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CIRCULATORY DISTURBANCES

Shannon Martinson, January 2018

Office: 418N Email: smartinson@upei.ca

All lecture notes and slide shows are available online: http://people.upei.ca/smartinson

REFERENCE TEXTS: Pathologic Basis of Veterinary Disease, Zachary (Ed): 6

th edition (2017), Chapter 2.

Robbins & Cotran, Pathologic Basis of Disease, Kumar, et al (Ed); 9th

edition (2015), Chapter 4.

NORMAL CIRCULATORY SYSTEM [for background information only]

Important Concepts • Distribution of fluid in the body is a carefully controlled homeostatic mechanism.

• Deviations from normal may have profound pathological effects.

• Normal functions require intact blood and lymph vessels.

• Endothelial cells play important roles in fluid distribution.

Components of the Circulatory System

• Heart ➝ pump.

• Arteries ➝ distribution system.

• Microcirculation system ➝ nutrient / waste exchange between blood and tissue.

• Veins & lymphatics ➝ collection system.

Endothelial cells • All components of the circulatory system are lined by a single layer of endothelial cells

• These cells synthesize & secrete substances which effect fluid balance, hemostasis,

inflammation / immunity, angiogenesis / healing.

Microcirculation • Called microcirculation because it is microscopic. There are 3 main components

1) Arterioles

• Walls contain innervated smooth muscle cells (myocytes); contract to control blood flow.

2) Capillaries

• Enormous volume (1300 times the cross-sectional area of the aorta), but normally contain

only ~5% of the blood; this means ~95% of capillary beds are not open during normal

conditions.

• Site where nutrients and wastes are exchanged and a critical area in fluid balance.*

3) Postcapillary venules

• Similar structure to capillary, but acquire thin layer of muscle as they move away from

capillary bed.

Mechanisms for substance transport across the capillary wall: • The capillary wall is a semipermeable membrane; influences movement of fluid (water and

solutes), nutrients and waste between blood and interstitial space.

1) Direct diffusion

• Most small molecules move by passive diffusion through the endothelial cell membrane (eg

gas, lipid soluble molecules) or via interendothelial pores (eg water, ions, glucose, amino

acids, waste).

• Normal interendothelial pores too small to allow escape of large proteins (eg albumin).*

o During inflammation, endothelial cells contract allowing larger molecules to escape.

2) Transcytosis

• With some endothelial cells, fluids / macromolecules can be transported across the cell by

vesicles.

Regional Differences in Capillary Lining: 1) Continuous capillaries

• Lined by a complete simple endothelium and a basal lamina.

• Found in muscle, brain, thymus, skin, bone, lung and other tissues.

2) Fenestrated capillaries

• Have many small openings; found in tissues with abundant fluid transport.

• Often have a diaphragm (egs intestinal villi, kidney interstitium, choroid plexus).

• Can act as a filter (eg renal glomerulus).

3) Discontinuous capillaries

• Larger gaps than fenestrated with discontinuous basal lamina; allows large molecules or even

cells to exit (eg red blood cells in the spleen).

• Hepatic and splenic sinusoids are lined by this type of endothelium.

Fluid Distribution & Homeostasis • Total Body Water (~60% of lean body weight)

• Extracellular fluid (20%)

o Plasma (5%)

o Interstitial tissue fluid (15%)

• Intracellular fluid (40%)

Interstitium • Interstitium = space between microcirculation and the cells*.

• Functions:

o It binds cellular and structural elements into discrete organs and tissues.

o Acts as a medium through which all metabolic products must pass between

microcirculation and cells.

• Structure:

o Interstitium is composed of extracellular matrix (ECM) + supporting cells (eg

fibroblasts)

o ECM provides structural support and has adhesive & absorptive properties:

➀ Structural molecules: collagen, reticulin & elastin fibers.

➁ Adhesive glycoproteins: fibronectin, laminin.

➂ Absorptive (hydroscopic) molecules: glycosaminoglycans, proteoglycans.

Movement of Fluids*

Distribution of fluids, nutrients & wastes between blood ↔ interstitium ↔ cells is

controlled by physical structures, pressures gradients, and ion concentration (osmotic)

gradients.

In most areas, the capillary allows the free passage of water and ions and opposes the

passage of plasma proteins.

Water distribution between plasma and interstitium is primarily determined by the

differences in hydrostatic and osmotic pressure between the two compartments.

Starling's equation

Hydrostatic pressure in the vascular system (aided slightly by interstitial colloidal

osmotic/oncotic pressure) is the force that moves fluid out of the vessels.

Plasma oncotic pressure (= osmotic pressure exerted by plasma proteins - especially

albumin), and to a lesser extent, tissue hydrostatic pressure around blood vessels are the

forces that contain the fluid within the vascular system.

ARTERIOLAR VENULAR Plasma Hydrostatic Psi 30 mm Hg 17 mm Hg

Tissue Hydrostatic Psi 8 mm Hg 8 mm Hg

Plasma Colloidal Osmotic Psi 25 mm Hg 25 mm Hg

Tissue Colloidal Osmotic Psi 10 mm Hg 10 mm Hg

(30-8)- (25-10) = 7 mm Hg (17-8)-(25-10) = 6 mm Hg

Net filtration Pressure Net absorption Pressure

The difference between the two pressures indicates that there is constant net movement of fluid

out of the capillary bed into the interstitium – this fluid is removed by the lymphatics*.

EDEMA*

• Edema = Excess accumulation of fluid in interstitial tissues or in body cavities.

o Edema fluid is outside both the vascular and cellular compartments.

• Gross:

o Organs are swollen, wet (gelatinous) and heavy; clear fluid weeps from cut surface.

o In several species (eg horses, some cattle) fluids are slightly yellow.

• Histology:

o Lightly staining eosinophilic (↑protein) or clear/colorless (↓protein) fluid.

o Tissue spaces are distended by the edema (collagen bundles separated by increased

clear space) and lymphatics are dilated.

Four Mechanisms of Edema Production:

1. Increased intravascular hydrostatic pressure • Results from an impediment to venous blood flow

o Can be generalized (eg heart failure)

o Can be localized (eg tightly bandaged limb resulting in venous occlusion).

2. Decreased plasma colloidal osmotic (oncotic) pressure • Results from hypoproteinemia

o Proteins are lost from the body (egs glomerular disease, intestinal damage).

o Proteins are not absorbed from the diet (egs starvation, GI malabsorption).

o Proteins are not produced (eg liver disease).

3. Decreased lymphatic drainage / Lymphatic obstruction • Results from damage or obstruction of lymphatics (by surgery / trauma, neoplasia, or

inflammation [lymphangitis]).

4. Increased vascular permeability / Endothelial damage • Mostly due to the initial reaction of the microvasculature to inflammatory / immunologic

stimuli ➝ release of inflammatory mediators ➝ vasodilation and increased vascular

permeability ➝ inflammatory edema

o This mechanism will be further discussed in your inflammation lectures.

• Note: The endothelium can also be damaged directly by some bacteria, viruses, toxins, and

autoimmune diseases, resulting in increased vascular permeability.

Mechanisms 1, 2 and 3 result in "non-inflammatory edema" - protein poor effusion referred to

as transudate.

o Transudate:

↓Protein content < 30 g/L

↓Specific gravity < 1.017

↓Total nucleated cell count < 1.5X109/L

Mechanism 4 results in “inflammatory edema" - protein rich effusion referred to as exudate.

o Exudate

↑ Protein content > 30 g/L

↑Specific gravity > 1.025

↑Total nucleated cell count > 7.0X109/L

Localized versus Generalized Edema:

1) Local Edema

a) Mechanisms ➀ Local impaired venous drainage.

➁ Local lymphatic obstruction.

➂ Local inflammation.

2) Generalized Edema

a) Mechanisms ➀ Increased generalized hydrostatic pressure of blood (heart failure).

➁ Decreased colloid osmotic pressure of blood (hypoproteinemia).

b) Common Locations of Generalized Edema • With edema is generalized, we often see a combination of ascites, hydrothorax &

subcutaneous (“dependent”) edema.

o Dependent edema:

Subcutaneous tissues of the ventrum ("brisket edema")

Subcutaneous tissues of the ventral mandibular/cervical region ("bottle jaw") - subcutis of the limbs ("stocking up")

Terminology of Edema: Pitting Edema = when pressure is applied to an area of subcutaneous edema and a depression or

dent results as excessive interstitial fluid is forced to adjacent areas.

Anasarca = Severe and generalized edema with profound subcutaneous tissue swelling (fetuses).

Hydrothorax = Non-inflammatory fluid (transudate) in the thoracic cavity.

Hydropericardium = Non-inflammatory fluid (transudate) in the sac around the heart.

Ascites (= Hydroperitoneum) = Non-inflammatory fluid (transudate) in the peritoneal cavity.

Clinical Significance of Edema • The clinical significance of edema is dependent upon:

➀ Extent - mild vs moderate vs marked/severe

➁ Location - site of accumulation: skin (relatively insignificant) vs lung or brain (often lethal).

➂ Duration - tissues may become more firm and distorted due to increased fibrous connective

tissue after prolonged edema.

Pulmonary Edema • Definition = accumulation of edema fluid in the interstitium and alveoli of the lungs.

• This is a common cause of death in many disease processes.

a) Mechanisms of pulmonary edema ➀ Circulatory failure (especially due to left-sided heart failure)

• Due to increased hydrostatic pressure of blood in the pulmonary veins (congestion) ➝

transudation of fluid into the alveolar spaces.

• It is the most common cause of pulmonary edema.

➁ Damage to pulmonary capillary endothelium (microvascular injury)

• Usually occurs with acute inflammation (ie inflammatory edema) or less commonly toxins.

o Due to a sudden increase in vascular permeability.

• Often results in sudden death (when peracute); can be followed by pneumonia in survivors.

b) Gross appearance of pulmonary edema • The lungs are expanded, heavy and wet.

• Froth (edema fluid + air bubbles) may be present within the trachea and bronchi and is

obvious on cut section.

• The interlobular septa are prominent / thickened due to the increased fluid within this space.

• Often accompanied by congestion of the pulmonary vessels (especially when there is left-

sided heart failure).

c) Histopathology of pulmonary edema • See edema fluid in the interstitium and alveolar spaces; eventually see dilated interlobular /

pleural lymphatics.

• The edema fluid can be clear or pink in color (depending on the protein content: ↑protein =

pink fluid).

• The blood vessels are often congested.

d) Chronic Pulmonary Edema • Most commonly seen with chronic cardiac failure and accompanying pulmonary congestion

(discussed later).

• Over a long period, pleura and alveolar walls may become thickened with fibrous connective

tissue.

Edema of the Brain (Cerebral Edema) • Can be caused by: trauma (head injury), obstruction of venous outflow, inflammation of the

brain (eg meningitis, encephalitis).

a) Gross appearance of cerebral edema • Brain is heavier than normal.

• Gyri are swollen and become flattened and the sulci are narrow.

• When severe can see:

➀ Cerebellar coning - herniation of the cerebellum through the foramen magnum.

➁ Cerebral herniation - herniation of the caudal cerebral cortex beneath the tentorium

cerebella.

b) Histopathology of cerebral edema • Expansion of perivascular (Virchow-Robin) spaces.

DEHYDRATION* • Definition = Deficiency of water; resulting from an imbalance between uptake and loss of

water from the body.

• Causes include: uncontrolled diarrhea, vomiting, renal failure, heat-stroke, water deprivation.

a) Mechanisms • A decrease in the total body water results in water deficit, which is shared among plasma,

intracellular and interstitial fluid compartments.

• Tissue perfusion is reduced.

• Severe dehydration may result in hypovolemic shock as plasma water is drawn into the

interstitium.

b) Gross appearance of dehydration • Folds of skin pulled out from the body hesitate before returning to their normal position

("skin tenting").

• Eyes are sunken, mucous membranes and subcutaneous tissues are dry and sticky.

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ALTERATIONS IN BLOOD FLOW AND PERFUSION

HYPEREMIA*

Definition= Active engorgement of vascular beds due to increased arteriolar inflow.

Types of Hyperemia: 1. Physiologic Hyperemia – examples:

o ↑ blood flow to the stomach and intestines during digestion

o ↑ blood flow in the muscles during exercise

o ↑ blood flow in skin to dissipate heat

o ↑ neurovascular hyperemia (blushing)

2. Pathologic Hyperemia

o Results from an underlying pathologic process (usually inflammation).

o Arteriolar dilation is a response to inflammatory stimuli / mediators.

o Red coloration is a cardinal sign of inflammation = "Hyperemia of Inflammation"

o Often accompanied by edema (because of increased vascular permeability).

• Gross Appearance of hyperemia:

o The affected tissue is red and warm, as arterioles and capillaries are filled with

oxygenated blood.

• Histology:

o Capillaries engorged with blood and usually some edema. May see evidence of

inflammation (neutrophils and other inflammatory cells).

• The effect of hyperemia:

o Hastens movement of metabolites into an area

o Flushes catabolites from the area

CONGESTION* • Definition = Passive engorgement of a vascular bed generally caused by a decreased

outflow of blood.

• Gross appearance of congestion:

o Tissues are dark red to blue/black (cyanotic), depending on degree of stagnation

(deoxygenated blood).

o Cut surfaces ooze blood and tissues are often wet (due to accompanying edema).

• Histology:

o Acute: Capillaries engorged with blood and usually some edema.

o Chronic: Engorgement by poorly oxygenated venous blood ➝ chronic local hypoxia

➝ atrophy, degeneration or even necrosis of parenchymal cells.

• The effect of congestion:

o Leads to hypoxia and accumulation of catabolites

o Often edema occurs (due to increased hydrostatic pressure)

o Interference with normal tissue function

o May get thrombosis of congested veins

o +/- Proliferation of connective tissue (if chronic)

Two factors are considered in defining the type of congestion:

1) Duration:

• Acute: Implies abrupt onset with rapid development.

• Chronic: Slowly developing or present for a long time.

2) Extent:

• Localized congestion: Confined to a discrete area (eg isolated venous obstruction).

• Generalized congestion: Indicates a systemic change (eg cardiac failure).

Localized Congestion • Local obstruction to venous drainage (eg intestinal torsion / intussusception / splenic

torsion).

• Blood backs up into the microvascular bed ➝ passive venous engorgement of the

drainage area.

Generalized Congestion

• Congestion associated with pathology of the heart or lung tends to be generalized and

can be acute or chronic:

o With left-sided heart failure ➝ Congestion of lungs (= pulmonary congestion) and

pulmonary edema.

o With right-sided heart failure ➝ Systemic congestion (especially the liver) and

systemic edema (eg ascites, dependent edema).

o With certain types of primary pulmonary disease ➝ progressive loss of pulmonary

vascular bed ➝ pulmonary hypertension ➝ right heart failure secondary to

pulmonary disease = Cor Pulmonale.

• Acute generalized congestion is most commonly seen with acute heart failure or

following euthanasia with barbiturates

Pulmonary Congestion

Most commonly caused by left heart failure.

• Left ventricular failure ➝ impedes forward flow of blood from the lungs ➝ congestion

of the lungs ➝ alveolar capillaries become engorged with blood (↑ hydrostatic

pressure in alveolar capillaries).

Gross appearance of acute congestion:

• Diffuse red lungs (congestion) which are wet (edema) and heavy.

Histology of acute congestion:

• The capillaries are filled with RBCs, +/- proteinaceous fluid in the alveoli (edema)

Gross appearance of chronic congestion:

• Lungs can be lightly tan in color (due to presence of hemosiderin - see below).

Histology of chronic congestion:

• The capillaries are filled with RBCs and there is proteinaceous fluid (edema), RBCs

and hemosiderin laden macrophages (heart failure cells) in the alveolar spaces

Consequences of Chronic Pulmonary Congestion:

1. Intra-alveolar hemorrhage o Small capillaries rupture ➝ focal hemorrhage into the alveolar spaces ➝ RBCs are

phagocytized by alveolar macrophages ➝ the iron from the heme of RBCs is

stored as hemosiderin pigment within macrophages = "heart failure cells".

2. Pulmonary Edema (see previous discussion on edema)

o Causes interference with gaseous exchange.

3. Interstitial fibrosis o Fibroblasts secrete excess collagen in response to increased pressure in alveolar

capillaries and chronic edema in alveolar interstitium.

4. Pulmonary Hypertension • Increased pressure in the alveolar capillaries ➝ increased pressure in pulmonary

arteries ➝ pulmonary hypertension.

• Can result in right heart failure (cor pulmonale)

Hepatic congestion

Most commonly due to right heart failure

• Right ventricular failure ➝ impedes forward flow of blood from the body (vena cava)

➝ congestion of the liver, also ascites and dependent edema

• Cor pulmonale (see above)

a) Gross appearance of hepatic congestion

Liver is usually enlarged and dark red-brown with rounded edges.

o Acutely there is an increase in liver size due to increased volume of added blood.

o Chronically there is low-grade hypoxia & ↑ blood pressure ➝ atrophy & death of

centrilobular hepatocytes & fibrosis (with a possible decrease in size of the liver).

On cut surface has a reticular appearance (= regular dark red and tan-brown zonal pattern)

= "nutmeg liver".

o Dark red areas correspond to the congested zones around the central veins (zone 3)

and the tan-brown areas correspond to the less affected parenchyma around the

portal / midzonal areas (zone 1 & 2).

b) Histology

Acute congestion

o Central veins and sinusoids in zone 3 are distended with erythrocytes.

o Centrilobular hepatocyte (zone 3) atrophy, degeneration and/or necrosis due to

hypoxia in stagnant blood.

o Midzonal hepatocyte (zone 2) fatty change due to partial hypoxia.

o Periportal hepatocytes (zone 1) mostly normal.

Chronic congestion

o As above with these additional changes in the centrilobular region (zone 3):

Hemosiderin-filled macrophages (Kupffer cells) due to RBC phagocytosis.

Dilation of sinusoids ➝ atrophy/ loss of centrilobular hepatocytes.

Low-grade hypoxia and increased pressure in zone 3 ➝ fibrous connective

tissue deposition ("cardiac cirrhosis").

Hyperemia and Congestion vs Hemorrhage • Hyperemia / congestion → blood is inside a blood vessel (ie: intravascular)

• Hemorrhage → blood is outside the vessel wall (ie: extravascular)

SHOCK

Shock is characterized by systemic hypotension due to either reduced cardiac output or to

reduced effective circulating blood volume which results in impaired tissue perfusion and

cellular hypoxia*

Brain and heart are the organs most susceptible to ischemic damage from shock.

Shock is the final common pathway for many potentially lethal clinical events which

include microbial sepsis, severe hemorrhage, extensive trauma or burns, myocardial

infarction, severe pulmonary embolism, etc.

Three General Categories of Shock*

1. Cardiogenic Shock

Results from failure of the heart to adequately pump blood; ie cardiac output is decreased.

Can occur with a variety of heart diseases.

o Eg: myocardial infarction, ventricular tachycardia, arrhythmias, cardiomyopathy, or

an obstruction of the flow of blood from the heart

2. Hypovolemic Shock

Results from decreased circulating blood volume.

Can be due to blood loss from hemorrhage (internal or external) or fluid loss (dehydration)

secondary to vomiting, diarrhea or burns.

3. Vasogenic shock (Blood Maldistribution)

See a decrease in peripheral vascular resistance and resultant pooling of blood in peripheral

tissues due to vasodilation.

Many causes, including neural or cytokine induced vasodilation, trauma, systemic

hypersensitivity to allergens (anaphylaxis) or endotoxemia.

Three main causes:

o Anaphylactic Shock - vasodilation due to release of vasoactive amines.

o Neurogenic Shock - vasodilation due to loss of the autonomic nervous system

signals to the smooth muscle in vessel walls.

o Septic Shock*- vasodilation due to release of inflammatory mediators associated

with overwhelming infections (especially Gram-negative bacteria→endotoxemia)

o Pathogenesis of Septic Shock o Inflammatory cells have a number of receptors (Toll-like receptors) that

respond to a variety of substances (such as endotoxin = lipopolysaccharide)

derived from microbes.

o When microbial components (eg LPS) bind to a WBC surface receptors ➝

WBCs release cytokines→ activation/injury of endothelial cells ➝

vasodilation, coagulation cascade (→DIC), complement activation, etc.

Three Stages of Shock*

1. Nonprogressive (compensated) shock

Reflex compensatory mechanisms are activated and perfusion of vital organs is maintained

(eg increased heart rate, peripheral vasoconstriction, etc).

2. Progressive shock

Characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic

imbalances, including acidosis.

3. Irreversible shock

Sets in after the body has incurred cellular and tissue injury so severe that even if the

hemodynamic defects are corrected, survival is not possible.

Lesions of Shock Shock is characterized by failure of multiple organ systems:

• Pulmonary congestion and edema

• Liver congestion

• Kidneys: Acute tubular necrosis.

• Heart: Subendocardial hemorrhage and myocardial necrosis.

• Blood vessels: Endothelial damage with possible thrombosis / DIC.

• Brain: Neuronal cell death.

• Adrenal glands: Hemorrhage.

• Gastrointestinal tract: Mucosal congestion and necrosis.

• Skeletal muscle: Pallor (probably due to peripheral vasoconstriction).

HEMOSTASIS • Hemostasis refers to the arrest of bleeding.*

• Normally it’s a well-regulated process which maintains blood in a fluid, clot-free state

within a normal vessel.*

• Rapid clot formation (hemostatic plug) will occur at the site of vessel injury*.

• Thrombosis can be considered an inappropriate activation of the normal hemostatic

processes.

• Three general components are required for hemostasis and thrombosis:*

o Endothelial cells (vascular wall)

o Platelets

o Coagulation Cascade

Sequence of events in normal hemostasis following vascular injury:*

1. Arteriolar vasoconstriction

• Transient effect mediated by the ENDOTHELIUM

• Due to reflex neurogenic mechanisms and local secretion of endothelin.

2. Primary hemostasis

• Mediated by PLATELETS

3. Secondary hemostasis

• Mediated by the COAGULATION CASCADE

4. Antithrombotic Counter-Regulation

• Release of components to limit the size of hemostatic plug.

ROLE OF ENDOTHELIAL CELLS IN HEMOSTASIS • Injury to the endothelium is the major initiating event for thrombosis and coagulation.

• The endothelium modulates many aspects of normal hemostasis.

o Provides a surface that promotes the smooth, laminar (non-turbulent) flow of

blood (→antithrombotic property).

o When required it can also enhance vasodilation and inhibit platelet adhesion,

aggregation and coagulation (→antithrombotic property).

o When necessary it produces and responds to substances to form a thrombus or

blood clot (→prothrombotic property).

Antithrombotic Properties of Endothelial Cells*

1. Antiplatelet

• Acts as a barrier - prevent platelets and plasma factors from being exposed to

subendothelial extracellular matrix.

• Prostacyclin & nitric oxide (NO) - inhibit platelet adhesion / aggregation and maintains

vascular relaxation (vasodilation).

• Adenosine diphosphatase (ADPase) - degrades ADP (ADP promotes platelet aggregation).

2. Anticoagulant properties

• Heparin-like molecules

o Are membrane binding sites for antithrombin III ➝ inactivates thrombin + clotting

factors

• Thrombomodulin

o Thrombomodulin binds to thrombin converting it to an anticoagulant which can

activate Protein C.

Active Protein C (with Protein S) ➝ cleaves / inhibits clotting factors.

• Tissue factor pathway inhibitor (TFPI)

o Synthesized and expressed on endothelial cell membrane ➝ complexes and

inactivates TF and clotting factors.

3. Fibrinolytic properties

• Tissue plasminogen activator (tPA)

o Synthesize tPA ➝ activates plasmin (fibrinolytic cascade) ➝ removes fibrin from

endothelial surfaces.

Prothrombotic (Procoagulant) Properties of Endothelial Cells* Endothelial cells may be injured directly or activated by infectious agents (eg bacterial

endotoxin), hemodynamic factors, plasma mediators and cytokines. When this happens,

prothrombotic factors are expressed.*

• von Willebrand factor (vWF)

o Endothelial cells synthesize, store & release vWF; essential cofactor for platelet

binding to collagen and other surfaces

• Tissue Factor (TF = Factor III = thromboplastin)

o Injured endothelial cells are induced to secrete TF which activates the extrinsic

coagulation cascade.

• Plasminogen activator inhibitor (PAI)

o Endothelial cells secrete PAI which suppresses fibrinolysis (via counteracting

tPA).

ROLE OF PLATELETS IN HEMOSTASIS* • Platelets are derived from megakaryocytes; circulate as round, smooth discs with

glycoprotein receptors.

o Platelets are also referred to as thrombocytes

• Play a central role in normal hemostasis.

o Major role is to form the initial (1o hemostatic) plug that covers and seals a small

damaged area.

If injury is minimal a primary hemostatic plug may suffice

If injury is more severe, secondary hemostasis (coagulation) occurs

o Contain mostly procoagulant (& few anticoagulant) mediators in their granules or at

other cell sites.

Platelet Response (=Primary Hemostasis) • Vascular injury exposes extracellular matrix (ECM); especially collagen, which is normally

hidden by the intact endothelium. This stimulates a 3 step reaction by platelets.

• Platelets + ECM ➝ 3 step formation of the primary hemostatic plug:**

1. Adhesion and shape change

• Adhesion mediated via interactions with vWF ➝ acts as bridge for platelet surface

receptors and ECM.

2. Secretion of granules

• Release of dense granules is important because Ca2+

is required for coagulation cascade

and adenosine diphosphate (ADP) is an important mediator of platelet aggregation.

• Leads to surface expression of phospholipid complexes (binding site for Ca2+

&

coagulation factors)

3. Recruitment and Aggregation

• Thromboxane A2 (TxA2) and ADP secreted by platelets; induces vasoconstriction &

platelet aggregation → enlarging platelet aggregation = 1o hemostatic plug.

Platelet Defects*

1. Thrombocytopenia*

Definition:

• Circulating platelet numbers are decreased when compared to normal reference ranges

(<200 x 109/L is thrombocytopenia in most species; horses <100 x 109/L).

Diagnosis • History of bleeding and low platelet counts

Mechanisms • Deficient formation of platelets (eg estrogen toxicity suppresses marrow production)

• Excessive utilization of platelets (eg consumptive coagulopathies)

• Premature destruction of platelets (eg antibodies to platelets)

2. Thrombocytopathy*

Definition:

• Defective platelet function.

Diagnosis • History of bleeding with normal platelet counts, but abnormal platelet function tests

Mechanisms • Defect in adhesion (eg von Willebrand’s disease)

• Defect in aggregation

• Defect in release of granules

Both thrombocytopenia and thrombocytopathy result in small foci of hemorrhage*

ROLE OF THE COAGULATION CASCADE IN HEMOSTASIS

• Coagulation is often initiated by Tissue Factor, which is exposed at sites of vascular injury.

• The coagulation cascade is responsible for stabilization of the primary hemostatic plug with

fibrin → secondary hemostatic plug

• The coagulation cascade is an amplifying series of enzymatic conversions.

• An enzyme (activated coagulation factor) + a substrate (non-activated coagulation

factor) ➝ newly activated coagulation factor.

• Reactions are assembled on a phospholipid complex (provided by platelets) which is

held together by calcium ions.

• The cascade culminates in the production of thrombin (bound to platelet surface) ➝ thrombin

converts soluble fibrinogen to fibrin which stabilizes the hemostatic plug.*

• Generation of thrombin is the most important factor in the progression and

stabilization of the clot (thrombus).*

• In the classic model of coagulation, thrombin can be generated at the site of injury by either

the intrinsic or extrinsic coagulation pathway, both which converge where factor X is

activated → common coagulation pathway.

1. Intrinsic Coagulation Pathway

All factors of the intrinsic system (factors XII, XI, IX, and VIII) are present in normal

plasma; the cascade is activated by contact of factor XII (Hageman factor) with the

subendothelial collagen (ECM) following vascular damage.

2. Extrinsic Coagulation Pathway

Tissue factor (TF = Factor III = thromboplastin) is a cell surface protein on injured

endothelial cells that interacts with circulating factor VII to initiate the extrinsic pathway.

3. Common Pathway

Activated factor X (Xa) is produced by proteolysis of Factor X, which occurs at the end of

both the intrinsic & extrinsic coagulation pathways.

• Calcium and platelet surface phospholipids are necessary for factor Xa to be activated.

• Xa converts prothrombin to thrombin (factor II → IIa).

o Thrombin cleaves peptides from plasma fibrinogen (factor 1, which is soluble) to

form fibrin monomers (factor 1a).

Monomers self-polymerize into larger fibrin polymers (insoluble); then are

cross-linked/stabilized by factor XIIIa.

Contraction of fibrin-platelet thrombus ➝ reduced size of thrombus (restore blood flow)

and draws damaged vessels edges closer (for healing).

Cell based model of coagulation. An alternative model or coagulation breaks this process into 3

phases: Initiation, Amplification, and Propagation. The end-result is the same.

Coagulation Disorders* • In general, large hematomas (in the absence of trauma or other disease processes) suggest a

coagulation disorder whereas petechial or ecchymotic hemorrhage on a mucosal surface

may indicate a platelet deficiency or abnormality.

• Coagulation disorders can be inherited or acquired.

• Inherited Deficiencies of Coagulation • Numerous (see PowerPoint slide - for your information only)

• Acquired Deficiencies of Coagulation* • Can be due to decreased production of coagulation factors:

o Accompany many severe diseases:

o As a transitory depression of factor synthesis

o Many factors may be affected

o Liver failure causes a general decrease in production (most coagulation factors

are produced in the liver)

o Can be more specific:

o Vitamin K deficiency causes a more specific decrease in production

• Factors II, VII, IX, X (and protein C and S) are vitamin K dependent

• Can be due to increased use of coagulation factors (ie consumptive coagulopathy):*

o Disseminated intravascular coagulation (DIC)* = The sudden or insidious onset

of widespread fibrin thrombi in the microcirculation.

DIC is not a primary disease but rather a potential complication of any

condition associated with widespread activation of thrombin.

Causes include: severe burns, heatstroke, systemic viral disease,

shock, toxemia, sepsis, neoplasia, pancreatitis, heartworm, etc

o With the development of the multiple thrombi, there is a rapid consumption of

platelets and coagulation proteins

o In addition fibrinolytic mechanisms are activated, thus an initial thrombotic disorder

can evolve into a serious bleeding disorder (hence the term consumptive

coagulopathy).

FIBRINOLYTIC SYSTEM / ANTICOAGULATION

Coagulation must be restricted to the site of vascular injury to prevent extensive clotting

away from the site.

See previous discussion of "Antithrombotic Properties of Endothelial Cells".

Fibrinolytic cascade limits the size and/or dissolves the thrombus (which is supposed to be a

temporary patch).*

o Primarily by the activation of circulating inactive precursor plasminogen*

Plasminogen is activated by tissue plasminogen activator (tPA) and the

coagulation pathway (XIIa-kallikrein).

o Plasminogen once activated → plasmin

Plasmin breaks down fibrin and fibrinogen (and some clotting factors and plasma

proteins) dissolving the hemostatic plug.*

Fibrin degradation products (FDPs) have anticoagulant activity and can be used

as a measure of thrombotic states.*

HEMORRHAGE*

• Definition: Escape of blood from the cardiovascular system (extravasation).

• Can be discharge of blood from the vascular compartment to the exterior of the body or

enclosed within a tissue or body cavity.

Causes of Hemorrhage 1. Trauma➝ Causes subcutaneous, body cavity, intramuscular or tissue hemorrhage.

2. Septicemia, viremia or toxic conditions➝ widespread petechiae and ecchymoses.

3. Abdominal neoplasia➝ rupture of masses can cause hemoperitoneum.

4. Coagulation Disorders➝ often causes large hemorrhages.

5. Thrombocytopenia (decreased numbers of platelets) ➝ often causes small mucosal

hemorrhages.

6. Severe congestion ➝ can cause capillary bleeding.

Outcome / Significance of Hemorrhage

Depends on: 1) Location: There are two critical sites:

a. Central nervous system (CNS): Subdural (or epidural) hematomas

• Blood accumulation beneath (or above) the dura; can compress brain.

b. Pericardial sac: Cardiac Tamponade due to hemopericardium

• Massive blood accumulation within the pericardial sac causes restriction

of diastolic cardiac filling →compressive effect → may cause heart

failure.

2) Rate and Volume of Blood Loss

a. High rates and volumes are worse

• Can cause anemia and inadequate oxygenation of tissues

• With rapid severe blood loss (more than 1/3 of the volume lost over

minutes-hours), can lead to hemorrhagic shock (hypovolemic shock).

TERMINOLOGY OF HEMORRHAGE Subdural / epidural hemorrhage = Blood accumulation beneath / above the dura

Cardiac Tamponade = Compression of the heart caused by the accumulation of fluid/blood in

the pericardial sac.

Can cause acute heart failure due to restriction of diastolic cardiac filling.

Hemorrhage by Rhexis = Hemorrhage due to a substantial tear (rent) in a blood vessel or heart.

Occurs with trauma, necrosis of the vessel wall, vascular invasion by neoplasia, etc

Moderate / marked flow of blood out of vascular system.

o Tends to result in massive or submassive hemorrhage – involving all or most of the

affected organ or body cavity or hematomas

Hemorrhage by Diapedesis = Hemorrhage due to small defect

RBCs passing through the vessel wall in inflammation or with congestion.

o Can also occur with hypoxia, toxic injury, and with coagulation abnormalities.

Hemorrhage is usually mild.

Tends to result in petechiae, purpura, ecchymoses, and paint brush hemorrhages (see

definitions below)

Hemorrhagic Diathesis = Increased tendency to hemorrhage from usually insignificant injuries.

Seen in a wide variety of clinical disorders (eg coagulation deficiency / platelet disorders).

Hematoma = Accumulation of blood in tissue (3D extravascular clot); may be small or large.

Hemopericardium = Blood in the pericardial sac.

Hemothorax = Blood in the pleural cavity.

Hemoperitoneum = Blood in the peritoneal cavity.

Hemarthrosis = Blood in a joint space.

Hemoptysis = Coughing up of blood from the lungs or airways.

Epistaxis = Bleeding from the nose.

Hematemesis = Vomiting up blood.

Hematochezia = Presence of (fresh) blood in the stool.

Melena = Presence of tarry (digested) blood in the stool.

Petechia (pl. petechiae) = Small, up to 1-2 mm, hemorrhages

Most often occur on skin, mucosal / serosal surfaces.

Often caused by platelet disorders

Purpura = Hemorrhages measuring 3 mm to 1 cm

Most often occur on skin, mucosal / serosal surfaces.

Often seen with diseases that cause petechiae (platelet disorders) but also with vasculitis /

blood vessel damage.

Ecchymosis (pl. ecchymoses) = Hemorrhages larger than petechiae & purpura (>1 cm).

Often blotchy or irregular, as seen in bruises (contusions).

Occur with vasculitis / moderate blood vessel damage.

Paint Brush Hemorrhages = Hemorrhages which look as though red paint was hastily applied

with a paint brush.

Most commonly found on serosal or mucosal surfaces.

Suffusive Hemorrhage = Affected areas of hemorrhage are larger than ecchymosis and are

contiguous.

Agonal Hemorrhages = Small hemorrhages (petechiae and ecchymoses) associated with the

death struggle (ie terminal hypoxia).

RESOLUTION OF HEMORRHAGE

Arrest of hemorrhage occurs as a result of hemostasis (covered in the next lecture)

Resolution depends on amount of hemorrhage:

o Resorption • Small amounts of hemorrhage can be resorbed.

o Organization • Larger amounts of hemorrhage require phagocytosis and degradation by

macrophages.

• Pigments from degraded hemoglobin form sequentially:

• Hemoglobin ➜ Bilirubin ➜ Hemosiderin

(red-blue) (blue-green) (yellow-brown)

• Organizing hematoma:

• Central mass of fibrin and RBCs → surrounded by vascularized

connective tissue (supplies nutrients and support) →

Macrophages phagocytize and degrade the fibrin and RBCs (see

pigment from degraded hemoglobin)

THROMBOSIS* Terminology

• Thrombosis o Inappropriate activation (occurring in uninjured or mildly injured vessels) of the

hemostatic process resulting in the formation or presence of a solid mass

(thrombus) within the blood vessels or heart.

• Thrombus (pl. thrombi)

o Aggregate of blood factors, primarily platelets & fibrin, with entrapment of

cellular elements (RBCs/WBCs) causing partial or complete vascular obstruction.

o Often adherent to the vessel wall (differentiates it from a post-mortem blood clot).

Pathogenesis of Thrombosis:

Three primary influences favour thrombosis = Virchow's triad:

1. Endothelial injury

Dominant influence = can lead to thrombosis by itself.

Eg Inflammation of heart valves (endocarditis) ➝ exposure of the subendothelial ECM ➝

platelet adherence / release of tissue factor ➝ primary and secondary hemostatic plug

formation➝ thrombosis.

2. Alterations in normal blood flow

Normal blood flow is laminar with the cellular elements in the middle of the vessel lumen

and surrounded by plasma.

With turbulence or stasis ➝ disruption of normal laminar flow allows platelets to contact

endothelium:

o Turbulence also promotes endothelial cell injury / activation

o Stasis also prevents dilution of activated clotting factors by fresh-flowing blood and

allows the build-up of thrombi (causes hypercoagulability).

3. Hypercoagulability

Definition = any alteration of the coagulation pathways that predisposes to thrombosis.

Due to:

o Increased prothrombotic factors (eg with sepsis)

o Decreased inhibitory factors (eg loss of antithrombin III with glomerular disease).

Locations for thrombi

Thrombi may develop anywhere in cardiovascular system: on the valves, in the cardiac

chambers or within the lumina of arteries, veins and capillaries.

Thrombi grow towards the heart (ie, arterial thrombi grow against blood flow, while venous

thrombi grow with blood flow). Pieces of a thrombus can break off and travel

downstream forming emboli.

Arterial thrombi o Arterial thrombi usually form at sites of endothelial injury or turbulence.

o They tend to grow towards the heart.

o Often paler & "meatier" than venous thrombi.

Composed mainly of platelets & fibrin, because rapid blood flow tends to

exclude RBCs.

o Can have alternating dark and pale laminations called lines of Zahn:

Reflects continued waves of thrombosis: pale layers (mostly fibrin /

platelets) alternating with dark red layers (more entrapped RBCs).

Venous thrombi o Grow towards the heart.

o Usually form in static (slow flow) environment.

o Contain more entrapped RBCs and therefore are more uniformly dark red.

o Often occlude the lumen of the vessel.

o Attachment to wall is often focal and loose which can make it difficult to

differentiate from a postmortem blood clot.

Blood Clot = Clotted blood within a blood vessel (blood clot can refer to thrombus or post-

mortem blood clot, so be specific).

Post-mortem blood clots are not associated with a pathological condition and are not

attached to the vessel wall.

A thrombus and a post-mortem blood clot can look very similar.

Chicken-Fat Clot = Common gelatinous, yellow, post-mortem blood clot seen at necropsy

(especially horses).

Plasma clot that develops because of rapid erythrocyte sedimentation in animals with high

fibrinogen.

Yellow areas represent fibrin and plasma and dark red areas represent sedimented RBCs.

Morphological Differentiation of Thrombi and Post-Mortem Clots

Arterial Thrombus Venous Thrombus Postmortem Clot

Colour Pale to dark red Red Yellow or red

Lamination Yes Not frequent No

Attachment Yes Focal / loose (can be difficult to detect) No

Size Often small Often fill lumen Fill lumen

Outcome of Thrombi

1. Lysis (dissolution)

Lysis occurs when thrombi are small and in the early phases due to potent thrombolytic /

fibrinolytic activity of blood.

2. Organization and recanalization

The presence of a thrombus induces inflammation and fibrosis (organization); the latter

reduces the size of the thrombus.

New small blood vessels can penetrate / grow within the organizing thrombus (=

recanalization).

Both of the above aid in the restoration of blood flow

3. Propagation

An increase in size of the thrombus → may eventually occlude the vessel.

4. Embolization

Can occur if pieces (thromboemboli) break off the thrombus and travel downstream.

EMBOLISM*

Terminology of Embolism*

Embolism = Passage through the venous or arterial circulation of any material capable of

lodging in a blood vessel and thereby obstructing the lumen.

o Most common form of embolism is thromboembolism: piece(s) broken off of a

thrombus.

Embolus (pl. emboli) = Detached intravascular material (solid, liquid, or gaseous) carried

via the blood to a site distant from its origin.

Thromboembolism = Occlusion of a blood vessel by an embolus that has broken away

from a thrombus.

o They travel in the direction of blood flow until it they no longer "fit" through the

blood vessel and they become lodged.

o Thromboembolus (pl. thromboemboli)

o The piece of thrombotic material transported in the bloodstream to another site.

Composition of Emboli o Remember that most emboli are thromboemboli, however many other types exist:

o Parasites Nematodes - Dirofilaria immitis (heartworm)

Nematode larvae - Ascarid or Strongyle larvae

o Fat (or bone marrow) Can originate from several sources: Eg bone fractures, surgery,

osteomyelitis, hyperlipidemia.

o Other Foreign material (air bubbles, hair, etc), tumour cell clusters ("tumor

emboli"), amniotic fluid…

Infectious causes of thrombosis or thromboembolism*

o Infectious agents can damage the endothelium, thereby causing thrombosis and/or

thromboembolism:

o Many bacteria can cause valvular endocarditis with resultant thrombosis and

thromboembolism.

o Several viral agents can damage endothelium leading to thrombosis.

INFARCTION*

Infarct = an area of ischemic necrosis caused by occlusion of either the arterial supply or

the venous drainage.

Most infarcts result from thrombotic or embolic events or vascular occlusion due to

compression of a vessel (eg intestinal volvulus, testicular torsion, etc).

A large percentage of human deaths in North America are due to cardiovascular disease,

mostly from myocardial or cerebral infarction; whereas pulmonary, intestinal and renal

infarction are more common in domestic animals.

Factors that Influence the Development / Characteristics of an Infarct 1. Nature of the vascular supply.

Tissues with a single blood supply (egs kidney, brain, heart, spleen) are more prone to

infarction than those with dual or collateral blood supply (egs lung, liver, intestine,

skeletal muscle).

2. Rate of development of occlusion of the vessel.

If slow, allows time for the collateral supply to fully open.

3. Vulnerability to hypoxia.

Certain cell/tissue types are more vulnerable to ischemic damage (especially the brain and

heart).

4. Oxygen content of blood at time of infarct.

Underlying anemia would increase the likelihood of ischemia resulting in infarction.

Gross appearance of an infarct

Often wedge-shaped, with the base at the periphery and the occluded vessel at the apex.

Early they are ill defined (+/- irregular margins) and often hyperemic.

Later (by 48 hours) most become pale.

1. Red Infarct

Due to the presence of blood in the infarcted region (also called hemorrhagic infarct).

o Occurs in some acute infarcts due to RBCs leaking in from adjacent arteries and

veins (eventually the RBCs lyse ➝ pale).

o In venous occlusions, where blood is prevented from draining from the organ (eg

volvulus, strangulations); called a venous infarct.

o Also occurs in organs with dual blood supply (eg lung, liver) or where blood

collects in loose tissue.

2. White Infarct

Lack of blood in the infarct (also called pale or anemic infarct).

o Mostly occurs with arterial occlusions in solid organs with end arterial circulation

(eg heart, kidney).

Usually has a red zone at periphery because the capillaries at the border of infarct undergo

dissolution and blood seeps into this marginal area.

Histopathology of an Infarct

Ischemic necrosis of affected parenchyma:

o Discrete areas of coagulative necrosis (+/- hemorrhage) in all tissues except brain

where liquefactive necrosis will occur

o Peripheral rim of inflammation and hemorrhage.

o Infarcts arising from septic (bacterially infected) emboli may be converted to an

abscess with time.

Repair of Infarcts • Fibrous connective tissue (scar tissue) replaces necrotic parenchyma.

• As fibrous tissue matures and condenses (contracts), it forms a depression / indentation on

the organ surface.

Septic Infarct

Develop from a bacterially infected thromboembolus or when the necrotic tissue of an

infarct is seeded by bacteria (necrotic tissue is a good growth medium for these

pathogenic organisms).

Venous Infarct

Severe venous obstruction can cause venous infarction.

Mostly due to twisting of vessels (eg intestinal volvulus / torsion / strangulation) ➝ shock /

death.

Also seen with obstruction (eg thrombosis or tumor invasion) of the cranial or caudal vena

cava

o Obstruction may be incomplete causing slowly developing stasis with engorgement

of the tributary veins.

Important examples of venous obstruction/infarction

o Acute Blockage of the Portal Venous System o Mostly with twists in portions of GI tract / portal venous system ➝ venous

infarction of stomach or intestine; twisted vessels are compressed, but because

arterial pressure > venous pressure ➝ blood enters the tissue but cannot leave.

Sequelae: shock and death unless corrected with surgery.

Eg: gastric volvulus (dogs) ➝ obstruction of gastric portion of portal vein ➝

severe venous congestion ➝ vascular stasis ➝ ischemic necrosis

(infarction) ➝ loss of endothelial integrity ➝ hemorrhage ➝ shock.

o Blockage of the posterior vena cava o Possible etiologies:

Severe dirofilariasis (heartworm) or adrenal tumors in dogs

Hepatic abscesses in ruminants.

o Possible result:

Acute and complete occlusion ➝ death.

Chronic occlusion ➝ possibility of collateral circulation developing from

azygous vein.

Important example of arterial blockage / infarction

Pulmonary Artery Thrombosis / Thromboembolism o Thrombosis / thromboembolism of the pulmonary artery can be due to a variety of

causes, eg pneumonia, parasite infestations (eg heartworm), hypercoagulability

(eg hyperadrenocorticism, nephrotic syndrome), liver abscess rupture into the

vena cava with subsequent thromboembolism to the lungs, etc

o Possible result:

If acute and involves large branch of artery ➝ can cause death.

If incomplete and smaller branches ➝ variably altered circulation or possibly

pulmonary infarcts (dual circulation makes infarction less likely).