THE YALE JOURNAL OF BIOLOGY AND MEDICINE 66 (1993), 27-36

The Microvascular Pathophysiology of Chronic VenousInsufficiency

PAUL F. McDONAGH, Ph.D.

Department of Surgery, The University ofArizona, Tucson, ArizonaReceived April 28, 1992

Severe chronic venous insufficiency (CVI) demonstrates as chronic, hard-to-heal wounds ofthe lower extremity. The wound is the result of poor skin perfusion due to a complex series ofpathologic events, often initiated by a deep vein thrombosis (DVT). As years pass, the DVTcauses venous valvular damage and incompetence. The calf muscle pump fails to augmentvenous return, and venous blood pressure is chronically elevated upon standing. Mechanismsthat normally prevent the transmission of venous hypertension back upstream to the dermalmicrocirculation are lost. Early dermal microvascular responses include increased fluid filtra-tion and edema. An inflammatory response induces white cell activation and adhesion. It isthought that activated white cells are trapped in dermal capillaries and increase microvascularpermeability. Plasma proteins leak into the tissue space, increasing the edema. Ischemicdamage to the epidermis leads to epithelial cell necrosis and ulceration. The ulcer is often slowto heal, due to inadequate perfusion and delivery of substrates required for proper woundhealing. Current treatments aim to improve calf pump function, reduce edema, improveperfusion, and enhance wound healing.

INTRODUCTION

The development of improved strategies to treat cardiovascular diseases havebeen enhanced by research aimed at understanding the underlying pathophysiology.In recent years, a great deal of information has been gathered in clinical researchcenters around the world, dealing with the involvement of the microcirculation in theetiology of chronic venous insufficiency (CVI). The recent World Congress for theMicrocirculation provided a timely forum to assemble several key investigators inthis area in order to present their findings, derived primarily from research studies inman. The papers that follow represent selected presentations from that symposiumon the microangiopathy and treatment of CVI.As an introduction and orientation to the topic, this paper gives an overview of the

pathophysiology of CVI. Normal calf muscle pump function is considered first,followed by a general description of calf pump failure. The primary topic ofmicrovascular pathology in CVI is then presented, with attention to the functional

27Abbreviations: AVP: ambulatory venous pressure CPF: calf pump failure Cs: arterial solute concen-

tration Ct: solute concentration in the tissue CVI: chronic venous insufficiency DVT: deep veinthrombosis Es: solute extraction Js: transvascular solute flow Jv: transcapillary fluid flux Lp: hydrau-lic conductance coefficient Pa: pre-capillary (arteriolar) hydrostatic pressure Pc: capillary hydrostaticpressure rrc: capillary oncotic pressure nrt: tissue oncotic pressure Ps: microvascular permeabilitycoefficient for solute "s" Pt: tissue hydrostatic pressure Pv: post-capillary (venular) hydrostatic pres-sure Q: blood flow Ra: pre-capillary vascular resistance Rv: post-capillary vascular resistance S:exchanging microvascular surface area v: macromolecular reflection coefficient V-A: venoarteriolar[reflex]Address reprint requests to: Paul F. McDonagh, Ph.D., Dept. of Surgery, The University of Arizona,

Health Sciences Center, Tucson, AZ 85724

Copyright ©3 1993 by The Yale Journal of Biology and Medicine, Inc.All rights of reproduction in any form reserved.

brought to you by COREView metadata, citation and similar papers at core.ac.uk

provided by PubMed Central

PAUL F. McDONAGH

consequences of these changes on transvascular transport and exchange. Finally, anintegrated model of the microvascular, lymphatic, and hematologic alterations isdescribed.

HEMODYNAMIC CHANGES IN CHRONIC VENOUS INSUFFICIENCY

CalfPump Function and Failure

When one is standing, the blood pressure in the venous circulation of the lowerextremity is insufficient to force blood effectively uphill to the right heart. The calfmuscle pump serves as a cardiovascular assist device to aid venous return from thelower extremities; it pumps venous blood from the lower extremity during calf musclecontraction by compressing the deep veins. One-way valves in the deep venoussystem ensure that blood is ejected toward the heart during muscle contraction.Furthermore, competent venous valves prevent retrograde flow during leg musclerelaxation. Valves in the perforator veins ensure that, during contraction, blood doesnot flow from the deep to the superficial veins. Leg muscle pumps also exist in thefoot and the thigh; however, the most physiologically significant is the calf pump.Normal function of this pump requires both functional calf skeletal muscles andcompetent venous valves. If either component is dysfunctional or if a markedobstruction seriously impedes venous outflow, then venous return from the leg maybe chronically compromised.

Calf pump failure (CPF), the term coined by Browse et al. [1], is the inability of thecalf muscle pump to maintain venous return from the lower extremity. CPF is oftencaused by venous valvular incompetence secondary to a deep venous thrombosis,post-thrombotic syndrome, but may be due to primary valvular incompetence as well.CPF leads to accumulation of blood in the deep venous system and venous disten-sion. Further valve failure increases venous distension and venous hypertension.When the communicator valves become compromised, pressures developed in thedeep system are freely transmitted to the superficial system. Superficial venoushypertension is, in turn, transmitted back upstream to the dermal vasculature.Some of the most convincing evidence supporting the relationship between calf

pump failure and chronic venous ulceration was reported by Nicolaides and col-leagues [2]. Using the air plethysmograph, a pneumatic device designed specificallyto measure calf pump function, Christopoulos et al. [3] found that, when patientsdemonstrated either poor pump function (as measured by reduced ejection fraction)or severe valvular incompetence (shortened refill time), the probability of ulcerationwas markedly increased. When both poor ejection fraction and significant refluxwere observed, that patient had a 70 percent probability of ulceration [4].

Microvascular Function and Failure

Fluid Exchange and Edema: How then does calf muscle pump failure lead tochronic edema and ulceration? Figure 1 is a schematic diagram of the microcircula-tion of the skin. As the top panel suggests, parallel pathways exist for blood flow tothe epidermal capillary loops or the subpapillary plexus. Perfusion of the nutrientcapillary loops is normally sufficient to meet the metabolic needs of the tissue as wellas to function, when necessary, as a heat exchanger. Any net fluid filtration in theepidermis and dermis is managed by a competent lymphatic system. The bottompanel outlines some of the structural and functional changes that occur in the

28

MICROCIRCULATION IN CHRONIC VENOUS INSUFFICIENCY

Microcirculation of SkinNormal

Py

Chronic Venous Insufficiency Exudate

-*z/dV ama-M99SoX\x\s

pt *Lymphatic Drainage

;/F/Fibrin I

FIG. 1. Microangiopathy of theskin in chronic venous insufficiency.Top Panel: Normal conditions of perfu-sion and exchange: Protein-poorplasma is filtered from blood to tissue.The net filtered fluid is taken up by thecompetent lymphatic system.Bottom Panel: Chronic venous insuf-ficiency: Insufficient perfusion ofnutrient capillary loops. Increased mi-crovascular permeability to macromol-ecules, coupled with increased capillarypressure, Pc, causes a "permeability"type of edema. Lymphatic vessels arecompromised.

microcirculation in CVI. Chronic superficial venous hypertension upon standing setsin progress a cascade of events that ultimately affects skin perfusion, fluid and soluteexchange, lymphatic function, tissue morphology, and blood rheology. Edema is theresult of uncompensated fluid filtration from blood to tissue in the lower extremity.

Transvascular fluid exchange is governed by the Starling relationship [5]:

[1]Jv = LpS{(Pc -Pt) -Qr(c - Trt)}

where:

Jv = Transcapillary fluid fluxLp = Hydraulic conductance coefficientS = Exchanging microvascular surface area

Pc = Capillary hydrostatic pressurePt = Tissue hydrostatic pressurea = Macromolecular reflection coefficient

,rc = Capillary oncotic pressureTrt = Tissue oncotic pressure

Under normal conditions, Pc is about 25 mm Hg, Pt is roughly atmospheric, thereflection coefficient is close to one, rrc is 25 mm Hg, and the tissue oncotic pressure,7rt, is a few mm Hg. Generally, there is a slight, positive balance of driving forces,tending to filter fluid out of the vascular space into the interstitial space. The net fluidfiltered is removed by the lymphatic system.The driving force for fluid filtration, subject to moment-to-moment change, is the

capillary hydrostatic pressure (Pc). Upon one's standing, Pc initially increasessharply. If no compensatory mechanisms come into play, fluid filtration increases,and "edema" rapidly develops. The blood pressure in the capillary exchange vessels,

29

PAUL F. McDONAGH

Pc, is directly related to the upstream and downstream pressures. This relationshipwas described by Folkow and Neil [6] as:

p Pa(RvIRa) + Pv1 + (Rv/Ra) [2]

where:

Pc = Capillary hydrostatic pressurePa = Pre-capillary (arteriolar) hydrostatic pressurePv = Post-capillary (venular) hydrostatic pressureRv = Post-capillary vascular resistanceRa = Pre-capillary vascular resistance

Normally, the vascular resistance upstream of the capillaries, Ra, is about five timesthat of the downstream resistance. In other words, roughly 20 percent of thearteriolar blood pressure is transmitted to the capillaries. As equation 2 alsoindicates, all of the post-capillary venous pressure is transmitted directly to thecapillaries.To appreciate the changes that occur in Pc upon standing, assume the subject is

initially supine, with Pa = 100 mm Hg and Pv = 5 mm Hg. From equation 2, thecapillary blood pressure near the ankle is:

100(0.2) + 5Pc=- = 21 mm Hg1 + 0.2

Upon standing, an 80 mm Hg hydrostatic head is immediately added to both theupstream and downstream pressures. In this case, the capillary pressure initiallyincreases to:

180(0.2) + 85Pc-= 1+0 = lOlmmHg1 + 0.2

A sudden and sustained increase in capillary hydrostatic pressure of this magni-tude causes a marked imbalance of the Starling forces in equation 1, favoring fluidfiltration and edema.The increase in Pc upon standing is normally offset by two physiologic mecha-

nisms, the venoarteriolar (V-A) reflex and the functional calf muscle pump. The V-Areflex attenuates the increase in Pc by causing an intense pre-capillary vasoconstric-tion upon standing [7,8]. The resulting increase in vascular resistance decreases thearterial contribution to Pc by decreasing RvIRa in equation 2. Figure 2 demonstratesthe venoarteriolar reflex in a normal subject. Skin blood flow was measured with alaser doppler blood perfusion monitor (Laserflo Model 403 A, skin temperature35°C, probe located one inch above the medial malleolus). The Laserflo reading isproportional to skin blood flow. In this case, skin perfusion measured 6 Laserflo unitsin the supine position. Within three minutes after standing, skin flow decreased to0.6, roughly a tenfold decrease in flow. Assuming this tenfold decrease in flow wasdue to a tenfold decrease in Rv/Ra, the capillary pressure is:

180(0.02) + 851 + 0.02

30

MICROCIRCULATION IN CHRONIC VENOUS INSUFFICIENCY

20 . -.,.,,. . -.. ....... _..

0 o 15... .;t.X :....:. ?''.4.__...__FIG. 2. The venoarteriolar re-

zDX 10--g$t, i w^vt..,.,,..--.-.. + -flex in a normal subject: Skin per-(A I-t-H ~~~~~~~~~~~~~fusionwas measured with a laser

* = 5 _=l S S E..Jr+- doppler perfusion monitor (La-5 ~~~~~~~~~~~~~serflo)at 350C near the medialw -- <@t- x it..-..:: .......... malleolus. Upon the subject'sstanding, the skin flow decreased

jt qI i-I min. by a factor of ten, indicating an

intense pre-capillary vasoconstric-Stand tion.

Thus, upon standing, the capillary pressure increased to only 87 mm Hg, i.e.,essentially the venous pressure, rather than 101 mm Hg. An active V-A reflex, then,almost completely offsets the arterial contribution to the increased pressure uponstanding. This reduction in Pc is certainly an improvement, but a marked imbalanceremains, and filtration and swelling will occur if no other mechanisms come into play.The other mechanism that is normally operative is the calf pump. The calf muscle

pump decreases superficial venous blood pressure upon exercise. As the calf musclesrelax, the blood pressure in the deep veins briefly drops below the superficial venouspressure. This transient pressure gradient causes blood to be drawn from thesuperficial veins into the deep system through the perforator veins. The suctioningeffect is remarkably effective. After several calf contractions, this mechanism candecrease superficial venous pressure from 85 mm Hg to an ambulatory venouspressure (AVP) of roughly 30 mm Hg [2]. In this case, Pc decreases to:

180(0.02) + 30PC= -~ =33mmHg1 + 0.02

Thus, a functional calf pump can cause a significant decrease in Pc when one isstanding. Increased tissue pressure, Pt, during exercise will reduce further theeffective filtration pressure (equation 1), and a functional lymphatic system caneasily handle any remaining net fluid filtration.

In chronic venous insufficiency, these compensatory mechanisms are compro-mised. For example, upon standing, the post-capillary pressure is again increased to85 mm Hg. In severe grade III CVI, however, the one-way valves in the perforatorveins are often incompetent. Calf muscle relaxation then does not effectively siphonblood from the superficial system, lowering Pc. Rather, the increased pressuresdeveloped in the deep veins during muscle contraction are transmitted to thesuperficial veins. Post-capillary pressures in the dermal circulation remain elevated.Furthermore, grade III CVI patients may not demonstrate a normal V-A reflex uponstanding [4]. In this case, much of the increase in Pa is transmitted to the dermalexchange vessels. The failure of these two compensatory mechanisms causes asustained elevation of Pc when the patient stands. The resulting fluid filtration mayoverwhelm the lymphatic drainage system, causing edema. A chronic increase in Pcupon standing may contribute to the heavy exudation often observed in venousulcers.

31

PAUL F. McDONAGH

Solute Delivery and Exchange in CVI: The supply of substrates to tissue isgoverned by both the rates of substrate delivery and transvascular exchange. Solutedelivery is the product of the blood flow, Q, and the arterial solute concentration, Cs.Transvascular solute exchange is described by the relationship [9,10]:

Js = Jv(1- ) + PsS(Cs - Ct) [3]

where:

Js = Transvascular solute fluxJv and a, as defined abovePs = Microvascular permeability coefficient for solute "s"S = Microvascular surface area available for exchangeCt = Solute concentration in the tissue

Equation 3 states that transvascular solute exchange is a function of both convectionand diffusion. For small solutes, such as oxygen and glucose, exchange by diffusion ismuch greater than by convection, and the first (i.e., Jv) term on the right-hand side ofequation 3 can be ignored. Under normal conditions of proper nutrition andpulmonary function, the blood levels of nutrients, Cs, are adequate. The permeabil-ity coefficients, Ps, are fixed, and the capillary surface area available for exchange, S,is largely a function of the number of perfused microvessels. Normally, blood flow iswell regulated, and nutrient supply meets nutrient demand.

In CVI, both solute delivery to the skin and transvascular exchange are compro-mised. The interrelationship of delivery and exchange can be described by expressingequation 3 in terms of solute clearance. Multiplying both sides of equation 3 by bloodflow, Q, and defining solute extraction, Es, as (Cs-Ct)/Cs, yields, for small solutes:

JsQ = (QCs)(PsSEs) [4]

Equation 4 states that the tissue uptake or "clearance," JsQ, of a small solute "s" isa function of solute delivery, QCs, and microvascular exchange parameters Ps, S, andEs. Each of the factors in equation 4 is affected by CVI. Although total blood flow tothe skin may be normal, nutritional flow to the capillary loops may be reduced, asdescribed below and illustrated in Fig. 1. Reduced perfusion to the epidermalexchange vessels will reduce solute delivery and clearance. Improper nutrition andanemia can also reduce delivery by lowering nutrient concentrations, Cs.

It has been proposed that the permeability coefficients, Ps, to small solutes arereduced in CVI due to pericapillary cuffing [11]. Burnand et al. [12] proposed thatfibrin cuffs found around dermal capillaries prevent the passage of oxygen into thetissues. Fibrin accumulation around capillaries has been observed by several investi-gators [13], but the significance of fibrin cuffs as a diffusion barrier to small soluteshas been questioned. Using a Krogh cylinder model, Michel [14] concluded that it isunlikely that pericapillary fibrin cuffs significantly decrease oxygen exchange in CVI.Cheatle et al. [15] measured the clearance of radioactive xenon, a solute withdiffusion characteristics similar to oxygen's, in normals and CVI patients. They foundno significant difference in the xenon clearance rates and concluded that pericapil-lary cuffs do not significantly compromise oxygen transport. From equation 4, it canbe seen that clearance is a function of microvascular permeability, but it is also afunction of other factors, such as flow and capillarity. Thus, Cheatle et al.'sconclusion may not be fully justified. Their results, however, taken together with the

32

MICROCIRCULATION IN CHRONIC VENOUS INSUFFICIENCY

theoretical analysis of Michel, raise doubts that fibrin cuffing explains totally thecompromised solute exchange and reduced tcPO2's [16-18] commonly observed inCVI patients.A key exchange parameter in equation 4 that is likely to be reduced is the

microvascular surface area available for exchange, S. The principal exchange vesselsare the capillaries and post-capillary venules. In an ultrastructural study of CVImicroangiopathy, Wenner et al. [19] observed reduced capillary numbers and alteredmorphology of those remaining. Using intravital microscopy, Fagrell [20] observedfewer skin capillaries in the lower extremity in patients with deep venous insuffi-ciency (DVI). Bollinger et al. [21] found a total absence of capillaries in regions of"atrophy blanche" and enlarged capillaries in the area near the ulcer edge. Thefunctional consequences of reduced capillarity in CVI were studied by Franzeck etal. [16]. Using intravital microscopy to observe perfused capillaries combined withsimultaneous measurements of transcutaneous oxygen tension, Franzeck and col-leagues found a direct correlation between tcPO2 and nutritional capillary density.Microscopy revealed reduced capillary numbers in regions of hyperpigmentation andhyperkeratosis. The capillaries were dilated and tortuous, surrounded by a halo offluorescence. In regions with white atrophy, perfused capillaries were again absent,as described by Bollinger et al. [21], resulting in a tcPO2 that was essentially zero.One mechanism to explain the decrease in perfused capillarity is capillary plugging

by white cells [22]. Reduced blood flow and/or an inflammatory stimulus can inducewhite blood cell activation and sequestration in the microcirculation of severalvascular beds, including skeletal muscle [23], the heart [24], and the lower extremity[25]. In CVI patients, Coleridge-Smith et al. [22] observed a decrease in the numberof functioning capillary loops after the legs were dependent for 30 minutes. Thomaset al. [26] reported a decrease in the ratio of white cells to red cells in the venousreturn from dependent limbs of CVI patients. Taken together, these observationssuggest that, when the legs were dependent, some of the dermal capillaries wereplugged by white cells. If so, nutritional flow through these vessels will be stopped,reducing perfused capillarity and limiting nutrient exchange. As suggested in Fig. 1,the blood may shunt through other "preferential" channels offering less resistance[27,28]. Thus, in CVI, Cs, Ps, and S are reduced. Measures of total skin flow may benormal or even elevated [17,29], yet the epidermis is undersupplied. When themismatch of supply and demand becomes severe, the skin is more vulnerable totraumatic injury, ulceration, and susceptible to chronic infection. Furthermore,wound repair is impeded, due to the inadequate supply of blood components,vitamins, and subtrates required for healing.

Macromolecular exchange is also altered in CVI. The transvascular exchange ofmacromolecules, such as plasma proteins, is governed by convection, the first term onthe right-hand side of equation 3. The factors leading to increased protein extravasa-tion are increased Jv and decreased protein reflection coefficient a. In CVI, Jv isincreased, as described above. The protein reflection coefficient also appears to bedecreased. Wenner et al. [19] observed increased numbers of Weibel-Palade bodiesand endothelial vesicles in dermal capillaries from CVI patients. Often, transendo-thelial channels were formed by the vesicles. In addition, interendothelial gaps largeenough to allow extravasation of red cells were observed. White cell activation andrelease may also contribute to increased microvascular permeability to proteins inCVI. In other vascular beds, reduced flow or an inflammatory stimulus has been

33

PAUL F. McDONAGH

MICROVASCULAR DYSFUNCTION INCHRONIC VENOUS INSUFFICIENCY

E

VENOUS HYPERTENSION

DECREASED A-V FLOW GRADIENTDERMAL CAPILLARY HYPERTENSION

ISCHEMIA VASODILATIONWBC ACTIVATION

INCREASED CAPILLARY PERMEABILITY

INCREASED EDEMALYMPH _ PROTEIN LEAKAGE LOSS OF V-AFLOW REFLEX

TISSUE FIBRIN ACCUMULATIONDECREASED PERFUSED CAPILLARITY

REDUCED MICROVASCULAR TRANSPORT

ULCERATION, INFECTIONLYMPHATIC COMPROMISE

FIG. 3. Microvascular pathophysiol-ogy of chronic venous insufficiency:Calf pump failure leads to microvascu-lar hypertension, edema, and a perfu-sion defect. Chronic vasodilation maycontribute to failure of the V-A reflex.Lymphatic failure aggravates edema.

shown to increase protein extravasation [30]. Since the net effect of CVI appears tobe an increase in microvascular permeability [16,19,31], the hydraulic conductivity,Lp, probably increases as well. These convective changes-namely, increased Jv, Lp,and decreased u-all contribute to a "permeability" type of edema. The extravasa-tion of plasma proteins aggravates further fluid filtration. Extravasation of plasmafibrinogen is the chief source of tissue fibrin.The extravasation of plasma in the terminal vasculature is often complicated by

lymphatic compromise in CVI. Some studies report an increase in lymph flow [32];however, the weight of current evidence indicates that lymphatic function is de-creased both at the level of the terminal lymphatics [33] and in larger lymph vessels[34].

In addition to the microangiopathy, several hematologic changes have beenreported in CVI patients. Browse et al. [1] demonstrated a reduction in thefibrinolytic activity of tissue and plasma in patients with grade III CVI. A decrease inthe ability to lyse fibrin compounds the accumulation of fibrin in the tissue. Ernst etal. [35] reported increased plasma viscosity and reduced red cell filterability in theblood of CVI patients. These changes increase the viscous component to vascularresistance and can enhance platelet aggregation, further compromising perfusionand delivery. As mentioned earlier, leukocyte sequestration is increased in thedependent limbs of CVI patients [26].

Figure 3 is a proposed model of the microvascular changes thought to take place inCVI. These microvascular alterations will cause a protein-rich edema, limit nutrientdelivery and exchange, and cause tissue accumulation of fibrin. Lymphatic dysfunc-tion further compromises the normal compensatory mechanisms that accommodate

34

MICROCIRCULATION IN CHRONIC VENOUS INSUFFICIENCY 35

enhanced fluid filtration. Hematologic changes aggravate tissue accumulation offibrin and further compromise capillary perfusion. Several questions remain to beanswered [36]: Are the fibrin cuff, white cell trapping, or loss of the V-A reflexsignificant components of the microangiopathy of CVI? How do the lymphaticsbecome compromised? What is the interrelationship of the vascular endotheliumand blood components in this disease? The development of more effective treat-ments must address the key components of the microangiopathy described above andin the papers that follow.

REFERENCES

1. Browse NL, Burnand KG, Thomas ML: Diseases of the Veins: Pathology, Diagnosis and Treatment.London, UK, Edward Arnold, 1988, 694 pp

2. Nicolaides A, Christopoulos D, Vasdekis S, et al: Progress in the investigation of chronic venousinsufficiency. Ann Vasc Surgery 3:278-292, 1989

3. Christopoulos D, Nicolaides AN, Cook A, Irvine A, Galloway JMD, Wilkinson A: Pathogenesis ofvenous ulceration in relation to the calf muscle pump function. Surgery 106:829-835, 1989

4. Belcaro G, Christopoulos D, Nicolaides A: Lower extremity venous hemodynamics. Ann Vasc Surgery5:305-310, 1991

5. Gore RW, McDonagh PF: Fluid exchange across single capillaries. Ann Rev Physiol 42:337-357, 19806. Folkow B, Neil E: Circulation. New York, Oxford University Press, 1971, pp 58-597. Hassan AAK, Rayman G, Tooke JE: Effect of indirect heating on the postural control of skin blood

flow in the human foot. Clin Sci 70:577-582, 19868. Levick JR, Michel CC: The effects of position and skin temperature on the capillary pressures in the

fingers and toes. J Physiol 274:97-109, 19789. Taylor AE, Granger DN: Exchange of macromolecules across the microcirculation. In Handbook of

Physiology 2, The Cardiovascular System, Vol 4, Microcirculation, part 1. Edited by EM Renkin, CCMichel, SR Geiger. Washington, DC, American Physiological Society, 1984, pp 467-520

10. McDonagh PF, Roberts DJ: Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Direct observations in isolated rat hearts. CircRes 58:127-136, 1986

11. Browse N, Burnand K: The cause of venous ulceration. Lancet ii 243-245, 198212. Burnand KG, Whimster I, Naidoo A, Browse NL: Pericapillary fibrin in the ulcer-bearing skin of the

leg: The cause of lipodermatosclerosis and venous ulceration. Br Med J 285:1071, 198213. Falanga V, Mossa HH, Nemeth AJ, Alstadt SP, Eaglstein WH: Dermal pericapillary fibrin in venous

disease and venous ulceration. Arch Dermatol 123:620-623, 198714. Michel CC: Oxygen diffusion in oedematous tissue and through pericapillary cuffs. Phlebology

5:223-230, 199015. Cheatle TR, McMullin GM, Farrah J, Coleridge-Smith PD, Scurr JH: Skin damage in chronic venous

insufficiency: Does an oxygen diffusion barrier really exist? J Roy Soc Med 83:493-494, 199016. Franzeck UK, Bollinger A, Huch R, Huch A: Transcutaneous oxygen tension and capillary morpho-

logic characteristics and density in patients with chronic venous incompetence. Circulation 70:806-811, 1984

17. Sindrup JH, Avnstorp C, Steenfos HH, Kristensen JK: Transcutaneous P02 and laser doppler bloodflow measurements in 40 patients with venous leg ulcers. Acta Derm Venereol 67:160-163, 1987

18. Travers JP, Berridge DC, Makin GS: Surgical enhancement of skin oxygenation in patients withvenous lipodermatosclerosis. Phlebology 5:129-133, 1990

19. Wenner A, Leu HJ, Spycher M, Brunner U: Ultrastructural changes of capillaries in chronic venousinsufficiency. Expl Cell Biol 48:1-14, 1980

20. Fagrell B: Local microcirculation in chronic venous incompetence and leg ulcers. Vascular Surgery13:217-225, 1979

21. Bollinger A, Jager K, Geser A, Sgier F, Seglias J: Transcapillary and interstitial diffusion ofNa-fluorescein in chronic venous insufficiency with white atrophy. International Journal of Microcir-culation Clinical and Experimental 1:5-17, 1982

22. Coleridge-Smith PD, Thomas P, Scurr JH, Dormandy JA: Causes of venous ulceration: A newhypothesis. Brit Med J 296:1726-1727, 1988

36 PAUL F. McDONAGH

23. Braide M, Amundson B, Chien S, Bagge U: Quantitative studies on the influence of leukocytes on thevascular resistance in a skeletal muscle preparation. Microvascular Research 27:331-352, 1984

24. McDonagh PF, Rauzzino MJ: Myocardial ischemia-reperfusion damages the cardiac muscle, thecoronaries and the blood. Nisoldipine affects all components. In New Aspects on Nisoldipine. Editedby PR Lichtlen, HP Krayenbuhl. Germany, Schattauer, 1990, pp 9-19

25. Nash GB, Thomas PRS, Dormandy JA: Abnormal flow properties of white blood cells in patients withsevere ischaemia of the leg. Brit Med J 296:1699-1701, 1988

26. Thomas PRS, Nash GB, Dormandy JA: White cell accumulation in dependent legs of patients withvenous hypertension: A possible mechanism for trophic changes in the skin. Brit Med J 296:1693-1695, 1988

27. Ryan TJ, Copeman PWM: Microvascular pattern and blood stasis in skin disease. Clin Lab Invest81:563-573, 1969

28. Hopkins NFG, Spinks TJ, Rhodes CG, Ranicar ASO, Jamieson CW: Positron emission tomography invenous ulceration and liposclerosis: Study of regional tissue function. Brit Med J 286:333-336, 1983

29. Partsch H: Hyperaemic hypoxia in venous ulceration. Br J Dermatol 110:249-251, 198430. Arfors KE, Smedegard G: Permeability of macromolecules as affected by inflammatory cells. In

Microcirculation and Inflammation: Vessel Wall-Inflammatory Cells-Mediator Interaction. Edited byK Messmer, F Hammersen. Basel, Switzerland, Karger, 1987, pp 90-96

31. Belcaro G, Rulo A: A study of capillary permeability in patients with venous hypertension by a newsystem: The vacuum suction chamber (VSC) device-a preliminary report. Phlebology 3:255-259,1988

32. Stewert G, Gaunt JI, Croft DN, et al: Isotope lymphography: A new method of investigating the roleof the lymphatics in chronic limb edema. Br J Surg 72:906-909, 1985

33. Franzeck UK, Isenrigh G, Bollinger A: Lymphatic microangiopathy in chronic venous insufficiency(CVI). In The Initial Lymphatics. New Methods and Findings. Edited by A Bollinger, H Partsch, JHNWolfe. New York, Thieme-Stratton Inc, 1985, pp 171-177

34. Hammond SL, Gomez ER, Coffey JA, et al: Involvement of the lymphatic system in chronic venousinsufficiency. In Venous Disorders. Edited by J Bergan, J Yao. Philadelphia, PA, WB SaundersCompany, 1991, pp 333-343

35. Ernst E, Matria A, Marshall M: Limited blood fluidity as a contributory factor of venous stasis inchronic venous insufficiency. Phlebology 4:107-111, 1989

36. McDonagh PF: Hemodynamic concepts underlying the etiology and treatment of chronic venousedema and ulcers. Wounds 3:182-191, 1991