CHAPTER FOUR

HEALING

Dr. Motea Eskandar

Assisstant Prof. of Clinical
Pathology-
Hematology,Faculty of Medicine,
Sana’a University
 HEALING
o Definition of healing
The word healing, used in a pathological context, refers to the body’s
replacement of destroyed tissue by living tissue.
o Processes of healing
The healing process involves two distinct processes:
- Regeneration, the replacement of lost tissue by tissues similar in type and
- Repair (healing by scaring), the replacement of lost tissue by granulation
tissue which matures to form scar tissue. Healing by fibrosis is inevitable
when the surrounding specialized cells do not possess the capacity to
proliferate.
Tissue Inflammation Removal of dead tissue & Damage
injurious agent

Replacement
by

Fibrous tissue Specialized

tissue
(scarring) (Regeneration)

Healing

Figure(1) Processes of healing: Removal of dead tissue & injurious

agent and replacement
occur simultaneously
 Types of cells
Based on their proliferative capacity there are three types of cells.
1. Labile cells:
These are cells which have a continuous turn over by programmed
division of stem cells. They are found in the surface epithelium of the
gastrointestinal treat, urinary tract or the skin. The cells of lymphoid and
haemopoietic systems are further examples of labile cells. The chances of
regeneration are excellent.
2. Stable cells
Tissues which have such type of cells have normally a much lower level
of replication and there are few stem cells. However, the cells of such tissues
can undergo rapid division in response to injury. For example, mesenchymal
cells such as smooth muscle cells, fibroblasts, osteoblasts and endothelial
cells are stable cells which can proliferate. Liver, endocrine glands and renal
tubular epithelium has also such type of cells which can regenerate. Their
chances of regeneration are good.
3. Permanent cells:
These are non-dividing cells. If lost, permanent cells cannot be replaced,
because they don not have the capacity to proliferate. For example: adult
neurons, striated muscle cells, and cells of the lens.
 Types of Healing Processes
a. Healing by regeneration:
Regeneration (generare=bring to life) is the renewal of a lost tissue in which
the lost cells are replaced by identical ones.
Regeneration involves two processes
1. Proliferation of surviving cells to replace lost tissue
2. Migration of surviving cells into the vacant space.
The capacity of a tissue for regeneration depends on its
1) Proliferative ability,
2) Degree of damage to stromal framework and
3) On the type and severity of the damage.
Tissues formed of labile and stable cells can regenerate provided that stromal
framework are intact.
b. Repair (Healing by connective tissue)
Repair is the orderly process by which lost tissue is eventually replaced by a
scar. A wound in which only the lining epithelium is affected heals exclusively by
regeneration. In contrast, wounds that extend through the basement membrane
to the connective tissue, for example, the dermis in the skin or the sub-mucosa in
the gastrointestinal tract, lead to the formation of granulation tissue and
eventual scarring. Tissues containing terminally differentiated (permanent) cells
such as neurons and skeletal muscle cells can not heal by regeneration. Rather
the lost permanent cells are replaced by formation of granulation tissue.
 Phases of Granulation-Tssue Formation
In granulation-tissue formation, three phases may be observed.
1. Phase of inflammation:
At this phase, inflammatory exudate containing polymorphs is seen in
the area of tissue injury. In addition, there is platelet aggregation and fibrin
deposition.
2. Phase of demolition
The dead cells liberate their autolytic enzymes, and other enzymes
(proteolytic) come from disintegrating polymorphs. There is an associated
macrophage infiltration. These cells ingest particulate matter, either
digesting or removing it.
3. Ingrowth of granulation tissue
This is characterized by proliferation of fibroblasts and an ingrowth of
 Wound
new bloodcontraction
vessels into the area of injuty, with a variable number of
Wound contraction
inflammatory cells. is a mechanical reduction in the size of the defect.
The wound is reduced approximately by 70-80% of its original size.
Contraction results in much faster healing, since only one-quarter to one-
third of the amount of destroyed tissue has to be replaced. If contraction is
prevented, healing is slow and a large ugly scar is formed.
 Causes of contraction:
It is said to be due to contraction by myofibroblasts. Myofibroblasts
have the features intermediate between those of fibroblasts and smooth
muscle cells. Two to three days after the injury they migrate into the
wound and their active contraction decrease the size of the defect.
 Factors that influence wound healing
A number of factors can alter the rate and efficiency of healing, which
are
1) Local Factors
1. Type, size, and location of the wound
A clean, aseptic wound produced by the surgeon’s scalpel heals faster
than a wound produced by blunt trauma, which exhibits aboundant necrosis
and irregular edges. Small blunt wounds heal faster than larger ones.
Injuries in richly vascularized areas (e.g., the face) heal faster than those in
poorly vascularized ones (e.g., the foot). In areas where the skin adheres to
bony surfaces, as in injuries over the tibia, wound contraction and adequate
apposition of the edges are difficult. Hence, such wounds heal slowly.
2. Vascular supply
Wounds with impaired blood supply heal slowly. For example, the
healing of leg wounds in patients with varicose veins is prolonged.
Ischemia due to pressure produces bed sores and then prevents their
healing. Ischemia due to arterial obstruction, often in the lower extremities
of diabetics, also prevents healing.
3. Infection
Wounds provide a portal of entry for microorganisms. Infection delays or
4. Movement
Early motion, particularly before tensile strength has been established,
subjects a wound to persistent trauma, thus preventing or retarding
healing.
5. Ionizing radiation
Prior irradiation leaves vascular lesions that interfere with blood supply
and result in slow wound healing. Acutely, irradiation of a wound blocks
2) cell
Systemic Factors
proliferation, inhibits contraction, and retards the formation of
1. Circulatory
granulation tissue.
status
Cardiovascular status, by determining the blood supply to the injured
area, is important for wound healing. Poor healing attributed to old
age is often due, largely, to impaired circulation.
2. Infection
Systemic infections delay wound healing.
3. Metabolic status
Poorly controlled diabetes mellitus is associated with delayed wound
healing.The risk of infection in clean wound approaches five fold the
risk in non- diabetics. In diabetic patients, there can be impaired
circulation secondary to arteriosclerosis and impaired sensation due
to diabetic neuropathy. The impaired sensation renders the lower
extremity blind to every day hazards. Hence, in diabetic patients,
4. Nutritional deficiencies
A. Protein deficiency
In protein depletion there is an impairment of granulation tissue and
collagen formation, resulting in a great delay in wound healing.
B. Vitamine deficiency
Vitamin C is required for collagen synthesis and secretion. It is required in
hydroxylation of proline and lysine in the process of collagen synthesis.
Vitamin C deficiency (scurvy) results in grossly deficient wound healing,
with a lack of vascular proliferation and collagen deposition.
C. Trace element deficiency
Zinc (a co-factor of several enzymes) deficiency will retard healing by
preventing cell proliferation. Zinc is necessary in several DNA and RNA
polymerases and transferases; hence, a deficiency state will inhibit
mitosis. Proliferation of fibroblasts (fibroplasia) is, therefore, retarded.
D. Hormones
Corticosteroids impair wound healing, an effect attributed to an inhibition
of collagen synthesis. However, these hormones have many other
effects, including anti-inflammatory actions and a general depression
of protein synthesis. It also inhibits fibroplasia and neovascularization.
Both epithelialization and contraction are impaired. It is, therefore,
difficult to attribute their inhibition of wound healing to any one specific
 Thyroid hormones, androgens, estrogens and growth hormone also
influence wound healing. This effect, however, may be more due to their
regulation of general metabolic status rather than to a specific
modification of the healing process.
E. Anti-inflammatory drugs
Anti-inflammatory medications do not interfere with wound healing
when administered at the usual daily dosages. Asprin and indomethalin
both inhibit prostaglandin synthesis and thus delay healing.
 CHAPTER FIVE
HEMODYNAMIC DISORDERS
 HEMODYNAMIC DISORDERS
Edema
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:
a) Hydrothorax – fluid accumulation in pleural cavity in a pathologic
amount.
b) Hydropericardium – pathologic amount of fluid accumulated in the
pericardial cavity.
c) Hydroperitoncum (ascites) – fluid accumulation in peritoneal cavity.
d) Anasarca – is a severe & generalized edema of the body with
profound
o Mechanism of edema formation:
subcutaneous
Approximatelyswelling.
60% of the lean body weight is water, (2/3) 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 & Oncotic pressure
2) Vascular permeability
3) Lymphatic channels
4) Sodium and water retention
We will discuss each of the above sequentially.

1) Hydrostatic and oncotic pressures:

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:
a. The capillary hydrostatic pressure (Pc)
This pressure tends to force fluid outward from the intravascular
space through the capillary membrane to the interstitium.
b. The interstial fluid hydrostatic pressure (Pif)
This pressure tends to force fluid from the interstitial space to the
intravascular space.
c. 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.
d. 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:
A. Edema due to decreased plasma oncotic pressure. The
plasma oncotic pressure is decreased when the plasma proteins
are decreased in various diseases such as:
1. Protein loosing glomerulopathies like nephrotic syndrome
with
leaky glomerulus.
2. Liver cirrhosis which leads to decreased protein synthesis by
the
damaged liver.
3. Malnutrition
4. Protein loosing enteropathy.
B. Edema resulting from increased capillary hydrostatic pressure
as in the following diseases:
1. Deep venous thrombosis resulting in impaired venous return.
2. Pulmonary oedema
3. Cerebral oedema
4. Congestive heart failure
Clinical classification of edema:
One can also clinically classify edema into localized & generalized
types.

No. Localized Generalized

1 Deep venous Nephrotic syndrome
thrombosis
2 Pulmonary edema Liver cirrhosis

3 Brain edema Malnutrition

4 Lymphatic edema Heart failure

5 Renal failure
1. Localized 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 - Herniation 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.
2. Generalized edema (anasarca) occurs due to
a. Reduction of albumin due to excessive loss or reduced synthesis as
is caused by:
1) Protein loosing glomerulopathies like nephrotic syndrome
2) Liver cirrhosis
3) Malnutrition
4) Protein-losing enteropathy
b. Increased volume of blood secondary to sodium retention caused by
congestive heart failure:
 Mechanism of edema formation in congestive heart failure:
Reduced Cardiac Output
↓
Reduced tissue perfusion

Renal hypoperfusion Release of arginin Sympathetic nervous system

vasopressin
Rennin angiotensin Vasoconstriction, Salt and water
retention
System (RAS) activated

Rennin release
- A proteolytic enzyme
- Secreted by myoepithelial cells
of juxtaglomerular apparatus
- Secreted in response to
1. A fall in renal afferent arteriolar perfusion
2. Decreased sodium concentration
In distal renal tubules
3. Via stimulation of sympatethic
nervous system

Cleavage of (angiotensin converting enzyme ACE )

angiotensin I angiotensin II Aldosterone
Angiotensin II
a. Stimulate release of aldosterone
b. Causes vasoconstriction
c. Degraded to angiotensin III which has similar functions
2) Vascular permeability:
Increased vascular permeability usually occurs due to acute
inflammation. In inflammation, chemical mediators are produced. Some
of these mediators 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 oedema (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]
⇒
3) Lymphatic
Specific channels:
gravity < 1.012
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:
1) Parasitic infection. E.g filariasis which causes massive lymphatic
and
inguinal fibrosis
2) Lymphatic obstruction secondary to neoplastic infiltration. E.g.
breast
cancer
4) 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.
Hypermia and Congestion

Definition: Both of them can be defined as a local increase in volume of

blood in a particular tissue.

 Hypermia
- 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.
 Congestion
- 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
- Inobstruction.
long-standing congestion (also called chronic passive congestion
- Affected tissue appears blue-red due to accumulation of
states),
deoxygenated →
blood. blood causes hypoxia results in parenchyma
poorly oxygenated
cell degeneration or cell death.
a) Pulmonary congestion
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
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, Haemorrhage
there is a grossly evident hepatic fibrosis called cardiac cirrhosis
Definition:
Hemorrhage is extravasation of blood outside the blood vessel.
Causes:
1.Physical trauma – Stabbing
- Stick injury
- Gunshot
- Motor vehicle accident
2. Inadequacies in blood clotting which can be due to:
A. Too few or poorly functioning platelets (i.e. qualitative & quantitative
defect
of platelets)
B. 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
Terminology:
is important in the synthesis of the clotting factors by the liver.
1) Haemorrhage enclosed within a tissue or a cavity is knownas
hematoma.
2) Minute 1-2 mm hemorrhages occurring in the skin, mucosal
membrane, or
serosal surface are called petechiae.
3) Slightly > 3mm hemorrhage occurring in the skin is referred to as
purpura.
4) 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:
 Hemostasis and Blood Coagulation
 Hemostasis
Definition:
Hemostasis is the maintainence of the clot-free state of blood &
the
prevention of blood loss via the formation of hemostatic plug.
Hemostasis depends on three general components:
a) Vascular wall
b) Platelets
c) Coagulation pathways
Whenever a vessel is ruptured or severed, hemostasis is achieved by
several
mechanisms:
A. Vascular spasm
B. Formation of platelet plug
C. Formation blood clot as a result of blood coagulation
D. Eventual growth of fibrous tissue in to the blood clot to close
the hole in the vessel permanently.
 Thrombosis
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:
There are three factors that predispose to thrombus formation.
These factors
are called Virchow’s triad:
A: Endothelial injury
B: Stasis or
A: Endothelial turbulence of blood flow
injury
 C: Blood
It is hypercoagulability
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
• 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
a. Disrupt the laminarconditions normal
flow and bring blood flow
platelets in tois laminar,
contact that
with is, the
the
cellular elements flow centrally in the vessel lumen separated from
endothelium
endothelium
b. by slowing
Prevent dilution movingclotting
of activated clear zone of plasma.
factors by freshlyStasis & turbulence
flowing blood
c.therefore:
Retard or make a time lag in the inflow of clotting factor inhibitors and
permit
the build up of thrombi.
d. Turbulence causes reduction in endothelial PGI2 and tissue-type
Stasis is a major factor in the development of venous thrombi while
turbulence
contributes to arterial & cardiac thrombosis by causing direct
endothelial injury
• Examples:
or by forming countercurrents & local pockets of stasis.
a)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.
b) Aneurysms are favoured sites of stasis
c) 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.
d) Mitral valve stenosis after chronic rheumatic fever may result in left
atrial
dilation, usually associated with atrial fibrillation. A dilated left atrium is
a
site of stasis & a prime location of thrombus development.
e) Hypervisicosity syndrome, i.e an increase in hematocrit in excessive
C: Hypercoagulablity
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)
o Mutations in factor V[Lieden factor]
o Anti thrombin III deficiency
2. Secondary
o (Acquired)
Protein which, in turn, can be categorized into:
C or S deficiency
A: High-risk for hypercoagulablity
o Prolonged bed rest or immobilization
o Myocardial infarction
o Tissue damage (surgery, fracture, burns)
o Cancers (Cancers release procoagulant tissue products to cause
thrombosis)
o
Prosthetic cardiac valves
o Disseminated intra vascular coagulation
B: Low risk factor for hypercoagulablity
o A trial fibrillation
o Cardiomyopathy
o Nephrotic syndrome
o Smoking
o Oral contraceptives
o Hyperestrogenic state eg. Pregnancy.
 Morphology of Thrombi
• 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
Thecertain
mostsimilarities
common sitebetween
of arterial
the two).
thrombi
Theindifferences
descendingbetween
order are:
arterialo Coronary arteries
& ovenous
Cerebral
thrombi
arteries
are:
o 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.
 Differences between Arterial thrombi and Venous thrombi

No Arterial thrombi Venous thrombi

1 Arise at the site of endothelial injury Arise at area of stasis

2 Grow in a retrograde fasion, against Grow in the direction of blood flow

site of attachment.flow towards the from its
heart
3 Has firm attachment Has loose attachment, hence,
propagating tail may undergo
fragmentation.
4 They usually occlude the blood flow Almost invariably occlusive

 Fates of a thrombus
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.
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
 Clinical significance of thrombi
subendothelial swelling of the vessel wall.
• Thrombi are significant clinically because:
- They cause obstruction of arteries and veins &
- They are possible source of emboli.
A. 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
- Has the following predisposing factors:
1. Trauma, surgery, burns which usually result in:-
a:Reduced physical activity leading to stasis
b:Injury to vessels
c:Release of procagulant substance from the tissue
d:Reduced t-PA activity (fibrinolysis)
2. Pregnancy & puerperal states increase coagulation factors &
reduce the
synthesis of antithrombotic substances. Myocardial infarction &
heart
3. Malnutrition, debilitating conditions and wasting diseases such as
failure cause venous stasis to the left side.
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.
B. 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
VIII. Embolism
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:
o Thrombus (99% of emboli arise from a thrombus. Such an embolus
is
called thromboembolus)
o Platelets aggregates
o Fragment of material from ulcerating atheromatous plaque
o Fragment of a tumour
o Fat globules
o Bubbles of air
o Amniotic fluid
o Infected foreign material
o Bits of bone marrow
o Others.
Unless otherwise specified, the term embolism should be
Thromboembolism
Based on its sites of origin & impaction, thromboembolism can be divided into:
a) Pulmonary thromboembolism (PTE)
o 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
b) Systemic thromboembolism
systemic
o veins
Systemic emboli
or the ariseof
right side from
the the left side of the heart or from thrombi
heart.
&
atheromatous debris in large arteries. And they impact in the
systemic
arteries.
c) Crossed embolism (Paradoxical embolism)
o 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 thrombeomblism (PTE)
 , 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
b) Systemicpatient
thromboembolism
previously
• Systemic had cardiac or pulmonary
thromboembolism disease),
refers to emboli then obstruction
travelling of a
within arterial
circulationmedium
& impacting in the systemic arteries.
sized pulmonary artery by a medium-sized embolus can lead to
• 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
Next, we willembolization
arteriolar briefly touchare
upon
thesome
lowerrare forms of (75%)
extremities embolism.
& 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
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
5. Air embolism
progress to delirium
Gas bubbles & coma.
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.
 • Neck wounds penetrating the large veins
• Cardio thoracic surgery.
• Arterial catheterisation& intravenous infusion.
• Etc.
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
6) occlude
Amnioticmajor vessels.
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.
IX. Infarction
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:
A. The nature of the vascular supply
B. The rate of development of occlusion
C. Suceptibility of the tissue for hypoxia
D. Oxygen content of the blood
E. 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:
A) the basis of their colour (reflecting the amount of haemorrhage) into:
1. Hemorrhagic (Red) infarcts
2. Anemic (White) infarcts
B) the presence or absence of microbial infection into:
1. Septic infarcts
2. Bland infarcts
1. Red infarcts occur in:
a) Venous occlusions as in ovarian torsion
b) Loose tissues such as the lung which allow blood to collect in infarct
zone.
c) Tissues with dual circulations (eg. the lung), permitting flow of blood
from
unobstructed vessel in to necrotic zone.
d) In tissues that were previously congested because of sluggish
outflow of
blood.
2. White
e) Wheninfarcts
bloodoccur in:reestablished to a site of previous arterial
flow is
a) Arterial
occlusion & occlusion in organs with a single arterial blood supply.
b) necrosis.
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,
Microscopy: some of the infarcts may show recovery, however, most are
ultimately replaced
The dominant with scars
histologic except
feature of in the brain.
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
o Usually results from occlusive thrombosis supervening on ulcerating
atheroma
of a major coronary artery.
o Is a white infarct.
o Can cause sudden death, cardiac failure, etc...
B. Cerebral infarcts
o May appear as pale or hemorrhagic
o 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.
C. Lung infarcts
o
oIs
Areone type ofdark
typically cerebrovascular
red & conical accidents (CVA) or stroke which has various
(wedge-shaped).
clinical manifestations.
o Can cause chest pain, hemoptysis, etc…
D. Splenic infarcts
o Conical & sub capsular
oInitially dark red later turned to be pale.
X. Disseminated Intravascular Coagulation (DIC)
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 andPathogensis
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.
1. Tissue thromboplastin substance may be derived from a variety of
sources
such as:
A: Massive trauma, severe burns & extensive surgery. The major
mechanism of
DIC is believed to be autoinfusion of thromboplastin from the tissues.
B: Obstetric conditions in which thromboplastin derived from the
placenta, dead
retained fetus, or amniotic fluid may enter the circulation. .
C:
D: Cancers
Gram negative
such assepsis
acute(an
promyelocytic
important cause
leukaemia,
of DIC)adenocarcinoma
in which bacterial
of
endoxins
the lung
in
cause
whichincreased
a varietysynthesis,
of thromboplastin
membrane substances
exposure,like
& release
mucus of
aretissue
factor
released
from
which
monocytes.
directlyFurthermore,
activate factor
activated
X, VII, &monocysts
proteolyticrelease
en 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
2. 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
 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.
XI. Shock
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:
1. Cardiac output (CO)
2. Peripheral vascular resistance (PVR)
• CO = stroke volume X heart rate
In turn, stroke volume depends on:
a) Preload i.e. blood volume,
b) Afterload i.e. arterial resistance, &
c) 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:
A. Hypovolemic
A. Hypovolemic shock
shock
Definition:shock
B. Cardiogenic
This is shock
C. Distributive 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
Causes of hypovolumic shock include:
a) Haemorrhage
b) Diarrhoea & vomiting
c) Burns
d) Trauma
e) etc
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
B. 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:
oDBP<60mm Hg
o Left ventricle filling pressure > 18mm Hg
oCardiac index< 1.8 l/min/m2
oUsually pulmonary oedema coexists.
Causes of cardiogenic shock can be divided
into:
A) Myopathic causes of cardiogenic shock include:
1. 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.
2. Mycocarditis
3. Dilated cardiomyopathy/hypertrophic
cardiomyopathy
4. Myocardial depression in septic shock
5. Etc….
B) Mechanical
i) Intracardiac
a)Left ventricle outflow obstruction E.g.Aortic stenosis,
hypertrophic cardiomyopathy
b) Reduction in forward cardiac output E.g. Aortic or
mitral
 c) Arrhythmia
ii) Extracardiac:
This can be called obstructive shock. The
extracardiac causes of cardiogenic shock can be
caused by:
a) Pericardial tamponade (gross fluid
accumulation in
the pericardial space) results in a decreased
→↓
ventricular diastolic filling CO
b) Tension pneumothorax (gas accumulation in
pleural
space). This decreases the venous return by
creating
a positive pressure.
c) Acute massive pulumonary embolism
C. 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
1) Septic shock – the commonest among the group
& clinically very important.
2) 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
3) Anaphylactic shock
- Initiated by generalized IgE – mediated hypersensitivity
response, associated with systemic vasodilatation &
increased vascular permeability.
4) 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.
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
1. Hypotention, arterial blood pressure less than
90mmHg or 40mmHg less than the patient’s
normal
blood pressure,
2. Organ dysfunction, &
3. 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,
 Depending on the dosage of LPS – protein
complex, initiation of a cascade of cytokine-mediated
events
takeThe
place.
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
Stages
(ARDS). of shock
Uncorrected shock passes through 3 important
stages:
1) An initial nonprogressive phase
oIt is also called a period of early compensatory
period, during which compensatory mechanisms are
activated & perfusion of vital organs maintained.
Mechanisms
oA variety of neurohumoral mechanisms operate:
i) 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.
ii) 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
 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 septic 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.