Post CA1 Pathology
Circulation 1
Hyperaemia and Congestion
Increased blood volumes within tissues (terminal vascular bed)
Hyperaemia
Reserve capillaries filled
Increased blood in terminal vascular bed
Arterioles and capillaries
Increased erythrocytes in vessels causes redness
Active process
Blood is well oxygenated (red) = erythema (reddening of skin)
Can be physiological or pathological
Physiological= exercise, thermoregulation
Pathological= inflammation
Congestion
Impeded outflow of blood from tissue
Physical obstruction of the vessels
external compression
internal blockage
Failure of forward blood flow can lead to congestive heart failure
Poorly oxygenated venous blood (bluish)= cyanosis
Localised Congestion
locally restricted blood flow
thrombus, external pressure, torsion
Generalized
Cardiac failure
Hypostatic
Gravity combined with peripheral circulatory failure
Blood pools to dependent organs
Effects of Congestion
Gradual onset leads to development of collateral circulation
Chronic congestion= oedema, hypoxia, diapedesis
In the lungs, leads to increased blood flow in the capillaries= fluid leaking out due to high pressure
Pulmonary congestion= heart failure cells
left sided heart failure
Hepatic congestion= nutmeg liver
right sided heart failure
Ischaemia
Decreased blood in terminal vascular bed
Inadequate blood supply of a tissue relative to its needs
Consequences:
Hypoxia
can occur without ischemia in cases of anemia and high altitudes
Build up of waste products
Malnutrition
More rapid and severe cell and tissue damage than hypoxia
Causes of Ischaemia
Cardiac arrest
whole body affected
severity depends on sensitivity of specific tissue
Arterial obstruction
thrombosis
embolism
arterial spasm (ergot poisoning)
arteritis (intravascular parasites)
external pressure (tourniquet)
arterial occlusion (volvulus)
may also show congestion, hemorrhage and hyperemia
Venous obstruction
indirect effect via transmission of pressure
will show signs of congestion
Capillary damage
pressure sores: due to constantly sitting on one side leading to inadequate blood flow
Hypovolemia
low blood pressure
Severe vasodilation
Consequences of Ischaemia
Modifying factors
Specific tissue involved
brain (very sensitive) vs fibrous tissue (more tolerant)
Duration and speed of onset
Collateral circulation important: gradual onset allows compensation
Oxygenation of blood
severity increases in anemic animals
Temperature of tissues
Lowers metabolic rate = more tolerant to ischemia
Reperfusion Injury
Restoration of blood flow can promote recovery if they are reversibly injured
It can also exacerbate the injury and cause cell death
Mechanisms
Oxidative stress : ROS and nitrogen species
Intracellular calcium overload
Inflammation
Activation of the complement system
Infarction
Ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage
Arterial obstruction is more important
Gangrene = ischemic necrosis of the extremities
Development
Degeneration and necrosis of ischaemic tissue
Redness, swelling: initial hemorrhage and inflammation around the area
Wedge-shaped
Tissue lightens in colour and swelling resolves
Line of hyperaemia
inflammatory response trying to contain and remove dead tissue
Removal of necrotic tissue
scarring
Healing via fibrosis
Factors that influence infarctions
Anatomy of the vascular supply
End-arterial: kidney, spleen, heart
No collateral blood supply, so higher risk of complete infarction
Alternative blood supply: Lung, liver, GIT
Lower risk
Rate of occlusion
Slow vs fast
Development of collateral circulation if slow
Tissue vulnerability to hypoxia
Metabolically active, highly specialized tissues have a higher oxygen demand
Higher O2 demand= neurons, cardiomyocytes
Hypoxemia
Examples
Common organs: kidney, brain, spleen, limbs, intestines
poor collateral circulation
Sterile vs septic (secondary infected emboli) circulation
Can result in an abscess
Renal Infarct
Acute
swelling of affected tissue and dark red colour
backflow of blood
Hemorrhage, congestion and hyperemia along the edges
Subacute
Pale with hyperaemic margins
Less blood present
Necrosis setting in
Chronic
Affected tissue is pale and shrunken due to fibrosis
Circulation 2
Hemorrhage
Interruption of vascular integrity
Bleeding from a damaged vessel
Vascular disease may predispose to hemorrhage
Local high blood pressure also predisposes
Diffuse hemorrhaging may occur in coagulation disorders
Definitions
Diapedesis: loss of individual erythrocytes between endothelial cells
Hematoma: local accumulation of blood, usually clotted
Petechiae: pin-point hemorrhages
Ecchymoses: “paintbrush” hemorrhages
Hemopericardium: blood in the pericardial sac
Hemothorax: blood in the thoracic cavity
Hemoperitoneum/hemoabdomen: blood in the abdominal cavity
Hemarthrosis: blood in the joints
Local Effects
Depends on location
Retina and brain
Space-occupying lesions
Pericardium, lungs- issues as the pressure can result in interfered function
Small hemorrhages
no residual effects
Larger hematomas
Fibrosis, hemosiderin in macrophages
Systemic Effects
Repeated minor blood loss can lead to iron deficiency
GI ulcers= melena
Acute blood loss (less than 20%) can be handled by compensatory mechanisms
Acute blood loss of 30% or more may induce hypovolemic shock
Slower losses of 30% can be handled by compensatory mechanisms
Compensatory Mechanisms
Blood Redistribution
Selective arteriolar constriction
Sympathetic nervous system
Epinephrine/norepinephrine
Diverts blood to essential organs
Concurrent splenic contraction
Restoration of Blood Volume
Extravascular fluid moves into vascular system
Helps maintain blood pressure
Causes hemodilution
Takes 48 hours
PCV
Estimation of blood loss
Reflects relative proportions of plasma and erythrocytes
50% PCV is typical
Dehydrated animals may have a higher value
Replacement of Lost Erythrocytes
Bone marrow response
Maximal at 5-6 days post-hemorrhage
Abates around day 12
Indicated by reticulocyte count
immature RBCs indicate replacement
Hemorrhagic Tendencies
Or Hemorrhagic diathesis
Associated with
Vascular diseases
Disorders of blood clotting mechanism (or warfarin poisoning)
Vascular Diseases
Purpura
Diffuse superficial hemorrhage in skin, mucus membranes and viscera
Ecchymoses or petechiae
Systemic purpura
Due to infectious disease
Bacterial toxins damaging endothelium
Intra-endothelial viruses
Rickettsias
Purpura haemorrhagica
horses
Hemorrhage and edema
Allergic reactions causing damage to arteriolar endothelium
Often follows strangles (Streptococcus equi spp equi)
Vitamin C deficiency
Results in weakness of connective tissues
Hemorrhage from multiple vessels and delayed wound healing
Only seen in humans, guinea pigs, non-human primates
Shock
Failure of circulatory system to adequately perfuse vital organs
Circulatory dyshomeostasis
Due to disparity between circulating blood volume and size of vascular space
Reduced cardiac output or reduced effective circulating blood volume
Circulatory failure that impairs tissue perfusion leads to hypoxia
Basic Mechanisms
Decreased circulating blood volume
hemorrhage
Inappropriate peripheral vascular resistance
Massive vasodilation
Reduced cardiac output
Compensatory mechanisms may prevent death
Categories of Shock
Cardiogenic
Hypovolemic
Decreased blood volume
Blood maldistribution
decreased peripheral vascular resistance and pooling of blood
Sepsis, septic shock, SIRS (Systemic inflammatory response syndrome)
Anaphylactic
Neurogenic: trauma, emotion, shock
Cardiogenic Shock
Decreased cardiac output
Acute severe myocardial failure
Diastolic dysfunction
improper filling
Systolic dysfunction
improper emptying
Increased vascular resistance
Ruptured chordae tendinae
Dysrhythmias
Decreased myocardial contractility
Hypovolemic shock
Pronounced decrease in blood volume
Loss of fluid from vascular compartment
Fluid loss may be
External
Internal
External Fluid Loss
Hemorrhage
Diarrhea
Excessive urination: Diuresis
Internal Fluid Loss
Due to increased vascular permeability
Burns
Trauma
Gastrointestinal volvulus
Blood trapped in intestine
Sepsis, Septic Shock, SIRS
Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection
Septic shock is a subset of sepsis. It is the most common type of blood maldistribution shock
SIRS is a sepsis-like condition associated with systemic inflammation
Triggered by non microbial insults
Septic Shock
Inflammatory and counter-inflammatory responses
Endothelial activation and injury
Induction of a procoagulant state → thrombus formation which worsens tissue hypoxia
Metabolic abnormalities → hypoglycemia
Organ dysfunction
Lipopolysaccharide- LPS
Vascular mediators
Activate macrophages/monocytes
IL1-β, TNF-⍺
Activation of the coagulation cascade
Factor XII
Complement- anaphylatoxins - C3a, C5a
Maldistribution- Other Causes
Anaphylaxis
Type I hypersensitivity
Vasodilation
Increased vascular permeability
Neurogenic Shock
Trauma to the nervous system
Electrocution
Autonomic discharges responsible
Cytokine release not a major factor in initial vasodilation
Stages of Shock
Non Progressive
Compensatory mechanisms
Perfusion of vital organs maintained
Progressive
Increase cell injury
Compensatory mechanisms slowly overwhelmed
Irreversible
Compensatory Mechanisms
Maintain blood flow to the heart and brain
Divert blood from periphery
cool extremities
pale
Mediated by sympathetic nervous system
Sympathetic stimulation = increased heart rate and increased myocardial contractility
Vasoconstriction maintains blood pressure
Improved tissue perfusion
Net effect=
Tachycardia
Peripheral vasoconstriction
Renal conservation of fluid
Consequences of Inadequate Perfusion
Endothelial cells
Leaky vessels
Loss of vascular fluid
Sludging of red blood cells
Kidney and liver
Cell necrosis
Heart
Arrhythmias
Brain
Loss of consciousness
Brain damage
Anaerobic metabolism
Buildup of metabolites
Lactic acid
Perpetuates failing cardiac output and worsens tissue perfusion
Irreversible shock
Irreversible Shock
If compensatory mechanisms fail
Inadequate tissue perfusion
Ischaemic injury to cells
Disseminated Intravascular Coagulation (DIC)
Widespread clotting within the vascular system
Multiple fibrin clots within terminal vascular beds
Triggers fibrinolysis
Resulting fibrin degradation products (FDPs) inhibit coagulation
Causes consumption of platelets and coagulation factors
End result is widespread hemorrhage
Causes of DIC
Vasculitis, blood stasis, coagulopathies
Endotheliotropic viruses
Canine herpesvirus
Rabbit calcivirus
Endotoxaemia
Intravascular hemolysis
Severe extensive tissue damage
Shock
DISTURBANCES IN CIRCULATION 3
OEDEMA
The accumulation of excess fluid in the interstitial (extracellular ) space or body cavities
Types of fluid accumulation
Ascites
Hydro Abdomen
Hydroperitoneum - in reptiles
Hydrothorax
Hydropericardium
Characteristics of oedema fluid
NOTE: anasarca - oedema is generalised throughout the body and the animal is very puffy
Development of oedema
Movement of fluid between vascular and extravascular compartments depends on balance of hydrostatic & osmotic pressure.
Under normal conditions some fluids move out of vessels at an arterial end.
Balanced by lymphatic drainage plus resorption of fluid at venous end
Oedema ensues when excessive fluid movement out of vessels.
Lymphatic drainage can increase markedly to compensate
Insufficient lymphatic drainage if there's too much fluid coming in
Oedema and can be inflammatory or non-inflammatory
Hyperaemia is always active so it's always inflammatory
MECHANISMS OF OEDEMA
4 main mechanisms
Increased hydrostatic pressure
Increased blood volume & increased pressure within capillaries
Venous pressure determines capillary hydrostatic pressure
May be local(occuring in one area) or systemic
Systemic has to do with typically heart failure→ increased BV & accumulation in certain areas. Can lead to activation of the RAAS system. Results in expansion of plasma volume & hence increased venous pressure
RAAS
Decreased cardiac output
Blood shunted away from kidney → decreased renal perfusion causes release of renin
Renin catalyses conversion of plasma angiotensinogen to angiotensin I
Angiotensin I passes to lungs and converted to angiotensin II which passes to adrenal cortex
This triggers aldosterone release which stimulates sodium retention and water is retained along with sodium
Increased BV in circulation but the heart is messed up so blood is seeping out of blood vessels. (treat - drugs that will block ADH)
Strangulation of intestine - can have congestion, hyperaemia, haemorrhage and hydrostatic pressure
Other conditions leading to increased hydrostatic pressure
Pulmonary hypotension
Left sided heart failure
High altitude disease
Localized venous obstruction
Gastric dilation & volvulus
Intestinal volvulus & torsion
Uterine torsion
Venous thrombosis
Fluid overload
Kidney disease - Na retention with renal disease
Iatrogenic
Decreased osmotic pressure
Always generalized
Albumin is most important osmotically active substance in plasma
Hypoalbuminemia may be due to
Decreased formation (hepatic /starvation)
Increased loss (parasitism) - main cause. Because worms are sucking the blood or getting proteins out
Because hypoalbuminemia is systemic, generalised oedema develops
Causes of hypoalbuminemia
Decreased albumin synthesis
Decreased AA supply (starvation)
Severe hepatic disease (cirrhosis)
NOTE: bone marrow is the last placed for serous atrophy so if there is fat there, it is severe
Increased albumin loss
Whole blood loss - repeated haemorrhages
Gastrointestinal loss - whole blood → haemonchosis or gastric ulcers. Protein loss alone→ inflammation, protein losing enteropathies
Nephrotic syndrome
Protein losing renal disease
In serum chemistry & U/A, 3 findings - proteinuria, hypoalbuminemia (hypoproteinemia) and triglyceridemia (hyperlipidemia)
Animal has generalised oedema
NOTE : animals can lose up to 30% BV but it has to be gradual
Lymphatic blockage
Causes localised oedema
Known as lymphoedema or lymphatic oedema
Obstruction may be internal or external
Tumor invasion of regional lymph node
Overly Tight bandaging
Lymphangitis
Fibrosis
Congenital
Increased vascular permeability
Usually local
In this mechanism of oedema the vessels are undamaged
Most often results from inflammation
Inflammatory mediators cause increased endothelial “leakiness” - TNF, IL1
Loss of fluid, cells, protein into tissues
Resulting in high protein fluid known as exudate (high protein, high cellular fluid)
Causes of increased vascular permeability
Infectious agents
Viruses, bacteria, rickettsia
Affects the endothelial cells
Immune mediated
Type III hypersensitivity
Ag-Ab complexes landing on epithelial cells and causing increased vascular permeability
Neovascularization
Anaphylaxis : Type I hypersensitivity
Toxins : Paraquat
Clotting abnormalities : DIC
Metabolic abnormalities
Diabetes mellitus
Thiamine deficiency
EXAMPLES OF OEDEMA SYNDROME
Nephrotic syndrome
Hepatic disease
Often seen in ascites esp if associated with fibrosis (cirrhosis)- portal hypertension
Decreased protein (albumin) synthesis central mechanism
Pulmonary oedema
Left sided heart failure: causes backflow of pressure into pulmonary vessels
Increased pulmonary hydrostatic pressure results in transudate forming in alveoli
may also occur due to endothelial damage by inhaled irritants, anaphylaxis, acute respiratory infections
Cerebral oedema
No room for expansion
Pushed through foramen magnum
Causes clinical signs via pressure on brain tissue
Oedematous brain is swollen, heavy, gyri flattened
Brain tumors, head trauma, widespread endothelial damage
GROSS APPEARANCE OF OEDEMA
swollen, soft, cool tissues
wet, shiny surfaces
can be clear fluid (transudate) or protein rich
Serous cavities increase in fluid
Solid tissues : wet, heavy, enlarged
Subcutaneous tissues - distension swelling, pitting on pressure, gravity dependent, infected tissue may pour fluid
CLINICAL SIGNIFICANCE OF OEDEMA
Depends on:
Extent (volume of fluid): large volumes may act as space-occupying lesions
Duration: chronic oedema may lead to fibrosis - impairs function
If there is a lot of fibrin and there is fibrosis→ impair function of certain organs or certain cavities
Location: tissue affected: pulmonary or cerebral oedema may be fatal
Excessive pulmonary oedema is fatal
Cerebral oedema affects brain function
Other types of oedema include subcutaneous oedema or inflammatory oedema and is not fatal
TYPES OF OEDEMA
DISTURBANCES OF CIRCULATION 4
THROMBOSIS, EMBOLISM, DIC
THROMBOSIS
Refers to blood clots that form within vessels during life. Formation of a solid mass of blood components within the blood vessels or heart during life.
These must be differentiated from post mortem clots (which are gelatinous and not attached to the vessel wall)
Most thrombi resolve without complications
CAUSES OF THROMBOSIS
Virchow’s Triad - the 3 major causes of thrombosis
Endothelial damage
Most important factor
Damage to vessel lining
Clot initiation - platelet activation. Activates clotting cascade via intrinsic & extrinsic pathways
E.g. trauma, vasculitis, endotoxemia
Organisms affecting endothelial cells:
Abnormal blood flow
Turbulence or stasis
Promote endothelial activation
Disrupt laminar flow
Prevent washout & dilution of activated clotting factors
Prevent inflow of coagulation inhibitors
Influences thrombus progression
Vascular stasis in veins= aneurysms, varicose veins
Loss of laminar flow:
turbulence- endothelial injury, form countercurrents.
Arterial & cardiac vessels if blood flows slow, then a lot of things can accumulate
Causes:
Local stasis/reduced flow
GDV, torsion, volvulus, varicocele, external compression
Cardiac diseases
Cardiomyopathy, hypertrophy
Aneurysm
Hypovolaemia
shock, diarrhea, burns
Abnormal blood composition
Hypercoagulability -favors clotting
Influences thrombus progression
Clotting factors
PCV
Platelets - too many platelets hypercoagulation
Misc - drugs, disease
Hypercoagulability
Increased tendency of blood to clot
Enhanced platelet activity
diabetes mellitus
malignant neoplasia
Increased clotting factor activation
DIC
nephrotic syndrome
Antithrombin III deficiency (molecule that destroys thrombin)
hepatic disease
glomerular amyloidosis
Metabolic disease
Hyperadrenocorticism
Hypothyroidism
E.g. protein-losing nephropathy, pregnancy, neoplasia
FORMATION OF A THROMBUS
Occurs in layers
Platelets adhere to damaged endothelium
Fibrin deposited on top
Onion-skin appearance
Complex patterns associated with flow variations
Laminated thrombi (lines of Zahn) form in larger arteries
TYPES OF THROMBI
Arterial thrombi
Usually occlusive
Pale(grey white) , platelets + fibrin rich
Coronary, cerebral & femoral arteries
Typically firm adherent to the arterial wall
Tangled mesh of platelets, fibrin, RBC and degeneration leukocytes
Venous thrombosis
RBC rich red, more likely to embolize
Occlusive
Phlebothrombosis
Long cast of vein lumen
Tend to contain more enmeshed erythrocytes
Red or stasis thrombi
FATE OF THROMBI
Propagation - thrombus grows & obstructs more of the vessel
Embolisation - part breaks off & travels → embolus
Dissolution - thrombus is broken down by fibrinolysis (early)
Organisation & recanalisation - fibroblasts grow in → new channels form through thrombus
Combinations
AM vs PM Blood Clots
EMBOLISM
Sudden blockage of a blood vessel by an embolus which is material traveling in the bloodstream that lodges in a vessel too small for it to pas through
Can be gas, solid or liquid and it causes dysfunction
NOTE: emboli travel, while thrombi form in place
Thromboembolism is a dislodged thrombus- most common type of embolus
TYPES OF EMBOLI
Thromboembolism
Most common type
Detached part of thrombus
E.g. pulmonary embolism
Gas or air embolism
Air bubbles entering circulation
E.g. IV catheter issues
Fat embolism
Fat droplets often from fractured long bones - fat enters circulation and cause emboli
E.g. orthopedic surgery, trauma
Cancers or tumor embolism
Fragments of malignant tumors
E.g. intravascular spread of neoplasia
Foreign bodies
More human medicine
IV, drug abuse
Cartilage from intervertebral disc
Septic embolism
Emboli containing infectious organisms
Endocarditis, abscess rupture
SEQUELAE OF EMBOLISM
Spread of tumor /infection
infarction
nothing
DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
Widespread clotting within the vascular system
Results in multiple fibrin clots within terminal vascular beds (microvasculature)
Consumptive coagulopathy
Triggers fibrinolysis
resulting fibrin degradation products (FDPs)
Inhibit coagulation
Causes consumption of platelets and coagulation factors
End result is widespread haemorrhage
Grossly see petechial & ecchymotic haemorrhage of lung, renal glomeruli, gastric mucosa, liver, skin plus congestion & infarction
NOTE: remember that DIC is not the primary disease so you have to treat the primary disease to fix this
Schematic fo DIC
Hemostasis 1
Hemostasis is the prevention or cessation of bleeding
Everyday trauma causes damage to vessel walls
In order to stop hemorrhages from this, thrombosis occurs (formation of blood clots)
Clot is also called a thrombus
Mechanisms are also needed to repair damaged endothelium
Once the defect his healed the clot is dissolved= fibrinolysis
Thrombosis and fibrinolysis occur simultaneously
Formation of a Thrombus
Vasoconstriction
Decreases surface area of the defect
Local axonal reflex
Simultaneously platelets stick to exposed collagen = platelet adhesion
Mediated by von Willebrand’s factor (vWF) that hastens formation by helping platelets bind to the basement membrane
Platelets
Primary hemostasis: form the primary plug
Provide a surface that binds and concentrates coagulation factors needed for secondary hemostasis
Two types of granules
⍺-granules: coagulation factors (attached, inactivated free form, and in the platelet)
Dense granules: ADP, ATP, Ca2+, serotonin
Primary Hemostasis
May be sufficient with small defects
Can’t seal large holes
Can’t withstand fast-flowing blood
Needs stabilizing
Steps
Platelets adhere to collagen glycoproteins, proteoglycans thanks to platelet receptor Gp1b
Adherence causes platelet activation and shape change
Platelets’ dense granules release ADP that recruit more platelets
Increase fibrinogen bind to platelet receptor CpIIbIIIa, forming the dense plug
Secondary Hemostasis
Stabilization of the platelet plug
Platelets become linked together by insoluble fibrin
Generation of fibrin is achieved by clotting cascade
Clotting Cascade
End point is production of insoluble fibrin
Consists of a chain reaction involving a series of proteases converting fibrinogen to fibrin
Principles
Calcium (factor IV) is essential for clotting
Acts as a bridge between factors
Useful in blood collection
Most factors and inhibitors are produced by the liver, thus normal liver function is essential in hemostasis
There is cross-activation between the extrinsic and the intrinsic pathway
Factor VIIa/tissue factor complex is the most important activator of factor IX
Factor IXa/Factor VIIIa complex is the most important activator of factor X
Intrinsic Pathway
Triggered by contact activation
Occurs when factor XII (in blood) contacts a -ve charged surface such as collagen
Can also be activated by thrombin (factor IIa)
XII-> XIIa-> kinin and kalikrein
Clot formation
Complement activation
Fibrinolysis
Cross talk between pathways as thrombin also activates factor XI
Extrinsic Pathway
Initiated by tissue factor
Factor III: produced by cells next to exposed collagen
Not free in plasma
Produced by activated endothelium via Endotoxins, TNF, IL1, TGFβ, thrombin
TF activates factor VII to VIIa
TF and Factor VIIa form a complex with calcium
Activate Factor X to Xa; Activate factor IX to IXa
Common Pathway
Factor Xa converts factor II to factor IIa (thrombin) which results in
Thrombin activating factor V to factor Va
Activates factor II to factor IIa
Thrombin activating factor XIII to factor XIIIa
Crosslinks fibrin
Thrombin activating factor I to factor Ia (fibrin)
Roles of Thrombin
Conversion of fibrinogen into cross-linked fibrin (factor I)
Platelet activation (factor XIII)
Shape, surface and recruitment
Pro-inflammatory effects
Anticoagulant effects
Fibrinolysis/thrombolysis
Prevents clots from getting too large
Dissolves thrombi once vessel damage is healed
Fibrin is cleaved by plasmin
Generation of plasmin
Plasminogen (inactive form) gets caught up in clots as they form
Becomes activated in clots
Urokinase
Tissue plasminogen activator- released by endothelial cells
Factor XIIa
Plasmin cleaves fibrin dissolving the clot and producing fibrin degradation products (FDPs)
FDPs inhibit
Clotting
Fibrin
Platelet aggregation
Inhibitors of Clotting
Circulating inhibitors
Activated factors bind to inhibitors and are removed by macrophages
Antithrombin 3 (AT III) is the most important
Anti-thrombin III
Most potent and significant
Lost in protein losing nephropathy
Degrades most of the factors
Thrombin and factor Xa
Inhibits kinin formation and complement activation
Protein C and S
Vitamin K dependent
Destroys factors Va and VIIIa
Effectiveness is enhanced by activation with thrombin
More effective when thrombin is bound to thrombomodulin
Neutralize plasminogen activator inhibitors
Protein S inhibits VIIIa, Xa, and Va
Other Inhibitors
Thrombomodulin found in endothelial membranes
Tissue Factor Pathway Inhibitor (TFPI)
Inactivation of tissue factor-VIIa complex
Inactivation of factor Xa
Endothelium
Not a passive cell layer
Important in clot formation, propagation and dissolution
Pro and anti-coagulation properties
Intact endothelium= antithrombotic/coagulation properties
Damaged/activated endothelium= pro-thrombotic/coagulation properties
Anti-coagulation Endothelium
Platelet inhibitory effects
PGI2- prostacyclin= opposes thromboxane
ADPase= degrades ADP preventing further platelet attraction
NO
Anticoagulant effects
Thrombomodulin
Heparin-like molecules
Anchor for Protein C and S
Fibrinolytic effects
t-PA= converts plasminogen to plasmin
Hemostasis and Other Responses
Kallikrein
Chemotactic
Cleaves C5 to C5a and C5b, and HMWK to bradykinin
Plasmin
Cleaves C3a to C3a and C3b
Activated endothelium: PDGF, TGFβ, VEGF= healing
Defects of Hemostasis
For hemostasis you need platelets, all clotting cascade components, fibrinolysis components
Defects may cause:
Excessive bleeding
Excessive clotting
Clinical Appearance
Defects of coagulation pathways
Severe bleeding
Hematomas
Body cavity bleeding
Bleeding into joint= hemarthrosis
Platelet defects (primary hemostasis defects)
Less severe bleeding
Bleeding from terminal vascular beds, mucous membranes
Ecchymoses or petechiae
Epistaxis: nose bleeds
Hematochezia: bright red blood in the stool
Hematuria: blood in the urine
Disorders of Primary Hemostasis
Vessel Wall Abnormalities
Trauma
Vasculitis
Endotoxemia
Disruption of wall by fungi
Viruses, toxins, immune complexes can also damage vessels
Excessively fragile vessels (involves supporting collagen)
Congenital
Osteogenesis imperfecta
Ehlers-Danlos syndrome
Acquired form= scurvy
Platelet abnormalities
Thrombocytopenia
Thrombopathies, thrombathenias, thrombocytopathies
Defective platelet function
Thrombocytopenias
Increased destruction
Immune mediated
Increased consumption
DIC
Decreased production
Bone marrow disease
Sequestration
Enlarged spleen
Functional defects
Thrombasthenias, thrombopathies, thrombocytopathies
Platelet count will be normal, but function will be abnormal
Can be inherited or acquired
Congenital functional defects
Glanzamann’s thrombasthenia
Great Pyrenees
Several horse breeds
Defect in GPIIbIIIa
Defective platelet aggregation
Chediak-Higashi syndrome
Aleutian mink, cattle, persian cats, killer whales
Defective LYST protein leading to lack of dense granules in neutrophils
Acquired functional defects
Associated with drugs
Aspirin
Uremia of renal failure also affects platelet function
Defects in adhesion, granule secretion and aggregation
Von Willebrand Factor Abnormalities
Secondary platelet defect
Various forms:
Decreased total amount of vWF
Normal amount present, but decreased function
More severe bleeding
Primary platelet plug very unstable
May be seen clinically as excessive bleeding (stopped by secondary hemostasis) after trauma or surgery
Especially common in dobermans and Scottish terriers
Disorders of Secondary Hemostasis
Hemophilia A (Factor VIII)
X-linked recessive therefore only males affected
Treatment by transfusions of factor VIII from donated blood
Affects primarily the intrinsic pathway
Other Types of Hemophilia
Hemophilia B- Factor IX
X linked
Cats and dogs
Hemophilia C- Factor XI
Dogs and Holstein cattle
Mild
Hageman’s disease- Factor XII (linked to other issues like fertility)
Cats and dogs
No clinically significant bleeding
Acquired Coagulation Factor Deficiencies
Vitamin K Antagonism
Most common
Essential for activation of
Factors II, VII, IX, X
Proteins C and S
Usually recycled in the liver so only tiny amounts needed in the diet
Coumarins prevent vitamin K recycling
Moulds on sweet clover
Commercially as rat poisoning
Heart disease treatment in humans
Bleeding begins once factors run out
Vitamin K is also needed for proper enzymatic function of Ɣ-glutamyl carboxylase (defects in this enzyme resemble Vitamin K deficiency)
Hepatic Disease
In severe generalized liver disease, decreased numbers of clotting factors are synthesized
DIC
Consumptive coagulopathy
Widespread clotting leads to depletion of clotting factors
Run out of clothing factors
Clinical Assessment of Bleeding Disorders
Contraindicated with thrombocytopenia
Primary Hemostasis
Platelet count
Anti coagulated blood using an electronic particle counter
Bleeding time
Buccal mucosal bleeding time
Used for vWd
Platelet function tests
Screening for vWd, thrombasthenias, or vascular disorders
Tests of Coagulation Cascade
Vitamin K deficiency will affect all
Most require citrated plasma (blue tube)
Common pathway test: Thrombin time
Activated partial thromboplastin time
Intrinsic pathway
Addition of ground glass, phospholipids and calcium
Time to form clot recorded
Type A and B hemophilia
Prothrombin time
Extrinsic pathway
Tissue factor, phospholipids and calcium are added to plasma
Time to form clot recorded
Hemostasis 2- Defects of Hemostasis
Hemostasis requires platelets, all clotting cascade components and fibrinolysis components
Defects results in:
Excessive bleeding
Excessive clotting
Clinical Manifestations
Severe bleeding
Hematomas
Body cavity bleeding
Bleeding into joints
Hemoarthosis
Platelet defects/1º hemostasis defects
Less severe bleeding
Bleeding from terminal vascular beds, mucus membranes
Ecchymoses or petechiae
Epistaxis
Hematochezia
Hematuria
Disorders of Primary Hemostasis
Vessel Wall Abnormalities
Can be due to trauma
Vasculitis
Endotoxemia
Disruption of the wall by fungi
Viruses, toxins, immune complexes
Excessively fragile vessels
congenital
Involves supporting collagen
Osteogenesis imperfecta
Ehlers-Danlos syndrome
Acquired form Scurvy
Platelet Abnormalities
Thrombocytopenia
Deficient platelet numbers
Thrombopathies, thrombasthenias, thrombocytopathies
Defective platelet function
Thrombocytopenia
Increased destruction
Immune mediated
Increased consumption
DIC
Decreased production
Bone marrow disease
Sequestration
Enlarged spleen
Functional Defects
Platelet count will be normal but function will be abnormal
Inherited or acquired
Glanzmann’s thrombasthenia
Seen in great Pyrenees and several horse breeds
Defect in GPIIbIIIa
Defective platelet aggregation
Chediak-Higashi syndrome
Seen in Aleutian mink, cattle, Persian cats, killer whales
Defective LYST protein leading to lack of dense granules
Acquired Functional Defects
Associated with drugs= Aspirin
Uremia of renal failure also affects platelet function
defects in adhesion, granule secretion and aggregation
von Willebrand Factor Abnormalities
Secondary platelet defect
vWF glues platelets to collagen
Inherited vWF
decreased total amount of vWF
Normal amount present, but decreased function= more severe bleeding
Results of vWF defects
Primary platelet plug very unstable
Clinically seen as excessive bleeding after trauma or surgery
Common in: Dobermans and Scottish terriers
DIC
Consumptive coagulopathy
Run out of clotting factors
Disorders of Secondary Hemostasis
Hemophilia A (Factor VIII)
X-linked recessive= only males affected
Treatment: transfusion of factor VIII
Affects primarily the intrinsic pathway
Other Types of Hemophilia
Hemophilia B- factor IX
X-linked
Cats and dogs
Hemophilia C- factor XI
Dogs and Holstein cattle
Milkd
Hageman’s disease- factor XII
cats and dogs
No clinically significant bleeding
Acquired Coagulation Factor Deficiencies
Vitamin K Antagonism
Most common
Vit K needed for
factors II, VII, IX, X
Proteins C and S
Usually recycled in the liver, so only small amounts are needed in the diet
Coumarins prevent vitamin K recycling
Found in moulds on sweet clover
commercially as rat poison
bleeding begins once activated factors run out
Vit K also needed for proper function of 𝛾-glutamyl-carboxylase
defects in this enzyme can resemble Vit K deficiency
Hepatic Disease
Decreased numbers of clotting factors are synthesized
Clinical Assessment of Bleeding Disorders
Bleeding time
Buccal mucosal bleeding time
Used for vWD
Platelet function tests
screening for vWd, thrmonasthenias or vascular disorders
Contraindicated with thrombocytopenia
Tests of Coagulation Cascade
Vitamin K deficiency influences all
Most require citrated plasma: blue tube
Activated Partial Thromboplastin Time
Intrinsic pathway
Addition of ground glass, phospholipids and calcium
Time to form clot recorded
Prothrombin Time
Extrinsic pathway
tissue factor, phospholipids and calcium are added to plasma
time to form clot recorded
Thrombin time
Neoplasia and Tumor Biology
Neoplasia
Abnormal mass
Growth exceeds and is uncoordinated with normal tissue
Persists after cessation of the stimulus which evoked the change
Serves no useful function
Preneoplastic Changes
Hypertrophy
Increased size of tissue/organ by the addition of cytoplasm and/or organelles
Can be the whole organ or parts of the organ
Reversible
Examples include: cardiac hypertrophy and pregnant uterus
Hyperplasia
Increase in size of tissue/organs due to cellular replication
Reversible
Responds to body signals
Examples:
epidermal hyperplasia during wound healing
Goiter: thyroid gland hyperplasia
Metaplasia
Reversible/irreversible change in which one differentiated cell is replaced by another cell type
Most common: columnar to squamous
Example: vitamin A deficiency results in a change of glandular to squamous
Dysplasia
Disordered growth
Disorderly arrangement of cells within the tissue
Many features of anaplasia
Precursor to neoplasia but can still be reversible
Anaplasia
Lack of differentiation
Reversion to more primitive cellular morphologic features
Indicates irreversible progression to neoplasia
Classification of neoplasms
Mesenchymal tumors
Embryonic mesodermal origin
Benign rumors= -oma to the name of the cell of origin
Fibrocyte- fibroma
Rhabdocyte- rhabdomyoma
Malignant tumors take the suffix -sarcoma
Fibrocyte- fibrosarcoma
Osteocyte- osteosarcoma
Round cells of the hematopoietic system are also mesenchymal
Lymphosarcoma (shortened to lymphoma)
Situated in organ or extravascular and forms a mass
Malignancies in the circulating blood are termed leukemias
No primary mass but well vascularized organs will still enlarge
Benign vs Malignant
Benign has a more typical cell structure
Malignant presents a different arrangement of cells and more fibrocytes are present
Epithelial tumors
Benign
Use the suffix -oma
Adenoma- glandular tissue
Mammary adenoma
Papilloma- exophytic, cutaneous or subcutaneous
Broad base connection
Polyp- projecting from a mucosal surface
Narrow stalk
Malignant
Use the suffix -carcinoma
Adenocarcinomas- glandular growth
Examples
Liver
Hepatoma- benign
Hepatocellular carcinoma- malignant
Bile duct
Cholangiocellular carcinoma- malignant
Lung
Pulmonary carcinoma- malignant
Kidney
Renal carcinoma- malignant
Neural Crest Cells
Occurs when the neuroectoderm separates from the overlying ectoderm
-oma for benign
“Malignant” in front of malignant tumors
Examples:
Adrenal gland (medulla)
Pheochromocytoma
Malignant pheochromocytoma
Melanocytes
Melanoma, melanocytoma
Malignant melanoma (can be found in dogs: oral, around digits, eyes; cats: intraocular)
Mixed Tumors
Multiple cell types: pluripotent or totipotent
Mixed mammary tumor
Mesenchymal and epithelial
Other apocrine glands can be affected
Teratomas: tumors with cells from multiple origins
Totipotent germ cells
At least 2 or 3 types are present
Tumor-Like Lesions
Hematoma: bruise
Granuloma: inflammatory reaction
Choristoma: well organized nest of cells in the incorrect location
Hamartoma: disorganized nest of cells in the correct anatomical location
Cells are hypoplastic (E.g. skin tags)
Classification of Neoplasms
Tumor Growth
Carcinomas and sarcomas tend to be firm, tan nodules
Liver carcinomas look like the liver
Bone tumors produce bone
Hemangiosarcomas are red, blood filled spaces
Endothelial cells lining blood vessels
Umbilication
Cavitation
Center part of tumor becomes necrotic, causing it to shrink in size
Rapidly growing neoplasms outgrow their blood supply and become necrotic
Commonly seen in metastatic carcinomas
Round Cell Tumor
Usually leukocytes
Soft and may bulge from surface on cut section
Lymphomas, Mast Cell Tumors, Plasmacytoma, Histiocytoma, TVT
Anaplasia and Cellular Atypia
Anisocytosis: wide variation in cell size
Pleomorphism: wide variation in cell shape
Karyomegaly: large nuclear size
Anisokaryosis: wide variation in nuclear size
Giant tumor cells
Multinucleation
Increased mitotic rate
Normal for some layers of skin and the intestines
Emperipolesis
Cell passing through another cell
E.g. neutrophil passing through epithelial cell
Carcinogenesis
Initiator (polycyclic hydrocarbon)
produces mutations in proto-oncogenes or tumor suppressor genes
There needs to be constant promoter application (croton oil) for tumor formation to occur
Multistep process
Initiation
Non-reversible genetic change (mutations)
Has memory
Cannot cause neoplasia alone
Promotion
Induces neoplasia in induced cells
Has no memory
Leads to benign tumors
Progression
Epigenetic and genetic changes
Accumulation of further mutations
DNA methylation, history modifications, microRNA dysregulation
Environmental factors
Angiogenesis and tumor microenvironment support malignant changes
Malignancy (end product)
Clonality and Heterogeneity
Originally all cells clonal, derived from a single transformation cell
Accumulation of mutations in stepwise fashion overtime
Formation of sub clonal population= intratumoral heterogeneity
Clonal selection, tumor evolution
Subclones with advantageous traits outcompete others
Tumor evolved towards more aggressive, therapy-resistant forms
Tumor Microenvironment
Stromal and Parenchymal Interactions
PDGF by tumor cells can lead to fibroblasts to proliferate
Desmoplastic or scirrhous response (exaggerated response of the stroma= high amount of fibrous tissue)
Tumor cells embedded in dense collagen stroma
Angiogenesis
Tumors can't enlarge beyond 2mm in diameter without angiogenesis
Angiogenic switch
Neoplastic cells express pro-angiogenic factors
Occurs during progression from benign to malignant
Increase in VEGF
Downregulation of thrombospondin (anti-angiogenic) by tumors
Tumor immunity
Tumor antigens: molecules that may be recognized by the immune system as foreign antigens
Tumor specific antigens are restricted to tumor cells
Tumor associated antigens present both on tumor cells and normal cells, which can lead to the destruction of normal cells
Antitumor Effector Mechanisms
Innate immune response
NK cells
Adaptive immune response
Cell-mediated response most important
Cytotoxic T cells
Evasion of the Immune Response
Altered MHC expression
Loss of class I MHC down regulates CTLs response
More susceptible to NK cell response as they can detect stress markers when MHC Class I is absent
Loss of class II MHC down regulates Th response
Less effective CTLs response
Antigen masking
Altered glycosylation or by binding to receptors to prevent immune recognition
Tolerance
Decreased antigen presenting cells or promote immature APCs
Tregs may be involved
Immunosuppression
Fas ligand leads to apoptosis of T cells
TFG-⍺ produced by tumor cells immunosuppressive to lymphocytes and macrophages
Metastasis
Epithelial-mesenchymal transition
Loosening of cell-cell contact
Inactivation of e-cadherin
Degradation of ECM
Mediated by proteases
MMPs and cathepsins
Attachment to novel ECM components
Caused by proteases
Migration of tumor cells
Intravasation
Tumor emboli in lymphatic circulation
Extravasation in new location and invasion into surrounding tissue
Spread of neoplasms
Lymphatic spread
Primary route of carcinomas
Regional lymph nodes affected first.
Metastasis to regional lymph nodes indicates systemic spread has likely already occurred
Hematogenous spread
Primarily sarcomas but can happen with carcinomas
Veins easier to invade than arteries
Lungs and liver: vascular organs common sites of metastasis
Transcoelomic spread
Carcinomatosis: widespread dissemination of carcinoma across serosal surfaces, leading to the development of numerous small metastatic deposits.
Peritoneal and pleural cavities
Common causes: Ovarian, gastrointestinal and lung cancers
Neoplasms arising on the surface of an abdominal or thoracic structure encounter few anatomical barriers to spread
Neoplasia: Clinical Aspects
Direct Effects
Tumor cells cause damage based on
Occupation of space
Location (E.g. Pedunculated lipomas are benign, but due to location are still able to kill the animal)
Indirect Effects
Paraneoplastic syndromes
Tumor cell products
Aberrant expression of molecules
Remote effects
Importance of paraneoplastic syndromes
Recognition of syndromes helps diagnosis
Need to treat both metabolic abnormalities and tumor to control the problem
Monitoring abnormalities to help modify treatment
Cachexia
Hyper catabolic state defined by a loss of muscle mass that cannot be explained by diminished food intake
Inflammatory mediators: TNF-⍺, IL-1, IL-6, prostaglandins
Feline Hyperthyroidism
Elevated T3 and T4
Weight loss despite increased appetite
Polydipsia (increased thirst) and polyuria (increased urination)
Tachycardia
Cardiac hypertrophy
Hypocalcemia and secondary hyperparathyroidism (increased PTH) as a response to hyperphosphatemia
Pituitary Adenoma (Dog)
Functional corticotropin adenoma with compression of hypothalamus
ACTH secretion (overproduction)= bilateral adrenal cortical hyperplasia → Cushing’s Syndrome
Canine Pituitary-dependent Cushing’s Syndrome
Excessive ACTH secretion
Adrenal cortical hyperplasia= excessive cortisol
Redistribution of fat
Ravenous appetite
Muscle atrophy and pot belly
Endocrine dermatosis
Steroid hepatopathy
Equine Cushing’s- Pituitary Pars Intermedia Dysfunction (PPID)
Pituitary tumor (pars intermedia)
POMC and ⍺-MSH excessive secretion
POMC is cleaved to produce ACTH and ⍺-MSH
Adrenal glands are unaffected
Disruption of the Hypothalamic-Pituitary-Adrenal Axis
Causes hirsutism (excessive coarse hair growth)
Pancreatic Tumors
Insulinomas
Tumors of pancreatic islets β-cells
Hyperinsulinemia leading to severe hypoglycemia
Neurologic signs and lethargy, incoordination, muscle weakness
Other tumors can produce hypoglycemia
Ectopic Hormone Production
When non-endocrine neoplasms produce molecules that act as hormones
Humoral hypercalcemia of malignancy
Anal sac adenocarcinoma
Lymphoma
Multiple myeloma (plasma cell tumor) → osteolysis leading to hypercalcalemia
Caused by Parathyroid hormone related peptide (PTHrP)
Skeletal Syndromes
Hypertrophic osteopathy
Extensive periosteal new bone growth in the limbs
Secondary to underlying thoracic diseases, especially pulmonary neoplasia
Myelofibrosis
Overgrowth of non-neoplastic fibroblasts in the bone marrow
Result of neoplastic processes, including leukemia
Vascular and Hematologic Syndromes
Hyperviscosity syndrome
Multiple myeloma
Excessive production of antibodies resulting in hyperproteinemia
Neurological disorders, congestive heart failure, bleeding disorders
Heritable Alterations in Cancer
Genetic Changes in Cancer
Point mutations
DNA strand breaks
insertions
Deletions
Frameshift mutation
amplification
More than one copy of a DNA sequence
Aneuploidy
Abnormal numbers of chromosomes
Chromosomal instability
Translocations: pieces of two separate chromosomes break off and reattach inappropriately
Germline Mutations and Cancer Syndromes
Germline mutations are heritable
Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis of German Shepherds
BHD gene locus
MET germ-line mutation in rottweilers
Renal carcinoma
Epigenetic Changes in Cancer
Heritable changes in gene expression
Post translational changes
Histone modification
DNA methylation and acetylation
Can be modulated
Genomic imprinting
Allele-specific expression of certain genes whereby only the maternal or paternal allele is expressed
DNA Methylation
Addition of a methyl group to the 5’ carbon of a cystine that is located immediately 5’ to guanine
Essential for regulating gene expression in normal cells
Methyltransferase enzymes
Hypomethylation- gene activation
Hypermethylation- gene silencing
Cancer cells have aberrant methylation compared to normal cells
Hypermethylation of promoter regions= silencing tumor suppressor genes, preventing transcription and disabling cell cycle checkpoints, DNA repair, and apoptosis
LOI leading to abnormal growth
Histone Modification
Euchromatin is accessible to transcription factors
Heterochromatin is inaccessible to transcription factors
Post-translational histone modifications alter DNA transcription
Acetylation, methylation, and phosphorylation
Histone-code: specific combination of histone modifications acts like a code to instruct the transcriptional machinery determining which genes are expressed, when and how much.
Determine which genes are expressed and at what level
Noncoding RNAs and Cancer
Unregulated expression can contribute to cancer development
MicroRNAs (miRNAs) post transcriptionally regulate genes, usually by blocking their expression
MiRNAs bind target mRNAs that have a complementary sequence
Degradation of their target mRNAs
Prevent translation of these mRNAs into proteins
Pattern of miRNA expression is dysregulated in cancers by many mechanisms
Altered pattern of their expression create extensive changes in cellular processes related to neoplasia
Molecular Basis of Cancer
Driver mutations are primarily responsible for tumor development
Involve tumor suppressor genes or oncogenes
Oncogenes and Tumor Suppressor Genes
Growth-promoting proto-oncogenes
Participate in signaling pathways during mitosis
Mutated proto-oncogenes are called oncogenes
Oncogenes can produce oncoprotein
Promote cell growth in the absence of normal signals
Drive increased cancer cell proliferation
Ras genes (oncoprotein)
Continued signaling to proliferate in the absence of appropriate growth factor binding
Growth-inhibiting tumor suppressor genes
Tp53 (p53)
Haploinsufficiency
One normal copy of a tumor suppressor is not enough to maintain homeostasis
Can lead to tumor development
TP53
Senses DNA damage and hypoxia as well as “oncogenic” stress (Excessive Myc or Ras activity)
Induces
Transient cell cycle arrest for DNA fix
P21, GADD45 (repair)
Senescence
Permanent withdrawal from cell cycle
P21, stops cell cycle
Apoptosis
BAX activation
Defects in DNA Repair
Mismatch repair enzymes proofread DNA to locate and fix single nucleotide mismatches that occur on a regular basis during normal DNA synthesis
MLH1 and MSH2
Nucleotide excision repair (NER) requires a large cohort of DNA repair proteins
Larger defects
Defects in these can result in:
Increased mutational burden
Genomic instability
Higher chance of oncogene activation or tumor suppressor inactivation
Carcinogenic Agents
Chemical
Direct
Effective form in which they enter the body
Alkylating agents
Bracken fern in cattle
Ptaquiloside
Indirect
Procarcinogens that require metabolic activation by cellular enzymes
Aflatoxin B1- found in moldy feed
Animal hepatic cancers
G:C to T:A change in p53 gene leading to tumor development
Radiation
Complete carcinogen: initiator and promoter
Ultraviolet
Produces pyridine dimers in DNA
Corrected by nucleotide excision repair
Melanoma —> Squamous cell carcinomas
Those with lighter fur or at higher altitudes are more at risk
Ionizing
Forms breaks in DNA strands and eliminates bases
X-rays, gamma rays
Both can have ROS
Oncogenic Viruses
Dominant Oncogenes
Go around the host’s tumor suppression system
Feline sarcoma and retroviruses
Papillomaviruses
E6 and E7 inactivate p53
Insertional Mutagenesis
Viral genome inserts in host genome, displacing reading frames
Avian leukosis virus
Inserts before promoter regions of promo-oncogenes
C-myc
Hit and Run
Transient residence of viral genome can also affect the host genome
Virus not present in tumor, acts as an initiator
Bovine papillomaviruses
Indirect Mechanism
Virus modulates how host immune system suppresses tumors
Marek’s disease
Suppresses the ability of the host to eliminate transformed cells
Kills lymphocytes in infection
Shope fibroma virus
Rabbit poxvirus
Encodes for EGF= cell proliferation
Transmissible
Transfer of intact neoplastic cells
Canine transmissible venereal tumor
Benign
Cure: vincristine
Tasmanian devil facial tumor disease
Malignant
Difficulty eating
Conservational problems
Cancer in Animals
Natural disease
Virus induced
Virus-induced cancer is not a large proportion of human cancers
Animal model of cancer
Tools for understanding the cause of human cancer
Experimentally induced
Administration of carcinogenic substances
Naturally occurring tumors
Dog as model for human cancer
Incidence is comparable
Both are outbred
Similar environment
Tumors in dogs progress faster
Dogs are larger than mice models, so there is abundant tissue for diagnosis and experiments
More therapeutic approaches can be done in dogs compared to rodents
Clinical trials are easier
Experimentally induced tumors in animals
Use of rodents
Inbred
Doesn’t reflect human genomic diversity
Use of gene technology
Transgene- gene introduce into mouse genome
Knockout- a strain lacking a specific gene
Conditional gene expression- modulate gene expression as required for studies