
in 1920 estab-
11
Table 7.1 Thrombus versus sclerosis: comparison of vein content during
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a thrombosis and during a sclerosing process
Thrombus Sclerosis
A
B
C
Figure 7.1 Diagrammatic representation of the mechanism of action for
sclerotherapy. A, Proper placement of needle into the vein and release of
sclerosing solution. B, Early stage of endothelial destruction and minimal
organizing thrombosis. C, Late stage demonstrating fibrous cord formation.
Pathophysiology Hematological
phenomenon
Activation of Virchow’s
triad
Recanalization without
fibrosis
Clinical Painful More discomfort than
Inflammatory No inflammation
Indurate plaques No indurate plaque
Biology Positive d-dimers Negative d-dimers
B-mode
ultrasound
Pathology No parietal lesion Inflammatory infiltration
RBCs, red blood cells; WBCs, white blood cells.
From Chleir F, Vin F: Actualités Vasculaires Internationales 35:18, 1995.
Convex toward junction Concave toward
‘Rosette’ picture Parietal thickening
No parietal adhesion Parietal adhesion
Dilatation Retraction
Thrombus rich in RBCs
and platelets
Rare WBCs
Tissue phenomenon
Parietal mechanism
Fibrosis
pain
junction
of venous wall
Sclerosis contains more
WBCs and less RBCs
than thrombus
Categories of Sclerosing Solutions
Endothelial damage
Thrombosis
?
Organization of thrombus
Fibrous cordRecanalization
Figure 7.2 Chain of events occurring after sclerotherapy. Ideally, the
treated vessel will progress directly from damaged endothelium to a fibrous
cord. However, some degree of intravascular thrombosis usually occurs.
cells, which are found in significant concentration within
superficial veins (see Chapter 2), have a large number of functions, including the synthesis of collagen, elastin, and proteoglycans.12 It is hypothesized that if they remain viable, they
can regenerate a foundation that promotes migration of
undamaged adjacent endothelial cells that allow recanalization of the treated vessel.
13,14
In addition, for effective destruction of a varicosity or tel-
angiectasia, the entire vessel must be sclerosed to prevent
recanalization. Recanalization occurs easily in vessels where
only a section of endothelium is damaged. This is due to rapid
endothelial regeneration, which has been measured at a turnover rate of 0.1% to 10% per day, or higher.
15
Endothelial
migration has been estimated to proceed at a rate of 0.07 mm/
day in the circumferential direction and six times faster in an
axial direction in rat aortas.
tion may be sufficiently rapid to replace dying endothelium
after small areas are denuded.
16
In fact, endothelial cell regenera-
17
In the future, the practitioner
may be able to estimate total endothelial destruction as a
marker for effective sclerosis by counting circulating endothelial cells.
18,19
Categories of Sclerosing Solutions
All sclerosing solutions can be placed into three broad categories based on their mechanisms for producing endothelial
injury:
• Detergent
• Osmotic
• Chemical.
There are an infinite number of potential solutions that,
when injected intravascularly, can cause endothelial and vascular wall necrosis. In addition, an infinite variety of combinations or mixtures of solutions can be used to produce
endosclerosis. The ideal sclerosing solution should be painless
on injection, free of all adverse effects, and specific for damaged
(varicose) veins. Although such a solution has not been discovered for all types of vein, this chapter examines solutions
commonly used for this purpose.
157
Chapter
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7
Mechanism of Action of Sclerotherapy
Detergent solutions
Detergent sclerosing solutions commonly used to treat varicose and telangiectatic veins include sodium morrhuate (SM),
ethanolamine oleate (EO), STS, and POL (lauromacrogol 400,
laureth-9). They produce endothelial damage through interference with cell surface lipids (Fig. 7.3). Strong detergents,
such as STS and SM, produce maceration of the endothelium
within 1 second of exposure.
disrupted, causing desquamation of endothelial cells in
plaques. Because the hydrophilic and hydrophobic poles of
the detergent molecule orient themselves so that the polar
hydrophilic part is within the water and the hydrophobic part
is away from the water, they appear as aggregates in solution
(micelles) or fixed onto the endothelial surface (Fig. 7.4).
Because the practitioner cannot ensure that the solution is
entirely in contact with the endothelial surface (if the injected
vein contains blood), the decrease in surface tension on the
endothelial cells may not be in direct proportion to the concentration of the solution. Strong detergent sclerosants therefore have a low safety margin.
Detergents act as micelles when injected into a nondetergent environment (blood). Their destructive action on
endothelial cells is enhanced when they act as aggregates
rather than monomers. Thus, the concentration of the sclerosing solution in the vessel is an important factor regarding
endothelial destruction and activity (Fig. 7.5). They have been
20
The intercellular ‘cement’ is
20
found to aggregate to a significant extent at lower temperatures
as opposed to room temperatures (Fig. 7.6).
Detergent sclerosing agents have been studied regarding
their direct toxic effects on the formed elements of blood. One
study found that the addition of SM, EO, STS, or POL to citrated plasma did not cause clotting nor shorten either the
prothrombin time (PT) or the partial thromboplastin time
21
(PTT).
However, all of the sclerosing agents examined were
directly toxic to both granulocytes and red blood cells (RBCs)
at dilutions of up to 1 : 1000. When tested against cultured
endothelial cells, all solutions were toxic to approximately
60% to 80% of cells at 1 : 100 dilutions, but only SM and EO
were toxic at a further dilution of 1 : 1000. None of these tested
solutions were toxic at 1 : 10,000 dilutions. Therefore, this
study confirms that effective endosclerosis occurs through
damage to endothelium and not through thrombosis induced
by destruction or damage to red and/or white blood cells.
Another in vitro study, however, found that the activated PTT
was prolonged in proportion to the fall of factor XII and
prekallikrein activity when POL was added to citrated serum.
22
This indicates that in addition to its action on endothelial
cells, POL is capable of acting on blood coagulation through
activation of the early phase of the intrinsic pathway. The
clinical relevance of this finding is unclear because additional
studies have failed to demonstrate its significance, as explained
later in this Chapter.
23,24
Figure 7.3 Diagrammatic representation of the action of a detergent
sclerosing solution on the vessel wall, showing formed elements of the
blood.
O
OH
O
O
O
H-O
O
OH
H-O
H-O
O
O
O.
OH
OH
OO
H-O
H-O
H-O
O
O
H-O
H-O
O
.O
OH
OH
OH
OO
O
O
O
Figure 7.4 Diagrammatic representation of the probable molecular
orientation of detergent sclerosing solutions into aggregates.
158
100%
80%
60%
Aggregates
Monomers
40%
20%
0
0 0.8 0.6 0.4 0.2
0.9 0.7 0.5 0.3 0.1 0.01
Concentration
Figure 7.5 Diagrammatic representation of the percentage of detergent
aggregates versus monomers is a correlation of the solution concentration.
(From Feid C, Presentation at the American College of Phlebology Sclerotherapy Workshop,
Atlanta, Ga., November 2000.)
O
OH
OH
H-O
H-O
O
H-O
O
O
H-O
H-O
O
100%
80%
60%
Aggregates
Monomers
40%
20%
0
22 26 30 34 38 40
20 24 28 32 36
Temperature (°C)
Figure 7.6 Diagrammatic representation of the percentage of detergent
aggregates versus monomers is a correlation of the solution temperature.
(From Feid C, Presentation at the American College of Phlebology Sclerotherapy Workshop,
Atlanta, Ga., November 2000.)
Figure 7.7 Diagrammatic representation of the action of a hypertonic
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sclerosing solution on the vessel wall, showing formed elements of the blood.
Figure 7.8 Diagrammatic representation of the action of a caustic chemical
sclerosing solution on the vessel wall, showing formed elements of the blood.
Osmotic solutions
Hypertonic solutions, such as hypertonic saline (HS), probably cause dehydration of endothelial cells through osmosis,
causing endothelial destruction (Fig. 7.7).
22
It is speculated that
fibrin deposition with thrombus formation on the damaged
vessel wall occurs through modification of the electrostatic
charge of the endothelial cells.
pletely destroyed, the osmotic solution must be of sufficient
concentration to diffuse throughout the entire vein wall.
20
For the vessel wall to be com-
25
In
contrast to the immediate action of detergent sclerosing solutions, experimental studies have shown that endothelial
destruction with HS 22% or glucose 66% occurs only after 3
minutes.
desquamated as with detergent sclerosing solutions.
20
The destroyed endothelial cells do not appear to be
20
Hypertonic solutions have a predictable destructive power
that is proportional to their osmotic concentration. This was
demonstrated in a comparative study of multiple hypertonic
solutions used on the superficial and internal saphenous veins
of 27 dogs.
26
The degree of endothelial damage was assessed
histologically at multiple times from 30 minutes to 8 weeks
after sclerotherapy. The authors ranked the solutions from
strongest to weakest as follows:
1. Sodium salicylate 40%
2. Sodium chloride 10% sodium salicylate 30%
3. Invert sugar 75%
4. Saccharose 5%
5. Phenol 1%
6. Dextrose 66%
7. Sodium chloride 20%
8. Sodium salicylate 30%
9. Glycerin.
The authors concluded that maximal endothelial destruction occurred as early as 30 minutes to 4 days after injection,
after which time the injected vessel went through either a
reparative or a fibrotic process. Because dilution occurs with
intravascular serum and blood, osmotic solutions have their
greatest effect at or near the site of injection. In contrast, detergent sclerosing solutions can exert effective sclerosis for 5 to
10 cm along the course of the injected vessel. Sadick27 examined the sclerosing effect of HS 23.4% and POL 0.5%. He
found equal sclerosing effect (length) for these two solutions
injected in a similar type of vein using identical techniques.
Unfortunately, HS 23.4% is more potent (about two to three
times more) than POL 0.5%. Therefore, he inadvertently demonstrated that detergent solutions have about twice the therapeutic efficacy of osmotic solutions. A better comparison
would have been with HS 11.7%.
Chemical solutions
Chemical irritants also act directly on endothelial cells to
produce endosclerosis. Lindemayr and Santler
28
studied the
sclerosing effect of 4% polyiodinated iodine (PII; Variglobin)
with standard and immunofluorescent microscopy and demonstrated fibrin deposition on the sclerosed veins only. Platelets fixed only to elastin, collagen, the basement membrane,
and the amorphous material of the subendothelial layer, not
to intact endothelial cells. It is also thought that the chemical
destruction is in part related to the dissolution of intercellular
cement, which has been demonstrated to occur after 30
seconds of exposure.
20
Thus, this chemical irritant sclerosing
solution produces its end result of vascular fibrosis through
the irreversible destruction of endothelial cells with resultant
thrombus formation on the subendothelial layer (Fig. 7.8).
The aforementioned mechanism of action has been demonstrated visually with scanning electron microscopy of
sclerosed rabbit veins (agent not noted) by Merlen.
29
He
demonstrated intimal cracks and fissures that left intimal connective tissue fibers and elastic lamina exposed. Ultrastructural
damage involving stasis of blood and platelet aggregation on
intact endothelial intima occurred in 5 minutes in the dorsal
rabbit ear vein.
Factors Predisposing to Thrombosis
As discussed previously, optimal clinical results occur when
sclerotherapy-induced thrombosis is minimized. Factors predisposing to thrombus formation include decreased velocity
of blood flow, hypercoagulability, and endothelial cell
damage.
sclerosing agent itself, but flow in general is usually slower in
varicose veins and telangiectasia. This relative decrease in
blood flow may predispose to thrombus formation in varicose
veins and may be a significant contributing factor to the
increased incidence of thrombophlebitis and deep vein thrombosis (DVT) in patients with varicose veins (see Chapter 2).
mation. Wuppermann
with POL and found a slight, statistically insignificant hyperfibrinolysis in blood drawn from the antecubital vein. He
hypothesized that because coagulation factors II, VII, VIII, and
IX and platelet function are damaged directly by the sclerosing
solution, coagulation at the injection site is delayed. Endosclerosis, as measured by fibrinogen, gradually occurred over 5
days only at the injection site and did not result in systemic
hypercoagulability. Therefore, sclerotherapy should not cause
a sudden thrombosis. In fact, a hemolytic effect was detected
with STS even at a 0.1% concentration, with POL at a 0.05%
dilution, and with PII at a 2% concentration.
thrombin time (TT) were unchanged with injection of these
agents into whole blood. Earlier work also demonstrated the
lack of effect of POL on coagulation parameters in rabbits.
MacGowen et al33 combined STS with whole normal blood,
causing a homogeneous RBC lysate without the formation of
30
The velocity of blood flow is unaffected by the
Hypercoagulability predisposes the patient to thrombus for-
31
studied fibrinolysis in subjects injected
23
The PTT, PT, and
32
Factors Predisposing to Thrombosis
159
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Mechanism of Action of Sclerotherapy
160
thrombin. In vivo studies have also demonstrated a lack of
hypercoagulability from sclerosing solutions. Cepelak
24
found
that platelet aggregation occurs only at the site of the sclerosing
solution injection, with aggregation-inhibiting effects occurring in the efferent deep veins distal to the femoral vein. Thus,
endothelial damage probably causes a release of various factors
that produce anticoagulant effects, lowering the risk of thrombotic complications of sclerosing therapy. This effect was confirmed by Raymond-Martimbeau and Leclerc,
34
who measured
fibrinopeptide A and fibrin degradation of D-dimer fragments
after injection of sodium iodine. They found no evidence for
activation of blood coagulation. Therefore, experimental findings do not support the theory of intrinsic hypercoagulability
of sclerosing solutions as the mechanism of action for thrombus formation during sclerotherapy (see Chapter 1).
The lack of hypercoagulability just mentioned correlates
with clinical experience using POL. When POL is used in
patients who are taking systemic anticoagulants, a decrease in
its sclerosing action does not occur.
to STS also had no effect on the sclerotherapy results in a
paired comparison of 100 patients.
mechanism of action of POL and STS is to produce endothelial damage,
37
but not thrombus formation associated with
35
The addition of heparin
36
Thus it appears that the
platelet aggregation. This mode of action is also seen with
other (nondetergent) sclerosing agents. The low incidence of
DVT after sclerotherapy (less than 1 per 10,000 sessions
38
) is
the ultimate evidence that thrombosis is an epiphenomenon
of the sclerosing process, not a goal.
Factors Predisposing to Endofibrosis
Whether vessels altered by changes of being varicose or
stretched are more susceptible to the action of sclerosing
agents than are normal vessels is unknown. At times, human
varicose and telangiectatic vessels are noted to sclerose focally
after the injection of various solutions. The focal nature of
endothelial necrosis and thrombus formation may be related
to toxic effects of the sclerosing solutions on the surrounding
media. This effect is commonly observed when injecting varicose veins under duplex control. With this technique
(described in Chapter 9), the sclerosing solution is injected
and/or held in place until the varicosity is seen to spasm. This
indicates effective sclerosis. Venograms of varicose veins
injected with STS demonstrate segmental, intense, and diffuse
spasm, both proximally and distally, at the time of injection
and 6 minutes after injection.
at points of vessel spasm where the entire endothelium is
adherent. This agrees with the clinical impression that total
compression of the sclerosed vessel is necessary for ideal, longlasting, and complication-free sclerosis.
At one time it was thought that ‘any solution which will
not produce a slough when injected perivenously will generally not be strong enough to obliterate a vein.’
some very effective sclerosing solutions are thought to act
selectively on ‘damaged’ varicose endothelium. In fact, experimental studies have documented that effective sclerosing solutions do not have to produce tissue necrosis on intradermal
injection (see Chapter 8). The manufacturers of POL state that
this agent acts selectively on damaged vessels.
number of histologic studies of the effect of sclerotherapy on
varicose veins have also concluded that damaged varices are
preferentially sclerosed.
a
Product description on hydroxypolyethoxydodecane, Dexo SA Pharmaceuticals, France, May 1985; product insert for Aethoxysklerol,
Kreussler & Co GmbH, Wiesbaden-Biebrich, Germany, 1985.
b
Henschel O: Sclerosing of varicose veins sclerotherapy with
Aethoxysklerol-Kreussler (product booklet), Kreussler & Co GmbH,
Wiesbaden-Biebrich, Germany.
39
Effective endosclerosis occurs
40,41
a
In addition, a
b,8,20,29
However, experimental injec-
42
However,
tion of sclerosing agents into normal dorsal veins of rabbit
ears yields effective vessel sclerosis in a concentrationdependent manner.
43,44
Therefore, in addition to the type and
concentration of sclerosing solution, other factors, including
vessel diameter, rate of blood flow, and anatomic site of the
vessel, may also be important.
Sclerosing solutions affect arteries in a different manner
than they do veins. Although thrombosis occurs, intimal
damage may not. MacGowen et al33 studied the local effects
of intra-arterial injection of STS. They injected STS 3.0% into
the central auricular artery at the base of the rabbit ear and
visualized the resulting chain of events through a Perspex ear
chamber (Lucite International, Southampton, UK) with highpower and oil-immersion lenses. Spasm was not noted in any
vessels, but within minutes the erythrocytes appeared distorted and broken, with the formation of a central homogeneous thrombus that moved down the arteriole and lodged in a
capillary. Intimal damage did not occur. Thus, the major effect
of STS was on the blood cell mass that it destroyed and converted into an intravascular embolus. Subsequent biopsies of
the ears at 1 hour and at 5 days demonstrated thrombus only,
without evidence of intimal damage. These results are distinctly contrary to the effects of sclerosis on veins.
The reason for the different mechanism of action is
unknown but may relate to the difference in velocity of blood
flow in arteries and veins. Specifically, STS injected intraarterially may not have enough time to react with endothelium, being both absorbed and inactivated by formed elements
in the blood and serum factors and thereby being diluted to
a ‘safe’ concentration by the more rapid arterial flow. Safe is
a relative term, since inadvertent intra-arterial injections of
STS have produced gangrene through thrombosis of vessels
downstream of injection (see Chapter 8).
Experimental Evaluation of Sclerosing
Solutions
Since physicians in the United States are especially limited in
the type of sclerosing solutions available, an analysis of the
following studies was performed to compare the efficacy of
various sclerosing agents.
An important question regarding the studies in this section
is whether the experimental animal model is an appropriate
system in which to compare the efficacy of various sclerosing
solutions. The dorsal marginal rabbit ear vein is similar in size
(0.35 to 0.45 mm in diameter) to telangiectasias in humans.
Reiner45 found that it was difficult to measure the rate of dilution of sclerosing solutions in the rabbit ear vein because of
the greater number of collaterals and rapid blood flow caused
by the thermoregulatory nature of the ear. Therefore, after
injection of the solution, 20 seconds of occlusion on the
proximal and distal aspects of the injected vein wall caused by
firm pressure helped simulate the more sluggish blood flow
of human telangiectasias.
sclerosing solution on saphenous veins harvested for coronary
bypass surgery have confirmed the histologic effect of sclerosing solution type and concentration with the rabbit ear vein
46
model.
However, study of an animal model may not produce
accurate data because the researcher is comparing the action
of a sclerosing solution on a normal vessel. In addition, the
injected vessels are not compressed in rabbit ear vein studies,
thereby resulting in the formation of a larger thrombus, which
may allow for a more rapid or increased incidence of recanalization. Finally, thrombogenesis and thrombolytic effects are
different in the rabbit ear than in the human artery and vein.
However, despite all these shortcomings, as a model the rabbit
ear vein does allow the physician to compare the mechanism
of action of various sclerosing solutions both clinically and
43,44
In vitro studies of the effect of
47
Table 7.2 Relative potency of sclerosing solutions
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Vein Diameter Sclerosing Solution
0.4–1 mm Glycerin 70%
Chromated glycerin 50%
Polidocanol 0.25%–0.5%
Sodium tetradecyl sulfate 0.1%
Hypertonic saline 11.7%
Sclerodex
Ethanolamine oleate 2%
Polyiodinated iodine 0.1%
Sodium morrhuate 0.25%–0.5%
1–3 mm Sodium tetradecyl sulfate 0.25% foam
Polidocanol 0.5% foam
Polyiodinated iodine 0.5%–1.0%
Ethanolamine oleate 5%
Hypertonic saline 23.4%
Sodium morrhuate 1.0%–2.5%
3–5 mm Polidocanol 1% foam
Sodium tetradecyl sulfate 0.5%–1.0% foam
Sodium morrhuate 5%
Polyiodinated iodine 2%
>
5 mm
Perforators Sodium tetradecyl sulfate 2%–3% foam
Saphenofemoral/popliteal
junctions
Polidocanol 3%–4% foam
Polyiodinated iodine 3%–12%
histologically. On the basis of these studies, the physician can
achieve a similar therapeutic effect in humans by varying the
concentration and type of solution (Table 7.2).
In the 1920s, the first studies to elucidate the mechanism
of action of sclerosing agents were performed using the dorsal
vein of the rabbit ear. Sclerosing agents tested included 1%
bichloride of mercury,
49,50
sugar,
and SM.
30% sodium salicylate,51 50% to 60% calorose,
54,55
All of these solutions achieved venous oblitera-
48
30% sodium chloride and 50% grape
52,53
tion through endothelial cell alteration, with inflammation
resulting in thrombus formation and the eventual production
of a fibrous cord.
An evaluation of foamed sclerosing solutions has also been
performed in vivo on isolated saphenous veins before strip-
56
ping.
Pathologic damage from 3% STS foam prepared with
1 mL of STS and 4 mL of air was extremely rapid, with complete damage to the endothelium within 2 minutes. Edema of
the intima with progressive separation from the tunica media
and formation of thrombus occurred at 15 and 30 minutes.
Sodium tetradecyl sulfate
The mechanism of sclerosis for intravascular STS was elucidated by Schneider
varicose veins, by Dietrich and Sinapius
jugular veins, and by Imhoff and Stemmer
rabbit ear vein. With STS, endothelial damage is dependent
on concentration and occurs immediately after injection, with
8
and by Schneider and Fischer55 in human
57
in rabbit external
20
in the dorsal
Figure 7.9 Endothelial cells and the vascular wall are entirely destroyed
1 hour after injection of sodium tetradecyl sulfate 0.5%. Hemolysis of red
blood cells and early thrombosis are also present. (Hematoxylin–eosin,
×200.)
Figure 7.10 Microangiopathic recanalization is apparent 14 days after
injection with sodium tetradecyl sulfate 0.5% (hematoxylin–eosin, ×100).
(From Goldman MP et al: Arch Dermatol 123:1196, 1987.)
resulting rapid thrombus formation leading to vascular
sclerosis.
In two studies, sclerosis with STS produced similar results
in a concentration-dependent manner.
43,44
Endothelial damage
occurred within 1 hour (Fig. 7.9), followed by the rapid onset
of vascular thrombosis with subsequent organization (Fig.
7.10). Histologic recanalization occurred after 30 days with
solution concentrations of 0.1% to 0.5%. The histologic findings explained the clinical appearance, which demonstrated
initial thrombosis, followed by partial reappearance of the
vessel injected with STS 0.1%. Therefore, there may be a concentration gradient in which an ideal concentration depends
on many factors, including vessel diameter, rate of blood flow,
animal model, and anatomic region within each animal
model.
Sodium morrhuate
Sodium morrhuate, a mixture of sodium salts of the saturated
and unsaturated fatty acids present in cod-liver oil, has been
studied in the rabbit ear vein model.
of SM produced no clinical evidence of endothelial damage.
Temporary histologic evidence of thrombosis was noted at 1
hour only, with a mild perivascular mixed cellular infiltrate
(MCI). There was no evidence for extravasation of RBCs.
Vessels injected with SM 1.0% were thrombosed between 2
58
A 0.5% concentration
Experimental Evaluation of Sclerosing Solutions
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Mechanism of Action of Sclerotherapy
Figure 7.11 Vessel 2 days after injection of sodium morrhuate 1%. Note
the large numbers of perivascular mast cells (hematoxylin–eosin, ×400).
and 10 days, after which the vessels normalized. Histologically, the SM 1.0%-injected vessel demonstrated a partially
destroyed endothelium with extravasation of RBCs. The vessels
injected with SM 2.5% demonstrated clinical fibrosis with
histologic evidence of microangiopathic recanalization
through a fibrotic cord at 45 days after injection. A unique
finding noted with injection of SM, both 1.0% and 2.5%, was
the presence of large numbers of perivascular mast cells (Fig.
7.11). This finding may correlate with the increased inflamma-
tory nature and allergenicity of SM as compared with other
sclerosing solutions.
Ethanolamine oleate
A synthetic mixture of ethanolamine and oleic acid, EO is
another sclerosing solution that has been studied in the rabbit
ear vein model.
58
No histologic or clinical changes were noted
with injection of EO 0.5%. Although an organizing thrombus
was produced, complete recanalization occurred in the vessel
injected with EO 1%, causing the returned clinical appearance
of the injected vessel. Vessels injected with EO 2.5% had a
partially destroyed endothelium followed by luminal recanalization. Evidence of phagocytosis of lipid-like material was
noted in a vessel injected with EO 2.5% at 48 hours (Fig. 7.12).
This may indicate extravasation of sclerosing solution either
during injection or with endothelial destruction. Large
numbers of perivascular mast cells were also noted 2 days after
injection with EO 1% and 2.5%. Extravasated RBCs occurred
in vessels injected with EO 1% and 2.5% at 1 hour and 2 days,
but not in vessels injected with EO 0.5%.
A previous study comparing EO with STS was performed
using the rat tail vein model.
59
In this model, EO 5% was
compared with STS 3% and 1%. Solution measuring 0.1 ml
was injected and the veins were biopsied at 4 weeks. In this
study, EO 5% was effective in sclerosing only 25% of the
treated veins, as opposed to a 73% efficacy with STS 1% and
a near 100% efficacy with STS 3%. Therefore, results in the
rabbit ear vein compare well with those in the rat tail vein.
Polidocanol
A concentration gradient was also demonstrated in a study of
POL in concentrations of 0.25%, 0.5%, and 1.0%.
vessels injected with POL 0.5% and 1% were clinically sclerosed, and only the vessels injected with POL 1% maintained
sclerosis without revascularization by 60 days.
An examination of the histologic effects of POL on the
endothelium specifically, between 1 hour and 4 days after
injection, illustrates the effect of varying the concentration of
sclerosing solutions. Endothelial cells exposed to POL 0.25%
162
43
Only
Figure 7.12 Vessel 2 days after injection of ethanolamine oleate 2.5%. Note
the extensive phagocytosis of lipid-like globules (hematoxylin–eosin, ×200).
Figure 7.13 Partially damaged endothelial cells with thrombosis is
seen 8 hours after injection of polidocanol 0.25% in the rabbit ear vein
(hematoxylin–eosin, ×40).
were at first only partially damaged (Fig. 7.13). Mitotic figures
indicating endothelial regeneration were noted 4 days after
injection (Fig. 7.14). Likewise, with POL 0.5%, partial luminal
recanalization occurred through an initial fibrotic cord in
vessels (Fig. 7.15). Only vessels sclerosed with POL 1.0% devel-
oped complete endosclerosis (Fig. 7.16). Therefore, POL is
probably a weaker detergent type of sclerosing solution than
STS, and higher concentrations are necessary to produce complete vascular sclerosis.
Polidocanol: liquid versus foam
Hamel-Desnos et al and Wollmann have demonstrated both
60,61
clinical
liquid. In vitro studies have been conducted on single layers
of endothelial cells in contact for 1.5 seconds with various
concentrations of foam and liquid POL. Histologic examination demonstrated identical cell destruction with 0.5% foam
and 3% liquid. As indicated by Hamel-Desnos et al, better
efficacy had been supposed to be related to a longer time of
contact; they have observed that the effect happened in a very
short time, therefore there should be missing explanatory
links. From a macroscopic point of view, foam seems to work
because of the delayed dilution and closer contact between
nondiluted sclerosing agent and endothelium; some microscopic phenomena will perhaps be found explaining more
precisely what happens. (Foam sclerosants are described in
detail at the end of this chapter and in Chapter 9.)
and microscopic62 superior efficacy of foam versus
Hypertonic saline
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The sclerosing effect of HS was examined histologically in the
external jugular vein of the dog by Kern and Angle,
human varicose veins by McPheeters and Anderson.
investigators noted endothelial damage with thrombus formation within 1 hour of injection, with ultimate conversion into
a fibrous cord within 2 to 4 weeks. This was confirmed in the
rabbit ear vein model
43
both clinically and histologically.
Examination of the marginal ear vein 1 hour after exposure to
HS 23.4% demonstrated complete endothelial destruction
(Fig. 7.17).
Figure 7.14 Endothelial regeneration is apparent 4 days after injection of
polidocanol 0.25% in the rabbit ear vein (hematoxylin–eosin, ×100).
63
and in
53
These
However, subsequent evaluation of HS 11.7% in the rabbit
ear vein model58 demonstrated an immediate thrombosis that
lasted only 48 hours before complete normalization. Endothelial destruction was patchy at 1 hour with perivascular and
intraluminal margination of polymorphonuclear cells and
eosinophils. There was no evidence of extravasation of RBCs
in the veins injected with HS 11.7%, whereas extravasation
was noted in 30% of vessels injected with HS 23.4%. Therefore, the degree of endothelial damage and resulting extravasation of RBCs is proportional to the concentration of HS used.
Hypertonic glucose/saline
Sclerodex (SX; Omega Laboratories, Montreal) is a mixture of
dextrose, sodium chloride, propylene glycol, and phenethyl
alcohol. When SX was studied in the rabbit ear vein model,
58
it produced an immediate thrombosis that lasted for 2 days,
after which the vessel recanalized. At 1 hour, perivascular and
intraluminal margination of polymorphonuclear cells and
eosinophils were present with patchy endothelial destruction.
Endothelial mitoses were present at 2 days within a regenerative endothelium. Extravasation of RBCs was not noted. Therefore, SX has a potency similar to HS 11.7%.
Chromated glycerin and 72% glycerin
The effect of chemical irritant sclerosing solutions has been
studied in the rabbit ear model.
Sclérémo, Laboratoires Bailleul, Paris, France), 50% and
100%, was injected into the dorsal marginal rabbit ear vein,
producing clinical and histologic thrombosis that lasted only
2 to 8 days, after which the vessel appeared clinically and
histologically normal. As noted with POL 0.25% above, the
44
Chromated glycerin (CG;
Experimental Evaluation of Sclerosing Solutions
A B
Figure 7.15 Advanced luminal recanalization is present 60 days after injection of polidocanol 0.5%, as seen in cross-section. A, ×100. B, ×200; note
endothelial lining on recanalized lumen (hematoxylin–eosin).
A B
Figure 7.16 Fibrous cord formation is present 30 days after injection of polidocanol 1.0%. The darker areas within the fibrous cord represent hemosiderin-
laden macrophages. A, Cross section, ×40. B, Longitudinal section, ×100 (hematoxylin–eosin). (B from Goldman MP et al: Arch Dermatol 123:1196, 1987.)
(A from Goldman MP et al: Arch Dermatol 123:1196, 1987.)
163
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