pathophysiology of chronic venous disease

7/27/2019 Pathophysiology of Chronic Venous Disease

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Pathophysiology of chronic venous disease

Authors

Patrick C Alguire, MD, FACP

Barbara M Mathes, MD, FACP, FAADSection Editors

John F Eidt, MDJoseph L Mills, Sr, MDDeputy Editor

Kathryn A Collins, MD, PhD, FACS

DisclosuresAll topics are updated as new evidence becomes available and ourpeer review processis

complete.

Literature review current through: Jun 2013. | This topic last updated: may 1, 2013.

INTRODUCTIONChronic venous disease is a common medical problem that can result

in significant morbidity and mortality. The clinical presentation of this disorder spans a

spectrum from asymptomatic but cosmetically troublesome small blue ectatic veins andvaricosities, to severe fibrosing panniculitis, dermatitis, edema, and ulceration. (See

"Clinical manifestations of lower extremity chronic venous disease".)

The final common pathway that leads to chronic venous insufficiency is the development of

venous hypertension. In most cases, venous hypertension results from obstruction to venous

flow, dysfunction of venous valves, and/or failure of the "venous pump." In thesesituations, flow is directed abnormally from the deep to the superficial system, producing

local tissue inflammation fibrosis, and occasionally ulceration.

This topic will review normal venous anatomy and physiology, and the pathophysiology of

venous hypertension with its clinical consequences. Other aspects of chronic venous

insufficiency are discussed separately.

NORMAL VENOUS ANATOMY AND PHYSIOLOGYThree major vascular

pathways are responsible for draining blood away from the superficial vessels of the skinand subcutaneous fat and include: (See"Classification of lower extremity chronic venous

disorders", section on 'Anatomy'.)

Superficial veinsThe superficial veins are a network of subcutaneous veins thatare superficial to the deep muscular fascia and include the great saphenous and

small saphenous veins. (figure 1andfigure 2).

Deep veinsThe deep veins are located deep to the muscle fascia (figure 3). Deepveins are either within the muscle (ie, intramuscular, such as the gastrocnemius and

soleus) or between the muscles (ie, intermuscular); the latter are more important in

the development of chronic venous insufficiency [1]. The intermuscular veins,which accompany the lower extremity arteries, include the anterior tibial, posterior

tibial, peroneal (fibular), popliteal, and femoral veins. The lower leg intermuscular

veins are exposed to high subfascial pressures during calf muscle contraction.

Perforating veinsThe perforating veins communicate between the deep andsuperficial venous systems. One very important group of perforating veins,
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Cocketts perforators, connect the posterior tibial veins to the posterior accessory

great saphenous vein (ie, vein of Leonardo), indirectly draining into the deep venous

system.

Determinants of venous flowThe venous valves and "venous pump" are the two major

determinants of venous flow.

Venous valves are typically bicuspid. Venous valves direct flow from distal toproximal and from the superficial system to the deep system except in the foot,where flow is directed from the deep system to the superficial system. Venous

valves increase in number in direct relation to the hydrostatic pressure; in the distal

deep veins, for example, they may occur every 2 centimeters [1].

The venous pump refers to the pumping effect of leg muscles on venous flow. Asblood is directed proximally in the deep venous system by muscular contraction, it

enters the deep venous system from the superficial system, draining the skin and

subcutaneous tissues.

The effectiveness of the pump is dependent upon the presence of competent venous valves.

Competent valves serve two main functions: they prevent the transmission of sudden risesin venous pressure in the superficial veins and capillaries during muscular contraction; and,

at the end of muscle contraction, the valves prevent retrograde flow back into the

superficial system. When this system is functioning appropriately, the ambulatory venouspressure in the superficial system is maintained between 20 and 30 mmHg.

GENESIS AND CONSEQUENCES OF CHRONIC VENOUS HYPERTENSIONInthe presence of venous obstruction, incompetent venous valves, or inadequate muscle

contraction, ambulatory venous pressures can reach 60 to 90 mmHg. This level of venous

pressure constitutes venous hypertension, and is capable of initiating the anatomic,

physiologic, and histologic changes associated with chronic venous insufficiency (table 1)[2-5].

Anatomic changesValvular incompetence is the primary anatomic abnormalityassociated with venous hypertension. Deep vein thrombosis is an example of a disorder that

causes venous hypertension (because of diminished proximal flow of venous blood) and

chronic venous insufficiency via this mechanism. The increase in pressure is transmittedbackward into the superficial venous system; thrombosis also destroys the valves, resulting

in persistence of venous hypertension even if the thrombosed veins are recanalized.

Chronic venous insufficiency is also associated with fewer valves per unit length which

contributes to higher venous pressures [6].

This process becomes a vicious cycle. As deep and superficial veins become distended with

excess volume, anatomic distortion of the vessel wall produces further valvularincompetence.

The actual volume of refluxed blood in patients with venous insufficiency may be relatively

small. However, when the superficial veins are already maximally distended, small

increases in volume produce large increases in pressure [7]. It is the transmission of this
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excess pressure that is responsible for most of the skin changes characteristic of chronic

venous insufficiency. (See'Lipodermatosclerosis'below and"Clinical manifestations of

lower extremity chronic venous disease".).

Physiologic changesStanding is normally associated with reflex constriction of the

precapillary arterioles; by diminishing the transmission of arterial pressure to the capillarybed, this response protects the capillary bed from surges in venous hydrostatic pressure

when assuming an upright posture. Patients with venous hypertension may lose this reflex;

as a result, large increases in venous pressure are transmitted directly to the superficial

capillary system [8-10].

Histologic changesSustained venous hypertension is associated with characteristichistological and ultrastructural changes that underlie the cutaneous manifestations of

chronic venous insufficiency.

Venous hypertension is associated with changes in the venous wall, including variation inwall thickness, increases in type 1 collagen, decreases in type III collagen, degradation of

extracellular matrix, and reductions in the number of smooth muscle cells [11-13]. These

changes weaken the vessel wall and may lead to abnormal venous dilation [14]. Thechronic release of inflammatory mediators is a fundamental cause for the trophic skin

changes associated with venous insufficiency.

Leukocytes accumulate and adhere to the endothelium of small vessels and becomeactivated [15,16]. This microvascular leukocyte-trapping hypothesis is supported by

histological findings of increased numbers of macrophages, T lymphocytes, andmast cells in the tissue of patients with chronic venous hypertension [17,18].

Increased expression of matrix metalloproteinases and other proteinases by thevessel cells breaks down the vascular extracellular matrix and leads to abnormal

vascular permeability and edema.

The presence of proteolytic enzymes in subcutaneous tissues leads to the formationcutaneous ulcers, which heal poorly and can become chronic [19].

Migration of erythrocytes from the vascular space into tissue, and their subsequentdegradation, results in the characteristic brown hyperpigmentation in the gaiter area.

The release of ferritin and ferric oxide from the erythrocytes may result in oxidative

stress and additional metalloproteinase activation, promoting tissue damage, ulcerformation, and delayed ulcer healing [20].

LipodermatosclerosisPatients with significant venous insufficiency can develop a

severe fibrosing panniculitis of the subcutaneous tissue; the clinical representation of thepanniculitis is known as lipodermatosclerosis. (See"Clinical manifestations of lower

extremity chronic venous disease".)

Lipodermatosclerosis presents as an area of indurated inflammatory tissue that binds the

skin down to the subcutaneous tissue (picture 1A-C). Lipodermatosclerosis is associated

with abnormal, elongated, glomerular-like capillaries with increased vascularpermeability [21]. Dermal fibrosis may be the result of TGF-1 fibrogenic cytokine release

from activated leukocytes that have migrated out of the abnormally permeable vessels into
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the tissues. TGT-1 cytokine increases the production of collagen and subcutaneous

fibrosis [18]. Capillaries are virtually absent in areas of fibrotic scars, leading to a condition

known as atrophie blanche or livedoid vasculopathy (picture 2)[22]. The lack of blood

flow may explain the proclivity for these areas to develop ulcers. (See"Livedoidvasculopathy".)

As with valvular incompetence, worsening lipodermatosclerosis may become part of a

vicious cycle. As the fibrosis increases, it may become so extensive and constrictive as to

girdle and strangle the lower leg, further impeding lymphatic and venous flow.

Low shear stressShear stress is inversely related to venous pressure. Thus, venous

hypertension is associated with low shear stress. Leukocytes aggregate and activate whensubjected to low shear stress, promoting inflammatory and thrombotic reactions [23-25]. It

is not known how low shear stress promotes inflammatory events in the venous system;

however, this process seems important in causing the pathological changes in veins and

valves.

SUMMARY AND RECOMMENDATIONS

Chronic venous disease is a common medical problem that can result in significantmorbidity and mortality. The final common pathway that leads to chronic venous

insufficiency is the development of venous hypertension, particularly within thedeep venous system. (See'Introduction'above.)

Deep veins are classified as within the muscles (ie, intramuscular) or between themuscles (ie, intermuscular). Abnormalities of the intermuscular veins (anteriortibial, posterior tibial, peroneal [fibular], popliteal, and femoral veins) play a more

significant role in the development of chronic venous insufficiency. The

intermuscular veins of the lower leg veins are exposed to high subfascial pressures

during calf muscle contraction. (See'Normal venous anatomy and physiology'above.)

Venous valves direct flow from distal to proximal and from the superficial systemto the deep system except in the foot, where flow is directed from the deep systemto the superficial system. Blood is directed proximally within the deep venous

system by muscular contraction (ie, the venous pump). The effectiveness of this

pumping action is dependent upon the presence of competent vein valves to preventtransmission of sudden increases in venous pressure, and prevent retrograde flow.

When this system is functioning, the ambulatory venous pressure in the superficial

system is maintained between 20 and 30 mmHg. (See'Determinants of venous flow'

above.)

Valvular incompetence is the primary anatomic abnormality associated with venoushypertension, but obstruction (eg, deep vein thrombosis) and failure of the venous

pump may contribute. Anatomic distortion of the vessel wall from excess venous

pressure exacerbates valvular incompetence. (See'Anatomic changes'above.)

Sustained venous hypertension is associated with histologic and ultrastructuralchanges that lead to increased vascular permeability (edema) and the chronic release

of inflammatory mediators that are the fundamental cause of cutaneous
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hyperpigmentation, trophic skin changes, and ulceration. (See'Physiologic changes'

above and'Histologic changes'above.)

Lipodermatosclerosis refers to areas of indurated inflammatory tissue that bind theskin to the underlying subcutaneous tissue. The severity of lymphatic destruction isdirectly correlated to the degree of venous hypertension. (See'Lipodermatosclerosis'

above.)

Use of UpToDate is subject to theSubscription and License Agreement.

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