Patophysiology of blood and lymph circulation in lower extremities Assoc' prof' Jana Plevkova MD, Ph

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Patophysiology of blood and lymph circulation in
lower extremities Assoc. prof. Jana Plevkova
MD, PhD 2009Department of Pathophysiology
Jessenius Faculty of Medicine in Martin 
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Blood circulation is sophisticated system which
conduct the blood from the heart and lungs into
the tissues- it's main function is to provide
suitable metabolic supply to the cells /oxygen,
substrates/, aw well as the cleavage of metabolic
products from the tissue

• vessels resistance, capacity, capillary
  network, other specific vascular structures
• high pressure / low pressure part of circulation
• regional specific circulations

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Arterial system of lower extremities
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Arterial system of lower extremities
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Principles of blood flow

• science discipline analyzing the flow of the
  blood within the circulation

?P. ?.r4 8.?.l
Q
Q blood flow ?P pressure gradient between
two different points of the tube /vessel/ r
vessel diameter l vessel length ? - blood
viscosity
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Arterial system of lower extremities

• -a part of high pressure circulation
• Energy of the heart ejection /systolic effort/
  continues into
• 1)  frontal pressure, responsible for the forward
  movement of the blood within the vessel
• 2)  lateral pressure affecting the wall of the
  artery causing it's distension, giving the base
  for the pulse wave
•  
• laminar flow (flow within individual layers
  smoothly gliding one on another )
• - This mutual gliding is responsible for the
  tangential tension among the layers and most
  external layer and endothelium, as well (shear
  stress)

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• shear stress this mechanism is able to
  influence some of the regulatory and secretory
  functions of the endothelium
• Turbulent flow within the blood stream could be
  physiological only at the sites of wide vessels
• aortal arc, pulmonary artery, site of the vessel
  branching, sudden bending of the vessel
• Predisposition for turbulent blood flow
• -   wide vessel
• -    sudden change of the diameter
• - high blood flow velocity
• -    low blood viscosity   
• -    uneven endothelial surface
•  

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• The blood flow in the arteries has three phases,
  due to elastic properties of the vessel wall
• 1st phase forward movement of the blood
  caused by ventricular contraction systolic
  ejection. Vessel wall is distended during this
  phase, because of lateral pressure applied onto
  the vessel wall
• 2nd phase is characterized by return of the
  distended vessel diameter into the former size
  elastic recoil the flow is directed to the beds
  with low resistance
• 3rd phase of the diastolic period the flow is
  directed forward again
•  

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• Regulation of the blood flow in lower extremities
• Relative constant pressure gradient diving
  pressure is constant, so regulation is secured
  predominantly by the change of vessel resistance
  change of vessel diameter  
• myogenic (Bayliss regulation)
• metabolic (autoregulation) lactic acid, CO2, H,
  K, adenosin
• other humoral factors (catecholamine, histamine,
  acetylcholine, angiotensin)
• nerve regulation - sympathetic fibers
•  

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Endothelium is not only a mechanical
barrier It has high metabolic activity,
participates in vessel reactivity, regulation of
thrombogenesis, influences the functions of
circulating cells Endothelial surface 500 -
1000 m2 contact surface for the mediation of
signals between circulating cells and intimal
surface It seems to be the largest endocrine
organ /1500g/ Metabolic and secretoric systems
influence mainly vessel tone therefore resistance
and blood flow Physiological tendency to
vasodilatation
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Endothelial vasodilators

• production of NO from L arginine by NO
  synthasis enzymatic process, new molecule of NO
  is released into the smooth muscle cells layer
  beneath the endothelium activation of
  guanylatcyclase - ? production of cGMP leads to
  relaxation of muscle cells and thus to
  vasodilatation
• production of NO is responsible for permanent
  natural tendency to vasodilatation in arterial
  system
• production of NO is stimulated by shear stress,
  platelets derived molecules like (ATP, ADP,
  serotonin), vessel distention flow dependent
  dilatation
• NO is dominant vasodilator in basal conditions
• endothelium produce also other vasoactive
  substances like - PGI2 (prostacyclin) PGE2, PGD2

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Endothelial vasoconstrictors

• endothelins, tromboxan A2, nonstable
  endoperoxides, and molecules of local RAA system
• Endothelins (1, 2, 3) group of peptides
  containing 21 AA, derived from molecule of
  proendothelin, which is fragmented to active
  molecules
• ETA a ETB receptors vasoconstricting response,
  long lasting effects involve proliferative
  effects on smooth muscle cells within the vessel
  wall

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Endothelial dysfunction

• Functional changes of the endothelial cells
• predominance for production of vasoconstricting
  mediators
• increased production of cytokines
• increased permeability for plasmatic proteins and
  lipoproteins
• predominance of procoagulating processes
• increased production of CAM molecules

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Pathogenesis of diseases of arterial system of
lower extremities

• Diseases with different ethiology may have the
  same, or very similar signs and symptoms
• So it is not correct to talk about arterial
  occlusion only
• Ischemia of lower extremities
• acute sudden onset of ischemic attac
  /dangerous, bc of the risk of the lost of the
  extremity/
• chronic long lasting ischemization, trophic
  changes...
• - Degenerative processes - atherosclerosis /ATS/
• - Aneurysmal arterial disease
• - Inflammation and thrombosis
• - Vasospastic disease

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Atherosclerosis obliterans Risk factors

• fatty and cholesterol containing diet
• less fruits/vegetable/fiber diet
• hypercholesterolaemia
• smoking
• hypertension
• low concetration of HDL
• family history for CVS diseases
• obesity
• increased fibrinogene level
• male sex

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• (Atherosclerosis obliterans - ASO)
•  patogenesis of ATS response of the vessel wall
  to injury
• functional changes of endothelial cells
• deposition of lipid particles into the vessel
  wall with subsequent reaction creation of
  fibromuscular plaque
• chemotactic activity of monocytes fagocythosis
  of lipid particles of macrophages (foam cells) ?
  lipid plaque 
• Formation of ATS plaques of different size and
  position in the arterial system of lower
  extremities

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• Consequences
•  
• turbulent flow at the site of the plaque location
• presence of the plaque may lead to serious
  stenosis limiting the blood flow
• damage of the vessel wall due to plaque may lead
  to weakening of media and formation of aneurysma
• bleeding into the plaque with possibility for
  formation of false aneurysma
• dysrupture of the plaque with subsequent
  thrombosis of the artery
• abruption of the plaque and embolization of
  those fragments into more peripheral circulation
  acute or chronic ischemization of extremity 

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• Arterial aneurysms localized dilatation of the
  vessel wall
• True aneurysms consist of all three layers of
  arterial wall, usually has fusiform or
  circumferential shape, the underlying condition
  for such a dilatation is weakening of the vessel
  wall due to some pathological process mainly
  ATS
• The damage of the vessel wall with weakening of
  media could be
• acquired (atherosclerosis, inflammation, toxic
  ifl.) or inherited (syndroms with weak connective
  tissue like sy. Marfan)
• 2)  False aneurysms extra vascular accumulation
  of blood with disruption, two or all three
  vascular layers ? the wall of the aneurysms is
  formed by thrombus and adjacent tissues, or
  adventitia
• False aneurysms is usually consequence of trauma,
  or complication of ATS plaque 

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• Whatever the cause, the aneurysm becomes
  progressively larger !
• tension within the vessel wall is directly
  influenced by the diameter and the lateral blood
  pressure
• localized dilatation of the vessel at the site of
  aneurysms leads to increase of diameter and
  therefore enhance the tension within the vessel
  wall, what again may enhance its enlargement
•  
• Consequences
• Ischemia below the location of aneurysma
• Acute thrombosis at the site of aneurysma
• Dysrupture of aneurysma
• Embolization of the thrombus into the more
  peripheral circulation
•  
•  

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• Inflamatory diseases Thrombangitis obliterans
• Burgers disease
• Inflammatory disease of small peripheral arteries
•  
• chronic inflammatory process
• inflammation is localized at the intima of
  affected vessels, and thrombosis is just a
  secondary consequence of it
• affected vessels are prone to vasospasm
• affected are mainly tibial and plantar arteries
•  

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• Etiopathogenesis of the disease is unknown
• affected population - men 20 40 yrs, smokers,
  autoimmunity
• Disease has three stages
• 1)    inflammatory and spastic phase
  (phlebitis saltans, migrans)
• 2)  obliterative phase with symptoms and signs of
  ischemia
• 3)   gangrene
•  

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• Vasospastic diseases
• Attacks of sudden constrictions of small diameter
  arteries and arterioles of upper and also lower
  extremities, commonly fingers, sometimes toes
• Raynaud disease primary vasospastic without
  any obvious or clear cause, most affected are
  young ladies
• Raynaud phenomenon syndrome, secondary problem
  usually linked with systemic collagen diseases,
  autoimmune diseases, toxic influences, long
  lasting vibration exposition, ...

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• Raynaud disease
• In spite the cause is unknown, there was
  identified hypetrophy of myoepithelial cells,
  which participate in regulation of blood supply
  to the capillary bed and hyperplastic changes of
  a-v- anastomoses
• cold or emotional stimulus is usually the
  provoking factor, leading to severe
  vasoconstriction, blood is redirected through a-v
  anastomoses into the venous system, while the
  capillaries are compromised
• Typical three phasic color changes of the skin,
  changes are always symetric
• a)      sudden pallor (dogiti mortui)
• b)      followed by cyanosis
• c) finally redness caused by reactive
  hyperaemia
•  

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• Raynaud phenomenon
• It is only a sign (manifestation/ of other
  primarily well defined disease
• Example systemic lupus erythematodes, primary
  pulmonary hypertension, some endocrine disorders
  myxedema-, exposition to vibrations,
  intoxication with ergot (claviceps purpurea)
• Symptoms are asymetric, affected persons are
  both men and women
•  

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• All mentioned diseases may lead to acute or
  chronic progressive obliteration of the vessel
  lumen.
• Obliteration of the lumen increases the vessel
  resistance.
• Increased resistance means - decreased blood
  supply to the affected region with a possibility
  of ischemia.

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Occlusive arterial disease
Chronic occlusive arterial disease ? ischemia as
a result of arterial obstruction
Obstructive arterial lesions occur more
frequently in the lower extremities than in the
upper extremities.Obstruction influencing the
blood flow to lower extremities is usually
localised. at
- aortoiliac level
- femoropopliteal level
- popliteo-tibial level
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Development
- arterial lumen is progressively narrowed ??
resistance to blood flow?blood flow to the
tissue below the lesion is reduced ? tendency
to tissue ischemia
- vessel lumen must be reduced by approximately
50 in diameter or 75 in crossectional area
to produce clinically significant interference
with blood flow
- in combination (stenosis occurring in
sequence), less significant lesions can
seriously impair blood flow
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Stenosis less than 75 of crossectional area is
not compromising blood flow during the rest
condition, but during the physical exercise it
could interfere with the blood supply leading to
ischemia

• At the site of stenosis and below the stenosis we
  can see changes of the blood flow like
• acceleration of the blood flow at the site of
  stenosis
• turbulent blood flow below the stenosis with
  recirculation of the blood, whirls (murmors
  present above the affected vessel?
• poststenotic dilatation with possibility for
  thrombogenesis

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• Example for stenosis occurring in sequence, less
  significant lesions can seriously impair blood
  flow  
• When small nonsignificant stenosis may lead to
  ischemia?
• During physical exercise (?O2 requirements,
  vasodilatation in working muscle, decrease of
  driving pressure)
• During elevation of the extremity (no hydrostatic
  effect supporting the blood supply)

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• Intensity of ischemic damage depends on
• the site /level/ of the vessel occlusion
  aortoilic, femoropopliteal, popliteotibial level
• extent and seriousness of stenosis
• time course of occlusion development /acute vs.
  chronic/
• presence and quality of collateral circulation
• Collateral circulation is unique and important
  compensatory mechanism of long lasting,
  progressively worsening ischemia. Increased
  resistance of affected arteries is responsible
  for opening of collateral circulation. Mainly
  muscular arterial branches could be base for
  collateral circulation.

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• Symptoms and signs of occlusive arterial disease
•  chronic course - usually ATS     
•  
• claudicatio intermittens
• pain at rest
• no pulse
• postural changes of the skin color
• temperature gradient bellow and above stanosis
• neurologic symptoms paresthesis
• trophic changes of the skin, hair, nails
• atrophic muscles and soft tissues
• ulceration and gangrene (dry, wet)

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• Symptoms and signs of occlusive arterial disease
• acute course thrombosis, embolisation, trauma
• dominant severe ischemic pain
• no pulse
• distal part below the stenosis is pale
• temperature gradient
• decreased filling of superficial venous system
• no trophic changes there is no time for their
  development

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• Occlusive arterial disease in patients with DM
• macroangiopathy ATS (in DM patients is
  accelerated)
• hypertension
• hyperlipidaemia and dyslipidaemia
• impaired nutrition of vessel wall because of
  dysfunction of vasa vasorum
• microangiopathy
• Damage of small diameter arteries and capillaries
  by generaliezed chronic complication of DM
• endothelial damage (diffusion of glucose into
  the cells, change into sorbitol, endothelial
  swelling endothelial dysfunction....)
• In this group of patients ischemic problems
  with lower extremities are very common, shifted
  to younger age, and are usually complicated by
  immunodeficiency and metabolic disorder /worse
  healing of wounds/

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Venous system of lower extremities
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• Blood flow in veins lower extremities     
• vis a tergo rest of left ventricle ejection
  energy
• vis a fronte suction of right atrium caused by
  up and down movement of AV junction
• negative thoracic pressure during inspiration
• craniocaudal movement of diaphragm
• corresponding changes of abdominal pressure
• horizontal body position
• rhythmic compression and decompression of deep
  venous system by muscles /walking/
• valves
• plantar venous mechanism
• pulsation of commitant arteries

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• Venous system of lover extremities
•   
•  

superficial venous system (10 of venous
returs) deep venous system (90 of venous
return) system of perforating veins   Physiologica
l pattern of venous return from lower extremity
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• Function of the valves
• If the valves are working properly
• they completely prevent pervasion of the blood
  from deep into superficial system
• they redirect central blood flow within the deep
  system
• they prevent retrograde blood flow from the upper
  level, if once the blood was ejected by muscle
  pump to upper level. During the muscle relaxation
  they completely prevent backward blood flow to
  more distal levels.  

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• Trombophlebitis
•  
• Pathological process affecting mainly superficial
  venous system. Primary affection is inflammation
  of spa. vein by the process spreading from the
  surrounding tissue
• Creation of thrombus is usually secondary
  phenomenon superimposed to inflammation.
• Thrombus is fixed to the vein wall by fibrin
  connections between the thrombus and inflamed
  vessel wall. The process is usually localized to
  the site of inflammation, no or minimal systemic
  symptoms, only local signs of inflammation.
• No risk of emboli, b/c the thrombus if fixed onto
  the vein wall, and as well is localized within
  the superficial system.

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• Deep venous thrombosis DVT
•  
• - intravital coagulation of the blood inside the
  vessels
• - physiological mechanisms against thrombosis
• continual blood flow
• intact endothelium
• balance in production of pro and anti coagulating
  factors
•  
• Impairment of those three mechanisms , known as
  Virchows trias has crucial role in pathogenesis
  of DVT.
•  

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• Predisposing factors for DVT
•  
• history of DVT
• immobilization (slowness of venous return from
  LE DK)
• senior age (polymorbidity, dehydration, change
  of rheologic properties of the blood)
• obesity, malignity (production of procoagulating
  factors)
• heart failure, decompensation (venous congestion
  in backward failure)
• surgical procedures, trauma (release of tissue
  tromboplastin)
• pregnancy, puerperium, abortion (occlusion of
  pelvic veins by pregnant uterus, enhanced
  coagulation, tissue of trophoblast)

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• Pathogenesis
• Slowing of the blood flow during immobilization,
  or in case of procoagulative status the blood
  there is a possibility of deposition of small
  amounts of fibrin at the site of vein valves
• The fibrin deposition is growing progressively by
  apposition of new fibrin fibers and platelets
  trapped into the fibrin matrix formation of
  thrombus
• The thrombus is a serious occlusion, which
  impairs or completely blocks the venous return
  through the affected deep vein
•  

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• Venous return from affected extremity
•  

• the blood flow in central direction through
  affected vein is blocked by the thrombus
• muscle contraction eject the blood into the
  surrounding deep vein /deep veins are usually
  doubled/ via anastomosis
• this deep vein provide central flow of the
  blood, which is of course limited so venous
  return as a complex process is impaired
• In this phase of DVT the blood does not flow
  into the spf. System, b/c perforators and their
  valves are not affected/destroyed, YET.

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• Venous return in a stage of recanalisation
•  

• Muscle contraction ejects the blood into three
  directions
• through partially recanalized vein upwards
• through anastomosis into surrounding deep vein
• through perforating veins /which valves are
  destroyed/not working / into the spf. system.
• During muscle relaxation spf. veins are
  emptying only partially into the deep veins, with
  sudden balancing of the pressure in both systems.
• Blood is cumulating in spf. veins leading to
  permanent hypertension in spf. system and
  recanalized part of deep venous system.

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• Venous return after total recanalisation
• Total recanalisation means healing of the vein,
  desobliteration, consequence of this process
  unfortunately is fibrotisation, or destruction of
  the valves.
• During muscle contraction the blood from deep
  vein is ejected into three directions
• -to SPF veins b/c of insufficient valves of
  perforating veins
• -to central direction through recanalised vein
  upwards
• -to central direction through surrounding deep
  vein
•  
• Muscle relaxation tendency for downward blood
  flow with rise of pressure in deep system,
  therefore emptying of spf. veins which had to be
  enhanced by the suction of negative pressure is
  limited  

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• Consequences
•  
• physiological pattern of venous return is
  affected
• onset of hypertension in spf. system and
  retrograde venostasis
• Venous congestion consequence for the capillary
  balance
• Congestion leads to
• rise of hydrostatic pressure at the venous end of
  the capillary
• hypoxic damage to the endothelial cells
• increase of capillary permeabilityh and therefore
  transudation of fluids into the pericapillary
  space

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Symptoms and signs of DVT

• Depends on the level of deep system which is
  altered by thrombosis, crural thrombosis pain,
  asymetric edema, fever not so severe symptoms
• Ileofemoral level
• severe pain
• edema, feeling of heavy leg,
• dilatation of superficial veins
• skin is stretched, pale or cyanotic /according
  the progress of disease/
• phlegmasia alba/coerulea dolens
• always fever, shivering, general symptoms,
  restlessness, anxiety

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• Varices
•  Cyllindric or saccular dilatation of spf. veins
  usually linked with relative valve insufficiency
• Primary varices
• Secondary varices
• Primary varices
• genetic predisposition, inherited insufficiency
  of connective tissue, abnormal collagen
  moleculle,
• The veins wall is weakened because of abnormal
  connective tissue, less tonus of muscular layer ?
  passive dilatation of the vein
• Supporting risk factors
• repeated increases of the pressure in spf. veins
• long lasting sitting, or standing without muscle
  contractions, obesity, pregnancy
•  
•  

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• Secondary varices
• Always as a consequence of DVT, and valve damage
• dilatation of vein enhances more and more
  relative insufficiency of the valves in
  perforating and spf. Veins
• Muscle contraction ejects the blood upwards, but
  also into the spf. system, what is not
  physiological - spf. venous hypertension

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• Chronic venous insufficiency
• CHVI due to inappropriate venous return form
  the lover extremity as a consequence of severe
  impairment of hemodynamic mechanisms of venous
  return itself, is always linked with hypertension
  in spf. system
• Venous hypertension in lover extremities
• Retrograde venostasis with simultaneous imbalance
  of hydrostatic pressures within the capillary
  Starling mechanism
• transudation of fluids into IST space ? edema
• endothelial hypoxic damage
• increase of capillary permeability
• transudation of proteins, RBC into he IST space
• fibrotic processes within IST space
•  

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• Symptoms and signs of CHVI
• pain venous claudication, improves during
  elevation of extremity
• edema
• induration and thickness of subcutaneous tissue
• hyperpigmentation of the skin caused by
  hemosiderine from RBC trapped and destroyed
  within the tissue
• trophic changes (sclerosis of the skin,
  ulcerations, scars after ulcers healing) edema
  and fibrotisation limit transport of oxygen and
  substrates to the tissues, thats why we have
  trophic changes
• ulcus cruris

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Lymphedema
Lymphatic system provide filtration of the blood,
participates in immune reaction and production
and outflow of lymph is a part of Starling
balance. Lymphedema edema of the tissue due
to impaired production and/or outflow of the
lymph.
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• Lymphedema 
• - no pain
• - in this case the fluid contains considerable
  amount of proteins
• Dysfunction of lymphatic system could be
• inherited (inherited hypoplasia of lymphatic
  capillaries and vessels Sy. Nonne Milroy) ,
  lymphedema is usually symmetric, affecting both
  extremities, in kids
• acquired (obstruction of lymphatic vessels or
  nodes by tumor, scar tissue, parasites, external
  compression, etc), lymphedema is usually
  asymmetric, mainly adults

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• Mechanisms involved
• static insufficiency of lymph. system decrease
  of the transport capacity of the normal ly.
  system, volume of produced lymph within the
  tissue is normal /block of ly. flow/
• dynamic insufficiency of lymph. system ly.
  system is intact, but is not able to drain lymph
  from the tissue, because of overproduction of
  the lymph
• - localized regional inflammation
• - venous congestion
•  

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• Lymphedema is chronic progressive pathological
  process
• accumulation of the protein molecules within the
  tissue
• edema (osmotic action of proteins)
• chronic inflammation
• fibrosis
•  
• Consequence fibrotic obliteration of ly. Vessels
  and/or nodes ? decreased transport capacity
  leading to total block of lymphatic flow
• onset of blisters in affected area
• repeated inflammations of the skin and
  subcutaneous structures
• hyperkeratosis and papilomatosis of the skin

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Signs and symptoms

• soft edema of the extremity, dough like
  consistence
• touching or pressing with the finger can make
  several hollows, with slow alignment
• edema progressively gets more solid, creates
  folding
• typically it is not painful
• pallor, cold extremity, because of compromising
  of normal blood supply
• lymph edema could crate bizarre shapes, leading
  to deformation of affected part of the body
• Long lasting lymphedema could lead to secondary
  skin affection like repeated inflammations caused
  by spteptococcus sp., or trophic changes

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