By Dr Vijay Richard

1. VENOUS PATHOPHYSIOLOGY
VIJAY RICHARD

2. INTRODUCTION
• Venous diseases represent a major concern in the general population
• Influenced by genetics, environment, and acquired conditions.
• Understanding the pathophysiology is essential for designing effective
and safe therapies
• GENETIC – eg – Klippel-Trenaunay syndrome and Parkes – Weber
syndrome

3. ENDOTHELIUM
• Inner lining of all blood vessels in the body
• Covers a surface area of 5000sq metres
• Primary determinant of pathophysiology
• Target for collateral damage in most disease processes
• Critical role in balancing procoagulant and anticoagulant mechanism
• Involved in mediating hemostasis

4. Homeostasis
• Endothelial cells – in normal condition maintain a vasodilatory and
local fibrinolytic state

5. Non thrombogenic endothelial surface
maintained by
• Thrombomodulin and APC
• Heparan and dermatan sulphate - accelerate AT & heparin cofactor2
• Tissue factor pathway inhibitor
• Tissue plasminogen activator and urokinase type PA
NO and prostacyclin from endothelium inhibits adhesion and activation
of leukocytes and produces vasodilation

6. VENOUS BIOMECHANICS
• 70% of circulating blood is stored in vein nd venules
• Large capitance vessels
• Essential for filling of the heart and compensate for orthostatic
changes
• Average venous pressure at foot – 100mmHg
• Pressure drops during ambulation and recumbence
• Veins undergo alteration in shape, depending on blood volume

7. VEIN WALL - structure
• Vein wall is much thinner, being anywhere from one third to one
tenth as thick as that of the systemic arteries
• Venous media is almost exclusively a muscular layer
• Venules have no media and no smooth muscle
• Major part of the walls of the larger veins is composed of adventitia.

8. Vein wall
• Vein are thin walled compared to artery
• Venous valves are present
• Veins have more smooth muscle and elastin content, unlike arteries
which have collagen content
• High distensibility and have a high breaking pressure (4 atm)
• Vein wall compliance decreases after thrombosis – bcos of increase
collagen and disrupted elastin

9. Vein wall and inflammation
• Von willebrand factor is expressed more in endothelium of veins
compared to artery
• Systemic inflammation causes endothelial activation resulting in
Increased cell adhesion molecules, P-selectin,, E –selectin and ICAM
(intracellular)
• Promotes the adhesion and activation of platelets

10. VALVE
• Important characteristic feature of vein
• The distribution and number of valves correspond well to regions
in which the effects of gravity are greatest
• Bicuspid structure with connective tissue skeleton enveloped by
endothelium
• The major function of venous valves is to divide the column of blood into
segments ensure antegrade flow and
prevent reflux from the deep to the superficial veins

11. VALVE
• more valves in the lower leg (calf veins) reducing in number in the
more proximal veins, with only one or two in the femoral and
popliteal veins
• valves work in a four phase cycle: opening, equilibrium, closing and
closed
• foot and calf muscle pumps act in unison during walking to assist the
venous return and thus lower the hydrostatic pressure present in the
upright position.

12. DEEP VENOUS THROMBOSIS
• SIGNIFICANT HEALTH CARE PROBLEM IN WORLD
• VIRCHOW TRIAD- Stasis, vessel wall injury and thrombogenic changes
in the blood
• Recent studies – stasis is probably permissive and not a direct cause
Sytemic inflammation may be more causal

13. Coagulation cascade
• Extrinsic pathway – tissue factor & Factor 7
• Intrinsic pathway – Factors XI, IX and VIII
• Common pathway- factors X, V and thrombin
Others – Protein C pathway – APC activates Factor V and VIII
Fibrinolytic sytem

14. Coagulation cascade
• Hemostasis is intiated by vessel wall damage and endothelial
disruption
• Tissue factor – cell membrane protein – is released with activation of
extrinsic pathway
• Hemostasis in cardiac muscle – more dependent on extrinsic pathway
• Hemostasis in skeletal muscle is more dependent on intrinsic pathway
• Intrinsic pathway activated by conversion of XI to XIa

15. Coagulation
Cascade

18. THROMBIN
• CENTRAL TO COAGULATION
• Action of cleavage -- release of fibrinopeptide from fibrinogen
• Cross-linking of fibrin , which stabilizes the thrombus and the initial
platelet plug
• Thrombin also activates factor XIII, fibrin stabilizing factor
• Activates fibrinonectin and alpha 2 antitrypsin incorporation in the
thrombus – resistance to thrombolysis

19. PLATELETS
• XIIIa activates platelets, as well as factors V and VIII, further
amplifying thrombin production
• Two platelet activation routes are thought to exist physiologically.
• Tissue factor pathway – without vessel wall damage
• Endothelial injury – subendothelial collagen bind to GP VI and VWF
leading to platelet Capture and activation
• vwf, GpIb , GPIIb/IIIa, fibrin
• Platelet granules release contents with rec for Va and vIIIa
• Activated plt release Thrombaxane A2 promote platelet aggregation

20. PLATELETS
• CHANGE IN PLATELET SHAPE – exposure of negatively charged
Procoagulant phsopholipids in the inner side of plt membrane
• Platelets release microparticles rich in tissue factor, accelerate
concentration of thrombus
• TF may be more important in VT than in arterial thrombosis

21. NATURAL ANTICOAGULANTS
• ANTITHROMBIN
• ACTIVATED PROTEIN C
• TISSUE FACTOR PATHWAY INHIBITOR

22. ANTITHROMBIN
• Central anticoagulant protein that binds to thrombin and interferes
with coagulation by three major mechanisms
Inhibits fibrinogen Limits fibrin formation
Thrombin cannot activate Factor v and vIII
Thrombin mediated platelet activation and aggregation are inhibited
• Heparin accelerates inhibition of thrombin by AT results in systemic
anticoagulation
• AT directly inhibit factors VIIa, IXa, Xa, XIa, and XIIa
• Genetic deficiency of AT are at much higher risk for development of
VTE than the normal population

23. Activated protein C
• Natural anticoagulant
• Produced on the surface of intact endothelium when thrombin binds
to its receptor, thrombomodulin & protein C receptor
• Thrombin-thrombomodulin complex inhibits thrombin and also
activates protein C to APC
• APC in presence of cofactor Protein s inactivates Va and vIIIa

24. TFPI
• protein binds the TF-VIIa complex, thus inhibiting the activation of
factor X to Xa
• factor IX activation is not inhibited

25. Thrombolysis
• Physiological lysis is controlled to prevent pathologic intravascular
thrombosis
• Plasmin, the central fibrinolytic enzyme from plasminogen
• Substrates of plasmin - fibrin, fibrinogen, and other coagulation factor

26. Plasmin
• Activation of plasminogen occurs through several mechanisms
Tissue plasminogen activator from endothelial cells in the presence
of thrombin
Urokinase like plasminogen activator from endothelial cells
APC inactivate PAI type1 from endothelial cells

28. Fibrin degradation products
• Plasmin degrades fibrin polymers resulting in creation of fragment E
and two molecules of fragmentD
• They are released as a covalently linked dimer (D-dimer)
• Detection of D-dimer in the circulation is a marker for ongoing
thrombus metabolism and has been shown to accurately predict
ongoing risk of recurrent VT
• the deep veins of the lower limb have the lowest fibrinolytic activity
in soleal sinuses, as well as in the popliteal and femoral vein regions

29. Plasminogen Inhibitors – Stops fibrinolysis
• PAI-1 is the primary inhibitor of plasminogen activators.
• secreted in an active form from liver and endothelial cells
• PAI-1 is stored in the alpha granules of quiescent platelets
• PAI-1 levels are elevated by hyperlipidemia, and PAI-1 elevation
appears to synergize with factor V Leiden genetic abnormalities
• genetic polymorphisms correlate with increased risk of VTE.
• The highest levels of PAI-1 have been noted in those individuals
carrying the 4G/4G polymorphism – 4 fold increased risk of PE

30. DVT
• MULTIFACTORIAL
• PROCOAGULANT VS ANTICOOAGULANT FORCES
• ENDOTHELIAL INJURY
• INFLAMMATION
• Recent data suggest that elevated levels of
soluble P-selectin combined with a clinical examination
favoring DVT has a positive predictive value for diagnosing DVT far
exceeding that of D-dimer

31. Inflammation and Thrombosis
• Inflammation increases TF, fibrinogen, and the reactivity of platelets
• Microparticles shed from platelets, leukocytes and endothelial cells
have thrombogenic property
• MPs are prothrombotic and inhibit fibrinolysis
• Platelet microparticles are associated with VT
• Gal3bp was found to be upregulated in MPs collected from human
patients diagnosed with DVT
• gal3 could be a potential biomarker in patients with acute DVT.

32. Thrombus Resolution and Vein
Wall Remodeling
• Resolution of thrombus in acute DVT is complex
• PMN followed by monocytes and their products play a role
• HIF-Iα (hypoxia-inducible factor-1α) and VEgF has role in thrombus
resolution
• Reduced vein wall contractility
• Loss of venous endothelium likely also contributes to vein wall
fibrosis, as well as the predisposition to recurrent thrombosis.
• TGF-β profibrotic growth factor may be a key mechanism promoting
vein wall fibrosis.

33. Post thrombotic syndrome
• 20 – 50 % of DVT pts develop PTS
• OUTFLOW OBSRTUCTION and VALVULAR REFLUX
• Both superficial and deep venous reflux
• Preservation of valve function is better with early resolution of
thrombus(LYSIS)
• Ipsilateral recurrent DVT, multisegment involvement and Popliteal
vein involvement increased PTS

34. Varicose veins
• Axial veins - upright nature of humans
• By defn >3mm
• Primary or secondary
• Pregnancy, prolonged standing, female gender, and, rarely, congenital
absence of valves
• Prior DVT or trauma
• Genetic predisposition
• Sponatneous remission in pregnancy

35. Varicose veins
• Matrix dysregulation with altered expressions of collagen types I and
III,
• Altered vasoreactivity is present
• Decreased contractual response to vasoconstrictors – repeated
overdistension and persistent vein wall tension

36. Thrombophlebitis
• Venous wall inflammation associated with thrombosis – sterile and
associated with thrombosis
• Superficial venous system is affected
• Superficial trauma or iv cannula
• Pain, redness, swelling, and tenderness to palpation (often like a cord)
• systemic febrile response is usually absent in noninfected cases

37. Thrombophlebitis
• Sterile phlebitis may occur in varicosities, as well as after venous
stripping or endovenous ablation
• Migratory thrombophlebitis – pancreatic cancer
• Mondor disease – ca breast - veins of upper outer quadrant area
affected

38. Venous system below knee
• Area of greatest interest
• Most common site of venous thrombosis
• Region of the leg where the complications of post-thrombotic
syndrome are evident.

39. Soleal sinuses
• Veins of the soleus muscle are called soleal sinuses
• Capacious size and lack venous valves
• most common site for the development of venous
thrombosis

40. PERFORTORS
• veins that normally carry blood from the superficial to the deep veins
• These short channels have the following features:
• (1) they penetrate the deep fascia
• (2) they contain valves;
• (3) they are found predominantly below
the knee;
• (4) the majority are small and inconstant in
location
• (5) they vary in number from 90 to 200.

41. The constant perforator
• constant large perforator can be found on the medial aspect of the
distal thigh between GSV and the deep system
• PERFORATORS along medial aspect of lower leg drain into the
posterior arch vein usually 4 constant perforators contribute to post
thrombotic syndrome
• The region in the vicinity of the lowest two perforating
veins is often referred to as the gaiter area

42. Flow rate in vein
• wide range of flow rates that can be found—from
high flows to nearly complete stasis
• virtually impossible to measure instantaneous venous flow in either
the superficial or the deep veins, it is necessary to look at
measurements of venous pressure and relate these to specific
conditions

43. Resting Venous Pressure
• Pressure in absence of pulsatile flow in artery and vein in erect
position will be equal in standing position upto the zero point
• In alive person this point is HIP hydrostatic indifferent point which is
just below the diaphragm in erect position
• HIP is in right atrium in supine position - 4th intercostal space
• Arteriovenous pressure gradient in the foot remains the same in the
capillaries in supine and erect position

44. On Standing
• There is translocation of 500 ml of blood into the lower limbs on
standing
• There is also a marked increase in the
transmural venous pressure at the foot as a result of the
effect of gravity.
• With this increase in pressure, fluid is forced out of the capillaries into
the tissues.
• Compensated to some extent by lymphatics

45. Hydrostatic pressures – 6 foot dead upright
man – zero point

46. Intravacular pressures in normal person

47. CALF MUSCLE PUMP –Peripheral heart
• single most important element in preventing
the continued accumulation of interstitial fluid
• This can dramatically lower the pressure
in the veins and capillaries
• The muscle pump fulfills three useful
functions: (1) it lowers the venous pressure in the dependent limb; (2)
it reduces venous volume in the exercising
limb; and (3) it increases venous return

48. Saphenous
venous
pressure –
single step
Normal
person

50. Calf volume
• Normal person - Calf volume decreases initially and increases
immediately bcos of arterial blood flow
• Varicose vein – calf volume does not become that low and comes
back to normal faster

52. Venous pressure in foot
• Normal individual - calf muscle pump
essentially empties the local venous system during contraction. With
relaxation, the veins are nearly empty, and
the venous pressure is very low-- intact pump and valvular system
• Varicose vein patient -
pressure does not fall to normally low levels,
and it returns to the pre-exercise level much faster when
walking is stopped AMBULATORY VENOUS HYPERTENSION

53. Flow velocity
• Flow on the venous side of the circulation is influenced
by a variety of factors, including respiration, the filling
pressure of the right heart, body position, the activity of
the calf muscle pump, and the amount of arterial inflow.
• Flow velocity in the normal femoral vein is lowest at peak
inspiration
• A cough and a Valsalva maneuver result in a sharp
increase in pressure above the valve but not below it

54. Flow
velocity in
CFA and
CFV in
supine and
normal
respiration

55. Effect of cough and
valsalva
manoeuvre on the
venous pressure
above
and below the
valve

56. Abnormal Pressure and Flow Relationships
• The most common manifestations of abnormal venous function are
primary varicose veins and the post-thrombotic syndrome
• Current evidence suggests that primary
varicose veins are often familial.
• The initial abnormality in this condition appears to be incompetence
of the terminal valves of the great and small saphenous veins, which
permits reflux of blood.
• With the passage of time,
progressive incompetence of the other valves occurs.

57. Venous flow in
incompetent GSV
– antegrade and
retrograde

58. Pressure in
VARICOSED
ANKLE GSV
during 4
steps
A NO ULCER
B No ulcer, IC ankle perf
C Ulcer +, IC perf
D Ulcer+, IC perf

59. CVI
• CVI is a condition that affects the venous system of the lower limbs,
resulting in pain, skin changes and ulceration
• VEIN WALL weakness & abnormality and valvular incompetence
• Superficial veins get engorged and secondary valvular incompetence
• Alteration in the collagen deposition in the veins may result in a
weakness and decreased elasticity of the vessels
• The abnormalities caused by CVI can also be seen in the venous
microcirculation

60. Microcirculation in CVI
• The capillaries become elongated and dilated, they have damage to
their endothelium with widening of the endothelial spaces and there
is localised edema and inflammation.
• Increased localized pressure and capillary permeability allows for
macromolecules and extravasated red blood cells to leave the
capillary vessel and go into the interstitial spaces
• The exact mechanism for this localised damaged is unclear

61. Stasis Dermatitis
• chronic dermal inflammation occurs secondary to venous
hypertension
• Extravasation of macromolecules and red blood cell products into the
dermal interstitium, creates a secondary inflammatory response
• clinical appearance is that of brawny induration, skin thickening,
swelling, and tissue break down with ulceration in the gaiter regions

62. THEORIES – venous ulcer
• Fibrin cuff theory – fibrin cuffs around capillary vessels
• Decreased diffusion of gases and nutrition to tissues
• WHITE CELL TRAP THEORY – wbc trapped in capillaries
• Trapped cells subsequently release toxic oxygen metabolites and
proteolytic enzymes
• inflammatory process initiated by the trapped white blood cells and
the subsequent tissue destruction

63. Venous ulcer – why only in some
• Why some are predisposed in CVI – C282Y genotype, mutation
related to iron processing – 7 fold higher risk of developing ulcer

64. • Skin hypoxia occurs on the gaiter areas of limbs with severe venous
disease - tcpo2 – differs by 20mm
• Leukocytes, macrophages, and mast cells have all been observed in
immunohistochemical and electron microscopic examinations of
affected dermal tissue

65. Compression stockings
• Most common therapy for CVI provide
external compression and thus minimize the amount
of edema that occurs during ambulation
• the stocking should reduce the
transmural venous pressure gradient in a graduated
fashion, with the highest compression pressures in the
ankle area and diminishing pressures proximally up the
limb.
• C2-C4 -- 20-30mmHg
• C5-C6 – 40-50mmHg

66. Ideal stocking
• Amount of pressure exerted by a stocking depends on the elastic
tension in the garment and the radius of the limb.
• Compression pressure should be in the range of 80 to 90 mm Hg
while standing, 50 to 60 mm Hg while sitting, and 0 mm Hg in the
recumbent position
• obviously not possible with any single
stocking; therefore a compromise must be accepted

67. LIMB ELEVATION
• Elevation of the legs above the level of the heart is also
a standard method for relieving the symptoms of chronic
venous insufficiency
• The physiologic basis for the use of
elevation depends on three major effects
• (1) it reduces venous pressure by decreasing the hydrostatic component
related to gravity;
• (2) it promotes the reabsorption of edema fluid; and
• (3) it prevents ambulatory venous hypertension.

68. Iliocaval venous occlusion
• Presents with CVI, collaterals in limbs and abdomens
• May – thurner syndrome
• Pelvic congestion syndrome
• Nut cracker syndrome

69. CONCLUSION
• Hemodynamics seems remote from clinical management
• But actually form the basis for a rational approach to diagnosis,
treatment AND follow up of vascular disease
• Exciting time to study venous thrombogenesis and the
pathophysiology of the resulting vein wall damage, in part because
it has been relatively neglected compared with arterial disease

70. Thank you