This document discusses the anatomy, pathophysiology, and etiology of venous disease. It covers: - The three components of venous systems: superficial, deep, and perforating veins - Normal venous hemodynamics and the role of muscle pumps and valves in returning blood to the heart - Causes of venous disease including venous thromboembolism, varicose veins, and chronic venous insufficiency - The pathogenesis of venous thrombosis and role of coagulation, fibrinolysis, and inflammation - Classification of chronic venous disease using the CEAP system and characteristics of different disease stages

1. VENOUS DISEASE
ANATOMY
PATHOPHYSIOLOGY
ETIOLOGY
Moderator : Dr Shishira

2. ANATOMY
• Venous systems contain three components:
– Superficial
– Deep
– Perforating veins

3. SUPERFICIAL
• GREAT SAPHENOUS VEIN
• SHORT SAPHENOUS VEIN
• COMMUNICATING VEINS
– Eg : Intersaphanous vein (artery of Giacomini)
• RETICULAR VENOUS PLEXUS
• SUBPAPILLARY VENOUS PLEXUS

4. DEEP
• ANTERIOR TIBIAL
• POSTERIOR TIBIAL
• PERONEAL
• POPLITEAL
• FEMORAL

5. PERFORATING VEINS

7. Great Saphenous vein

8. Short Saphenous Vein

9. Deep Venous System

10. Normal Venous Hemodynamics
Two important functions
– Return of blood to the heart from the capillary
bed
– Maintenance of cardiovascular hemostasis
through changes in capacitance

11. Pressure-Flow Relationships and
Venous Return
• The pressure generated by cardiac pumping is
termed dynamic pressure
• In the upright position, venous flow in the
lower extremities is dominated by the effects
of hydrostatic pressure, which is derived from
the weight of the column of blood

13. • Return of blood from the dependent lower
extremity to the heart requires overcoming
the effects of hydrostatic pressure
• Accomplished by
– muscle pumps
– venous valves

14. • Muscle contraction propels venous blood
toward the heart
• During relaxation, valves close, and blood is
prevented from refluxing down the leg and
breaking up the hydrostatic pressure column
• The negative pressure generated by valve
closure also draws blood from the superficial
to the deep systems via perforating veins, thus
further enhancing return of blood to the heart

15. Venous Compliance and Capacitance
• Capacitance : The relationship between
pressure and volume at a given level of
smooth muscle tone in the venous system
• Compliance : is the change in blood volume
that occurs for each unit of change in
transmural pressure in a segment of vein

16. • Veins maintain cardiovascular hemostasis by
storing large volumes of blood by their ability
to change shape and maintain pressure
despite relatively large changes in volume
• The venous system at times contains as much
as 75% of the systemic blood volume
• Venous capacitance is governed by the
collapsible nature of the venous wall

17. • Transmural pressure : The difference between
intraluminal pressure acting to expand a vein
and tissue pressure acting to collapse the vein
is termed
• An increase in venous transmural pressure
corresponds to a change in shape from
elliptical to circular

19. VENOUS DISEASES

20. VENOUS THROMBOEMBOLISM
• Venous thromboembolism (VTE) is a significant
health care problem
• Understanding the pathogenesis of VTE has
centered on Virchow’s triad
– stasis
– changes in the vessel wall (now recognized as injury)
– thrombogenic

21. Venous Thrombosis Pathway
• Hemostasis
• Natural anticoagulant
• Physiologic thrombolysis

22. Hemostasis
• It is typically initiated by damage to the vessel
wall
• Vessel wall damage results in release of tissue
factor (TF)
• Activation of the extrinsic pathway of the
coagulation cascade
• Platelet activation and the formation of an
effective hemostatic “platelet plug”

23. Natural Anticoagulants
1. Anti-thrombin
• It is a central anticoagulant protein that binds
to thrombin and interferes with coagulation
• inhibition of thrombin prevents removal of
fibrinopeptides A and B from fibrinogen,
limiting fibrin formation

24. • Thrombin becomes unavailable for activation
of factors V and VIII, thus slowing the
coagulation cascade
• thrombin-mediated platelet activation and
aggregation are inhibited

25. 2. Activated protein C (APC)
• It is produced when thrombin binds to its
receptor
– Thrombomodulin and
– endothelial protein C receptor (EPCR)
• The thrombin-thrombomodulin complex inhibits
the actions of thrombin
• APC, in the presence of its cofactor protein S,
inactivates factors Va and VIIIa

26. 3. Tissue factor pathway inhibitor (TFPI)
• This protein binds the TF-VIIa complex and
inhibit the activation of factor X to Xa and
formation of the prothrombinase complex
4. Heparin cofactor II
• Is another inhibitor of thrombin whose action
is in the extravascular compartment

27. Physiologic Thrombolysis
• The central fibrinolytic enzyme is plasmin
• It is a Protease enzyme generated by the
proteolytic cleavage of the proenzyme
plasminogen
• Its main substrates include fibrin, fibrinogen, and
other coagulation factors.
• Plasmin also interferes with vWF mediated
platelet adhesion by proteolysis of GPIb

28. • Activation of plasminogen occurs by
– presence of thrombin
– vascular endothelial cells
– tissue plasminogen activator (tPA)
– α2-antiplasmin

29. • The degradation of fibrin polymers by plasmin
results in the creation of
– fragment E and
– two molecules of fragment D, which are released
as a covalently linked dimer (D-dimer)
• Detection of D-dimer in the circulation is a
marker for ongoing thrombus metabolism

30. • In Resting state
– fibrinolytic system within the vein wall is lower in
the area of the valvular cusps
• In comparison with other anatomic locations
deep veins of the lower limb have the lowest
fibrinolytic activity in
– soleal sinuses
– popliteal and femoral vein regions
• This observation underlies a popular
hypothesis as to why DVT most commonly
originates in the lower limb.

31. Endothelium and Hemostasis
• Most of the thrombosis-thrombolysis
processes occur in juxtaposition to the
endothelium
• endothelial cells maintain a
– vasodilatory
– local fibrinolytic state
– In which coagulation, platelet adhesion, and
activation are suppressed.

32. 1. endothelial production of thrombomodulin
and subsequent activation of protein C
2. endothelial expression of heparan sulfate
and dermatin sulfate, which accelerate
antithrombin and heparin cofactor II activity
3. constitutive expression of TFPI
4. local production of tPA and uPA

33. • In addition the production of NO and
prostacyclin by the endothelium inhibits the
adhesion and activation of leukocytes and
produces vasodilation

34. • After endothelial injury a prothrombotic and
proinflammatory state of vasoconstriction is
supported by the endothelial surface

35. • Vasoconstriction
– platelet-activating factor (PAF) and
– endothelin-1
• Thrombosis
– vWF,
– TF,
– PAI-1,
– factor V

37. Inflammation and Thrombosis
• Inflammation increases
– TF
– membrane phospholipids
– fibrinogen and the reactivity of platelets
• while there is decrease in
– thrombomodulin and
– inhibiting fibrinolysis

38. Thrombus Resolution and Vein Wall
Remodeling
• Early thrombus resolution
• Late thrombus resolution

39. Early thrombus resolution involves a
– large clot releasing interlukin-1β (IL-1β)
– cell necrosis products and
– platelet factors such as urinary platelet activator
(uPA)
• Concurrently matrix metalloproteinase-
9(MMP-9) is released, and plasmin is
upregulated.
• This allows for early thrombolysis

41. Late thrombus resolution (usually after 8 days)
• vein wall medial thickening occurs with decreased
compliance and decreased vasoreactivity
• Reendothelization commences but is incomplete
until a much later time point (>14 days)
• Thrombus neovascularity and are associated with
resolution which is a monocyte/macrophage-
driven process.
.

42. • Within the vein wall, matrix turnover occurs
with increased MMP-2 expression, as well as
collagen I and collagen III production
• IL-13 and transforming growth factor-β (TGF-
β) are two profibrotic growth factors that may
be involved with late vein wall remodeling

44. CHRONIC VENOUS INSUFFICIENCY
• In 1917, John Homans produced a clinical
treatise on the diagnosis and the management
of patients with CVI and coined the term “post
thrombotic syndrome.”
• Dr. Alfred Blalock put forth the hypothesis that
local hypoxia precipitated CVI

45. • Local tissue hypoxia and alterations in nutrient
in blood flow - were proposed as an
underlying etiology by Browse and Burnand
• Their study demonstrated the effect of venous
hypertension on the venous microcirculation
• They observed histologically that in large
capillaries, pericapillary fibrin deposition,
which they called the “fibrin cuff”

46. • Dr. P.D. Coleridge Smith proposed leukocyte
trapping in slow-flow and distended venous
segments may underlie much of CVI
development

47. • The pathogenesis of chronic venous insufficiency (CVI)
• CVI is caused by reflux, which increases hydrostatic
pressure in vein
• It is transmitted to the subcutaneous dermis and skin
• This process occurs with both primary and secondary
valvular insufficiency.
• Reflux also potentiates blood flow stasis, with vein
distention and endothelial activation

48. • extravasation of leucocyte and transudative
macromolecules and iron.
• Chronic dermal inflammation occurs with
increased matrix metalloproteinases (MMPs),
collagen alteration, and possibly apoptosis.
• A venous ulcer is the most severe
manifestation of CVI

50. The best way to categorize CVI is with
the CEAP

55. Varicose Veins (CEAP Class 2 to 3
Disease)
• varicose veins primarily affect the lower limb
• Because of the upright nature of humans
• specifically, the effect of hydrostatic pressure
on the pathophysiology of such veins

56. • Varicose veins do not thrombose
• Despite relatively slow blood flow and
distorted anatomy
• Because of natural anticoagulant nature of
venous endothelium

57. Risk factors
• Primary Etiologies
– Pregnancy
– prolonged standing
– female gender
– rarely, congenital
• Secondary
– DVT
– Trauma

58. • Congenital
– predominantly anatomic variants that are present
at birth
– Venous ectasias
– absence of venous valves and
– syndromes such as Klippel-Trenaunay syndrome

59. Pathology
• In varicose veins higher collagen content and
lower elastin content have been measured
• increase in tissue water and collagen type I
• collagen types III and V levels lower than in
normal veins
• less type III collagen is associated with
decreased elasticity

60. • The observed pathology is because of matrix
deposition
• Mechanism for these changes
– local upregulation of MMPs and
– fibrinolytic activity within the microenvironment

61. • This disordered vein structure correlates with
altered vasoreactivity
• Receptor downregulation
– feedback inhibition of endothelin (ETA) receptor
secondary to increased endothelin-1 is also
postulated to mediate the lower vasoreactivity
content in the walls of varicose veins

62. Stasis Dermatitis and Dermal
Fibrosis (CEAP Class 4 to 6 Disease)
• Stasis venous dermatitis is a disease of chronic
dermal inflammation
• It is secondary to venous hypertension
• Extravasation of macromolecules and RBC
into the dermal interstitium creates a
secondary inflammatory response

63. • The clinical appearance is
– brawny induration
– skin thickening
– swelling and
– tissue breakdown with ulceration in the gaiter
regions

64. • Fibroblasts in patients with CEAP class 2 or 3
CVI retained agonist induce proliferative
capacity
• those from patients with class 4 or 5 CVI
showed diminished agonist-induced
proliferation
• Fibroblasts from patients with class 6 CVI and
active ulcers did not proliferate with TGF-1β

65. • suggesting that these ulcer fibroblasts are
refractory to stimulation and may contribute
to the inability to promote healing.
• Histologically, these fibroblasts appear similar
to fibroblasts undergoing cellular senescence,
and therefore may be proapoptotic from
repeated injury

66. • the risk of ulcer development among patients
with class 4 to 6 CVI was sevenfold higher in
those with the C282Y genotype, a mutation
related to iron processing

67. • REFEREENCE
– Rutherfords 8th edition
– Sabiston 20th edition

68. Thank you