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64 Chapter 6 Epidemiology, genetics, and risk factors for chronic venous disease
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appealing, this must be hypothesis driven, and with our
current knowledge on the pathophysiology of varicose
veins—that it is a multifactorial process—it is difcult to
determine a true candidate gene hypothesis–directed study.
6.4.3 Gene expression studies
The gene expression approach looks for the expression
of specic genes in the diseased tissue. The limitation of
this approach is that it is difcult to distinguish whether
changes in the RNA expression of a gene are due to genetics or an environmental mechanism. Also, it is difcult to
determine if pathological change is the cause of or consequence of the disease. Atranscriptomic analysis published
in 2018 compared paired samples of varicose and normal
venous tissue from eight patients and found numerous differentially expressed genes enriched in pathways dictating
extracellular matrix organization and vascular morphogenesis [36]. For example, multiple human studies of varicose
veins have described changes in matrix metalloproteinases
(MMPs) and tissue inhibitor of matrix metalloproteinases
(TIMPs), their natural inhibitors, suggesting a critical role
for matrix remodeling in chronic venous disease [37, 38].
Although this approach has been useful in understanding
the changes in gene expression that occur within diseased
vessels, this approach cannot distinguish whether changes
in gene expression are the cause of or a consequence of the
disease process. Despite its limitations, major functional
gene expression differences in varicose veins and ulcers
have been discovered. These include genes for metabolic
pathways, extracellular matrix organization and regulation, response to external stimuli, and cell organization.
6.4.4 Venous leg ulcer genetics
Venous ulceration is the advanced form of chronic venous
disease, and its healing is compromised in subjects with
altered iron metabolism [39]. Venous ulcer development
is multifactorial, but some of the mechanism of ulcer formation is thought to be secondary to (1) necrosis of the
extracellular matrix due to TGF-β and MMP [40], (2)
destruction of collagen microbrils and proteoglycans
[40], and (3) increased apoptosis of keratinocytes and
caspase-2 leading to dermal-epidermal detachment [41].
Iron deposition, which occurs secondary to skin complications of chronic venous insufciency, generates free radicals
or activates a proteolytic hyperactivity of the MMP and
downregulates tissue inhibitors of MMP. Mutations of the
hemochromatosis gene (HFE gene), including HFE C282Y
and HFE H63D, which causes a deciency of iron metabolism, increase the risk by more than vefold for developing
a venous ulcer in subjects who have venous disease [39].
Another related gene is the SLC40A1 (FPN1) gene, which
codes ferroportin, a transmembrane protein involved in
the export of intracellular iron. FPN1-8CG, a single-nucleotide polymorphism (SNP) in the promoter region of the
SLC40A1 gene, appears to affect gene expression, and carriers of the SNP showed a vefold increase in venous ulcer
susceptibility [42]. Other genes that have been associated
with VLU and poor healing include MTHFR [43], MMP
[42, 41], FGFR2 [44], and FXIII [45].
6.4.5 GWAS
In GWAS, thousands of genetic variants across many
genomes are explored to detect sequence variations associ-
ated with a specic trait or disease. In doing so, the associ-
ation of genotypes with phenotypes can be evaluated, and
associations of thousands of SNPs with human traits and
diseases have been successfully identied. Upon detecting
SNP variations, the challenge is interpreting the results in
context. Most phenotypes are inuenced by causal vari-
ants that add negligible risk on their own but when pre-
sented together or associated with other traits, can express
changes, making it difcult to debunk its causal inference.
To explain causality, understanding how the respective loci
contribute to disease is necessary; thus, additional informa-
tion to decipher GWAS results becomes necessary. GWAS
generally targets genotyping specic and preselected vari-
ants using microarrays. GWAS data are routinely described
in Manhattan plots and quantile–quantile plots. Statistical
ne mapping is performed to identify causal SNPs to be
prioritized. Expression quantitative trait loci (eQTL) anal-
ysis seeks to identify SNPs that affect the expression of the
target gene. Thus, the SNP for the gene–SNP pair associ-
ated with a gene expression is called an eQTL. Identifying
eQTLs plays a key role in this disease deciphering process.
Although whole genome sequencing (WGS) requires sub-
stantially larger computational and biomedical resources,
it plays a signicant role in detecting rare variants com-
pared to GWAS, as this can capture all genetic variations.
Pathway analysis is another way to analyze high-through-
put data to detect relevant groups of related genes that are
altered in a functional signaling process. These techniques
help understand isolated genes in a biological context by
coupling existing knowledge from databases with statis-
tical testing, mathematical analyses, and computational
algorithms.
With the abundance of human biological information
in large data sets, several GWAS have been performed on
chronic venous disease. In a German data set, three novel
susceptibility loci, including EFEMP1 (bulin-3, an extracellular matrix glycoprotein), KCNH8 (a member of the
human Elk voltage-gated potassium channel), and SKAP2
(an adaptor protein involved in Src signaling), were discovered for chronic venous disease [46]. Another study using
the UK Biobank identied 855 new SNPs and notable
variant genes, including CASZ1 (a known blood pressure
locus), PIEZO1 (a mechanosensory channel), and GALNS
(a lysosomal exohydrolase required for the degradation of
the glycosaminoglycans keratan sulfate and chondroitin
6-sulfate), as genetic variants that may inuence varicose
vein susceptibility (Figure6.3). Additional eQTL analyses
suggested that several SNPs are associated with altered in
vivo expression of genes that have been related to vascular development/integrity (e.g., PPP3R125, PIEZO1, 39
SOX1848), limb development (e.g., LBH49), and conditions associated with skeletal abnormalities (e.g., GALNS,
26 FBN227) [6]. Another study also evaluated the UK Biobank data and then performed a replication study using
23andMe data and discovered 49 signals at 46 susceptibility loci, mapping 237 genes to these loci. Their pathway
analysis identied enrichment of these loci in extracellular
6.4 Genetic findings 65
-log
(p-value)
Chomosome
CASZI
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60
50
40
10
30
SLCI2A2
HISTIH3G
HCG9
HLA-B
20
10
PPP3R1
STIM2
EBF1
GATA2-ASI
LBH
0
12345678910111213141516171819202122
IGSF11
TENN3-ASI
AGGFI
6.3 Manhattan plot of GWAS analysis [6].
matrix biology, inammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis [47].
Disruption of PIEZO1 has previously been shown to
result in signicant disorganization of the vascular system,
suggesting the importance of PIEZO1 for mature vascular development [29]. There is emerging evidence for the
role of PEIZO1 channels in endothelial sensing shear stress
and secretion, NO generation, vascular tone, vascular permeability and remodeling, blood pressure regulation, and
baroreceptor reex, indicating that they may be key players in vascular force sensing [48]. Regarding the hemochromatosis gene HFE, in which mutations have previously
been associated with both venous ulceration and venous
thromboembolism, the lead SNP, rs7773004 on 6q14, is
located within 50 kB upstream [39]. Several other genes
have previously been linked to both varicose veins and
DVT, including THBD [49] and methylenetetrahydrofo-
PIEZO1
CTU2
LINC02549
RSPO3
ALDH8A1
PRKAR1B CNGB3
DECI HDAC7
DAOA
GLG1
LINC00924
KCNJ2
LINCO1152
late reductase (MTHFR) [50]. Mutations in these genes
are classically associated with inherited hypercoagulability.
Still, patients with varicose veins have also been found to
have a higher prevalence of thrombophilias and increased
levels of systemic inammatory and prothrombotic markers [51]. These ndings similarly support the shared genetic
associations between varicose veins and DVT and suggest
an overlap in their underlying pathophysiology.
6.4.6 Conclusion
Despite the strong genetic inuences in patients with
chronic venous disease, studies shed light on the fact that
this is a multifactorial disease with epigenetic inuences.
Further research will help to decipher the complex interplay of genomics and environmental factors in chronic
venous disease.
6
NFATC2
ZNF512B
Consensus Statements 6.0 of the American Venous Forum on the epidemiology, risk factors, and genetics of chronic
venous disease
No. Consensus Statements
6.1 Chronic venous disease affects >25million adults in the United States, with 6–7million having advanced venous disease.
6.2 Prevalence of varicose veins is 1%–73% of women and 2%–56% of men, and it varies widely in studies.
6.3 Risk factors for chronic venous disease include age, female sex, pregnancy, family history, prolonged standing with work,
history of deep vein thrombosis, and obesity.
6.4 Novel risk factors of varicosity include leg bioimpedance and increased height.
6.5 Family history is a contributing factor to chronic venous disease, with a high prevalence of varicose veins if both parents
were affected.
6.6 Chronic venous disease is a multifactorial disease with epigenetic inuences.
66 Chapter 6 Epidemiology, genetics, and risk factors for chronic venous disease
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6
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CHAPTER
7
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Pathogenesis and hemodynamics
of varicose veins and chronic venous
insufficiency of the lower limb
John Blebea
7.1 INTRODUCTION
The term chronic venous insufciency (CVI) is used rather
broadly by many physicians in reference to the entire spectrum of nonacute venous disorders. The development and
revision of the CEAP classication and the Venous Clinical Severity Scores (VCSS) provided a methodology for
describing specic venous disorders and claried that CVI
implies a functional abnormality of the venous system (see
Chapter9). Both CEAP and VCSS are recommended for use
by clinical practice guidelines.
for the description of more advanced disease, beginning
with venous edema (C3), but more commonly in conditions with skin changes (C4) or ulceration (C5–C6). In this
chapter, we will discuss the pathophysiology and hemodynamics impairing normal function of the supercial and
deep venous system. A distinction will be made between
the roles of obstruction and valvular incompetence.
1–3
CVI should be reserved
7.2 SUPERFICIAL VENOUS
INCOMPETENCE
In the supercial venous system, the obstruction that
occurs with thrombophlebitis is not a major consideration
from a hemodynamic perspective. This can be explained
by the multitude of supercial venous tributaries available to divert ow through perforating veins into the deep
venous system. In addition, the main venous outow of
the leg occurs through the deep veins. The mechanism of
valvular incompetence and reux in the supercial system,
however, is of great importance because of both its hemodynamic effects and associated clinical sequelae. Currently
used ultrasound technology provides reliable and quantitative diagnosis of supercial incompetence, and therapeutic
interventions to a large extent are focused on the ablation
of these incompetent venous segments. The duplex-derived
valve closure time for the diagnosis of supercial reux is
0.5 seconds.
The etiology of primary supercial valvular reux is still
disputed by some, although the majority of opinion favors
a weakness of the vein wall inducing venous dilation and
valve ring enlargement.
able to coapt completely, and valvular incompetence develops. This concept was originally proposed by Cotton more
than 50years ago when he demonstrated, using anatomical casts, that venous dilation developed below rather than
above the valves in patients with varicose veins.
of this hypothesis, numerous biochemical abnormalities
have been reported within the venous wall, which have an
impact on its distensibility. Varicose veins have abnormal
elastic properties, with increased collagen content, elastin
ber fragmentation, and degradation and accumulation of
extracellular matrix.
either an initial deciency in wall integrity or an induction
of structural degradation. An early study by Ackroyd et al.
showed that the valve ring and its leaets had far greater
tensile strength than the vein wall itself, favoring the theory
that valvular incompetence is secondary to a defect in the
vein wall.
Secondary valvular dysfunction following episodes of
thrombophlebitis undoubtedly occurs in the supercial
system, although with less important effects than within
the deep system. After the initial thrombotic event, intrinsic thrombolysis and recanalization allow for blood ow
to resume within the previously occluded vein. However,
the inammatory and brotic processes in the valve cusp
restrict the movement of the leaets, resulting in only a
partially mobile leaet or a completely “frozen valve”
(Figure7.1). The end result is valvular incompetence and
reux. In addition, inammation of the nonvalvular segments of the vein can lead to thickening and calcication in
the wall (Figure7.2). It is unclear to what degree this loss
of elasticity and distensibility affects venous ow hemodynamics, but, at a minimum, it decreases volume ow in
those segments because of the diminished luminal diameter.
An additional component to be considered is the gravitational pressure effect on supercial venous ow. The
additional hydrostatic pressure upon standing increases the
outward wall tension and thus the distension of the vessel.
Superimposed on a structurally weakened wall, this supplementary force can increase vein diameter and separate
the valve leaets even further, leading to an exacerbation of
4
The valve leaets are no longer
5
In support
6,7
These abnormalities have supported
8
DOI: 10.1201/9781003328971-8
6969
70 Chapter 7 Pathogenesis and hemodynamics of varicose veins and chronic venous insufficiency of the lower limb
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7.1 Longitudinal ultrasound image of a thickened and immobile
venous valve.
of great saphenous reux, as compared to 31 seconds in
controls.
10
This illustrates the reux and increased pressure
transmitted through the in-line column of uid without the
protective pressure separation of closed valves. In terms of
leg blood volume rather than pressure, the ejection fraction
with venous insufciency is less than 65% and the residual
volume fraction is greater than 30% as measured by air
plethysmography.
An understanding of these hemodynamic and pressure
changes with supercial venous incompetence has formed
the physiological basis of our treatment recommendations.
Both the original proximal saphenofemoral ligation and
complete great saphenous vein stripping sought to eliminate the entire axial pathways of reux and venous hypertension. Modern techniques of endovenous ablation or
closure, either by laser, radiofrequency, or cyanoacrylate
adhesive, have demonstrated equivalent clinical improvement with more limited closure of only proximal incompetent venous segments. To the surprise of many surgeons,
the doctrine that all the multiple branches at the saphenofemoral region needed to be ligated in order to achieve
clinical improvement has been contradicted by satisfactory
clinical outcomes after ablative procedures leaving those
branches intact. Afurther challenge to our classical treatment recommendation for ligation and stripping has been
the successful relief of supercial incompetence symptoms
following the CHIVA (Cure Conservatrice et Hemodynamique de l’Insufcience Veineuse en Ambulatoire) procedure, in which the great saphenous vein is spared and
only reuxing collateral branches are disrupted.
11
Finally,
an improvement of venous edema (C3) can be achieved
using compression stockings. Class II (20–30 mmHg) and
class III (30–40 mmHg) stockings reduce the volume of the
leg in which interstitial uid increases and possibly also
compress the deep veins in some positions in less diseased
12
legs.
7.2 Post-thrombotic vein demonstrating an irregular luminal
contour, thickening of the wall (lled arrow), and calcication
(open arrow).
reux. The clinical nding that, over time, reux progresses
from a more distal, higher-pressure location to more proximal, lower-pressure segments support the idea of gravitational pressure’s contribution to supercial venous reux.
9
The increased venous pressure on standing cannot be
relieved by walking or exercise in patients with supercial
reux. When exercising, the measured supercial venous
pressure in the dorsum of the foot decreased from an average of 87 mmHg to 22 mmHg in normal limbs. In those
with varicose veins, it decreased to only 44 mmHg with a
recovery or relling time of just 3 seconds in the presence
7.3 THE DEEP VEINS
Occlusion of the deep veins due to acute deep vein thrombosis (DVT) is a more serious event because of the mortality risk from pulmonary embolization and because of
the signicant hemodynamic impact of venous outow
obstruction. Acute proximal vein thrombosis of the femoral, common femoral, or iliac veins can limit blood outow
to such an extent that arterial inow to the leg is diminished. The resultant leg ischemia due to venous obstruction—phlegmasia cerulea dolens—is so severe that, if not
urgently relieved, it leads to limb loss. Fortunately, a variety of thrombolytic, mechanical, and interventional procedures are available to treat such extensive acute venous
occlusions. This is of major importance, as rapid thrombus
resolution has been found to be associated with a higher
incidence of valve competency.
ical trial, however, found that such interventions did not
prevent the later development of post-thrombotic syndrome (PTS), although it decreased the incidence of moderate to severe PTS.
14
In addition to the ischemic effects
13
Alarge prospective clin-
71
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of acute occlusion, signicant leg edema will occur if the
thrombus is above the conuence of the deep femoral or
great saphenous veins, which act as collateral channels for
occlusions involving the femoral and more distal veins.
In circumstances involving less extensive or partial
thrombosis of these proximal veins, or complete DVT in
more distal vessels, treatment historically included acute
heparin anticoagulation therapy to prevent thrombus
extension, followed by conversion and long-term treatment with oral anticoagulants. The expectation was that
intrinsic thrombolysis would subsequently take place if the
systemic thrombotic balance was favorably tilted toward
a lytic state. Indeed, with such treatment, approximately
half of venous thrombi resolve completely within 6 months
of presentation when assessed using Doppler ultrasound,
through the process of lysis and reorganization.
15
The anatomical location of the thrombus is predictive of outcome to
some degree. The femoral vein is likely to remain occluded,
whereas partial to full recanalization is more commonly
found in the external iliac, common femoral, and popliteal
veins. This may be a result of higher ow rates, as well as
the presence of collateral channels. Recanalization alone,
however, is always hemodynamically incomplete and often
results in relative obstruction and reux.
16
When early thrombus resolution does not occur, the
remaining occlusive clot is remodeled, replaced by brous
tissue, and even covered by neo-endothelium, preventing
further lysis. Thrombi lling the lumen and adhering to
the vein wall cause complete venous obstruction, which
becomes permanent after it has been reorganized. This permanent occlusion has important hemodynamic obstructive effects and induces a progressive increase in venous
outow through collateral vessels, which can be protected
from thrombosis by the systemic anticoagulation maintained in the initial 3–6 months or longer. The extent of
the obstruction and the amount of developed collateral
pathways determine the venous outow out of the leg,
the severity of the hemodynamic changes, and therefore
the severity of post-thrombotic symptoms (Figure 7.3).
7.3 The two panels on the left show a normal set of deep veins.
The two panels on the right show post-thrombotic femoral veins
with synechiae and collateral pathways.
With potentially fewer or less robust valves, collateral vessels themselves may become channels for reux into the
extremity. When the popliteal vein has been occluded, the
calf perforating veins become important collaterals that
ow retrograde to the supercial venous system. Popliteal
obstruction, either in isolation or in combination with calf
vein and iliofemoral damage, is usually associated with
more severe symptoms and subsequent leg ulcer development.
Even nonocclusive thrombus in the deep venous system
can be associated with signicant hemodynamic dysfunction. Clots located in a valve pocket or in direct contact
with valve cusps can irreparably damage their function.
17
Acutely, the valves cannot move when encased by thrombi.
Lysis is more problematic and limited in the valve cusps
due to the low vortex ow in this region as compared to
the central lumen.
18
The brotic process is most damaging
in the areas of the valve, as it causes retraction and shortening of the leaets and further limits their mobility. This
is not just a simple mechanical effect. There is evidence
to suggest local neurohormonal sympathetic activity that
controls venous wall tone and the base of the annulus.
19
Occlusion of the draining vasa venorum at the base of the
valve changes the local norepinephrine concentrations and
further limits both valve closure and vein dilation.
In this manner, permanent valvular incompetence
develops, and reux occurs (CEAP-Es), dened for the
deep system as being greater than 1 second.
20
In the portion of the veins in which there are no valves, synechiae can
develop. Synechiae are permanent endothelialized strands
of residual organized thrombus, often crisscrossing the
lumen of the vein and producing a cribriform meshwork
which limits blood outow (Figure 7.3). If extending to
areas with valves, they can entrap the valve leaets and
bind them to the vein wall. Furthermore, in many patients,
the perivenous inammatory brosis that follows intraluminal thrombosis prevents venous distension and may also
act as a functional obstruction limiting total blood ow,
even though no thrombus remains in the lumen.
Post-thrombotic damage within the deep veins is the
most important cause of CVI within C5 and C6 CEAP
classes. However, a third of patients with advanced CVI
may have primary deep valvular incompetence (CEAP-Ep)
with no history or evidence of an inciting thrombotic etiology. This could be secondary to primary dilation of the
wall of the deep veins, or a ow phenomenon associated
with supercial vein incompetence that resolved upon
ablation of the latter system. Incompetence may also be
a consequence of abnormal valves (the oppy valves of
Kistner) or true congenital valvular agenesis (CEAP-Ec). In
some patients (e.g., in the case of Klippel–Trenaunay syndrome), the deep veins are completely absent and are functionally replaced by a primitive axial vein.
21
In addition,
deep vein obstruction or internal damage may occur as a
consequence of extrinsic compression, direct or indirect
traumatic injury, interventional complications, or vascular
tumors such as leiomyomas and leiomyosarcomas.
22,23
The deep veins are more important hemodynamically
because they are responsible for a greater portion of the
7
72 Chapter 7 Pathogenesis and hemodynamics of varicose veins and chronic venous insufficiency of the lower limb
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success when used in the femoral and popliteal veins.
Although thrombolysis is commonly employed with reasonable results, venous stent patency and durability have
not reached acceptable levels in these areas, probably
because of the veins’ small diameter and lower ows.
Advancements in the treatment of deep venous occlusive disease have not been mirrored in the treatment
of valvular reflux and insufficiency.
28
The concept of
repairing or replacing nonfunctioning valves promised
to immediately and directly restore their hemodynamic
performance. However, earlier historical experience
with both valve repair and transplantation to the femoral and popliteal regions did not meet clinical expectations and were associated with early thrombosis, not
justifying such technically demanding interventions,
and precluded widespread clinical use. However, while
patent, they appeared to be associated with excellent
clinical results, supporting the important value of
valves to deep system hemodynamics. Formation of a
new valve, either through an open surgical technique
7.4 Venogram of a right-to-left femoral-femoral venous bypass
(Palma procedure) utilizing the left great saphenous vein
(arrows) in a patient with a thrombosed right iliac system following previous iliac stenting (open arrow).
blood ow out of the leg. However, because until recently
we had been much more limited in terms of interventional therapeutic options, much less attention has been
paid to the deep system. With deep venous obstruction, diversion of ow around the occluding segment
remains a viable surgical option. The Palma procedure
is a well-established and successful method, providing
venous outow when the iliac veins are occluded on one
side but are open in the contralateral limb (Figure7.4).
or percutaneous endovascular methodology, has shown
early encouraging results.
29,30
Restoring valve function
through the placement of an artificial valve, particularly
at the femoral level, continues to induce investigations.
Although previous attempts at artificial valves have
also been limited due to a lack of durable patency, a
recent bioprosthetic valve has shown high patency rates
at 6 months with anticoagulation.
31
It is hoped that
in the future, with further progress in technique and
stent technology, such valves will become available for
patients with severe venous insufficiency and nonhealing ulcers. In the meantime, surgical endophlebectomy
in the common femoral region is available for a small
subset of patients in order to extend the efficacy of iliac
interventions.
32
This procedure usually requires a patent femoral vein
and a non-diseased great saphenous vein of sufcient
diameter to be used as a conduit, which is a circumstance that is not routinely present. When the iliac veins
or the vena cava are involved with tumor and there
7.4 THE PERFORATING VEINS OF THE
CALF
are no prior thrombotic changes of the inow veins, a
bypass with a prosthetic graft can be successful with
high venous ows.
24
Amore frequent clinical condition
is found consisting of acute or even chronic occlusion of
the iliac veins or the vena cava in the presence of previously inserted lters. On these occasions, excellent and
enduring relief has been attained using percutaneous
pharmaco-mechanical lysis and the insertion of venous
stents. Successful treatment is now available for proximal venous obstruction in patients with May–Thurner
syndrome when the extrinsic compression by the right
common iliac artery has produced a clinically signicant hemodynamic obstruction.
23,25
Intravascular ultrasound provides a better quantication of the degree and
extent of stenosis as well as evaluating the efcacy of
interventions.
26
Venous-specic stents are now available
which are larger, longer, and with more exibility, but
of sufcient radial strength and durability to cross the
hip area of exion underneath the inguinal ligament.
Unfortunately, venous stents have not achieved clinical
In normal individuals blood ows from the supercial
to the deep venous system via the perforating veins of
the calf. However, venous hypertension and reux in the
supercial system can be transmitted to the communicating veins and induce their dilatation and lead to valvular incompetence with retrograde ow from the deep to
the supercial system. Perforating veins can also act as
re-entry veins, allowing blood to reux down the saphenous system to ow back into the deep system. In many
patients, after ablation of the saphenous veins, postoperative duplex ultrasound shows that perforator valve competence has been restored.
33
Incompetent calf perforating veins are also often asso-
ciated with primary deep vein obstruction or incompe-
16
tence.
Clinically relevant ow from the deep system
to the supercial system is most frequently present with
incompetence of valves in the axial and deep veins adja-
27
cent to the perforating veins. Under these circumstances,
the perforating veins act as safety valves or collateral
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Time (s)
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Exercise
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pathways, allowing blood under high pressure in the deep
veins to escape to the supercial veins. During calf muscle contraction, the increased blood pressures in the deep
veins are directly transmitted via the connecting perforating veins to the supercial venous system of the calf.
34
100
7
This in turn leads to venous hypertension extending into
the microcirculation, with increased hydrostatic pressure
in the capillaries. There is secondary enlargement of the
75
dermal capillary bed and excessive transcapillary ltration, causing interstitial edema formation with the exudation of brinogen and proteins into the interstitial space,
producing the characteristic changes of lipodermatosclerosis.
35,36
50
Incompetence of one venous system in isolation is usually associated with minimal signs of CVI. Incompetence
of all three, however, is much more likely to be associated
with active ulceration and higher residual venous volumes
following calf muscle pump contraction.
25
7.5 FOOT AND CALF PUMP FUNCTION
The hemodynamics in the venous system are more complex
than on the arterial side because ow is intermittent, and
the veins are collapsible. Flow within them is also dependent on both the effects of gravity/hydrostatic pressure
and extrinsic muscle compression. Let us rst review their
function in the normal condition without obstruction or
valvular incompetence.
The calf muscles and, to a lesser extent, the foot and
7.5 Changes in foot vein pressure during a heel-raising exer-
cise in a normal limb. The pressure drops by 80%–90% from
baseline and requires 20–35 seconds to return to resting levels.
Source: (Browse NL, Burnand KG, and Irvine A. Diseases of the Veins,
London: Arnold, 1999. With permission.)
thigh musculature act as physiologic pumps and play critical roles in the standing position for returning venous
blood against gravity from the lower limbs to the heart.
The calf pump is the most important because it contains
further decrease the venous pressure once a steady state has
been reached.
the largest venous capacitance within the soleal and gastrocnemius sinusoids and generates the highest pressures.
Muscle contraction within the fascial compartments drives
blood up the deep axial veins of the leg. The intramuscular
pressures generated in the gastrocnemius and soleus muscles can increase up to 250 mmHg from 9 to 15 mmHg
in their relaxed state.
37
With muscle contraction, the large
pressure gradients induced in the deep calf veins and the
popliteal vein induce rapid efux of blood from the calf to
the thigh. When muscles relax, venous pressure decreases
within the calf compartments, and to the greatest degree
in the deep veins, which, via the competent valves, allows
the perforating veins to direct blood ow from the supercial to the deep system.
38
This subsequently dilates the
deep veins and reduces the pressure in the supercial veins.
The effect is incremental until the arterial inow equals the
venous outow capacity of the venous pumps. After muscle
activity ceases, capillary inow slowly lls the supercial
veins, which causes a slow increase in venous pressure over
the next 20–35 seconds as the veins rell back to their original resting pressure.
39,40
The efciency of the calf pump in normal subjects is
around 70%. The resting venous pressure is approximately
100 mmHg, depending on the patient’s height, and is
reduced to about 30 mmHg after 10 or more repetitive calf
contractions (Figure7.5).
41
Additional contractions fail to
understood and appreciated despite its obviously smaller
size and venous capacitance as compared to the calf.
Venous pressure at the ankle increases from 10 mmHg
to over 90 mmHg in the upright position, which provides sufcient hydraulic pressure at rest to return blood
back to the heart. Ambulatory venous pressure measured in the foot is considered normal at 10–30 mmHg,
representing intermediate venous hypertension at 31–45
mmHg and severe venous hypertension when greater
than 45 mmHg.
nor functional. Of greater interest is the role of the foot
during exercise. The foot venous pump is mainly deep
lateral plantar veins directly draining into the posterior
tibial veins, as has been well documented by the injection studies of Uhl and Gillot.
the infra-malleolar perforators into the medial marginal
vein at the origin of the great saphenous vein below the
ankle. Interestingly, this demonstrates reversed blood
ow from the deep to the supercial system, rather
than in the opposite direction that is seen everywhere
else in the leg. Finally, there are the anterior communicating veins linking the plantar reservoir directly to
the anterior tibial veins. Normal efux takes place from
the foot through both the deep and supercial venous
0
03
0
The importance of the foot pump has become better
42
At rest, the foot pump is neither needed
43
It also communicates via
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