Blood Circulation – Hyperemia, Edema, Hemorrhage, Thrombosis etc.

Hemodynamic Disorders of Blood Circulation

In blood circulation disorder, The health and well-being of cells & tissues depend not only on an intact circulation to deliver nutrients but also on normal fluid hemostasis. This chapter reviews the major disturbances involving the hemodynamic system.

Edema (Disorder of Blood Circulation)

Definition: Edema is increased fluid in the interstitial tissue spaces or it is a fluid accumulation in the body cavities in excessive amount. Depending on the site, fluid accumulation in body cavities can be variously designated as:

  • Hydrothorax – fluid accumulation in pleural cavity in a pathologic amount.
  • Hydropericardium – pathologic amount of fluid accumulated in the pericardial cavity.
  • Hydroperitoncum (ascites) – fluid accumulation in peritoneal cavity.
  • Ancsarca – is a severe & generalized edema of the body with profound subcutaneous swelling.

Mechanism of edema formation (Hemodynamic Disorders of Blood Circulation)

Approximately 60% of the lean body weight is water, two-thirds of which is intracellular with the remainder in the extracellular compartment. The capillary endothelium acts as a semipermeable membrane and highly permeable to water & to almost all solutes in plasma with an exception of proteins. Proteins in plasma and interstial fluid are especially important in controlling plasma & interstitial fluid volume. Normally, any outflow of fluid into the interstitium from the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end. Therefore, normally, there is very little fluid in the interstitium. Edema formation is determined by the following factors:

  1. Hydrostatic pressure
  2. Oncotic pressure
  3. Vascular permeability
  4. Lymphatic channels
  5. Sodium and water retention

We will discuss each of the above sequentially.

1. Hydrostatic and oncotic pressures of edema formation

The passage of fluid across the wall of small blood vessels is determined by the balance between hydrostatic & oncotic pressures. There are four primary forces that determine fluid movement across the capillary membrane. Each of them can be listed under the above two basic categories, the hydrostatic pressure & the oncotic pressure. These four primary forces are known as Starling forces & they are:

  • The capillary hydrostatic pressure (Pc): This pressure tends to force fluid outward from the intravascular space through the capillary membrane to the interstitium.
  • The interstial fluid hydrostatic pressure (Pif):This pressure tends to force fluid from the interstitial space to the intravascular space.
  • The plasma colloid osmotic (oncotic) pressure (Пp): This pressure tends to cause osmosis of fluid inward through the capillary membrane from the interstitium. The plasma oncotic pressure is caused by the presence of plasma proteins.
  • The interstial fluid colloid osmotic (oncotic) pressure (Пif): This pressure tends to cause osmosis of fluid outward through the capillary membrane to the interstitium.

In addition, some fluid is normally derained by the lymphatic channels.Usually, excess fluid will accumulate in the interstitium (i.e. edema is formed) when the capillary hydrostatic pressure is increased or when the plama oncotic pressure is decreased or when the lymphatic drainage is blocked. Hence, basically, one can divide pathologic edema into two broad categories:

  1. Edema due to decreased plasma oncotic pressure. The plasma oncotic pressure is decreased when the plasma proteins are decreased in various diseases such as:
    • Protein loosing glomerulopathies like nephroticsyndrome with leaky glomerulus.
    • Liver cirrhosis which leads to decreased protein synthesis by the damaged liver.
    • Malnutrition
    • Protein loosing enteropathy.
  1. Edema resulting from increased capillary hydrostatic pressure as in the following diseases:
    • Deep venous thrombosis resulting in impaired venous return.
    • Pulmonary oedema
    • Cerebral oedema
    • Congestive heart failure

Clinical classification of edema (Hemodynamic Disorders of Blood Circulation)

One can also clinically classify edema into localized & generalized types.

I. Localized edema

  • Deep venous thrombosis
  • pulmonary edema
  • brain edema
  • lymphatic edema

a. Edema of the brain

  • May be localized at the site of lesion e.g neoplasm, trauma.
  • May be generalized in encephalitis, hypertensive crisis, & trauma
  • Narrowed sulci & distended gyri.
  • ↑ Edema → compression of medulla towards formen magnum → compression of → vital centers lead to → Hernation of the brain → patient dies

b. Pulmonary edema

  • Usually occurs in left ventricular failure.
  • May occur in adult respiratory distress syndrome (ARDS).
  • lung ↑ 2.3x its weight.

II. Generalized edema (anasarca)

occurs due to

  • Reduction of albumin due to excessive loss or reduced synthesis as is caused by:
    • Protein loosing glomerulopathies like nephrotic syndrome
    • Liver cirrhosis
    • Malnutrition
    • Protein-losing enteropathy
  • Increased volume of blood secondary to sodium retention caused by congestive heart failure.

2. Vascular Permeability (Edema of Hemodynamic Disorder of Blood Circulation:

Increased vascular permeability usually occurs due to acute inflammation. In inflammation, chemical mediators are produced. Some of these mediators (See the chapter on inflammation) cause increased vascular permeability which leads to loss of fluid & high molecular weight albumin and globulin into the interstitium. Such edema (i.e. that caused by increased vascular permeability) is called inflammatory edema. Inflammatory edema differs from non-inflammatory edema by the following features

a. Inflammatory edema (exudate)

  • Due to inflammation-induced increased permeability and leakage of plasma proteins.
  • Forms an exudate [protein rich]
  • Specific gravity > 1.012

b. Non-inflammatory edema (transudate)

  • A type of edema occurring in hemodynamic derangement (i.e. increased plasma hydrostatic pressure & decreased plasma oncotic pressure. See above)
  • Formed transudate [protein poor]
  • Specific gravity < 1.012

3. Lymphatic channels in edema:

Also important is the lymphatic system which returns to the circulation the small amount of proteinaceous fluid that does leak from the blood into the interstial spaces. Therefore, obstruction of lymphatic channels due to various causes leads to the accumulation of the proteinaceous fluid normally drained by the lymphatic channels. Such kind of edema is called lymphatic edema.

Lymphatic edema occurs in the following conditions:

  • Parasitic infection. E.g filariasis which causes massive lymphatic and inguinal fibrosis
  • Lymphatic obstruction secondary to neoplastic infiltration. E.g. breast cancer
  • post surgical or post irradiation, i.e surgical resection of lymphatic channels or scarring after irradiation
  • Sodium and water retention:

Sodium & subsequently water retention occurs in various clinical conditions such as congetive heart failure renal failure. In these conditions, the retained sodium & water result in increased capillary hydrostatic pressure which leads to the edema seen in these diseases.

Morphology of edema

Microscopy: Manifests only as subtle cell swelling. Clearing & separation of extracellular matrix.



Hyperemia and Congestion (Disorder of Blood Circulation)

Definition: In Disorder of Blood Circulation, Both of them can be defined as a local increase in volume of blood in a particular tissue.

Hyperemia (Disorder of Blood Circulation)

  • is an active process resulting from an increased inflow of blood into a tissue because of arteriolar vasodilation.
  • commonly occurs in exercising skeletal muscle or acute inflammation.
  • Affected tissue becomes red as there is engorgement with oxygenated blood.

Congestion (Disorder of Blood Circulation)

  • is a passive process resulting from impaired outflow of blood from a tissue.
  • occurs systemically as in cardiac failure or locally as in isolated venous obstruction.
  • Affected tissue appears blue-red due to accumulation of deoxygenated blood.
  • In long-standing congestion (also called chronic passive congestion states), poorly oxygenated blood causes hypoxia → results in parenchyma cell degeneration or cell death.

a. Pulmonary congestion (Disorder of Blood Circulation)

Cut surface: hemorrhagic & wet.

1. Acute pulmonary congestion

  • Alveolar capillaries engorged with blood
  • Septal edema

2. Chronic pulmonary congestion

  • Thickened & fibrotic septa
  • Alveolar spaces contain hemosiderin-laden macrophages resulting in an appearance termed brown indurations.
  • Can result in pulmonary hypertension.

b) Hepatic congestion (Disorder of Blood Circulation)

1. Acute hepatic congestion

  • Central vein & sinusoids are distended
  • There may be even central hepatocyte degeneration.
  • Peripheral hepatocytes better oxygenated & develop only fatty changes.

2) Chronic passive congestion of liver

  • Central lobules grossly depressed because of loss of cells & appear red brown (nutmeg liver).
  • Hemosiderin laden macrophages
  • In longstanding hepatic congestion, commonly associated with cardiac failure, there is a grossly evident hepatic fibrosis called cardiac cirrhosis.


Hemorrhage (Disorder of Blood Circulation)

Definition: Hemorrhage is extravasation of blood outside the blood vessel.

Causes of Hemorrhage (Disorder of Blood Circulation)

  • Physical trauma
    • Stabbing
    • Stick injury
    • Gunshot
    • Motor vehicle accident
  • Inadequacies in blood clotting which can be due to:
    • Too few or poorly functioning platelets (i.e. qualitative & quantitative defect of platelets)
    • Missing or low amount of clotting factors E.g. Low levels of prothrombin, fibrinogen & other precursors. Inadequate vitamin K leads to clotting factor deficiency because this vitamin is important in the synthesis of the clotting factors by the liver.

Terminology of Hemorrhage (Disorder of Blood Circulation)

  • Haemorrhage enclosed within a tissue or a cavity is knownas hematoma.
  • Minute 1-2 mm hemorrhages occurring in the skin, mucosal membrane, or serosal surface are called petechiae.
  • Slightly > 3mm hemorrhage occurring in the skin is referred to as purpura.
  • Larger than 1-2cm subcutaneous hematoma is called eccymosis (bruises). It is typical after trauma.

Effects of haemorrhage: depend on the rate and amount of blood loss:

  • If > 20% the total blood volume is rapidly lost from the body, it may lead to hypovolumic shock & death.
  • Chronic loss of blood leads to anemia.


Hemostasis and Blood Coagulation (Disorder of Blood Circulation)

Hemostasis (Disorder of Blood Circulation)

Definition: Hemostasis is the maintenance of the clot-free state of blood & the prevention of
blood loss via the formation of hemostatic plug.

Hemostasis depends on three general components:

  • Vascular wall
  • Platelets
  • Coagulation pathways

Whenever a vessel is ruptured or severed, hemostasis is achieved by several mechanisms:

  • Vascular spasm
  • Formation of platelet plug
  • Formation blood clot as a result of blood coagulation
  • Eventual growth of fibrous tissue in to the blood clot to close the hole in the vessel permanently.

Remark: The student is advised to revise his physiology lecture note on the above topics.


Thrombosis (Disorder of Blood Circulation)

Definition: Thrombosis is defined as the formation of a solid or semisolid mass from the constituents of the blood within the vascular system during life.

Pathogenesis of Thrombosis (Disorder of Blood Circulation)

There are three factors that predispose to thrombus formation. These factors are called Virchow’s triad:

  • Endothelial injury
  • Stasis or turbulence of blood flow
  • Blood hypercoagulability

A. Endothelial injury of thrombosis

  • It is the most important factor in thrombus formation and by itself can lead to thrombosis.
  • Endothelial injury is particularly important in thrombus formation in the heart & arterial circulation.
  • Some Examples:
    • Endocardial injury during myocardial infarction & eosinophilic endocarditis in which eosiophils release from their granules crystals called Charcot – Leyden damaging the endocardial endothelium.
    • Injury over ulcerated plaque in severely atherosclerotic arteries.
    • In hemodynamic stress like severe hypertension & turbulence of flow over scarred valves directly damaging the endothelium.
    • Bacterial endtoxin & hyperchloestrolemia, radiation & cigarette smoking may be sources of endothelial injury.
  • Irrespective of endothelial damage, the final event is exposure of the highly thrombogenic subendothelial extracellular matrix, mainly collagen & tissue factors up on which platelets undergo adherence & contact activation.

B. Turbulence or Stasis (Alterations in normal blood flow)

  • Under physiologic conditions normal blood flow is laminar, that is, the cellular elements flow centrally in the vessel lumen separated from endothelium by slowing moving clear zone of plasma. Stasis & turbulence therefore:
    • Disrupt the laminar flow and bring platelets in to contact with the endothelium
    • Prevent dilution of activated clotting factors by freshly flowing blood
    • Retard or make a time lag in the inflow of clotting factor inhibitors and permit the build up of thrombi.
    • Turbulence causes reduction in endothelial PGI2 and tissue-type plasminogen activator (t-PA) which has fibrinolytic activity causing endothelial cell activation. ???
  • Stasis is a major factor in the development of venous thrombi while turbulence contributes to arterial & cardiac thrombosis by causing direct endothelial injury or by forming countercurrents & local pockets of stasis.
  • • Examples:
    • Ulcerated atherosclerotic plaque, which forms a sort of irregularity on endothelial surface, not only exposes subendothelial extracellular matrix but are also sources of local turbulence.
    • Aneurysms are favoured sites of stasis
    • Myocardial infarction not only has endothelial injury but also has a region of noncontractile myocardium, creating an area of stasis resulting in mural thrombus formation.
    • Mitral valve stenosis after chronic rheumatic fever may result in left atrial dilation, usually associated with arterial fibrillation. A dilated left atrium is a site of stasis & a prime location of thrombus development.
    • Hypervisicosity syndrome, i.e an increase in hematocrit in excessive amount due to various reasons such as polycythemia causes stasis in small vessels.

C. Hyper-coagulablity of thrombosis (Disorder of Blood Circulation)

Definition: Hypercoagulability is any alteration of the coagulation pathway that predisposes to thrombosis. Hypercoagulability is a less common cause of thrombosis & & it can be divided into:

1. Primary (Genetic)

  • Mutations in factor V[Lieden factor]
  • Anti thrombin III deficiency
  • Protein C or S deficiency

2. Secondary (Acquired) which, in turn, can be categorized into

A: High-risk for hypercoagulablity

  • prolonged bed rest or immobilization
  • Myocardial infarction
  • Tissue damage (surgery, fracture, burns)
  • ancers (Cancers release procoagulant tissue products to cause thrombosis)
  • Prosthetic cardiac valves
  • Disseminated intra vascular coagulation

B: Low risk factor for hypercoagulablity

  • trial fibrillation
  • Cardiomyopathy
  • Nephrotic syndrome
  • Smoking
  • Oral contraceptives
  • Hyperestrogenic state eg. Pregnancy.


Morphology of Thrombi (Disorder of Blood Circulation)

Thrombi may develop any where in the cardiovascular system. According to their location, thrombi can be divided into venous & arterial thrombi. (Cardiac thrombi can be considered as arterial thrombi because of certain similarities between the two). The differences between arterial & venous thrombi are:

   venous thrombi                            arterial thrombi
Arise at the site of endothelial injury Arise at area of stasis
Grow in a retrograde fasion, against site of attachment Grow in the direction of blood flow from its
Has firm attachment Has loose attachment, hence, propagating tail may undergo fragmentation.
They usually occlude the blood flow Almost invariably occlusive
  • The most common site of arterial thrombi in descending order are:
    • Coronary arteries
    • Cerebral arteries
    • Temporal arteries
  • Damaged valves can be infected by bacteria or fungi (infective endocarditis) which leads to the development of small infected thrombi on the valves. These small infected thrombi (vegetations) can further damage the valve.

Fates of a thrombus (Disorder of Blood Circulation)

A thrombus can have one of the following fates:

A. Propagation

The thrombus may accumulate more platelets and fibrin & propagate to cause vessel obstruction.

B. Embolization

The thrombus may dislodge and travel to other sites in the vasculature. Such a traveling thrombus is called an embolus. An embolus may obstruct a vessel. The obstruction leads to the death of the tissue supplied by the blood vessel. Death of a tissue due to a decreased blood supply or drainage is called infarction. Therefore, an embolus can eventually lead to an infarction of an organ. E.g cerebral infarction can be caused by a thromboembolus. We will discuss embolism & infarction shortly (See p. ).

C. Dissolution

The thrombus may be removed by fibrinolytic activity.

D. Organization and recanalization

Organization refers to the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus. Organization is accompanied by the formation of capillary channels across the thrombus, re-establishing lumen continuity to some extent. This is known as recanalization. The recanalization eventually converts the thrombus into a vasscularized mass of tissue which is later on incorporated as a subendothelial swelling of the vessel wall.

Clinical significance of thrombi

Thrombi are significant clinically because:

  • They cause obstruction of arteries and veins &
  • They are possible source of emboli.

Venous Thrombosis (Phlebothrombosis)

Venous thrombosis affects veins of the lower extremity in 90% of cases. It can be divided into superficial & deep vein thrombosis:

1. Superficial venous thrombosis

  • Usually occurs in saphenous venous system, particularly when there are varicosities.
  • Rarely embolizes
  • Causes local edema, pain, and tenderness (i.e. it is symptomatic)
  • Local edema due to impaired venous drainage predisposes the involved overlying skin to infection after slight trauma leading to a condition known as varicose ulcer.

2. Deep venous thrombosis (DVT)

  • May embolize, hence, is more serious.
  • Usually starts in deep veins within the calf muscles.
  • Although they may cause local pain & edema, unlike superficial veinous thrombosis, they are entirely asymptomatic in approximately 50% of patients. This is because deep venous obstruction is rapidly offset or releaved by collateral bypass channels.
  • Has higher incidence in middle aged & elderly people due to increased platelet aggregation & reduced PGI2 production by the endothelium.
  • Has the following predisposing factors:
  1. Trauma, surgery, burns which usually result in:- Reduced physical activity leading to stasis, Injury to vessels, Release of procagulant substance from the tissue, Reduced t-PA activity (fibrinolysis)
  2. Pregnancy & puerperal states increase coagulation factors & reduce the synthesis of antithrombotic substances. Myocardial infarction & heart failure cause venous stasis to the left side.
  3. Malnutrition, debilitating conditions and wasting diseases such as cancer. DVT due to these conditions is known as marantic thrombosis.
  4. Inflammation of veins (thrombophlebitis) also predisposes to thrombosis.
  5. Migratory thrombophlebitis is a condition that affects various veins throughout the body & is usually of obscure aetiology, but sometimes it is associated with cancer, particularly pancreatic cancer. Migratory thrombophlebitis is also known as Trosseau syndrome.

Arterial Thrombosis

  • The rapid flow of arterial blood prevents the occurrence of thrombosis unless the vessel wall is abnormal.
  • In western society atheroma is by far the commonest predisposing lesion for arterial thrombosis. Atheromatous plaques produce turbulence and may ulcerate & cause endothelial injury, both of which can lead to thrombosis. These thrombi may narrow or occlude the lumen of arteries such as the coronary and cerebral arteries. Occlusion of these arteries will lead to myocardial infarction (MI) & cerebral infarction respectively.
  • Cardiac thrombi can be caused by infective endocarditis, atrial fibrillation,& myocardial infarcion.
  • Cardiac thrombosis is common on the heart valves & in the auricular appendages (especially, of the right atrium). A thrombus develops in the atrium in patients with atrial fibrillation & dilatation superimposed on mitral stenosis.
  • Myocardial infarction causes dyskinetic myocardial contraction & damage to the endocardium, which usually result in mural thrombi in the ventricles.
  • Apart from obstructive features, arterial thrombi (especially, cardiac mural thromi) may embolize to any tissue, but, particularly, commonly to the brain, kidney, & spleen because of large volume of blood flow to these organs.


Embolism (Disorder of Blood Circulation)

Definition:- An embolus is a detached intravascular solid, liquid or gaseous mass that is carried by blood to sites distant from its point of origin. After traveling via the blood, the embolus can obstruct a vessel.

Causes of embolism

An embolus can arise from:

  • Thrombus (99% of emboli arise from a thrombus. Such an embolus is called thromboembolus)
  • Platelets aggregates
  • Fragment of material from ulcerating atheromatous plaque
  • Fragment of a tumour
  • Fat globules
  • Bubbles of air
  • Amniotic fluid
  • Infected foreign material
  • Bits of bone marrow

Unless otherwise specified, the term embolism should be considered to mean thromboembolism. This is because thromboembolism is the commonest form of embolism. Next, we will discuss it in more detail.


Based on its sites of origin & impaction, thromboembolism can be divided into:

a. Pulmonary thromboembolism (PTE)

PTE is refers to the impaction of an embolus in the pulumonary arteries & their branches. Such an embolus is derived from a thrombus in the systemic veins or the right side of the heart.

b. Systemic thromboembolism

Systemic emboli arise from the left side of the heart or from thrombi & atheromatous debris in large arteries. And they impact in the systemic arteries.

c. Crossed embolism (Paradoxical embolism)

This occurs in the presence of patent foremen ovale when an embolus is transferred from the right to the left side of the heart, then into the systemic circulation. Now, we will elaborate the first two.

a. Pulmonary thromboembolism (PTE)

95% of PTE arise from thromi in the deep leg veins. The thromboembolus will travel long with the venous return & reach the right side of the heart. From there, it will go into the pulmonary trunk & pulmonary arteries. Depending on the size of the embolus and on the state of pulumonary circulation, the pulmonary embolism can have the following effects:

  1. If the thrombus is large, it may block the outflow tract of the right ventricle or the bifurcation of the main pulumonary trunk (saddle embolus) or both of its branches, causing sudden death by circulatory arrest. Sudden death, right side heart failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulumonary circulation is obstructed with emboli.
  2. If the embolus is very small (as in 60-80% of the cases), the pulmonary emboli will be clinically silent. Embolic obstruction of medium sized arteries manifests as pulmonary haemorrhage but usually does not cause infarction because of dual blood inflow to the area from the bronchial circulation.
  3. If the cardiorespiratory condition of the patient is poor (i.e., if the patient previously had cardiac or pulmonary disease), then obstruction of a medium sized pulmonary artery by a medium-sized embolus can lead to pulmonary infarction.
  4. Recurrent thromboembolism can lead to pulmonary hypertension in the long run. A patient who has had one pulmonary embolus is at high risk of having more.

b. Systemic thromboembolism

  • • Systemic thromboembolism refers to emboli travelling within arterial circulation & impacting in the systemic arteries.
  • Most systemic emboli (80%) arise from intracardiac mural thrombi. In turn, two thirds of intracardiac mural thrombi are associated with left ventricular wall infarcts and another quarter with dilated left atria secondary to rheumatic valvular heart disease.
  • • The remaining (20%) of systemic emboli arise from aortic aneurysm, thrombi on ulcerated athrosclerotic plaques, or fragmentation of valvular vegetation.
  • • Unlike venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites. The major sites for arteriolar embolization are the lower extremities (75%) & the brain (10%), with the rest lodging in the intestines, kidney, & spleen. The emboli may obstruct the arterial blood flow to the tissue distal to the site of the obstruction. This obstruction may lead to infarction. The infarctions, in turn, will lead to different clinical features which vary according to the organ involved.

Next, we will briefly touch upon some rare forms of embolism.

Fat Embolism

Fat embolism usually follows fracture of bones and other type of tissue injury. After the injury, globules of fat frequently enter the circulation. Although traumatic fat embolisms occur usually it is as symptomatic in most cases and fat is removed. But in some severe injuries the fat emboli may cause occlusion of pulmonary or cerebral microvasculature and fat embolism syndrome may result. Fat embolism syndrome typically begins 1 to 3 days
after injury during which the raised tissue pressure caused by swelling of damaged tissue forces fat into marrow sinsosoid & veins. The features of this syndrome are a sudden onset of dyspnea, blood stained sputum, taccycardia, mental confusion with neurologic symptoms including irritability & restlessness, sometimes progress to delirium & coma.

Air embolism

Gas bubbles within the circulation can obstruct vascular flow and cause distal ischemic injury almost as readily as thrombotic masses. Air may enter the circulation during:

  • Obstetric procedures
  • Chest wall injury
  • In deep see divers & under water construction workers.
  • In individuals in unpressurized aircraft
  • Neck wounds penetrating the large veins
  • Cardio thoracic surgery.
  • Arterial catheterisation& intravenous infusion.

Generally, in excesses of 100cc is required to have a clinical effect and 300cc or more may be fatal. The bubbles act like physical obstructions and may coalesce to form a frothy mass sufficiently large to occlude major vessels.

Amniotic fluid embolism

It is a grave but un common, unpredictable complication of labour which may complicate vaginal delivery, caesarean delivery and abortions. It had mortality rate over 80%. The amniotic fluid containing fetal material enters via the placental bed & the ruptured uterine veins. The onset is characterized by sudden severe dyspnea, cyanosis, hypotensive shock followed by seizure & coma of the labouring mother. If the patient survives the initial crisis, pulmonary oedema typically develops & 50% of the cases will develop DIC due to activation of the coagulation cascade by fetal material.

As discussed in this & the previous subtopics, the potential consequence of thromboembolic events is ischemic necrosis of distal tissue, known as infarction. Therefore, it is appropriate to discusss it next.


Infarction (Disorder of Blood Circulation)

Definition: An infract is an area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage in a particular tissue. Nearly 99% of all infarcts result from thrombotic or embolic events. Other mechanisms include [almost all of them are arterial in origin]:

  • Local vasospasm
  • Expansion of atheroma due to hemorrage in to athermotous plaque.
  • External compression of the vessels. e.g trauma
  • Entrapment of vessels at hernial sacks etc.

The development & the size of an infarct are determined by the following factors:

  • The nature of the vascular supply
  • The rate of development of occlusion
  • Suceptibility of the tissue for hypoxia
  • Oxygen content of the blood
  • The severity & duration of ischemia

A. The nature of vascular supply

The following organs have a dual blood supply.

Lung → pulumonary artery
→ Bronchial artery
Liver → hepatic artery
→ Portal vein
Hand & forearm → Radial arteries
→ Ulnar arteries.

The effect of such a dual blood supply is that if there is obsrtuction of one of the arterial supplies, the other one may offset the rapid occurrence of infarction in these organs unlike the renal & splenic circulations which have end arterial supply. Infarction caused by venous thrombosis is more likely to occur in organs with single venous outflow channels, such as testis &ovary.

B. Rate of development occlusion

Slowly developing occlusions are less likely to cause infraction since they provide time for
the development of collaterals.

C. Tissue suceptibility to hypoxia

The susceptibility of a tissue to hypoxia influences the likelihood of infarction. Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells die after 20-30 minutes of ischemia. Fibroblasts are more resistant, especially those in the myocardium.

D. Oxygen content of blood

Partial obstruction of the flow of blood in an anaemic or cyanotic patient may lead to tissue infarction.

E. The severity & duration of ischemia.

Types of infarcts

Infarcts are classified depening on:

  1. the basis of their colour (reflecting the amount of haemorrhage) into:
  2. Hemorrhagic (Red) infarcts
  3. Anemic (White) infarcts
  4. the presence or absence of microbial infection into:
  5. Septic infarcts
  6. Bland infarcts

1. Red infarcts occur in:

  • Venous occlusions as in ovarian torsion
  • Loose tissues such as the lung which allow blood to collect in infarct zone.
  • Tissues with dual circulations (eg. the lung), permitting flow of blood from unobstructed vessel in to necrotic zone.
  • In tissues that were previously congested because of sluggish outflow of blood.
  • When blood flow is reestablished to a site of previous arterial occlusion & necrosis.

2. White infarcts occur in:

  • a) Arterial occlusion in organs with a single arterial blood supply.
  • b) Solid organs such as the heart, spleen, & kidney, where the solidity of the tissue limits the amount of hemorrage that can percolate or seep in to the area of ischemic necrosis from the nearby capillaries.

Morphology of infarcts

Gross: All infarcts are wedge-shaped with the occluded vessel at the apex and the periphery of the organ forming the base of the wedge. THe infarction will induce inflammation in the tissue surrounding the area of infarction. Following inflammation, some of the infarcts may show recovery, however, most are ultimately replaced with scars except in the brain.


The dominant histologic feature of infarction is ischemic coagulative necrosis. The brain is an exception to this generalization, where liquifactive necrosis is common.

Clinical examples of infarction

A. Myocardial infarction

  • Usually results from occlusive thrombosis supervening on ulcerating atheroma of a major coronary artery.
  • Is a white infarct.
  • Can cause sudden death, cardiac failure, etc…

B. Cerebral infarcts

  • May appear as pale or hemorrhagic
  • A fatal increase in intracranial pressure may occur due to swelling of large cerebral infarction, as recent infarcts are raised above the surface since hypoxic cells lack the ability to maintain ionic gradients & they absorb water & swell.
  • Is one type of cerebrovascular accidents (CVA) or stroke which has various clinical manifestations.

C. Lung infarcts

  • Are typically dark red & conical (wedge-shaped).
  • Can cause chest pain, hemoptysis, etc…

D. Splenic infarcts

  • Conical & sub capsular
  • Initially dark red later turned to be pale.


Disseminated Intravascular Coagulation (DIC) – (Disorder of Blood Circulation)

Definition: -DIC is an acute, or chronic thrombohemorrhagic disorder occurring as a result of progressive activation of coagulation pathway beyond physiologic set point secondary to a variety of diseases resulting in failure of all components of hemostasis. Hence the other term for DIC is consumption coagoulopathy.

Etiology and Pathogenesis

At the outset, it must be emphasize that DIC is not a primary disease. It is a coagulopathy that occurs in the course of variety of clinical conditions. DIC follows massive or prolonged release of soluble tissue factors & /or endothelial-derived thromboplastin into the circulation with generalized (pathologic) activation of coagulation system. Therefore, DIC results from pathologic activation of the extrinsic &/or intrinsic pathways of coagulation or impairment of clot inhibiting influences by different causes. Two major mechanisms activating the coagulation pathway to cause DIC are: (1) release of tissue factor or thromboplastic substance into the circulation (2) widespread injury to the endothelial cells.

Tissue thromboplastin substance may be derived from a variety of sources such as:

  • Massive trauma, severe burns & extensive surgery. The major mechanism of DIC is believed to be autoinfusion of thromboplastin from the tissues.
  • Obstetric conditions in which thromboplastin derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation. .
  • Cancers such as acute promyelocytic leukaemia, adenocarcinoma of the lung in which a variety of thromboplastin substances like mucus are released which directly activate factor X, VII, & proteolytic enzymes.
  • Gram negative sepsis (an important cause of DIC) in which bacterial endoxins cause increased synthesis, membrane exposure, & release of tissue factor from monocytes. Furthermore, activated monocysts release intereukin-1 (IL-I), TNF-α, both of which:
    • Increase expression of tissue factor in endothelial membrane.
    • Decrease expression of thrombmodulin which is a potent activator of protein Can anti coagulant
    • TNF-α, an extremely important mediator of septic shock, in addition to the above up regulates the expression of adhesion molecules on endothelial cells and favours adhesion of leukocytes, with subsequent damage of endothelial cells by free radicals & preformed proteases.

Endothelial injury: Widespread endothelial injury may result from:

  • Deposition of antigen-antibody complexes as it occurs in systemic lupus erythematosus
  • Extreme temperature eg. Heat stroke, burns
  • Hypoxia, acidosis, shock

Clinical Course

The consequences of DIC are two fold. First, there is a widespread deposition of fibrin within the microcirculation. This may lead to ischemia of the more severely affected or more vulnerable organs and hemolytic anemia resulting from fragmentation of led cells as they squeeze through the narrowed microvasculature (Microangiopathic haemolytic anaemia). Second, a hemorrhagic diathesis may dominate the clinical picture because of consumption of the coagulation factors and increased fibrinolysis.

The onset may be fulminant when caused by endotoxic shock or amniotic fluid embolism or it may be chronic in the case of carcinomatosis or retention of dead fetus. The clinical presentation varies with stage & severity of the syndrome. Overall 50% of patients with DIC are obstetric patients & about 33% of patients have carcinomatosis. Clinically, patients with DIC may present with extensive skin & mucus membrane bleeding and haemorrhage from multiple sites, usually from surgical incision, vein punctures, or catheter sites. Respiratory symptoms such as dyspnea, cyanosis may occur.

They may present with convulsion & coma in the case of CNS bleeding or with acute renal failure with oliguria. Less often, they may present with acrocyanosis, pre-gangrenous changes in the digits, genitalia, & nose areas where blood flow may be markedly decreased. Circulatory failure may appear suddenly & may be progressing. The presentations of acute DIC, as it occurs in case of trauma or obstetric conditions, is dominated by bleeding diathesis.

Laboratory manifestations include thrombocytopenia secondary to platelets aggregation in the thrombus, schistocytes or fragmented RBCs, prolonged PT, PTT, thrombin time & reduced fibrinogen from depleted coagulation proteins. There is also increased fibrin degradation product (FDP) from intense fibrinolysis. The cardinal manifestation of DIC, which correlates most closely with bleeding is plasma fibrinogen level, i.e. low fibrinogen means increased tendency of bleeding.



Shock (Disorder of Blood Circulation)

Definition: Shock is a state in which there is failure of the circulatory system to maintain adequate cellular perfusion resulting in widespread reduction in delivery of oxygen & other nutrients to tissues. In shock, the mean arterial pressure is less than 60 mmHg or the systolic blood pressure is less than 90 mmHg.

  • Regardless of the underlying pathology, shock constitutes systemic hypoperfusion due to reduction either in cardiac out put or in the effective circulating blood volume. The end results are hypotension followed by impaired tissue perfusion and cellular hypoxia.
  • Adequate organ perfusion depends on arterial blood pressure (BP) which, in turn, depends on:
    • Cardiac output (CO)
    • Peripheral vascular resistance (PVR)
  • CO = stroke volume X heart rate. In turn, stroke volume depends on:
    • Preload i.e. blood volume,
    • Afterload i.e. arterial resistance, &
    • Myocardial contractility.
  • Therefore, shock (i.e. widespread decreased perfusion of tissues) occurs when the preload (i.e. the blood volume) is decreased, or when the afterload (the peripheral vascular resistance) is decreased, or when the myocardium fails to contract. These basic mechanisms of shock are used to classify it. Next, we will look at the

Classification of shock

Classification of shock Shock can be divided into:

  • Hypovolemic shock
  • Cardiogenic shock
  • Distributive shock

I. Hypovolemic shock

Definition: This is shock caused by reduced blood volume. Reduction in circulating blood volume results in the reduction of the preload which leads to inadequate left ventricular filling, reflected as decreased left & right ventricular end diastolic volume and pressure. The reduced preload culminates in decreased cardiac out put which leads to widespread tissue perfusion (shock).

Causes of hypovolumic shock include:

  • Haemorrhage
  • Diarrhoea & vomiting
  • Burns
  • Trauma

The effect of haemorrhage depends on the rate and amount of blood loss. Hypovolumic shock is the most common type of shock in clinical medicine .A normal healthy adult can lose 550ml (10%of blood volume) without significant symptoms. But loss of 25% or more of the blood volume (N=1250ml) results in significant hypovolemia.

II. Cardiogenic shock

Definition: This is shock that results from severe depression of cardiac performance. It primarily results from pump failure [myocardial failure]. Cardiogenic shock is hemodynamically defined as:

  • DBP<60mm Hg
  • Left ventricle filling pressure > 18mm Hg
  • Cardiac index< 1.8 l/min/m2
  • Usually pulmonary oedema coexists.

Causes of cardiogenic shock can be divided into:

  • Myopathic
  • Mechanical

A. Myopathic causes of cardiogenic shock include

  • Acute myocardial infraction. Usually shock occurs in this conditioin if ≥ 40% of the left ventricular mass & more on the right ventricle is involved by infarction.
  • Mycocarditis
  • Dilated cardiomyopathy/hypertrophic cardiomyopathy
  • Myocardial depression in septic shock.

B. Mechanical

  1. Intracardiac
  • Left ventricle outflow obstruction E.g.Aortic stenosis, hypertrophic cardiomyopathy
  • Reduction in forward cardiac output E.g. Aortic or mitral regurgitation
  • Arrhythmia
  1. ii) Extracardiac

This can be called obstructive shock. The extracardiac causes of cardiogenic shock can be caused by:

  • Pericardial tamponade (gross fluid accumulation in the pericardial space) results in a decreased ventricular diastolic filling → ↓CO
  • Tension pneumothorax (gas accumulation in pleural space) This decreases the venous return by creating a positive pressure.
  • Acute massive pulumonary embolism occupying 50-60% of pulumonary vascular bed.
  • Severe pulumonary hypertension (10 pulmonary hypertension).

III. Distributive shock

Definition: Distributive shock refers to a group of shock subtypes caused by profound peripheral vasodilatation despite normal or high cardiac output.

Causes of distributive shock

  • Septic shock – the commonest among the group & clinically very important.
  • Neurogenic shock – Usually occurs in the setting of anaesthetic procedure [cephalo-caudal migration of anaesthetic agent] or spinal cord injury owing to loss of vascular tone & peripheral pooling of blood.
  • Anaphylactic shock – Initiated by generalized IgE – mediated hypersensitivity response, associated with systemic vasodilatation & increased vascular permeability.
  • Endocrine shock – This is a type of shock that typically occurs in adrenal insufficiency.

Next, we will discuss septic shock in some detail. But before discussing septic shock in detail it would be useful to know some aspects of sepsis briefly. Bactermia is the presence of viable bacteria in the blood as evidenced by blood culture. Septicemia is systemic infection due the presence of microbes and their toxin the blood. Sepsis is a systemic response to severe infection mediated via macrophage-derived cytokines that target end organ receptors in response to infection. It is also called SIRS.

Septic shock

Definition: This is a kind of shock caused by systemic microbial infection, most commonly by gram – negative infection (endotoxic shock) but can also occur with gram – positive or fungal infections. or
It can be defined as sepsis with

  • Hypotention, arterial blood pressure less than 90mmHg or 40mmHg less than the patient’s normal blood pressure,
  • Organ dysfunction, &
  • Unresponsiveness to fluid administration.

Pathogenesis of septic shock

Septic shock has a mortality rate of over 50% ranking the first among the causes of death in intensive care units. It results from the spread & expansion of an initially localized infection like pneumonia into the blood stream. Most causes of septic shock (~70%) are caused by endotoxin-producing gram-negative bacilli, hence the term endotoxic shock.

Endotoxins are bacterial wall lipopolyschardes (LPS) released when cell walls are degraded. Analogues molecules in the walls of grampositive bacteria & fungi can also elicit septic shock. LPS bind with CD14 molecule on leucocytes, especially monocytes & macrophages, endothelial cells & others. Depending on the dosage of LPS – protein complex, initiation of a cascade of cytokine-mediated events take place.

The mononuclear phagocytes respond to LPS by producing TNF which, in turn, induces IL – 1 synthesis. TNF & IL-1 both act on endothelial cells to produce further cytokines like IL-6, IL-8, & secondary effectors like NO & PAF (platelet aggregating factor).

High levels of the above molecules or mediators (TNF-α, IL-1, etc…) cause septic shock by acting on:

  • The heart – causing decreased myocardial contractility which results in low cardiac output,
  • Blood vessel – causing systemic vasodilation which decreases the peripheral arteries. The mediators also cause widespread endothelial injury & activation of the coagulation system resulting in DIC, &
  • Lung – causing alveolar capillary damage resulting in adult respiratory distress syndrome (ARDS).

Stages of shock

Uncorrected shock passes through 3 important stages:

1. An initial non-progressive phase

It is also called a period of early compensatory period, during which compensatory mechanisms are activated & perfusion of vital organs maintained.


A variety of neurohumoral mechanisms operate:

  • A decrease in cardiac output will stimulate peripheral & central baro receptors with subsequent intense sympatho-adrenal stimulation. This sometimes leads to up to 200 fold increase in plasma catecholamine level. The net effect is → Tachycardia, ↑ HR → ↑ CO → Peripheral vasoconstriction → ↑ BP. This is a major autocompensatory response.
  • The fall in renal perfusion stimulates the renin – aldosterone secretion mechanism → renal conservation of fluid.

2. Progressive stage (Established shock)

  • This is characterized by tissue hypoperfusion with onset of worsening circulatory & metabolic imbalances including acidosis.
  • There is a widespread tissue hypoxia.
  • Anaerobic gycolysis results in excessive lactic acid production. The lactic acid reduces tissue PH & blunts vasomotor response. The hypoxic cells leak glucose leading to insulin-resistant hyperglycaemia and increased glycogenolysis. Impaired carbohydrate metabolism causes a fall in production of ATP, failure in function of Na+ – K+ ATPase, result in Na & water enterance into the cell, causing cellular swelling also called sick cell syndrome. Anoxic injury to endothelial cells results in DIC.

3. An irreversible stage

  • A sage at which, even if hemodynamic disorders are corrected survival is not possible.
  • Transition to irreversible damage is mediated via various mechanisms.

Morphology of shock

All organs are affected in severe shock. In shock, there is widespread tissue hypoperfusion involving various organs such as the heart, brain, & kidney. This leads to widespread hypoxic tissue necrosis. The widespread tissue necrosis manifests as multiple organ dysfunction [MODS]. Various organs may fail to perform their normal functions. And lungs may show ARDS or Shock lung.

Clinical course of shock

Patient with shock may manifest as having a weak and rapid pulse, tachypenia, & cool, clammy, cyanotic skin. In septic shock, the skin will initially be warm & flushed because of peripheral vasodilation. The patient may present with confusion, restlessnes, decreased urine output, coma, and death.