Circulatory Disorders

by
Djoko Legowo drh. Mkes
 Introduction
ENVIRONMENT

Circulatory
System I

End product

UNICELLULER ORGANISM MULTICELLULER ORGANISM

GANGGUAN HEMODINAMIK- PENGANTAR Pulmunary 4
circulation

Substrat & gas exchange

sinister dexter
GANGGUAN HEMODINAMIK- PENGANTAR 9

CAPILER
 EDEMA
HEMOSTASIS
HEMORRHAGE
TROMBOSIS
HYPEREMIA
CONGESTION
EDEMA

- An accumulation of fluid in interstitial resulting in an abnormality of

fluid distribution between plasma, interstitial and cell
- Edema occurs by four major mechanism :
1. increased microvascular permeability
2. increased intravascular hydrostatic pressure
3. decreased intravascular osmotic pressure
4. decreased lymphatic drainage
1. Mechanism of Increased Microvascular Permeability

inflamatory or immunogenic stimuli

histamine, bradykinin, leukotrienes, substance P, and cytokines such as
interleukin 1 (IL-1), tumor necrosis factor (TNF), and gamma interferon

vasodilataion and contraction of endothelial

widening of interendothelial gaps

Movement fluid into interstitial

Leukocytes migration
In progress edema

Endothelium
2. Mechanism increased intravascular hydrostatic pressure

- Increased of intravascular hydrostatic pressure is most often due to

- active increased flow of blood into microvascular (hyperemia),
such as occur with acute inflammation
- passive accumulation of blood (congestian), often caused by
heart failure, or localized venous compression or obstruction
- Increased microvascular volume and pressure cause increase filtration
and reduced fluid absorbtion back into the vassel
- When increased hydrostatic pressure affectecs as localized portion of
microvasculature, the edema is localized
- In the case of heart failure :
- right heart system : congestion and increased hydrostatic
pressure in portal venous (ascites)
- left heart failure : causing pulmonary edema
- Both (generalized heart failure) : causing generalized edema
- Generalized edema also can result in a reduction of circulatory plasma
volume and activates volume-regulating compensatory respon
3. Mechanism of decreased intravascular osmotic pressure
and Edema Formation
- Decreased intravascular osmotic pressure most commonly results from decreased
concentration plasma proteins, particularly albumin
-Hypoalbuminemia reduces the intravascular colloidal osmotic pressure resulting in
increased fluid filtration and decreased absorbtion
-Hypoalbumenemia can result from either decreased production of albumin by liver
or execessive loss from plasma
-Decreased hepatic production most commonly occurs because of lack of adequate
protein for synthetic pathway as result of malnutrition or intestinal malabsortion of
protein,
- Loss albumin plasma can occur in
a. gastrointestinal disease characterized by blood loss such as by parasitism
b. renal disease, in which glomerular and/or tubular function is impaired
c. plasma exudation accompanying severe burns
- Edema caused by decreased intravas ossmotic tend to be generalized
4. Mechanism of decreased lymphatic drainage and Edema
Formation

- Decreased lymphatic drainage reduce the ability of lymphatic system to

removed the slight excess of fluid that normally accumulates in
interstitium during fluid exchnge between the plasma and interstitium
- Occur in lymph vessel compression by neoplastic or inflamatory
swelling; lymph vessel constriction caused by fibrosis, or internal
blockage by thrombus.
 MORFOLOGIC CHARACTERISTIC OF EDEMA
- Clear to slightly yellow fluid and generally contains a small amount of
protein (transudate), which thickens and expands affected tissue
- When edema occour in tissue adjecent to body cavities such as
alveolar lumens the increased interstitial pressure often forces fluid into
these cavities.
- intraluminal of alveolar : pulmonary edema
- thoracic cavities : hydrothorax
- pericardial sac : hydropericardium
- abdominal cavity : Ascites
- Histologically : amorphous pale, eosinophilic fluid (because of protein)
- Subcutaneus edema result in fluctuant skin and cooler than adjecent
nonaffected tissue but commonly has minimal clinical impact.
- Edema in confined space (such as in brain incranial vault, hydrothorax,
hydropericardium) can result in pressure within the organ that result in
serious organ dysfunction
Subcutaneus edema, congenital
lymphedema skin dog.
Normal lung
 HEMOSTASIS

- Hemostasis is arrest of bleeding, that physiologically result in

response to vascular damage and provides a mechanism to seal an
injured vessel to prevent blood loss.
- This process regulated predominantly by :
a. Endothelium
b. Platelets
c. Coagulation factors
- It is normaly occur only at the site of vascular injury without affecting
fluidity and flow of blood in normal undamaged vasculature
- Disruption of the delicate balance of hemostasis can result in
pathological states of blood loss (hemorrhage) or inappropriate
thrombus formation (thrombosis)
 Hemostasis

Endothelium
Platelets
Coagulation factors
 Endothelium role on hemostasis

Normal endothelium provides a surface that promotes the smooth,

and nonturbulent flow of blood

Responsive to mediators that enhance vasodilatation and inhibit

platelet adhesion, aggregation and coagulation

In contras, following injury or activation, endothelium produces

or responds to mediators that induce vasocontriction, that enhance
pletelet adhesion and aggregation , and stimulate coagulation.
 Platelet role on hemostasis
Platelets are un nucleate cell fragments derived from megakaryocytes.
Their major role in hemostasis is to form the initial plug that cover
and seal a small area of vascular damage

Following vascular damage, platelets adhere to subendothelial collagen

and other extra cellular matrix (ECM) component (e.g. fibrinectin,
adhesive glycoproteins and proteoglycans).

Adhered pletelets express receptors that promote aggregation of

additional platelets and become activated to release the products of
their cytoplasmic granules and produce other mediator of coagulation
(e.g. tromboxane)

The phospholipid surfaces of platelet membranes also serve to

promote coagulation
 Coagulation factors role on hemostasis

Coagulation factors are plasma protein produced mainly by the liver.

Their major role in hemostasis is to form fibrin

Coagulation factors are devided into :

a. a structurally and functionally interdependent contact group
(prekallikerin, kinogen and factors XII and XI)
b. a Vitamin K-dependent group (factor II, VII, IX and X)
c. a highly labile fibrinogen group (Factors I, V, VIII, and XIII)
 Hemostasis process

The sequence events that contribute to hemostasis are ;

1. trasient vasocontriction and platelet aggregation to form a platelet

plug at the site of damage(primary hemostasis)

2. coagulation to form a meshwork of fibrin (secondary hemostasis)

3. fibrinolysis to remove the platelet/fibrin plug (thrombus retraction)

4. tissue repair at the damaged site

 Sequences of Primary Hemostasis

1. injury  induce vascular and platelet to release neurogenic mediators

following vasoconstriction immediately after damage.
2. Narrowing of the vessel lumen allow opposing endothelial surface
into contact each other to reduce blood loss
3. pletelets adhere to exposed subendothelial matrix of collagen, fibro
nectin, and other glycoproteins and proteoglycans
4. local activated endothelium release von Willebrand`s factor that
cause more platelet adhere
5. Platelets within the aggregate secrete the content of their dense
bodies and α-granuls and produce substances such as thromboxane
to accelerate hemostasis
6. ADP-ase released from dense granules triggers the binding of
fibrinogen to platelets receptor GpIIb-IIIa, resulting in th formation of
bridges that link platelets from loose aggregate into a dense plug
7. Mild injury  could be recovered just by platelet alone (plug)
severe injury  exposed collagen and plug promote to secondary
hemostasis
 vWF

After injury, local neurohumoral factors induce a transient vasocontriction

Platelets adhere to ECM via von Willebrand`s factors (vWF) and activated
(Change shape and granule release). Released ADP and Thomboxane`s
(TXA2) lead to further platelets aggregation to form primary hemostatic plug
 Secondary Hemostasis or Coagulation Process

In severe vascular damage, the formation of fibrin is important for prevention

of blood loss
Fibrin is end-product of a series of enzymatic reactions involving coagulation
factors, nonnzymatic cofactors, calcium and phospholipid membranes
injury of platelets.
There are three integreted pathway have been known in coagulation process
include :

1. Intrinsic pathway
2. Extrinsic Pathway
3. Common Pathway
 Intrinsic Pathway
- Intrinsic factor mean all factors derived from circulating plasma
- Intrinsic coagulation pathway is a complex and highly inter-related process
that is intitiatd by the contact group of coagulation from intrinsic factors.
- It is intiated by vascular damage than activation of prekallikrein and factor
XII in plasma which normaly bound to HMWK to form factor XIIa.
- Factor XIIa initiates a complex series of reaction that affect coagulation by
kinin formation, complement activation, and fibrinolysis.
- Factor XIIa activats factor XI to become XIa and intracts with prekallikerin
to form kallikerin, and interact with HWMK to form kinin
- Both Kallikerin and factor XIa with Ca2+, than activate factor IX to become
factor IXa
- factor IXa than binds to platelet phospholipids in a complex with Ca2+
and factor VIII
- following modification of factor VIII by thrombin into factor VIIIa, this complex
of (VIIIa-factor IXa/Ca2+ - phospholipid) than activates factor X to initiate
the common coagulation pathway
Extrinsic Pathway

- all factor derived from activated endothelium and all underlying cells of
endothelium (e.g. myocytes)
- The most important is Factor III (Tissue factor/TF) a high molecular wight
of phospholipid-containing glycoprotein that found in plasm membrane of
many cells, including in activated endothelium (not resting)
- Endotelial cell production TF stimulated by endotoxin, TNF-α, IL-1,
thrombin, and transforming growth factor-ß (TGF-ß).
- TF produced than contact with factor VII (from circulating) to form
Ca2+ -dependent TF-VII complex on the TF-expressing surface
- Those complex than activates factor X to initiate the common pathway
Common Pathway

- The intrinsic and extrinsic pathway merge with the activation of factor X to
become factor Xa
- Factor Xa is bound to endotleial or platelets membrane phospholipid where
it can direcly convert factor II into factor IIa (Thrombin)
- Thrombin is a multifunctional mediator whose major function is to cleave
fibrinopetides A and B from factor I (fibrinogen) to form fibrin monomers
(fibrin molecule)
- Factor XIIIa (formed by the activation of Xa and IIa on factor XIII, along
with
Ca2+), catalyzed the formation of covalent bond that cross-link adjecent
fibrin molecule to make the polymer insoluble
- Cross-linking of the fibrin network, caus retraction fibrin-platelet thrombus.
This retraction reduce the size of the thrombus to allow blood flow continue
HMWK : high molecule
wight kinogen
Local activation of coagulation cascade (involving TF and platelets phospholipid)
result in fibrin polymerization, cementing the platelets into a definitiv of
secondary hemostatic plug
Thrombus Dissolution (thrombolysis)

- The purpose of a fibrin-platelet thrombus is to form a temporary patch that

is dissolved following healing of the tissue (vassel wall)
- The rate of dissolution must be balance with healing process
- Fibrin dissolution initiated immediately upon vessel injury by cleavage of
the plasma protein plasminogen into plasmin
- Plasminogen activator present within endothelium and other tissue
- Plasmin reduce thrombus size by degrading both cross-linked (insoluble)
fibrin within the thrombus and fibrinogen, so that additional fibrin formation
is inhibited.
- Fibrin degradation products (FDPs) is the end product of insoluble fibrin
that result in plasmin action
- FDPs collectively inhibit trombin, interfere with fibrin plymerization, and
coat platelets membrane so can inhibit the more platlets aggregation
Counter-regulatory mechanism, such as releas of tissue plasminogn (tPA)
(fibrinoyitic) and Throbomodulin, limit the hemostatic procss to site of injury
 Disorders of Hemostasis :
Hemorrhage and Thrombosis

- The purpose of Hemostasis is to prevent blood loss

following vascular damage, at the same time maintaining
blood flow freely through normal vasculature.
- Failure of hemostasis can result in the extravascular loss
of blood (hemorrhage) or in approriate formation of
intravascular thrombus (thrombosis)
Hemorrhage

Trhrombus
 Hemorrhage
- is extravascular loss of blood that occur because of abnormal function of
one or more of major factors that influence hemostasis ;
1. VESSEL (ENDOTHELIUM)
2. PLATELET
3. COAGULATION FACTOR
- Extensive and fail to stop hemorrhage can lead to hypovolemic shock and
dead
- slow rates of blood loss compensated by increased hematopoiesis
Vessel Abnormality and Hemorrhage

Causative :
- Rhexis (breaking forth) due to trauma; vascular erosin by inflamatory
or neoplasmaa invasive  physically distrupt a vessel
- Endotoxemia (canine adenovirus-1 or chemical agent  endothelium
injury  widespread endothelial junc  diapedesis (erythrocytes
escape from small interendothelial junc.)
- Type III Hypersesitivity reaction  immune complex entrapped in vessel
wall result in endothelial damage
- Developmental collagen disorder  result in abnormal collagen in wall
 fragillity
- Vitamin C deficiency
Platelet Abnormality and Hemorrhage
a. Thrombositopenia result in ;
- decreased prod  megakarocyte damage (caused radiation)

- increase destruction  radiation, estrogen toxicity, viral and other

infectious agent (e.g. feline and canine parvovirus), autoimmune
destruction (increasing production of antibody against platelet
membrane component such as GP IIb and GP IIIa), colostrum-
containing antiplatelet antibody, artropod-borne agents.
- increasing platelets use  generalized endhotelial damage (result
in generalized hemostasis)
b.Platelet disfunction  commonly occur in uremia, and also because
of deficiency of von Willebrand`s factor that result in decreased
platelet adhesion
Thrombositopenia often occur in Otterhound and Pyreness dogs 
clinical sign  prologed bleeding and hematome
Coagulant factor Abnormality and Hemorrhage

Decreased coagulation factor ;

- severe liver disease  decreased sythesis of most coagulation factor
such as factor II, VII, IX, X, Protein C and K
Hemorrhage Appearances [Names]

Appearencee of hemorrhage depent on : causa; location; and severity

a. Petechia : is a pinpoint (1-2 mm)  occur in mainly

because of diapedesis associated with minor damage
b. Ecchymosis : is larger than petechia [Ǿ : 3-5 mm]  cause of
more extensive vascular damage
c. Suffusive : larger than two type above [ a and b]
d. Hematome : hemorrhage that occurs into focal and confined space
e. Hemoperitonium ; hemothorax; hemopericardium  respectively for

hemorrahage that occur in peritonium, thorax and pericardium cavities

 THROMBOSIS

IS AN INAPROPRIATE THROMBUS FORMATION OF FIBRIN AND

PLATELET WITH OTHER BLOOD ELEMENTS ON THE WALL OF A
BLOOD OR LYMPHATIC VESSEL OR HEART OR FREE IN THEIR
LUMEN [THROMBO-EMBOL]
Causes of Thrombosis

Virchow`s Triad
 Endothelial Injury The most important factor in
thrombosis

Endothelial Denuded

Subendothel expossed Collagen and fibronectin

Platelets aggregation

Thrombosis
Causes of Endothhelial Injury :

vasculitis (Infectious and immunologic reaction)

Toxin
Metabolic disorder
Neoplasia
Free radicals
 Turbulent
Heart Local
Blood
Failure Congstion
Flow

Reduced Blood flow

Accumulation of
Coagulation Factor

Increased contact of
Thrombosis platelets with endothelium
Increased hemostatic Coagulation factors
protein and fibrinolitic Inhibitors

Hypercoagulability Inflamation
Stress
surgery
neoplasia
pregnacy
Thrombosis renal diseases
 Appearance of Thrombosis

Relative Proprotion of :
Platelets
Fibrin and
Depent on erythrocytes

Composition

Cause

Location
 Types of Thrombi and Its
Composition

Predominantly :
Platelets and Erythrocyte
Fibrin

Tend to be pale Tend to red

 Cardiac and Arterial Thrombi Venous Thrombi


 Dull
Dull 
 Often
Often occur
occur inin areas
areas of
of stasis
stasis

 Firmly
Firmly attached
attached to to the
the vessel
vessel 
 soft
soft and
and Gelatinous
Gelatinous
wall
wall 
dark
dark red
red (red
(red thrombi)
thrombi)

 red-grey
red-grey (pale
(pale thrombi)
thrombi) 
 almost
almost always
always occlusive
occlusive vessel
vessel

 may
may oror may
may not
not occlude
occlude the the lumen
lumen
vessel
vessel lumen
lumen 
 large
large thrombi
thrombi have
have aa tail
tail that
that

 large
large thrombi
thrombi have
have aa tailtail that
that tend
tend toto extend
extend up up stream
stream fromfrom
tend
tend to
to extend
extend down
down stream
stream their
their point
point ofof origin
origin

 layers
layers of
of platelets
platelets often
often 
 have
have loose
loose attachment
attachment and and
intrspresed
intrspresed byby fibrin
fibrin intermix
intermix difficult
difficult to
to discern
discern (not
(not clear)
clear)
with
with erythrocyte
erythrocyte and
and leukocyte
leukocyte 
 similar
similar with
with postmortem
postmortem clot clot
(Lines
(Lines of
of Zahn)
Zahn)
 Thrombus Resolution

Small Thrombi Large Thrombi

Easy removed Difficult removed

Removal thromboitic debris

Thrombolysis
with macrophage

Little residual Result in granulation tissue and

vessel damage fibrosis

Regrowth endothelium over

healed areas
 Clinical Aspect of
Thrombosis

Arterial thrombus Venous thrombus

Block into the areas Block out of the areas

1 Ischemia
Decreased oxygenation of
tissue

2 Infark
Necrosis of tissue cause
lack of oxygent
 EMBOLUS

Is a part of thrombus or a piece of free-floating material wihin

the blood

 Thromboemboli  emboli derived from fragment of a thrombus

 Fat  from fractured-bone marrow
 Bacteria  from inflamatory lesion
 Parasites  heartworm (dirofilaria; Fasiola hepatica)
 Neoplastic emboli  neoplastic cell that inavaded in blood
 Hemopoetic cell  from the bone marrow
 Amniotic fluid
 Agglutinated erythrocyte
 Hepatocytes  from liver trauma
 Thromboemboli

embolization
thrombus

Venous thromboemboli  lodge in the pulmonary circulation

Result in : Pulmonary infraction or right-side heart failure

Arterial thromboemboli  lodge within smaller vessel downstream

Result in infraction of vascularized- tissue

 HYPEREMIA

The terms hyperemia and congestion both indicate a local increased

volume of blood in a particular tissue. Hyperemia is an active process
resulting of arteriolar dilation.

Congestion is a passive process resulting from impaired outflow from a

tissue.

Occur in :
. Normal Physiology Proceess :
a. Localized increased concentratation of Co2 ; acid and other metabolites
b. Heat dissipate of skin
c. Increased need of blood in tissue that active in metabolism
. Pathologic Process :
a. In response to inflamatory stimulus that release vasoactive substances,
include ; histamine, and prostaglandin
 Normal Process
Metabolism activite   metabolite, acid, and [CO2]   vasodilatation
 Blood flow  (hyperemia)

Pathologic Process

Vasoactives substances (histamin; prostaglandin) release from inflamatory

respon  vasodilatation → Blood flow  (hyperemia)
 Infarction
An infarct is an area of ischemic necrosis caused by occlusion of either the
arterial supply or the venous drainage in a particular tissue.

Infarction involving different organs is a common and extremely important

cause of clinical illness.

In the United States, more than half of all deaths are caused by
cardiovascular disease, and most of these are attributable to myocardial or
cerebral infarction.

Pulmonary infarction is a common complication in a number of clinical

settings, bowel infarction is frequently fatal, and ischemic necrosis of the
extremities (gangrene) is a serious problem in the diabetic population.
Nearly 99% of all infarcts result from thrombotic or embolic events, and
almost all result from arterial occlusion.

Occasionally, infarction may also be caused by other mechanisms, such

as local vasospasm, expansion of an atheroma owing to hemorrhage
within a plaque, or extrinsic compression of a vessel (e.g., by tumor).

Other uncommon causes include twisting of the vessels (e.g., in testicular

torsion or bowel volvulus), compression of the blood supply by edema or
by entrapment in a hernia sac, or traumatic rupture of the blood supply.

Morphology. Infarcts are classified on the basis of their color

(reflecting the amount of hemorrhage) and the presence or absence
of microbial infection. Therefore, infarcts may be either red
(hemorrhagic) or white (anemic) and may be either septic or bland.
Red (hemorrhagic) infarcts occur :

(1) with venous occlusions (such as in ovarian torsion);

(2) in loose tissues (such as lung), which allow blood to collect in the
infarcted zone;
(3) in tissues with dual circulations (e.g., lung and small intestine),
permitting flow of blood from the unobstructed vessel into the necrotic
zone (obviously such perfusion is not sufficient to rescue the ischemic
tissues)
(4) in tissues that were previously congested because of sluggish venous
outflow
(5) when flow is re-established to a site of previous arterial occlusion and
necrosis (e.g., following fragmentation of an occlusive embolus or
angioplasty of a thrombotic lesion)
White (anemic) infarcts occur with arterial occlusions in solid organs with
end—arterial circulation (such as heart, spleen, and kidney), where the
solidity of the tissue limits the amount of hemorrhage that can seep into the
area of ischemic necrosis from adjoining capillary beds.

Examples of infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary

infarct. B, Sharply demarcated white infarct in the spleen.
The dominant histologic characteristic of infarction is ischemic
coagulative necrosis. It is important to recall that if the vascular occlusion
has occurred shortly (minutes to hours) before the death of the patient, no
demonstrable histologic changes may be evident; if the patient survives
even 12 to 18 hours, the only change present may be hemorrhage.

An inflammatory response begins to develop along the margins of infarcts

within a few hours and is usually well defined within 1 or 2 days.

The brain is an exception to these generalizations; as with all other

causes of cell death, ischemic injury in the central nervous system results
in liquefactive necrosis
kidney infarct, now replaced by a large
fibrotic cortical scar.
 Shock
Shock, or cardiovascular collapse, is the final common pathway for a
number of potentially lethal clinical events, including severe hemorrhage,
extensive trauma or burns, large myocardial infarction, massive pulmonary
embolism, and microbial sepsis.

Shock gives rise to systemic hypoperfusion caused by reduction either in

cardiac output or in the effective circulating blood volume.

The end results are hypotension, followed by impaired tissue perfusion and
cellular hypoxia. Although the hypoxic and metabolic effects of
hypoperfusion initially cause only reversible cellular injury, persistence of
shock eventually causes irreversible tissue injury and can culminate in the
death of the patient.
Cardiogenic shock results from myocardial pump failure. This may
be caused by intrinsic myocardial damage (infarction), ventricular
arrhythmias, extrinsic compression (cardiac tamponade) or outflow
obstruction (e.g., pulmonary embolism).

Hypovolemic shock results from loss of blood or plasma volume.

This may be caused by hemorrhage, fluid loss from severe burns, or
trauma.

Septic shock is caused by systemic microbial infection. Most

commonly, this occurs in the setting of gram-negative infections
(endotoxic shock), but it can also occur with gram-positive and fungal
infections.
Anaphylactic shock, initiated by a generalized IgE-mediated
hypersensitivity response, is associated with systemic vasodilation and
increased vascular permeability. In these instances, widespread
vasodilation causes a sudden increase in the vascular bed capacitance,
which is not adequately filled by the normal circulating blood volume.
Thus, hypotension, tissue hypoperfusion, and cellular anoxia result.