Stasis microangiopathy: from pathogenesis to treatment

Abstract

Stasis microangiopathy includes all the pathological changes in the microcirculation and interstitium due to venous hypertension. Venous valve incompetence occurring in the superficial or deep venous system or in both is the most common cause of venous hypertension, a pathological condition that plays a key role in most or all clinical signs of chronic venous disease, including edema and venous ulcers. The aim of the first and main part of this review is to focus on the various pathogenetic mechanisms of stasis microangiopathy triggered by venous hypertension, including hemodynamic and hemorheological alterations, inflammation, and functional alterations. The rationale underlying the current available treatment options of stasis microangiopathy is mentioned briefly in the second part of the review.

Keywords

Stasis microangiopathy / microcirculation / venous hypertension / chronic venous disease / venous ulcer

References

[1] Merlen JF,Robert JL.Post-phlebitic disease, stasis microangiopathy.Phlebologie1984;37:409-15. (in French)

[2] Mansilha A.Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy.Int J Mol Sci 2018;19:1669 PMCID:PMC6032391

[3] Curri SB,Montorsi W.Microvalves in microvenules. Phlebologie 1987;40:795-801.(in French)

[4] Caggiati A,Lametschwandtner A.Valves in small veins and venules.Eur J Vasc Endovasc Surg 2006;32:447-52

[5] Vincent JR,Hill GB.Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg 2011;54:62S-9S.e1-3

[6] Mortimer BS.Lymphatic function in severe chronic venous insufficiency.Phlebolymphology 2004;44:253-257

[7] Secomb TW,Pries AR.Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells.Biorheology 2001;38:143-50

[8] Levick JR.Capillary filtration-absorption balance reconsidered in light of dynamic extravascular factors.Exp Physiol 1991;76:825-57

[9] Bräutigam P,Földi E,Moser E.[Involvement of the lymphatic system in primary non-lymphogenic edema of the leg. Studies with 2-compartment lymphoscintigraphy].Hautarzt 1997;48:556-67

[10] Allegra C,Carioti G,Cassiani D. Microlymphatics in chronic venous insufficiency. Proceedings of the New trends in atherosclerosis vascular diseases and cardiovascular therapy 3rd International Joint Workshop; 1995; Monte Carlo, Monaco.

[11] Cassiani D,Bartolo M Jr,Allegra C.Microlymphatic diameters in mild and severe chronic venous insufficiency. 18th European Conference on Microcirculation; 1994; Rome, Italy. Abstracts.Int J Microcirc Clin Exp1994;14 Suppl 1:1-262

[12] Eliska O.Morphology of lymphatics in human venous crural ulcers with lipodermatosclerosis.Lymphology 2001;34:111-23

[13] Cheatle TR,Farrah J,Scurr JH.Three Tests of Microcirculatory Function in the Evaluation of Treatment for Chronic Venous Insufficiency.Phlebology 1990;5:165-72

[14] Izzo M,Coscia V.The role of free iron in cardiovascular diseases. Part II.JTAVR 2017;2:83-95

[15] Browse N.The cause of venous ulceration.Lancet 1982;320:243-5

[16] Falanga V,Katz MH,Eaglstein WH.Pericapillary fibrin cuffs in venous ulceration. Persistence with treatment and during ulcer healing.J Dermatol Surg Oncol 1992;18:409-14

[17] Falanga V.The "trap" hypothesis of venous ulceration. Lancet 1993;341:1006-8

[18] Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis.Br Med J (Clin Res Ed) 1988;296:1726-7 PMCID:PMC2546102

[19] Lawrence MB,Eskin SG.Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion.Blood 1987;70:1284-90

[20] Antignani PL. News in inflammatory and microcirculatory mechanisms. In: Allegra C, Antignani PL, Kalodiki E, editors. News in phlebology. Minerva Medica Ed; 2013. pp. 211-4.

[21] Raffetto JD.Dermal pathology, cellular biology, and inflammation in chronic venous disease.Thrombosis Research 2009;123:S66-71

[22] Raffetto JD.Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease.Biochem Pharmacol 2008;75:346-59 PMCID:PMC2254136

[23] Gschwandtner ME.Microcirculation in chronic venous insufficiency.Vasc Med 2001;6:169-79

[24] Belcaro G,Rulo A.Blood Flow in the Perimalleolar Skin in Relation to Posture in Patients with Venous Hypertension.Annals of Vascular Surgery 1989;3:5-7

[25] Malanin K,Kolari PJ.Blood flux and venoarteriolar response of the skin in legs with chronic venous insufficiency measured at two different depths by using a double-wavelength laser Doppler technique.Angiology 1998;49:441-6

[26] Jochmann W,Partsch H.Postocclusive reactive hyperemia and postural vasoconstriction in different kinds of leg ulcers - investigations with laser Doppler.Vasa1993;22:306-15

[27] Bollinger A,Hoffmann U.Microvascular changes in venous disease: an update.Angiology 1997;48:27-32

[28] Mayrovitz HN.Periwound skin microcirculation of venous leg ulcers.Microvasc Res 1994;48:114-23

[29] Dodd HJ,Sarkany I.Skin oxygen tension in venous insufficiency of the lower leg.J R Soc Med 1985;78:373-6 PMCID:PMC1289717

[30] Partsch H.Investigations on the pathogenesis of venous leg ulcers.Acta Chir Scand Suppl1988;544:25-9

[31] Leu AJ,Pfister G,Franzeck UK.[Microangiopathy in chronic venous insufficiency].Dtsch Med Wochenschr 1991;116:447-53

[32] Speiser DE.Microangiopathy in mild chronic venous incompetence (CVI): morphological alterations and increased transcapillary diffusion detected by fluorescence videomicroscopy.Int J Microcirc Clin Exp1991;10:55-66

[33] Klyscz T,Steins A,Rassner G.[The effect of compression therapy on the microcirculation of the skin in patients with chronic venous insufficiency (CVI)].Hautarzt 1997;48:806-11

[34] Grenier E,McAdams E,Gobin JP.Effect of compression stockings on cutaneous microcirculation: Evaluation based on measurements of the skin thermal conductivity.Phlebology 2016;31:101-5

[35] Wollina U,Mani R.A review of the microcirculation in skin in patients with chronic venous insufficiency: the problem and the evidence available for therapeutic options.Int J Low Extrem Wounds 2006;5:169-80

[36] Pomella F. Microcircolo e malattia venosa cronica. In: Bilancini S (Italian Society for Microcirculation), editor. Le acrosindromi vascolari e non solo. Ed. Minerva Medica. Forthcoming 2021. (in Italian)

[37] Ivkov-Simić M,Matić M,Jovanović M.Chronic venous insufficiency and compression therapy. Med Pregl 2001;54:69-74.(in Croatian)

[38] Allegra C,Sarcinella R. Hemodinamic modifications induced by compression therapy in CVI evaluated by microlymphography. XII Congress Union Internationale de Phlébologie. 1995; London, UK. Phlebology 1995;Suppl 1:1138-49.

[39] Barros B, Kakkos SK, De Maeseneer M, Nicolaides AN. Chronic venous disease: from symptoms to microcirculation.Int Angiol 2019;38:211-8

[40] Raffetto JD,Dean SM,Mannello F.Pharmacologic treatment to improve venous leg ulcer healing.J Vasc Surg Venous Lymphat Disord 2016;4:371-4

[41] Maresca L,Leonardo G.Restoring microvascular efficiency with mesoglycan in women affected by moderate chronic venous disease.Minerva Cardioangiol2015;63:105-11

[42] Bignamini AA.Sulodexide for the Symptoms and Signs of Chronic Venous Disease: A Systematic Review and Meta-analysis.Adv Ther 2020;37:1013-33 PMCID:PMC7089759

[43] De Anna D,Intini ,Gasbarro V.Effects of therapy with aminaftone on chronic venous and lymphatic stasis.Minerva Cardioangiol1989;37:251-4

[44] Ruaro B,Paolino S,Sulli A.Aminaphtone Efficacy in Primary and Secondary Raynaud's Phenomenon: A Feasibility Study.Front Pharmacol 2019;10:293 PMCID:PMC6458253

[45] Nicolaides A,Baekgaard N.Management of chronic venous disorders of the lower limbs. Guidelines According to Scientific Evidence. Part I.Int Angiol 2018;37:181-254

[46] Kakkos SK,Lugli M.CEAP clinical classes C0S-C4: differences, similarities and role of Ruscus + HMC + vitamin C in patients with chronic venous disease.Int Angiol 2020;39:118-24

[47] Bouskela E,Marcelon G.Possible mechanisms for the inhibitory effect of Ruscus extract on increased microvascular permeability induced by histamine in hamster cheek pouch.J Cardiovasc Pharmacol1994;24:281-5

[48] Rauly-Lestienne I,Cussac D,de Almeida Cyrino FZG.Contribution of muscarinic receptors to in vitro and in vivo effects of Ruscus extract.Microvasc Res 2017;114:1-11