EDEMA

EDEMA

EDEMA

• Water is 60% of the body weight 2/3 of which is intracellular, the rest is interstitial fluid and only 5% is in the plasma.
• Edema means increase in interstitial fluid. It can also be collection of fluid in body cavity known as effusion. Anasarca is a severe and generalized edema with subcutaneous swelling.
• The hydrostatic and colloidal osmotic pressures control the movement of fluid between vessels and interstitial space.
• Normally outflow of fluid from the arteriolar end of the microcirculation is balanced by inflow in the venular end. A small leftover fluid is removed by lymphatics.
• The edema fluid of hydrodynamic derangement is typically poor protein content transudate with low specific gravity

Hydrostatic pressure increase

¨   Local-  from impaired venous outflow e.g. deep venous thrombosis

¨   Generalized increase of venous pressure commonly occurs in congestive heart failure affecting the right ventricle function. This is called cardiac edema

• Cardiac edema, in addition to hydrostatic pressure increase, has complex pathogenesis. The decease in cardiac output induce renal hypo perfusion which triggers the renin-angiotensin-aldestron axis resulting in salt and water retention to restore renal perfusion through the increase in the intravascular volume. If the heart cannot increase its output the extra fluid load results in increased venous pressure and hence edema.
• Unless cardiac output is restored or renal water retention is reduced (by slat restriction or diuretics) a cycle of renal fluid retention and worsening edema ensues.

Reduced plasma osmotic pressure

¨   Excessive loss or reduced synthesis of albumin which the most important plasma protein for the colloidal osmotic pressure.

¨   The excessive loss of proteins from protein losing gastroentropathy and nephrotic syndrome (loss of proteins due to glomerular leakage)

¨   Reduced synthesis: - from cirrhosis, protein malnutrition.

¨   In each case the reduction of plasma protein leads net fluid movement into the interstitial  space and plasma volume contraction. The reduced plasma volume results in renal hypo perfusion with consequent secondary aldosteronism. The retention of salt and water cannot correct the plasma volume deficit since the primary defect of low plasma protein persists.

Lymphatic obstruction.

¨   Lymph edema is usually localized and can result from inflammatory or neoplastic obstruction e.g. in the filariasis there is massive lymphatic and lymph node fibroses  in the inguinal region that causes  edema of external genitalia and lower limbs so extreme to be called elephantiasis.  Other example is breast cancer which gives early metastasis of the axillary lymph nodes and irradiation or surgical removal or even  fibroses of the nodes may result in edema of the omolateral upper limb.

Salt and water retention.

¨   They are the contributory factors of several forms of edema, however they can be the primary cause of edema. They cause both increase in hydrostatic pressure (owing to the expansion of intravascular fluid volume) and diminished vascular colloid osmotic pressure.

¨   Salt and water retention can occur with any acute reduction of renal function e.g. post streptococcal glomerulonephritis and acute renal failure.

Morphology

¨      Edema is most easily recognized grossly. Microscopically, edema fluid  only manifests as subtle cell swelling with clearing or separation of extra cellular matrix elements.

¨      Edema involves mostly subcutaneous, lung and brain.

Subcutaneous

¨   It can be diffuse or relatively more conspicuous at the site of highest hydrostatic pressure typically influenced by gravity and termed dependent edema. This edema is common in congestive heart failure and manifests in legs when standing and sacrum when recumbent.

¨   The nephrogenic edema is more severe than cardiogenic one and affects all body parts equally. It begins in the loss CT (eye lids)

¨   The finger pressure displaces the interstitial fluid of the subcutaneous tissue and leaves a finger-shaped depression, so called pitting edema.

Pulmonary edema

¨   It is a common clinical concern mostly associated in left ventricular failure. It also occurs in renal failure, adult respiratory distress syndrome, lung infection and hypersensitivity reactions.

¨   The lung’s weight increases and on section reveals frothy blood-tinged fluid representing a mixture of air, edema fluid and extravasated RBC.

Brain edema

¨   It may localized as in abscess and neoplasia or generalized as in encephalitis, hypertension crisis venous outflow obstruction.

¨   The brain is grossly swollen with narrowed sulci and distended gyri showing sings of flattening against the skull.

¨   If the edema is conspicuous and the brain expansion is sufficiently severe brain herniation will occur (tosillar, transtentorial, subfalcine herniation)

Hyperemia and congestion

¨   They are a local increase in blood volume in a tissue.

1. Hyperemia is an active process that results from blood inflow in a tissue due to arteriolar dilation e.g. skeletal muscles in exercise, a site of inflammation.

¨   The affected site is redder due to engorgement of oxygenated blood.

2. Congestion is a passive process that results from impaired outflow of blood from a tissue.

¨   The tissue appears blue-red in color (cyanotic) due to the presence of deoxygenated blood. Congestion and edema occur together.

¨   In the chronic congestion there is chronic hypoxia with resultant parenchymal cell degeneration, microscopic scaring, foci of hemorrhage from capillary rapture and presence of hemosiderin-laden macrophages.

Morphology

¨   The cut surface of hyperemic or congested tissue is hemorrhagic and wet.

¨   Acute lung congestion manifests with alveolar capillary engorged with blood and septal edema or focal intra-alveolar hemorrhage.

¨   Chronic lung congestion presents with thickened fibrotic septa and sometimes alveolar spaces with hemosedrin-laden macrophages (heart failure cells)

Hepatic congestion

¨   Acute form: - central veins and nearby sinusoids are distended with blood and central hepatocytes degeneration. Periportal hepatocytes are better oxygenated due to nearby hepatic arterioles. The latter sometimes develop fatty degeneration.

¨   Chronic passive congestion:- central regions of the hepatic lobules are red-brown and depressed owing to loss of cells contrasting the surrounding uncongested zone (nutmerge liver)

¨   Microscopically, there is Centro lobular necrosis with hepatocyte dropout and hemorrhage (hemosedrin-laden macrophages)

¨   In severe long-standing congestion is commonly associated with heart failure. This may predispose fibroses and hence cardiac cirrhosis.

 HEMORRHAGE

¨   Hemorrhage is extravasations of blood because of a vessel rupture.

¨   There are various disorders in which minor injuries can produce hemorrhage severe enough to be catastrophic. They are collectively called hemorrhagic diathesis.

¨   Rupture of larger vessel is almost always due to vascular injury from trauma, atherosclerosis, inflammatory or neoplatic erosion of the vessel wall.

¨   Hemorrhage may be external or enclosed within a tissue. The accumulation of blood in a tissue is called hematoma. The latter can be simple as in bruise or fetal as in brain hematoma or can be massive and cause death (retroperitoneal hematoma from dissecting aorta aneurism)

¨   Minute 1-2mm hemorrhages in the skin, mucosa and serosal surface are called petechiae. It is typically associated with local intravascular pressure increase, thromboastenia, thrombocytopenia, or clotting factor deficit.

¨   Slightly larger (≥3mm) hemorrhages are called purpura. They similar to petechiae in pathogenesis. It is also encountered in vasculitis and in trauma and increased vascular fragility.

¨   Larger (>1 to 2cm) subcutaneous hematoma (bruise) are called ecchymosis. It is associated with trauma. The RBC are depredated and phagocytosed, the hemoglobin (red blue in color) is converted into bilirubin (blue green color) and all is converted into hemosedrin ( golden brown.)  This shows the characteristic color changes in hematoma.

¨   Larger accumulation of blood occur in body cavities as in hem thorax, hem peritoneum, hem pericardium and hemoarthrosis.

¨    Patient with extensive hemorrhage occasionally develop jaundice from massive breakdown of RBC and systemic release of bilirubin.

¨   The clinical significance  of hemorrhage depends on the volume and the rate of loss. 20% of rapid blood removal or more than 20% in low rate removal has a little impact on a health person.

¨    Greater volume loss may induce hypovolumic shock. The site of hemorrhage is also important.

¨   Chronic hemorrhage may cause iron deficiency anemia.

HEMOSTASIS and THROMBOSIS

The normal hemostasis is the result of a set of regulated processes that accomplish 2 important functions:

1. Maintain the blood in a fluid, clot-free state in normal vessels.
2. Induce rapid local hemostatic plug at the site of vessel injury.

THROMBOSIS:

¨   Is an inappropriate activation of normal hemostatic process with formation of blood clot in uninjured vessel or thrombotic occlusion of a vessel after a relatively minor injury.

¨   Both thrombosis and hemostasis depend on the vascular wall, platelets and coagulation cascades.

Normal hemostasis

Sequence of events in hemostasis:-

1. After injury there is a brief period of vasoconstriction due to neurogenic reflex augmented by local secretion of endothelin (potent endothelial derived vasoconstrictor. ) The effect is transient and bleeding resumes if platelets and coagulation system is not activated.
2. The endothelial injury exposes highly thrombogenic sub endothelial ECM, which allows platelets to adhere and become activated releasing there secretory granules which induce additional platelets recruitment that forms hemostatic plug, primary hemostasis.
3. Tissue factors (membrane-bound procoagulant factors synthesized by endoth,) are also exposed at the site of injury. They act in conjugation with the platelet factors to activate the coagulation cascade, culminating in the activation of thrombin which converts the soluble fibrinogen into insoluble fibrin and hence the formation of secondary hemostatic plug. This plug takes more time to form.
4. Polymerized fibrin and platelets aggregates form a solid, permanent plug to prevent any further hemorrhage.

¨   At this stage contra regulatory mechanisms set in motion to restrict the hemostatic plug at the site of injury (e.g. tissue plasminogen activator)

ENDOTHELIUM & THROMBOSIS

¨   ENDOTHELIUM can have pro- and anti-thrombotic activities. They are activated by infectious agents, hemodynamic factors, plasma mediators and cytokines.

Anti-thrombotic properties of the endothelium

1. Antiplatelets:- 

¨   They inhibit the platelets and plasma factors to meet the highly thrombogenic sub endothelial ECM when they are intact.

¨   The endothelial cells on activation by cytokines, thrombin and ADP synthesize PGI2 and nitric oxide. These 2 substance inhibit the adhesion of platelets to the uninjured endothelium near the injury site. They are also vasodilatators and antiaggregante platelets

2. Anti coagulants

¨   Is mediated by membrane associated heparin-like molecules (MAHLM) They activate the antithrombin III to inactivate Xa and other coagulation factors.

¨   The thrombomodulin binds with thrombin converting into anticoagulant that activates protein C which inhibit coagulation by proteolytic cleavage of factors Va and VIIIa. This latter reaction requires protein S synthesized by endothelial cells as cofactor.

3. Fibrinlysis

¨   Endothelial cells synthesize tissue plasmenogen activator to promote fibrinolysis to clean fibrin deposits from the endothelial surface

Endothelial prothrombotic activities

• The adhesion between sub endothelial ECM and platelets is facilitated by vWF produced by endothelial cells.

• Endothelial cell stimulated by endotoxin, TNF, IL-11 synthesize tissue factor that activate the extrinsic coagulation pathway.
• They also secrete inhibitor of plasmenogen activator (PAI) to depress fibrinolysis.

In conclusion intact endothelium inhibit platelet aggregation and blood clotting while injured or activated endothelium is procoagulant and augments local clot formation.

Platelets & thrombosis

·      They are membrane bound smooth discs expressing glycoprotein receptors of the integrin family on their surface. They have α and δ granules.

·      α granules express the adhesive molecule P-selectin on their membrane and contain: fibrinogen, fibronectin, V, vWF , platelet factor IV, PDGF, TGF-β

·      δ granules contain ADP, ATP, Ca ions, histamine ,serotonin and epinephrine.

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When platelets encounter with ECM they undergo 3 general reactions:

1. Adhesion and change in shape
2. Release reaction
3. Platelet aggregation

Platelet’s adhesion to ECM

• Is mediated by the interaction with vWF which bridges the platelet surface receptors and exposed collagen. Sometimes adhesion to ECM occurs directly via  platelet collagen receptors and interaction with fibronectin. The receptors of vWF glycoprotein Ib interact with vWF producing the adhesion which resists the highly shearing forces of the flowing blood.
• The genetic defect of vWF (von Willebrand disease) and its receptor (GIb) are known as Bernard-Soulier syndrome which is a bleeding disorder due to platelet adhesive defect.

Release reaction

• Occur after adhesion. The process begins when platelets bind to the ECM following intracellular protein phosphorylation cascade. The δ granules’ release is particularly important because they provide Ca ions required in the coagulation cascade and ADP for platelets aggregation and further ADP release.
• Platelets activation also leads to surface expression of a phospholipids complex which provides a critical nucleation site for calcium and factor binding in the intrinsic clotting pathway.

Platelets aggregation

• Follows adhesion and release reaction. It is stimulated by ADP and TXA-2. the ADP and TXA-2 set up an autocatalytic reaction leading formation of large aggregates of platelets, the primary hemostatic plug. In the coagulation cascade, the thrombin formed binds platelet surface receptor and with ADP and TXA-2 further increase the size of the aggregate.
• After platelets aggregation, the platelets contract creating un irreversible fused mass constituting the definitive secondary hemosttic plug. At the same time throughout the platelet plug, thrombin converts the fibrinogen in fibrin essentially mortaring the platelets in place.
• Thrombin is the central figure in the thrombi formation and as such is a major target for therapeutic modulation of the thrombotic process.
• The ADP activated platelets bind with fibrinogen which in turn link to other platelets via a glycoprotein receptor (GpIIb-IIIa) to form large platelet aggregate. Patients with congenital defect of this receptor (Glanzmann thromboasthenia) present a severe bleeding disorder attributable to platelet aggregation defect.
• The endothelial derived PGI-2 and nitric oxide are vasodilatators and anti aggregation  for platelets while the platelet derived TXA-2 are vasoconstrictors and activate platelet aggregation. The PGI-2 and TXA-2 play a counterbalancing mechanism which modulates the platelet function. In normal state it prevents intravascular platelet aggregation but after endothelial injury it favors formation of hemostaic plug.
• The clinical utility of aspirin in patient at risk for coronaric thrombosis is due to its ability to acetylate irreversibly the cyclicooxygenase  and hence block the synthesis of TXA-2.
• Both WBC and RBC adhere to the endothelial and platelets with their adhesive molecules and are found in the hemostatic plug. They also contribute to inflammatory response that accompany thrombosis.

COAGULATION CASCADE

It is the third and most important component of the thrombosis.

General principals:

1. Coagulation cascade is a series of conversion of inactive proenzyme to activated enzyme culminating the formation of thrombin which converts fibrinogen into insoluble fibrillar protein  called fibrin.
2. Thrombin exerts a wide variety of effects on the local vasculature and inflammation and participate in limiting the extent hemostatic process.
3. Each reaction in the pathway is composed of an enzyme, (activated coagulation factor), a substrate (proenzyme form of coagulation factor) and a cofactor (reaction accelerator.)  These components are assembled on a phospholipids complex and held together by Ca ions. Thus clotting tend to remain localized to the site where such assembly can occur i.e. on the surface of activated endothelium or platelet

4. Intrinsic and extrinsic pathways converge at activation of FX.
• The intrinsic pathway begins with the activation of FXII while the extrinsic pathway is activated by tissue factors (lipoprotein exposed at the site of tissue injury) The 2 pathway are interconnected.
5. Once activated, the clotting system must be restricted at the site of vascular injury to prevent the clotting of the entire vascular tree. Beside this restriction, the clotting is also regulated by 3 natural anticoagulants

a)     Antithrombin III inhibit the activity of thrombin and other serine protease: IXa, Xa, XIa, XIIa. The antithrombin is activated by heparin-like molecules on the endothelium and hence the usefulness of giving heparin to minimize the thrombosis.

b)     Protein C and S are 2 vitamin K dependent that inactivate Va and VIIIa. The protein C is activated by thrombomodulin.

c)     Plasmin derived from the inactive precursor plasminogen breaks down the fibrin and interferes its polymerization. The fibrin degradation products are also weak anticoagulants. They are measured in labs and the increase of their concentration is a sign of thrombotic state (DIC, deep venous thrombosis, pulmonary thromboembolism)

Plasminogen is cleaved into plasmin by FXII dependent pathway or by 2 plasminogen activators (PA):

1. Urokinase-like PA in plasma and other tissue capable of activating plasminogen into plasmin. The plasmin in turn activate the pro-u-PA into u-PA creating amplification loop.

2.    Tissue type t-PA is primary PA produced by endothelial cells and become active when bound to fibrin.

THROMBOSIS

The Virchow’s triad that predisposes thrombus formation are:

1. Endothelial injury
2. Stasis or turbulence of blood flow
3. Blood hypercoagubility

1-Endothelial injury

• Is the most important of the 3. It occurs in heart and arterial circulation. In heart chamber, endocardial injury from infract or vavulitis; ulcerated plaques in severely atherosclerotic arteries and traumatic or inflammatory injury ( vasculitis)
• The injury may occur due to hemodynamic stress in hypertension, turbulence flow in over scared valves and endocarditis.
• Regardless of the type of injury the exposure of sub endothelial collagen initiate the sequence of events that end in the formation of thrombi.

2-Stasis or turbulence in blood flow

• Turbulences give rise to arterial and cardiac thrombosis by injury or dysfunction of endothelial cells and by forming countercurrents and local pockets of stasis.
• Stasis is major factor in the development of venous thrombi.
• Normal blood flow is laminar i.e. cells flow in the central zone of the lumen separated from the endothelium by slowly moving  plasma  at the periphery.

 Stasis and turbulence causes:

1. Disrupt laminar flow and bring platelets in contact with endothelium
2. Prevent dilution by fresh flowing blood of the activated clotting factors
3. Prevent the inflow of clot inhibiting factors permitting the build-up of thrombi.
4. Promote endothelial activation predisposing local thrombi, WBC adhesion and other endothelial effects

Diseases in which we can have thrombosis:

1. Ulcerated atherosclerotic plaques
2. Aneurism
3. Mitral valve stenosis with left atrial dilatation
4. Hyper viscosity syndrome (e.g. polycythemia)
5. Deformed RBC ( e.g. Sickle cell anemia.)

3-HYPERCOAGUBILITY

• It is an alteration of the coagulation pathway that predisposes to thrombosis. It can be primary (genetic) or secondary (acquired).

Primary hypercoagubility 

The most important of the primary is mutation of FV.

Mutation of FV

• Occurs in position 506 the arginine is substituted by glutamine which results in inability of cleavage of FVa by protein C, hence the lack of one of the antithrombotic counter-regulatory pathway. This is called LEIDEN mutation and occurs 2-15% of the whites. The patients present recurrent deep venous thrombosis as high as 60% of the carriers.
• Other primary hypercoagubility are genetic defects in antithrombin III, protein C, S. These patients present deep venous thrombosis and recurrent thromboembolia in early adult age.

Secondary hypercoagubility

• The secondary causes of the thrombotic diathesis are more important especially the heparin induced thrombocytopenia and antiphospholipid antibody system.
• The first occurs when unfractioned heparin is used for treatment. This results in the formation of circulating Ab that bind to heparin-platelet factor 4 complex on the surface of platelets or endothelial cells causing platelet activation or endothelial cell injury and hence prothrombotic state.
• To prevent this we use low molecular heparin with the desired anticoagulant effect and lacks the stimulation of Ab production.
• The antiphospholipid Ab system:   is cluster of clinical manifestations with multiple thrombosis associated with high titer of serum Ab anti anionic phospholips (e.g. cardiolipin) The Ab inhibit the assembly of phospholipid complex and hence inhibit coagulation in vitro. In vivo, the Ab induce hypercoagubility state (but how this occurs is not known.)

Possible explanations are

1. Activation of platelets,
2. Inhibition of PGI2 produced by endothelial cells  
3. Interfering protein C synthesis

Patients with these Ab are of 2 groups:

¨   Those with well-defined autoimmune disease like systemic Lupus erythematosus.

¨   The second group has not Lupus but presents hypercoagubility state.

The patients with anticardiolipin Ab are VDRL positive.

¨    Individuals with this disorder present wide variety of clinical manifestations:  recurrent venous and arterial thrombosis, repeated miscarriages (abortion), cardiac valvular vegetations, and thrombocytopenia.

The clinical presentation depends on the vascular bed involved.

Thrombi’s morphology:

¨    Thrombi can form in every vascular bed and in the heart. In arteries and heart they begin at the site of endothelial injury or turbulence (in the bifurcation) while in veins at the site of stasis. The thrombi are firmest at the site of origin where it attaches at the wall of the vessel. Arterial thrombi grow in retrograde way from the of origin while venous thrombi in the direction of blood flow ( the tail may be not attached and is prone to fragmentation creating embolus.

¨    Thrombus that forms in the heart and large arteries are laminated (alternating pale –platelet & fibrin and dark –admixed with RBC- lines called Zahn lines) the lines form where there is blood flow.

¨    In the veins and small arteries, where the flow is sluggish the lamination is not evident.

¨    Thrombi in the heart and aorta are adherent to the wall and are termed mural thrombi.

¨    Arterial thrombi are usually occlusive and are common in site like coronary, cerebral and femoral. The thrombi are firmly adherent, grey-white, friable and composed of tangled mesh of platelets, fibrin, RBC, degenerated WBC.

Venous thrombs

¨    Venous thrombi (phelebothrombosis) is always occlusive and create a long cast of vein lumen. They have more RBC duce to the sluggish flow and hence are red. 90% of these thrombi form in the lower extremities.

¨    Post mortal thrombi are gelatinous with dark red at the dependent portion of settled RBC due to gravity and yellow chicken fat supernatant not attached to the vessel.

Cardiac thrombs

¨    Thrombi can form on the cardiac valve due to endocarditis that damage the valve. These large thrombi are called vegetation (they contain infectious agent)

¨    Sometimes there are sterile vegetations from hypercoagubility state called nonbacterial thrombotic endocarditis.

¨    The verrucous endocarditis of Libman-sacks is attributed to high level of circulating immune complexes in patients with LES.

Fates of thrombus

   If the patient survives after some days or weeks the thrombi undergo:

1. Propagation: increase in size until the occlusion of the vessel
2. Embolization
3. Dissolution
4. Organization and recanalization.

Clinically thrombi are important because they cause vascular obstruction and are possible source of emboli.

Venous thrombosis:

¨    Occurs in legs. Superficial thrombi in the saphenous system especially occur in varicose and causes local congestion, swelling tenderness and pain along the involved vein but rarely embolize.

¨    Nevertheless the local edema and impaired venous drainage predisposes the over lying skin infection and development of varicose ulcers.

¨    Deep venous thrombosis of the knee and above of the lower limb (popliteale, femoral and iliac veins) are more serious because they cause embolization. The obstruction of these veins may be offset rapidly by collateral bypass channels. They are usually asymptomatic. This thrombosis can occur due to stasis, hypercoagubility state. Trauma, surgery, burns, postpartum, advanced age and bed rest or immobilization are all possible risk factors.

Arterial thrombosis

¨    Dyskinetic contraction and endocardial damage associated to myocardial infraction predisposes cardiac mural thrombi and so is the mitral stenosis of rheumatic origin.

¨    Arthrosclerosis provides arterial thrombi.

¨    In addition to obstruction, they embolize peripherally. Organs generally affected because of the large flow volume are: kidneys, brain, spleen.

Disseminated intravascular coagulation (DIC):

¨     Wide spread of fibrin thrombi in the microcirculation. The fibrin thrombi are only microscopically visible.

¨     They cause diffuse circulatory insufficiency particularly in the brain, lungs, kidneys and heart.

¨     There is consumption of platelets and coagulatory factors together with the activation of fibrinolytic mechanism and as a result there is a consequent serious bleeding disorder.

¨     DIC is a potential complication of any condition associated with wide spread activation of prothrombin into thrombin.

Embolism

¨     Is a detached intravascular solid, liquid or gaseous mass that is carried by blood to a site distant to its origin. 99% of the emboli are dislodged thrombi hence the name thromboembolism. Emboli lodge in vessels too small to permit further passage resulting in partial or complete occlusion of a vessel with potential ischemic consequence (infract)

•      Pulmonary thromboembolism

¨       Its incidence is 20-25/100,000 of hospitalized and 95% of the thrombi originate from the deep veins of the leg above the knee. They are carried through larger channels, pass the right heart into the lung vessels where they lodge vessels of its size. They may lodge at the bifurcation of the pulmonary artery (saddle emboli) or pass to smaller vessels. If the emboli pass through interatrial or interventicular defects they may gain access to systemic circulation (paradoxical embolism)

  

Saddle emboli 

  

Consequences of lung emboli:

1. Organization ( small emboli)
2. Sudden death for acute cor pulmonale when 60% or more of the pulmonary circulation is obstructed
3. Pulmonary hemorrhage (medium size artery occlusion)
4. Infraction from small end-arteriole occlusion
5. Multiple emboli over a long time produces pulmonary hypertension and right heart failure.

Systemic thromboembolism.

¨     80% arises from mural cardiac thrombi 2/3 of which from left ventricle wall infract, 1/4 from dilated atria due to rheumatic valvolar disease. The rest originate from aorta aneurism, ulcerate atherosclerotic plaques and fragmentation of valvular vegetation. 10-15% are from unknown origin.

¨     Unlike venous emboli which tend to lodge in lungs, arterial emboli can lodge to various sites depending on the volume of blood that this site receives and origin of the emboli.

¨      The major sites are lower extremities (75% of the cases), brain (10%.) Kidneys, spleen and intestine in lesser frequency.

¨     The consequence of arterial thrombi is infract. This effect depends the extent of the collateral supply, the caliber of the occluded vessel and tissue’s vulnerability to ischemia.

Infraction

¨     Is an ischemic necrosis caused by occlusion of arterial supply or venous drainage in a tissue.

¨     The venous occlusion is less important because bypass channels rapidly open which improves the outflow and in turn the arterial inflow improves.

¨      The venous infracts are more likely to occur in organs with a single venous outflow channels like ovary and tests.

Types of infracts:

¨     Infracts are classified according their color into red (hemorrhagic) and white (anemic)

  Red infracts:

¨     Occur in venous occlusion ( ovary); loose tissue which allows blood to accumulation like lung; tissue with dual circulation (lung, intestine); previously congested tissue before the infract; when flow is reconstituted  in the infracted site (because of the fragmentation of the emboli or angioplasty)

 White infracts.

¨     Occur with arterial occlusion or in solid organs like heart, kidneys where the solidity of the tissue limits the seeping of blood in the necrotic tissue from nearby capillary beds.

Factors that influence the development of the infract

The consequences of the vascular occlusion can range from non effect to death of the tissue or individual and this is determined by:

1. The nature of the vascular supply, availability of alternative blood supply. Tissue with dual circulation like lung, liver, hand and forearm. Kidneys, spleen have single circulation and are vulnerable to vascular occlusion.
2. The rate of the development of the occlusion:  In the heart there are small anstomoses in 3 principle coronary arteries and slow developing occlusion allows these to increase and prevent infraction in case of complete occlusion of one the 3 arteries.
3. Vulnerability of the tissue to hypoxia.

¨     Neurons die after3-4min of hypoxia, cardiac muscles can resist until 20min, and fibroblasts can survive for many hours of ischemia.

4. The oxygen content of the blood.

¨     Occlusion of small vessels in anemic or cyanotic patient may lead tissue infraction whereas the same occlusion has non effect in normal oxygen tension

Shock

¨     Shock is a cardiovascular collapse and is defined as:  systemic hypotension owing to reduction either in cardiac output or in effective circulating blood volume.

¨     It is the consequence of a number of potentially lethal clinical events e.g. severe hemorrhage, extensive trauma or burns, large myocardial infract, massive lung embolism and sepsis.

¨     It is the end result of hypotension followed by tissue hypo perfusion and cellular hypoxia.

¨     Although the hypoxia and the metabolic effects cause, initially, reversible cell injury, persistence of the shock causes irreversible cell injury and can culminate in the death of the individual.

Shock can be classified into 3 general categories:

1.  Cardiac:  results from heart pump failure cause by intrinsic myocardial damage, ventricular arrhythmias, cardiac tamponate or outflow obstruction (e.g. lung embolism)

2.    Hypovolumoic: results from hemorrhage or fluid loss e.g. trauma, burns.

3.    Septic : systemic microbial infection usually caused by gram negative bacteria and sometimes by G + and fungal infection.

Pathogenesis of shock

¨     The septic shock is mostly due to G- bacteria which produce endotoxin (endtoxic shock) which are bacterial wall lipopolysaccharide (LPS) released when the wall is degraded by inflammation. The LPS consist of toxic fatty acids core and a complexed polysaccharide coat (like Ag O) unique to every bacterial specie. Injecting LPS along can produce septic shock

¨     G+ have analogous molecules.

¨     The LPS complexed with blood proteins bind with CD14 on monocytes system, endothelial cells and other cells activating them. It also activates the complement system (this is intended to help bacterial eradication)

¨     Monocytes respond by producing TNF which in turn induce IL-1 synthesis. Both these cytokines act on endoth, to produce other cytokines (IL6-8) and induce also adhesive molecules. This cascade of cytokines enhance a local acute inflammation response and improve clearance of the infection.

The cascade:  TNF—IL-1---IL-6,8—PAF AND NO-----stimulate increased permeability, vasodilatation and coagulation cascade.

Higher doses of LPS produce higher level of cytokines and other mediators which result in:

1.     Systemic vasodilatation (hypotension)

2.    Diminished myocardial contractility

3.    Wide spread of endoth, injury and activation causing systemic leukocyte adhesion and lung capillary damage with ARDS.

4.    Activation of the coagulation system culminating in DIC.

¨   The hypotension is due to widespread vasodilatation and heart pump failure. The DIC results in multiorgan system failure in which kidneys, brain and liver are the most important resented organs.

¨   Septic shock can be called systemic inflammation syndrome. The pharmacological use of anti-inflammatory drugs like steroids and antibiotics is of a great use to control the septic shock.

¨   Super antigens (bacterial proteins) like that of staphylococcus can produce a shock similar to that of septic one.

Stages of shock

Shock is a progressive disorder that, if not corrected leads to death. It evolves into 3 general stages:

1. Initial non progressive phase in which compensatory mechanism are activated and perfusion of vital organs are maintained.

2. Progressive phase with tissue hypoxia and worsening circulatory and metabolic imbalance like acidosis.
3. Irreversible stage which sets in after the body has incurred cellular and tissue injury so severe that if corrected the hypovolumia survival is not possible.

   I.In the first phase, neuro-ormonal mechanism maintain cardiac output and blood pressure. These include the bar receptor reflex, increase sympathetic tone, release of catecholamine, ADH, renin-angiotensine reflex.

¨     All these produce tachycardia, peripheral vasoconstriction (responsible for the pallor and coolness of the skin.) In the septic shock there is vasodilatation and hence warm flushed skin.

¨     Coronary and cerebral circulation is less sensitive to these compensatory sympathetic responses and have normal blood flow.

 II.If the underlying cause is not corrected the shock passes to the progressive phase in which there are widespread hypoxia of the tissue. With the oxygen deficit the aerobic respiration is replaced by anaerobic glycolysis and consequent lactic acid formation, metabolic acidosis that culminate in PH reduction and blunting of the vasomotor responses. The latter induce arteriolar vasodilatation and pooling of blood to the microcirculation. The peripheral pooling not only worsen the cardiac output but also puts endoth, at risk for developing anoxic injury with subsequent DIC.

¨     The widespread tissue anoxia does not spare the vital organs which begin to fail. The patient is confused and urinary output decline.

III.Unless intervened, the shock enters in an irreversible stage.

The widespread cell injury is reflected by lysosomal enzyme leakage, further aggravating the shock:  

1)     Myocardial contractile worsens due to NO synthesis

2)    If the ischemic bowel allows intestinal flora to enter the circulation and endotoxic shock superimposes.

¨     Complete renal shutdown due top tubular necrosis.

¨     Thereafter, despite heroic measures death ensues.

Management and prognosis.

¨     Hypovolumic shock in young health individual has good prognosis in 80% to 90% of the cases if properly managed.

Large myocardial infract and gram negative septic shock carry mortality rate up to 75% of the cases, even with the best care currently available