CLINICAL PHYSIOLOGY OF THEVENOUS SYSTEM

BASIC SCIENCE FOR THE CARDIOLOGIST

1. B. Swynghedauw (ed.): Molecular Cardiology for the Cardio/ogist. Second Edition. 1998 1SBN 0-7923-8323-0

2. B. Levy, A. Tedgui ( eds. ): Biology of the Arterial Wa/1. 1999 ISBN 0-7923-8458-X

3. M.R. Sanders, J.B. Kostis (eds.): Molecular Cardiology in Clinica/ Practice. 1999 ISBN 0-7923-8602-7

4. B.Ostadal, F. Kolar (eds.): Cardiac /schemia: From !njury to Protection. 1999 ISBN 0-7923-8642-6

5. H. Schunkert, G.A.J. Riegger (eds.): Apoptosis in Cardiac Biology. 1999 ISBN 0-7923-8648-5

6. A. Malliani, (ed.): Princip/es ofCardiovascular Neural Regulation in Health and Disease. 2000 ISBN 0-7923-7775-3

7. P. Benlian: Genetics ofDyslipidemia. 2001 ISBN 0-7923-7362-6

8. D. Young: Role of Potassium in Preventive Cardiovascular Medicine. 200 l ISBN 0-7923-7376-6

9. E. Carmeliet, J. Vereecke: Cardiac Cellular Electrophysiology. 2002 ISBN 0-7923-7544-0

10. C. Holubarsch: Mechanics and Energetics ofthe Myocardium. 2002 ISBN 0-7923-7570-X

Il . J.S. Ingwall: ATP and the Heart. 2002 ISBN 1-4020-7093-4

12. W.C. De Mello, M.J. Janse: Heart Cel/ Coup/ing and Impuse Propaga/ion in Health and Disease. 2002 ISBN 1-4020-7182-5

13 . P.P.-Dimitrow: Coronary Flow Reserve- Measurement and Application: Focus on transthoracic Doppler echocardiography. 2002 ISBN 1-4020-7213-9

14. G.A. Danieli: Genetics and Genomicsfor the Cardiologist. 2002 ISBN l-4020-7309-7

15 . F.A. Schneider, I.R. Siska, J.A. Avram: Clinica! Physiology ofthe Venous System. 2003. ISBN 1-4020-7411-5

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

CLINICAL PHYSIOLOGY OF THE VENOUS SYSTEM

by

Francisc A. Schneider, M.D., Ph.D, Professor of Physiology

W estero U niversity "Vasile Goldiş" Arad University of Medicine and Pharmacy

Timisoara

Ioana Raluca Siska, M.D., Ph.D., Assistant Professor of Physiology

University ofMedicine and Pharmacy Timisoara

Jecu Aurel Avram, M.D., Ph.D., Professor of Surgery and Phlebology

University ofMedicine and Pharmacy Timisoara

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging-in-Publication Data

A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN 978-1-4613-4874-0 ISBN 978-1-4419-9282-6 (eBook) DOI 10.1007/978-1-4419-9282-6 Clinical Physiology ofthe Venous System by Schneider, Siska, Avram

Copyright © 2003 by Springer Science+Business Media New York Originally published by Kluwer Academic Publishers, New York in 2003 Softcover reprint ofthe hardcover lst edition 2003

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TABLE OF CONTENTS

INTRODUCTION XV

O. I. HISTORICAL ACCOUNT ,XV0.2. EMBRYOLOGY AND DEVELOPMENT OF VENOUS

SYSTEM XVII0.3. ANATOMICAL FEATURES XIXREFERENCES XXPREFACE XXIABBREVIATIONS XXIII

CHAPTER 1HYDRODYNAMIC AND RHEOLOGIC LAWS APPLIEDTO THE VENOUS CIRCULATION I

I. I . HYDROSTATIC PRESSURE IN VEINS .21.2. FLOW, PRESSURE AND RESISTANCE 3

1.2. I . Pressure in Veins 41.2.2. Distensibility and Compliance .41.2.3. Relation between Distending Pressure and Tension 6

1.3. VELOCITY 61.4. RESISTANCE, CONDUCTANCE AND VISCOSITY IN THE

VENOUS SYSTEM 8REFERENCES I 0

CHAPTER 2VEINS AND THEIR FUNCTIONS 1I

2. I. VEINS AS CONDUCT I I

2.2. VEINS AS A RESERVOIR 142.3. VENOUS RETURN AND THE FILLING PRESSURE 142.4. VENOUS RETURN AND REGULATION OF CARDIAC

FUNCTION 152.5. THE ROLE IN THE OPTIMIZATION OF THE

CIRCULATORY SYSTEM 162.6. THE ROLE OF THE VENOUS SYSTEM IN EXCHANGE

PROCESSES 162.7. THE ROLE OF THE VEIN IN SYNTHESIS OF

BIOLOGICALLY ACTIVE SUBSTANCES,COAGULATION AND FIBRINOLYSIS 16

2.8. SPECIAL REGIONAL FUNCTIONS OF THE VEINS 172.8.1. Veins of the Head and Face 17

2.8.1.1. Veins of the Brain 172.8.1.2. Facial Veins 18

2.8.2. Cardiac Veins 182.8.3. Hepatic Veins 182.8.4. Cutaneous Veins 202.8.5. Veins of the Limbs 202.8.6. Veins of the Lungs 21

REFERENCES 22

CHAPTER 3.VENOUS WALL - MORPHOLOGICAL ANDFUNCTIONAL ASPECTS 23

3.1. VENOUS ENDOTHELIUM 243. I.1. Microscopic Aspects 253.1.2. The Roles of Venous Endothelium 27

3.1.2.1. The Role of Endothelium in Regulation ofVascular Tone 27

3.1.2.2. The Role of Endothelium in Coagulationand Fibrinolysis .32

3.1.2.3. The Role of Endothelium in Inflammation andInteractions with Blood Cells 37

3.1.2.4 . Venous Endothelium and Vascular Remodeling 443.1.3. Heterogeneity of Endothelial Function within Circulation...483.1.4. Pharmacological Aspects .493.1.5. Hemodynamic Forces and the Endothelium 52

3.2. VENOUS SMOOTH MUSCLE 543.2.1. Microscopic Aspects 543.2.2. Contraction-Relaxation Cycle 573.2 .3. Regulation of Smooth Muscle Contraction .58

3.3 . VENOUS ADVENTITIA 64REFERENCES 65

CHAPTER 4.REGULATION OF THE VENOUS TONE 77

4.1. NEURAL CONTROL 784.1 .1. Sympathetic Control 78

4.1.1.1. Neurotransmitters Released by the SympatheticNervous Fibers (norep inephrine, ATP,neuropeptide Y, CGRP) 78

4.1.2. Cholinergic Innervation 844.1.3. Non-Adrenergic Non-Cholinergic Innervation (NANC) 86

4.2. HORMONES AND VENOUS TONE 884.2.1. Catecholamines 884.2.2. Angiotensins 914.2.3 . Estrogen and Progesterone 92

4.2.3.1 . Estrogens 924.2 .3.2. Progesterone 95

4.2.4. Other Hormones 964.2 .4.1. Vasopressin 964.2 .4.2. Somatostatin 964.2 .4.3. Insulin 984.2 .4.4. Thyro id Hormones 100

4.3 . LOCAL CONTROL 1004.3 .1. Metabolic Control (P02, PC02, pH, lactate,

adenosine, ADP and ATP) 1004.3.1.1. P02 1004.3.1.2. PC02 and pH 1014.3 .1.3. Lactate 1014.3 .1.4. Adenosine 1024.3 .1.5. ADP and ATP 102

4.3.2. Humoral control 103

4.3.2.1. Angiotensins 1054.3.2.2. Natriuretic Peptides 1074.3.2.3. Eicosanoids 1084.3.2.4. Bradykinin 1124.3.2.5. Histamine 1134.3.2.6 . Serotonin 1144.3.2.7. Substance P 115

4.3.3 . The Role ofIons in Local Control of Venous Tone 1164.3.3 .1. Sodium 1164.3.3.2. Potassium 1184.3.3.3. Calcium 1194.3.3.4. Magnesium 1214.3.3 .5. Chloride Ions 122

4.3.4 . Endothelium-derived factors and the Regulationof Venous Tone 1234.3.4 .1. Endothelium-Derived Relaxing Factors 1234.3.4 .2. Endothelium-Derived Vasoconstrictors 130

4.4. OTHER FACTORS INVOLVED IN THE MODULAnONOF VENOUS TONE 135

4.4.1. Reactive Oxygen Species (ROS) 1354.4.1 .1. Superoxide Anion 1364.4.1.2 . Hydrogen Peroxide 137

4.4.2. Cytokines 1394.4.3. Fibrinogen 1404.4.4. Thrombin 1414.4.5 . Oxidized Low-Density Lipoprotein (ox-LDL) 1414.4.6. Vasostatins 142

4.5. MYOGENIC CONTROL 1424.6. PHARMACOLOGICAL ASPECTS 143

4.6.1. Venodilator Drugs 1434.6.2. Venotonic Drugs 144

REFERENCES 146

CHAPTER 5VARICOSE DISEASE 171

5.1. GENERALITIES 1725.1.1. Definition 1725.1.2. Frequency 172

5.1.3. Genesis 1735.2. ETIOPATHOGENY 1745.3. PRIMARY VARICOSE VEINS (HYDROSTATICS) 175

5.3.1. Morphopathology 1815.3.2. Physiopathology 182

5.3.2.1. Soleus-Gastrocnemius Muscular Pump 1825.3.2.2. Cycle of the Walking Process 1835.3.2.3. Superficial, Deep and Mixed Vein

Insufficiency 1835.3.2.4. Siphon Effect 1845.3.2.5. Territorial Steal 185

5.3.3. Physical Examination 1855.3.3 .1. Evolution Stages of the Varicose Disease 1855.3.3.2. Types of Varicose Veins 1865.3.3.3. Hach Classification of the GSV Insufficiency 1885.3.3.4 . CEAP Classification System of the Infer ior

Limbs Varicose 1895.3.4. Functional Vein Tests 1915.3.5. Investigations 1935.3.6. Diagnosis 195

5.3.6.1. Positive Diagnosis 1955.3.6.2 . Differential Diagnosis 195

5.3.7. Evolution and Complications of Varicose Disease 1965.3.8. Treatment 197

5.4. RECURRENT VARICES AFTER SURGERY (REVAS) 203

CHAPTER 6THROMBOEMBOLIC VENOUS DISEASE 207

6.1. GENERALITIES 2086.2. ETIOPATHOGENY 208

6.2.1. Predisposing Factors 2086.2.2. Decisive Factors (Virchow Triad) 209

6.3. ETIOLOGIC CLASSIFICATION OF DVT 2116.4. STAGES OF THE THROMBUS FORMATION 2126.5. CLINICAL EVOLUTION 2156.6. CLINICAL FORMS 218

6.6.1. Topographic Clinical Forms 2186.6.2. Evolutive Clinical Forms 219

6.7. LABORATORY-IMAGING STUDIES 2206.7.1. Laboratory Studies 2206.7.2. Imaging Studies 220

6.8. EVOLUTION 2216.9. COMPLICATIONS 222

6.9.1. Pulmonary Embolism (PE) 2226.9.1.1. Anamnesis 2236.9.1.2. Symptomatology 2236.9.1.3. Clinical Examination 2236.9.1.4. PositiveDiagnosis 2246.9.1.5. Differential Diagnosis 225

6.9.2. Vein Gangrene 2256.9.3. Postthrombotic Syndrome (Postphlebitic) 225

6.9.3.1. Physiopathology 2266.9.3.2. Symptomatology 2276.9.3.3. Positive Diagnosis 2276.9.3.4 . Differential Diagnosis 228

6.10. TREATMENT OF THE ACUTE VEIN THROMBOSISAND OF THE COMPLICATIONS 228

6.10.1. Prophylactic Treatment 2286.10.1.1. Pharmacological Methods 2296.10.1.2. Mechanical Methods 229

6.10.2. Curat ive Treatment 2296.10.2.1. Medical Treatment 2296.10.2.2. Surgical Treatment 235

6.10.3 . Treatment in Case of Complications 2366.10.3.1. Treatment of Pulmonary Embolism 2366.10.3.2. Treatment of Postthrombotic Syndrome 237

6.11. PARTICULAR FORMS OF THROMBOPHLEBITIS 2386.11 .1. Migratory Thrombophlebitis 2386.11.2. Superior Limb Thrombophlebitis 2386.11.3. Pelvic Varicose and Thrombophlebitis 239

6.11.4 . Suprahepatic Veins Thrombosis(Budd-Chiari Syndrome) 240

6.11.5. Traveler's Thrombosis (Jet-leg Thrombosis,Economy Class Syndrome) (TT) 240

6.11.6. Thrombosis of the Inferior Cava Vein (ICV) 2436.1 1.7. Thrombosis of the Superior Cava Vein (SCV) 243

6.11.7.1. Etiology 2436.11.7 .2. Physiopathology 2446.11.7.3. Symptomatology 2446.11.7.4. Investigations 2456.11.7.5. Differential Diagnosis 2456.11.7.6 . Complications 2456.11.7.7. Treatment 2456.11.7.8. Prognos is 246

CHAPTER 7CHRONIC VENOUS INSUFFICIENCY OF THEINFERIOR LIMBS (C.V.I.) .247

7.1. DEFINITION 2487.2. ETIOLOGY 2487.3. PHYSIOPATOLOGY 2487.4. CLASSIFICATION OF CVI 2527.5. SYMPTOMATOLOGY IN CVI 2527.6. INVESTIGATIONS 254

7.6.1. Continuous Doppler Ultrasonography 2547.6.2. Pulsate Echosonography Doppler 2557.6.3. Duplex Doppler 2557.6.4. Plethysmography 2567.6.5. Phlebography 257

7.6.5.1. Ascending Phlebography 2587.6.5.2. Descending Phlebography 2587.6.5.3. Pelvic Phlebography 2597.6.5.4 . Selective Ovarian and Internal Iliac

Phlebography 2597.6.5.5 . Intraosseous Phlebography 2607.6.5.6. Upper Extremity Phlebography 2607.6.5.7 . Varicography 260

7.6.6. Liquid Crystal Thermography .2607.6.7. Femoral Vein Pressure Measurements 2617.6.8. Arm/Foot Pressure Differential 2617.6.9. FootVolumetry 2617.6.10. Microcirculation Study 2617.6.11. Laboratory Exams 262

7.7. PARTICULAR CLINICAL FORMS OF CVI 2627.7.1. Cockett Syndrome 2627.7.2 . Martorell Syndrome 2637.7.3. Calf Muscular Compartment Syndrome 2637.7.4. Solear Syndrome 2637.7.5. Popliteal Vein Entrapment Syndrome 263

7.8. CVI TREATMENT 2657.8.1. Medical Treatment 2657.8.2. Surgical Treatment 266

CHAPTER 8CONGENITAL DISTURBANCES OFVASCULAR GENESIS 269

8.1. GENERALITIES 2708.2. CLASSIFICATION 270

8.2.1. Hemangiomas 2708.2.2. Vascular Malformations (Angiodysplasias) 2718.2.3. Venous Malformations (VM) 272

8.2.3.1. Pathogenesis ofVM 2728.2.3.2. Anatomico-ClinicalClassification ofVM 2738.2.3.3 . Clinical Diagnosis .2738.2.3.4 . Imaging Diagnosis 2758.2.3.5. Treatment 275

CHAPTER 9MISCELLANEOUS VEINS PATHOLOGY 277

9.1. VEINS AND PREGNANCY 2789.1.1. Generalities 2789.1.2. Etiopathogeny 2789.1.3. Diagnosis 2809.1.4. Treatment 281

9.2. THE VEINS IN RECONSTRUCTIVE SURGERY 2829.3. VEIN CUFFS 2849.4. VENOUS ANEURYSM 2859.5. VENOUS TRAUMAS OF INFERIOR LIMBS .288REFERENCES CHAPTERS: 5 - 9 290

We dedicate this book to the memory ofProfessor Pius Branzeu, the founder of

the Romanian School ofPhlebology

INTRODUCTION

The circulatory system is made up of the heart and a vast array of vessels:arteries, capillaries and veins . The veins are vessels through which theblood flows from various organs or parts of the body to the heart.Phlebology is the study of the venous system and its diseases . Althoughthis definition of what we call today the venous system is no more than fivecenturies old, the sufferings of the veins go back to man's prehistory.

0.1. HISTORICAL ACCOUNT

Centuries of civilization have yielded numerous documents pertaining tomankind 's interests in veins (1, 2, 9).

Neolithic engravings discovered in Tassili caves (Sahara) showpeople with swollen and bandaged lower legs. Phoenicians and Egyptianswere the first to mention venous varices in the 2nd millennium BC (in Eber'spapyrus). As records of Hippocrates' work show, venous stasis and venousulcer were among the major concerns of physicians in the third and fourthcentury BC. Venous diseases also preoccupied physicians in Greek andRoman antiquity.

The medical treatises of Galen of Pergamon (129-201) and ofIbnSina-Avicenna (980-1037) contain descriptions and treatments for thevenous diseases of the lower limbs. Galen's concept concerning the

Clinical Physiology of the Venous System

circulation of the blood - according to which the veins transport the bloodto all the organs - was taken over by Vesalius, and was the accepted viewuntil the 16th century. But Vesalius was the first to accurately illustrate theanatomy of the veins , in "De Humani Corporis Fabrica", published in 1543.

Before him, it was Leonardo da Vinci who , in his drawings, clearlyillustrated the superficial veins of the lower limbs and arms. Eustachio(1520-1574) described the azygos veins and inferior vena cava .

In 1603, Fabricios d'Aguapendente named the valves of the veinsand elaborated a theory according to which the function of these valves wasto slow down the circulation of the blood.

Harvey's work , "Exercitatio Anatomica De Motu Cordis etSanguinis", published in 1628, combines physiology and anatomy. Theaccurate description of the venous system clearly demonstrates the bloodflow and the valvular arrest of the venous circulation.

In the 17th century, venous stasis and varicose veins were attributedto blows, contusions, excessive effort, or prolonged standing position,whereas in the 15th century, when Galen's theory of humours dominatedmedical thoughts, varicose elongation, tortuosity and deletion wereattributed to the weight of the stagnant blood on the venous walls . In thosetimes, physicians were convinced that varicosities contained black bile andthat healing of the ulcer would have been catastrophic.

The correct observations of Fabry (1589) and Bodie (1846),crystallized in the observations of Trendelenburg (1890) concerning thefunctions of the superficial and communicating veins, the venous valvesand the interplay of the muscle pump, elucidating the roles of veins.

In the twentieth century clinical observations and operations(Nobili, Unger, Keller, Mayo, Babcock, etc), physiological studies andnon-invasive determinations of venous filling recovery time, venouspressure recovery time, direct imaging by duplex scan, resonance imaging,continuous wave Doppler instrument for venous testing, color flowscanning and magnetic resonance imaging allowed a correct understandingof the anatomy and functions of the venous system .

In the field of applied physiology of the venous system , Romanianphysicians played an important part. Foremost among them are MarinPopescu, who was the first to point out the myogenic automatism of theportal vein (11), and Pius Branzeu, who carried out the first transplants ofvalved veins in the post-traumatic syndrome of lower limbs (3) .

The physiological significance of the veins has been reevaluatedonly in the last two decades. Scientists have recognized that veins comprisea multifunctional system . Some of these show close similarities with

XVI

Introduction

arterial functions, whereas others are specific for veins. Specific venousfunctions include the adaptive role in the maintenance of orthostatictolerance of the organism and cardiovascular reactions during exercise .Today , autologous venous grafts are frequently used as prostheses ofaffected arteries.

The growing interest in clinical physiology of the venous system isconnected with the very high incidence of varicosity, thrombophlebitis,phlebosclerosis, orthostatic intolerance and other vein diseases.

0.2. EMBRYOLOGY AND DEVELOPMENT OFVENOUS SYSTEM

Blood vessels are among the first organs to develop during embryogenesisand are essential for organogenesis and nutrition of the embryo.

Veins and arteries are morphologically, functionally, andmolecularly very different. This distinction is established duringvasculogenesis, angioblast precursors for the trunk vein and artery arespatially mixed in the lateral posterior mesoderm. The venous - arterialdecision is guided and preceded by an increase in expression of the venous- gene marker and diminution of expression of the arterial - gene marker,adjudicating a venous versus arterial decision (14).

There is an essential and early developmental distinction betweenvein and artery, in addition to those differences later imposed by bloodpressure (15). Initially, mesodermal cells differentiate in situ into earlyhemangioblasts and form cellular aggregates - blood islands, in which theinner cell population develops into hematopoietic precursors and primitiveendothelial cells (5, 6).

The second stage is a form of primordial vascular network (13).Lumen formation of the primitive capillaries may result from endothelialvascularization or from a continuation of the pre-existing lumen throughthe joining of the distal endothelial cells and intracellular lumen formation .These processes are controlled by growth factors and growth-inhibitorymetabolites (4).

In the third stage, the primitive vascular plexus develops into aninterconnecting network by splitting the preexisting vessel in daughtervessels by endothelial sprouting (10) .

XVII

Clinical Physiology of the Venous System

In this process, periendothelial cells play important roles,concerning sprouting, remodeling, and production of specializedextracellular matrices.

The blood vessels seem to be initially surrounded by a fibronectin­rich matrix, which is later incorporated into the basal lamina along withinteralia laminin.

Several layers of fibronectin-expressing cells can be seen aroundlarger vessels (12).

In the microvasculature, around endothelial tubes are perycites,which may be involved in capillary blood flow regulation and maintenanceof a selective permeability barrier for plasma constituents. Anotherproperty of pericytes is their plasticity in differentiating into smooth musclecells.

The next phase in development is the acquisition of a media for thelarger vessels, when the vascular network expands. The adventitia of thesevessels has a similar embryonic contribution on the media , suggesting acommon origin of fibroblasts and smooth muscle cells (8).

Anastomoses appear and disappear, capillaries fuse and give rise toarteries or veins, and the direction of the blood flow may reverse severaltimes. The tunica media of the vessels appear after a stable vascular patternhas been formed.

The fourth stage occurs during the organogenetic period, after theoutset of circulation, when a tree of veins, capillaries and arteries areremodeled by metabolic demands of the growing embryo.

The early embryonic veins are segregated into two groups, visceraland somatic. The visceral group comprises the derivatives of the vitellineand umbilical veins; the somatic group includes all remain ing veins. All ofthem develop initially with a symmetric bilateral array of channels - thecardinal venous complexes, divided into a precardinal vein for the rostralpart, and the postcardinal vein for the caudal part. These form the superiorand the inferior vena cava, where veins converge. Pulmonary veins draininto the precardinal complex.

The primitive tubular symmetric heart receives its venous returnthrough the right and the left sinusal horns.

The symmetric bilateral array of channels is changed by growthand differentiation of the nervous system, of the skeleton and musculature,the cardiac asymmetry and venous return to the right part; by repos itioningof the heart, lung and gut, and venous involvement, by the developing liver,pancreas, spleen etc (5).

XVIII

Introduction

0.3. ANATOMICAL FEATURES

Because the heart is a pair of muscular pumps, there is a minor loop - thepulmonary circulation, and a major loop - the systemic circulation. A singleartery - aorta, from the systemic circulation, and the pulmonary trunk, fromthe minor loop, emerge from the heart , giving origin by successivebranching to hundreds of arteries. By further branching, these produceabout 4x106 arterioles in systemic circulation and four times as manycapillaries. About a similar number of venules converge into each other,forming veins, but more numerous, and finally forming the superior and theinferior vena cava, which open in the heart. An identical pattern is found inthe pulmonary circulation, but the number of vessels is smaller.

The veins, as a whole, form three main systems: pulmonary,systemic and portal (7).

Pulmonary veins , usually four, two from each lung, returnoxygenated blood from pulmonary capillary networks in the left atrium.

Systemic veins are divided into:• Cardiac veins, which drain directly into the heart .• Veins draining into the superior vena cava are divided into three

groups:veins of the head and neckveins of the upper limbsveins of the thorax.

• Veins draining into the inferior vena cava , are divided into twogroups:

veins of the abdomen and pelvisveins of the lower limbs .

The portal vein includes the veins draining the abdominal part ofthe digestive tube, spleen, pancreas and gallbladder. It conveys the blood tothe liver, ending in the sinusoids, which converge in the hepatic veins andfinally in the inferior vena cava.

Two or more capillaries converge in a postcapillary venule, withoval or polygonal endothelial cells supported by basal lamina and a delicateadventitia of collagen fibers, fibroblasts and pericytes. Venules do notacquire musculature until a new convergence. The veins have a relativelythin wall in comparison with the arteries of similar size. The amount of

XIX

Clinical Physiology of the Venous System

muscle is considerably less than in the arteries, while collagen and elasticfibers are their predominant components.

The orientation of the muscle cells is variable. In the arm and legveins the musculature is circularly. In the iliac vein, the brahiocephalicvein, the vena cava, portal vein and renal vein, the musculature islongitudinal.

Muscular tissue is absent in maternal placental veins, the duralvenous sinuses and pial veins, the retinal veins, the veins oftrabecular thebone, and the venous spaces of erectile tissue .

REFERENCES

1. Avram J. "Short history of phlebology and perforant veins" . In Surgery of perforantveins, J Avram, ed. Editura Hcstia, Timisoara - Romania , 2000 [in Romanian]

2. Bergan J1. "Historical highlights in treating venous insufficiency" . In Venous disease, 11Bergan, ed. Saunders , 1991

3. Branzeu P, Great performances in surgery, Editura de Vest, Timisoara - Romania, 1997[in Romanian]

4. Carmeliet P. Mechanism of angiogenesis and arteriogenesis. Nature Med 2000; 6: 389­395

5. Collins P. "Embriology and development". In Gray's Anatomy, PL Williams, ed.Churchill Livingstone, 1995

6. Flamme I, Risau W. Induction of vasculogenesis and hematopoiesis in vitro.Development 1992; 116: 435-439

7. Gabella G. "Cardiovascular system". In Gray's Anatomy, PL Williams, ed. ChurchillLivingstone, 1995

8. Gittenberger-de Groot AC, DeRuiter MCBergwerff M, Poelman RI. Smooth muscleorigin and its relationship to heterogeneity in development and disease . ArteriosclThromb Vase Bioi 1999; 19: 1589-1594

9. Monos E, Berczi V, Nadasy G. Local control of veins . Physiol Rev 1995; 75: 611-66610. Patan S, Alvarez MJ, Schittny JC, Burri PH. Interssusceptive microvascular growth: a

common alternative to endothelial sprouting. Arch Histol Cytol 1992; 55: 65-7511. Popescu M. Physiology and pharmacodynamics of portal vein. Bul de l'Acad de Med de

Roumanie 1940; 1-3: 6-8 [in French]12. Risau W. Mechanism of angiogenesis. Nature 1997; 386: 671-67413. Wilting J, Christ B. Embrionic angiogenesis : a review. Naturwissenshaften 1996; 83:

153-16414. Yancoupoulos GO, Klagsbrun M, Folkman J. Vasculogenesis, angiogenesis and growth

factors : ephrins enter the fray at the border. Cell 1998; 93: 661-66415. Zhong TP, Childs S, Leu JP, Fishman MC. Gredlock signalling pathway fashions the

first embryonic artery. Nature 2001; 414: 216-220

xx

PREFACE

I visited Arad, a small and pleasant city next to Timisoara, located west ofRomania, some years ago. I am so glad that during my visit to this cityProfessor Schneider and I discussed the development of this wonderfulbook. It is a real privilege for me to introduce Professor Francisc Schneider,head of the Physiology Department of the University Vasile Goldis inArad, Romania, and his coworkers Ioana Raluca Siska and Jecu AurelAvram. They are active and creative people, who maintain and bring to lifegood science and research in Romania. This volume bespeaks the rebirth ofphysiology in Romania and its long scientific tradition . Every seasonedvascular physiologist certainly remembers Marin Popescu who was the firstto demonstrate in 1940 the myogenic regulation of the portal vein tone andthe contribution of Pius Branzeu to vein transplantation. The present.bookis an excellent overview on the physiology and pathophysiology of veins.There is currently no equivalent in the marketplace. The authors havesucceeded to write a comparable summary on what is known to be adifficult topic .

This volume on the venous system complements "Biology of the ArterialWall" which was published in the Basic Science for the Cardiologist bookseries a few years ago by B. Levy and A. Tedgui. Obviously the two typesof vessels are quite different , not only in terms of anatomy and physiology,but also in terms of tone regulation and capacity to produce cytokines andcoagulation elements. An interesting aspect of vein physiology is the

Clinical Physiology of the Venous System

transformation of vein structure when veins are used as grafts. This volumealso includes vein pathophysiology, an enormous problem in terms of costand a major target for pharmaceutical companies. This area of medicine isfrequently forgotten or neglected despite its relevance in current clinicalpractice. The reader will find at the end of the book an interesting anduseful chapter that summarizes all the particular forms of phlebitis. Thischapter is unique to this volume. The book includes an importantbibliography and for the reader pressed for time, several take homemessages at the beginning of each chapter.The first three chapters cover hemodynamic and biological functions of theveins at both the organ and cell levels. Chapter 4 describes tone regulation .The last five chapters are devoted to pathophysiology; information onvaricose veins and thromboembolic disease both from a diagnostic andtherapeutic point of view; and venous insufficiency and congenitalabnormalities.

Bernard Swynghedauw, PhD, MDSeries Editor: Basic Science for the Cardiologist book seriesDirecteur de Recherches ernerite al'INSERMPast president of the Federation of European Physiological Societies(FEPS)

ABBREVIATIONS

ACE = angiotensin-converting enzymeACh = acetylcholineANO =angiotensinAPC =activated protein CAPO = air pletysmographyAT = antithrombinATIII = antithrombin III

AV = arterio-venous

AVC = arterio-venous communicationBK = bradykininCaCB = calcium channel blockersCaD = caldesmon

CaM =calmodulinCaMK II = Caz+-calmodulin protein-kinase IICaP = calponinCORP = calcitonin gene-related peptideCOX = cyclooxygen aseCT = computer tomographyCVI = chronic venous insufficien cyDAO = diacylglycerolDVT =deep venous thrombosisEC = endothelial cell(s)ECE =endothelin-converting enzymeEDHF = endothelium-derived hyperpolarizingfactorER = estrogen receptorsET-I =endothelin-lFOF = fibroblast growth factorsOC = guanilate cyclaseOSV = great saphenous veinHMWK =high molecular weight kininogenHUVEC =human umbilical vein endothelialcellsICAM = intercellular adhesion moleculesICV = inferior cava veinlGF = insulin-like growth factorIL = interleukinIMA = internal mammary arteryIPO = impedance pletismography

ROS = reactive oxygen speciesrtPA = recomb inant tissular plasminogen

IP3 = inositol triphosphateLC = light chainLDL = low density lipoproteinsLMWH = low molecular weight heparinLSV =low saphenous veinLT = leukotrieneMAPK = mitogen activated proteinkinaseMAPKK = mitogen activated proteinkinase kinaseMLCK = myosin light chain kinaseMLCP = myosin light chain phosphataseMMP = matrix metalloproteinaseMRA = magnetical resonanceangiographyMRI = magnetical resonance imagingNA = noradrenalineNANC = non-adrenergic non-cholinergicNE = norepinephrineNO =nitric oxideNOS = nitric oxide synthaseNPY = neuropeptide YPAF = platelet-activating factorPAl = plasminogen activator inhibitorsPAR-I = protease-activated receptor-IPDOF = platelet-derived growth factorPE = pulmonary embolism

POIz = prostacyclinPKA = protein kinase APKC =protein kinase CPKO = protein kinase 0PLAz = phospholipase AzPLC = phospholipase CPLD = phospholipase D

PPO = photopletismographyPR = progesterone receptorsPS = pentasacharidesPTS = postthrombotic syndromePVC = central venous pressureRAS = renin-angiotensin system

activatorSCY =superior cava veinSEPS = subfascial endoscopic perforantsurgerySMC =smooth muscle cellsSOD = superoxide dismutaseSPG = strain gauge pletismographySR = sarcoplasmic reticulumSY = saphenous veinTAFI = thrombin-activatable fibrinolysisinhibitorTF = tissue factorTFPI = tissue factor pathway inhibitorTGF-131 = transforming growth factor-BlTIE/TEK = tyrosine kinase withimmunoglobulin and epidermal growth factorhomology domainsTIMP = tissue inhibitors of MMPTNFa = tumor necrosis factor-alphat-PA = tissue plasminogen activator(s)Tr T = thrombin timeTT = traveler's thrombosisTxA2 = thromboxane A2

UFH =unfractioned heparinu-PA = urokinase-type plasminogen activatorYCAM =vascular cell adhesion moleculesYEGF = vascular endothelial growth factorYSMC = vascular smooth muscle cellsYY =varicose veinsvWF = von Willebrand's factor