Editorial N°127

Venous valves: gateway to the circulation

by A. Caggiati, Italy


Department of Anatomy
Sapienza University of Rome

Although the anatomy of the cardiovascular system was depicted perfectly by Vesalius in his De Humanis Corporis Fabrica in 1534, the concept of “circulation” did not exist at the time; heart and vessel function were being explained by Galen’s theory of the “four humors.” Great advances in the description of the venous circulation took place between the mid-16th century and early 17th century. Venous valves were first mentioned in 1544 by the Spanish anatomist Ludovicus Vassaeus in De Anatomen Corporis Humani Tabulae Quator. Six years later in 1550, Sylvius Ambianus described the presence of valves in the veins of the lower limbs, and, in 1559, Andrea Cesalpino in De Re Anatomica clearly described the function of the valves and the centripetal direction of blood flow into the veins. Hieronymus Fabricius ab Aquapendente published an extensive treatise on venous valves entitled De Venarum Ostiolis in 1603. In his treatise, Fabricius not only meticulously described venous valve anatomy and topography of the whole venous system, but also, more importantly, a maneuver to locate venous valves in superficial veins. This maneuver led his student, William Harvey, to explain the circulation of blood in De Motu Cordis (1628). The only question Harvey was unable to answer was how blood passes from the arteries to the veins.

The term “blood circulation” was borrowed from Andrea Cesalpino, who coined it in 1571 after he described the centripetal direction of blood flow in the veins and hypothesized the existence of capillaries (vasa in capillamenta risoluta). The anatomy of the circulatory system was only completely defined in 1661, when Marcello Malpighi demonstrated in De Pulmonibus the existence of capillaries, arterioles, and venules. According to Fabricius, the predominant belief at the time was that venules were avalvulated. Nearly four centuries after Vassaeus’s description of venous valves, Canadian pathologist Nicholas Popoff demonstrated the existence of microscopic venous valves (MVVs) in the skin of human digits, in 1934.1 MVVs were then found in the venules of vascular territories with unfavorable venous hemodynamics,2-6 where they fragment the hydrostatic column at the microcirculatory level. the exact role of MVVs in the pathophysiology of venous diseases still needs to be comprehensively evaluated, but Van Rij and colleagues demonstrated in 2011 that MVV incompetence can occur in small superficial veins in the absence of reflux in the saphenous axis and tributaries.7 this could explain signs and symptoms of venous insufficiency in legs with effective valvular function in the greater veins. In 1998, Aharinejad and colleagues described the treatment of recalcitrant venous ulcers with a free fasciocutaneous flap taken from areas of the skin rich in MVVs.8 Unfortunately, technical difficulties in evaluating the morphological and functional characteristics of MVVs make this field of investigation very challenging.

The role of venous valves was clearly described by Cesalpino in 1559: “…certain membranes placed at the openings of the vessels prevent the blood from returning….” then it was postulated that venous valves should fragment the hydrostatic column. This has been the predominant belief since 2012, when Fedor Lurie and colleagues demonstrated experimentally that venous valves not only block reflux, but also play an important role in increasing the efficiency of venous return by creating a helical flow because of their respective angulation.9

How do venous valves work? It is generally thought that reverse flow is necessary for venous valve closure. In his studies of the heart, Leonardo da Vinci predicted that the blood stream should divide when passing valves; he found that half the aortic blood flow reverses into the aortic sinus, generating a vortex, while the other half follows the path of the aorta. Vortical flow at the level of the sinus was confirmed experimentally by Carrier in 1922, but it was only much later in 2002 and 2003 that Lurie and colleagues demonstrated the complexity of flow dynamics at the site of venous valves as well as the mechanism of venous valve closure10,11—just as Leonardo had predicted, thanks to a glass model of the aortic sinus. Venous valve closure coincides with the decrease of flow velocity and the ballooning of the sinus. This is one of the major bioengineering concepts underlying the construction of artificial valves.

Abnormalities of this sophisticated mechanism provoke blood reflux, the most frequent abnormality in legs with venous insufficiency. tommaso Rima was the first to identify the pathophysiological role of venous valve failure in 1806, followed by Brodie in 1846. Both of them had no idea about the causes of venous valve failure.

Bardeleben in 188012 suggested that involutive phenomena were responsible for the progressive reduction in the number of venous valves, and Klotz in 188713 demonstrated that the number of incompetent venous valves increases in venous disease. Powell in 195114 proposed that venous valve function was affected by age, and senile changes in venous valves were effectively demonstrated by Saphir in 1953: “…starting after the age of 30, venous valves undergo a progressive increase in collagen fibers….”15 However, senile changes do not necessarily imply venous valve dysfunction with significant reflux, with the exception of the “partial valves” described by Marinov in 1973.16

Venous insufficiency can also be caused by agenesia of venous valves, which is very rare. Agenesia was first reported in 1941 by Josephus Luke.17 Avalvulia syndrome was clearly defined by Lodin in 1958.18

Besides congenital and primary venous valve failure, there is also secondary venous valve failure, which was first reported in 1937 by Edwards and Edwards.19 they described the destruction of valves following venous thrombosis and related it to the onset of both deep vein insufficiency and varicose veins. Between these two antithetic conditions (physiologic involution and postthrombotic venous valve degeneration), the inflammatory theory of venous valve destruction was introduced in the late 1990s. Ono and colleagues demonstrated that venous hypertension can lead to a chronic inflammatory condition of venous valve leaflets characterized by monocyte infiltration.20

All these contributions, however, did not solve the dilemma of whether valve insufficiency or wall dilation occurs first. Is vein dilation due to or responsible for venous valve failure? In fact, primary structural changes of the valvesmay make them “leaky,” with progressive reflux causing secondary changes in the vein wall with dilation. Alternatively, or concurrently, the valves may become incompetent secondary to structural abnormalities and focal dilation of vein wall segments near the valve junctions. Accordingly, venous valve reflux ensues as an epiphenomenon of primary vein dilation. In 2008, Raffetto and Khalil evaluated the expression of matrix metalloproteinases, which influence the metabolism of extracellular matrix proteins as well as the function of the endothelium and smooth muscle, determining changes in venous constriction/relaxation properties.21 their observations suggest that vein wall dilation appears to precede valve dysfunction related to metalloproteinase activation, superimposed inflammation, and fibrosis.

Once the predominant role of venous valves in the pathophysiology of venous disease was recognized, how could their efficiency evaluated? In 1603, Fabricius ab Aquapendente involuntarily illustrated the test to evaluate valve competence, but unfortunately the test was not adopted by surgeons who followed him. It was only two centuries later, in 1806, that tommaso Rima proposed a specific test to evaluate venous valve competence of the saphenous system. This test was then refined by Sir Benjamin Brodie (1846) and trendeleburg (1890) and remained in use until the introduction of ultrasound in vascular diagnostics. the first clinical experiments in venous ultrasonography were done by Sigel in 196722 and Sumner in 1968.23 the method for detecting venous valve insufficiency was described in detail by Folse and Alexandre in 1970,24 after the introduction of directional Doppler instruments; this was followed six years later by the first report of venous echotomography of deep vein thrombosis.25 the next milestone in venous valve ultrasound semeiotics was in 2002, when Labropoulos and colleagues26 furnished the parameters to evaluate venous valve incompetence by duplex scanning (reflux duration greater than 500 ms in superficial and calf deep veins, and 1000 ms in the femoropopliteal axis).

Despite these technical improvements, semiological differences still remain to be clearly defined between the numerous maneuvers proposed for eliciting venous valve reflux (Valsalva, distal compression/release, and dynamic tests).

Once it was demonstrated that venous valve incompetence was the cause of reflux, the next obvious, clinically relevant question was: how do you treat venous valve failure?

The first to propose a “treatment” for incompetent valves was Astley Paston Cooper, a pupil of John Hunter, who in 1824 affirmed that limb compression by bandaging allowed the venous valves to regain their competence. The only alternative was to ligate the vein. No further suggestions to treat incompetent venous valves appeared until the middle of the 20th century, when Eisemann and Malette created valve-like structures,27 Warren and thayer proposed saphenopopliteal bypass,28 and Palma and Esperon put forward vein transplantation.29 After these first experimental procedures, it was finally in 1968 that Kistner popularized a technique to restore venous valve function by direct surgery30 and Psathakis proposed a “substitute valve.”31 Surprisingly, all the techniques for restoring venous competence proposed in the subsequent fifty years were based on the principles of these pioneers.

More recently, over the past 30 years, multiple methods have been developed to surgically restore valvular function, but only a few of them have been applied in humans. Half a century after Eisemann, Corcos reconstructed a monocuspid popliteal valve by intimal flap,32 whereas Maleti and Lugli proposed a technique to safely create an antireflux mechanism in both postthrombotic limbs and in veins with valve agenesis.33

However, the majority of these studies await confirmation by other investigators over extended periods of time. Guidelines or consensus documents that establish which patients should be considered for venous valve surgery as well the criteria for evaluating clinical results are eagerly awaited.


1. Popoff N. the digital vascular system. Arch Pathol. 1934;18:307-322. 
2. Pirro A. Dimostrazioni istologiche di anastomosi artero-venose e dispositivi di blocco nelle minute arterie dei muscoli articolari del ginocchio. Bollettino Societa Italiana Biologia Sperimentale. 1950;26:1. 
3. Miani A, Ruberti U. Sulla morfologia degli apparati valvolari delle venule efferenti delle anastomosi arterovenose arterovenose della pianta del piede. Minerva Cardioangiol. 1958;6:541. 
4. Braverman IM, Keh-yen A. Ultrastructure of the human dermal microcirculation. IV. Valve-containing collecting veins at the dermal-subcutaneous junction. J Invest Dermatol. 1983;81:438-442. 
5. Caggiati A, Curri SB. Sulla morfologia strutturale ed ultrastrutturale degli apparati microvalvolari nel tessuto muscolare striato dell’uomo. 4th Congress of the Italian Society of Phlebology, Napoli, 1987.
6. Phillips MN, Jones Gt, van Rij AM, Zhang M. Micro-venous valves in the superficial veins of the human lower limb. Clin Anat. 2004;17:55-60. 
7. Vincent JR, Jones Gt, Hill GB, van Rij AM. Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg. 2011;54(6 Suppl):62S-69S. 
8. Aharinejad S, Dunn RM, Nourani F, Vernadakis AJ, Marks Jr SC. Morphological and clinical aspects of scapular fasciocutaneous free flap transfer for treatment of venous insufficiency in the lower extremity. Clin Anat. 1998;11:38-46. 
9. Lurie F, Kistner RL. the relative position of paired valves at venous junctions suggests their role in modulating three-dimensional flow pattern in veins. Eur J Vasc Endovasc Surg. 2012;44:337-340. 
10. Lurie F, Kistner RL, Eklof B. the mechanism of venous valve closure in normal physiologic conditions. J Vasc Surg. 2002;35:713-717. 
11. Lurie F, Kistner RL, Eklof B. Kessler D. Mechanism of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg. 2003;38:955-961. 
12. Bardeleben K. Das Klappen-Distanz-Gesetz. Jenaische Ztschr Naturwisse. 1880;12:467-529. 
13. Klotz K. Unteresuchungen uber die Vena Saphena Magna bein Menschen. Arch Anat Physiol Anat Abt. 1887;159:174-178. 
14. Powell t, Lynn RB. the valves of the external iliac, femoral, and upper third of the popliteal veins. Surg Gynecol Obstet. 1951;92:453-455. 
15. Shapir O, Lev M. the venous valve in the aged. Am Heart J. 1952;51:843-850. 
16. Marinov G. Changes with age in the valvular apparatus of the superficial and deep veins of the leg [in Bulgarian]. Eksp Med Morfol. 1973;12:86-91. 
17. Luke JC. the diagnosis of chronic enlargement of the leg. Surg Gynecol Obstet. 1941;73:472-480. 
18. Lindvall N, Lodin A. Congenital absence of valves in the deep veins of the leg. Acta Dermato-Venereologica Scand. 1961;41:45. 
19. Edwards EA, Edwards JE. the effect of thrombophlebitis on the venous valve. Surg Gynecol Obstet. 1937;65:310-320. 
20. Ono t, Bergan JJ, Schmid-Schönbein GW, takase S. Monocyte infiltration into venous valves. J Vasc Surg. 1998;27:158-166. 
21. Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology. 2008;23:85-98. 
22. Sigel B, Popky GL, Boland JP, Wagner DK, Mapp EM. Diagnosis of venous disease by ultrasonic flow detection. Surg Forum. 1967;18:185. 
23. Sumner DS, Baker DW, Strandness DE Jr. the ultrasonic velocity detector in a clinical study of venous disease. Arch Surg. 1968;97:75-80. 
24. Folse R, Alexander RH. Directional flow detection for localizing venous valvular incompetency. Surgery. 1970;67:114-121. 
25. Day tK, Fish PJ, Kakkar VV. Detection of deep vein thrombosis by Doppler angiography. Br Med J. 1976;1:618-620. 
26. Labropoulos N, tiongson J, Pryor L, et al. Definition of venous reflux in lowerextremity veins. J Vasc Surg. 2003;38:793-798. 
27. Eiseman B, Malette W. An operative technique for the construction of venous valves. Surg Gynecol Obstet. 1953;97:731-734. 
28. Warren R, thayer tR. transplantation of the saphenous vein for postphlebitic stasis. Surgery. 1954;35:867-878. 
29. Palma EC, Esperon R. Vein transplants and grafts in the surgical treatment of the postphlebitic syndrome. J Cardiovasc Surg (Torino). 1960;1:94-107. 
30. Kistner RL. Surgical repair of a venous valve. Straub Clin Proc. 1968;34:41-43. 
31. Psathakis N. Has the “substitute valve” at the popliteal vein solved the problem of venous insufficiency of the lower extremity? J Cardiovasc Surg (Torino). 1968; 9:64-70. 
32. Corcos L, Peruzzi G, Procacci t, Spina t, Cavina C, De Anna D. A new autologous venous valve by intimal flap. One case report. Minerva Cardioangiol. 2003;51:395-404. 
33. Maleti O, Lugli M. Neovalve construction in postthrombotic syndrome. J Vasc Surg. 2006;43:794-799. 

Keywords: venous valve; venous circulation; microscopic venous valve; valve dysfunction; history; venous insufficiency