CIRCULATORY DISTURBANCES (pp.

1-19) o Capillary wall is a semipermeable membrane; influences

movement of fluid (water and solutes), nutrients and waste
NORMAL CIRCULATORY SYSTEM (for background info only) bw blood and interstitial space.
o The health of cells and organs critically depends on an a. Direct diffusion
unbroken circulation to deliver oxygen and nutrients and to - Most small molecules move by passive diffusion
remove wastes through the
o The well-being of tissues requires normal fluid balance; i. endothelial cell membrane (eg. gases, lipid
abnormalities in vascular permeability or homeostasis can soluble molecules) or
result in injury ii. interendothelial pores (eg. water, ions,
1. Important Concepts glucose, amino acids, waste)
a. Distribution of fluid is carefully controlled - Normal interendothelial pores too small to allow
b. Deviations from normal can have profound pathological escape of large proteins, eg. albumin, globulins.
effects - In inflammation, endothelial cells contract,
c. Normal function requires intact blood and lymph vessels allowing larger molecules to escape.
d. Endothelial cells play an important role in fluid distribution, b. Transcytosis
hemostasis, inflammation and healing. - With some endothelium, fluids/ macromolecules
2. Components of the Circulatory System can be transported across a cell by vesicles.
o Heart → pump 6. Regional Differences in Capillary Lining
o Arteries → distribution system Continuous o Lined by a complete o Muscle, brain,
o Microcirculation system → nutrient/waste exchange bw capillaries simple squamous thymus, skin, bone,
blood and extravascular tissue endothelium and lung, etc.
o Veins and lymphatics → collection system basal lamina
Fenestrated o Have many small o Often have a
o Blood travels from the left side of the heart to the right side capillaries openings diaphragm, eg.
of the heart via the systemic circulation o Found in tissues with intestinal villi, kidney
o From the right side of the heart to the left side via the abundant fluid interstitium, choroid
pulmonary circulation transport plexus, ciliary process
o Blood flow rate & pressure in the systemic arterial circulation of eye.
decrease in conjunction with increased total arterial cross- o With no diaphragm
sectional area can act like a filter,
o In the venous systemic circulation, blood flow rate, but not eg. renal glomerulus
pressure, increases in conjunction with decreased total Discontinuous o Larger gaps than o Hepatic, splenic
venous cross-sectional area. capillaries fenestrated sinusoids
o The flow, pressure, and cross-sectional area relationships are o With discontinuous
similar but reversed (i.e., veins deliver blood and arteries basal lamina
collect blood) in the pulmonary circulation. o Allows large
3. Microcirculation molecules to exit (eg.
o Called as such bc it is microscopic. RBCs in spleen)
a. Arterioles/ metarterioles 7. Fluid Distribution and Homeostasis
- Walls contain innervated smooth muscle cells Total body water ~65% of lean body weight
(myocytes); contract to control blood flow Plasma 5%
b. Postcapillary venules Interstitial tissue fluid 15%
- Similar structure to capillary, but acquire thin layer Intracellular fluid 40%
of muscle as they move away from capillary bed. Transcellular fluid 5%
c. Capillaries
- Enormous volume (1300 x cross-sectional area of
aorta), but normally contain only ~5% of the blood;
ie. 95% of capillary beds are not open during
normal conditions.
- Site where nutrients and wastes are exchanged
and a critical area in fluid balance.
4. Endothelial cells
o All components of the circulatory system are lined by a
single layer of endothelium.
o Synthesize and secrete substances which effect:
a. Fluid balance
b. Hemostasis
c. inflammation/ immunity
d. angiogenesis/ healing.
a. Interstitium
o Eg. in normal state they have antithrombotic properties, but
- Space bw microcirculation and the cells
when injured becomes prothrombotic.
- Binds most cellular and structural elements into
5. Mechanisms for Substance Transport Across Capillary Wall
discrete organs and tissues.
- Medium through which all metabolic products
must pass bw microcirculation and cells
 - Distribution of fluids, nutrients and waste bw o Organs swollen, fluid may weep from cut
blood-interstitium-cells is controlled by physical surface
structures, pressures, and ion concentration o May be yellow (horses, some cattle breeds)
gradients o Interstitial spaces get bigger bc of fluid
- Interstitium = ECM + supporting cells (eg. accumulation; lung fails to collapse
fibroblasts) Histologic o Lightly staining eosinophilic fluid (if some
- Extracellular Matrix: provides structural support appearance protein content)
and has adhesive and absorptive properties: o Clear/no staining (if protein content low)
i. Structural molecules: eg. collagen, reticulin, o Tissue spaces are distended by the edema
elastin fibers (collagen bundles separated by increased
Ground substance: clear space)
ii. Adhesive glycoproteins: eg. fibronectin, o Lymphatics are dilated
laminin o Large space identifies the abnormality esp.
iii. Absorptive (hydroscopic) molecules: eg.
when fluid is not pink (low protein content)
glycosaminoglycans, proteoglycans
Mechanisms of edema production
b. Movement of Fluids
1. Increased hydrostatic pressure
- Capillary (endothelial cell/basal lamina):
o Causes of impaired venous return
i. allows free passage of H2O and ions
a. Generalized: eg.
ii. opposes passage of plasma proteins
- right-sided heart failure; major organ: liver
- Water distribution bw plasma and interstitium is
- left-sided heart failure; major organ: lungs
primarily determined by the differences in
b. Localized: eg. tight bandage causing local obstruction of
hydrostatic & osmotic pressure bw the 2
venous return
compartments
Impaired venous return → ↑blood in organ (eg. liver) → edema
c. Starling’s equation
- Hydrostatic pressure in the vascular system (+
interstitial osmotic pressure) moves fluid out of
the vessels.
- Osmotic pressures of the plasma proteins (esp
albumin) (+ some tissue hydrostatic pressure)
contain the fluid within the vascular system.

2. Decreased plasma colloidal osmotic (oncotic) pressure

o Causes of Hypoproteinemia
a. Proteins not absorbed from diet
- Starvation
- Malabsorption
b. Proteins not produced
- Liver disease
c. Proteins lost
- Glomerular disease
- Intestinal damage

Circulatory DIstrubances
1. Edema
2. Congestion & Hyperemia
3. Hemorrhage
4. Hemostasis
5. Thrombosis & Embolism
6. Infarction 3. Lymphatic obstruction
7. Shock o Damage/obstruction of lymphatics
EDEMA o Causes of lymphatic obstruction
o Abnormal (excess) accumulation of fluid in interstitial tissue a. Surgery/ trauma (fibrosis)
spaces or in body cavities b. Neoplasm
o Edema fluid is outside both the vascular fluid and cellular fluid c. Inflammation (lymphangitis)
compartments (ie. Within interstitium)
o Lung: grossly, well-delineated lobules is characteristic in pigs
Gross appearance o Organs wet (±gelatinous) and heavy

o Fluid characteristics of 1 to 3: “non-inflammatory edema” =
protein poor
o Transudate:
o Low protein content <30 g/L
o Specific gravity <1.107
o Total nucleated cell count <1.5x109 /L
4. Increased vascular permeability/endothelial damage
o Mostly due to inflammatory/immunologic stimuli → release
of inflammatory mediators → vasodilation and increased
vascular permeability → “inflammatory edema”
o Endothelium can also be damaged by non-inflammatory
agents (eg. viruses, toxins)
o Leaking out of fluids
o Fluid characteristics
a. Inflammatory edema = protein rich
b. Exudate:
- high specific concentration of protein >30 g/L
- Specific gravity >1.025
- Total nucleated cell count >7.0x106 /L
LOCAL EDEMA
Mechanisms of local edema
1. Local impaired venous drainage
2. Local lymphatic obstruction
3. Local inflammation
GENERALIZED EDEMA
Mechanisms of generalized edema
1. Increased generalized hydrostatic pressure of blood (esp. right-
sided heart failure) (venous)
2. Decreased colloid osmotic pressure of plasma proteins
Common locations of generalized edema
o Often see combination of ascites, hydrothorax, & subcutaneous
(“dependent”) edema
1. Subcutaneous tissues of ventral abdomen: “brisket edema”
- eg. result of chronic congestive heart failure
2. Subcutis of ventral mandibular/ cervical region: “bottle jaw”
- eg. result of hypoproteinemia due to GIT parasitism in sheep
3. Subcutis of the limbs: “stocking up”
- Eg. due to protein losing enteropathy
TERMINOLOGIES OF EDEMA
-used when describing non-inflammatory edema
1. Pitting Edema
o When pressure is applied to an area of subQ edema and a
depression/dent results
o Due to excessive interstitial fluid forced to adjacent areas
2. Anasacara
o Severe and generalized edema with profound subQ tissue
swelling
3. Hydrothorax
o Non-inflammatory fluid (transudate) in the thoracic cavity
o Non-inflammatory → no neutrophil, pale/ no color fluid
4. Hydropericardium
o Non-inflammatory fluid (transudate) in the sac around the
heart (pericardial sac)
5. Ascites (= Hydroperitoneum)
o Non-inflammatory fluid (transudate) in the peritoneal cavity.
o Eg. ascites due to heart worm: ↑heart pumping → fluid
leaks outside
o Also when suddenly going at high altitudes
CLINICAL SIGNIFICANCE OF EDEMA
Dependent upon:
1. Extent: mild vs. moderate vs. marked/severe
2. Location: site of accumulation; eg. skin (relatively insignificant) vs.
lung or brain (often lethal)
3. Duration: tissues may become more firm and distorted due to
increased fibrous CT after prolonged edema.
PULMONARY EDEMA
- Accumulation of edema fluid in interstitium and alveoli of the
lungs
- Common cause of death in many disease processes
o Mechanisms of pulmonary edema
1. Circulatory failure
o Increased hydrostatic pressure (esp. left-sided heart failure)
→ “non-inflammatory” edema into alveolar spaces
2. Damage to pulmonary capillary endothelium (microvascular
injury)
o Usu. occurs with peracute inflammation (ie inflammatory
edema) or less commonly toxins
o Due to sudden increase in vascular permeability; if
substantial → death
o Often sudden death (when peracute) or followed by
pneumonia if animal survives.
o Dynamics of pulmonary edema
- Fluid accumulates in interstitium
→ fluid moves through BMs into alveoli
→ fluid drains via lymphatics; results in dilated interlobular &
pleural lymphatics and may eventually lead to pleural fibrosis
(chronic).
Gross appearance o Lungs are heavy and wet. (distended by
edema fluid → round edges)
o Froth (edema fluid + air bubbles) may be
present w/in trachea & bronchi and obvious
on cut sections.
o The interlobular septa are prominent/
thickened due to increased fluid within this
space.
o Accompanying congestion of pulmonary
 parenchyma with left-sided heart failure o Gross: Affected tissue is red (oxygenated blood) and warm,
Histologic o See edema fluid in interstitium/alveolar as arterioles and capillaries are filled with blood
appearance spaces
o dilated interlobular/ pleural lymphatics.
o Edema fluid can be clear or pale acidophilic
in color (depending on protein content)
(inflamm. > non-inflamm)
CHRONIC Pulmonary Edema
o Chronicity → fibrosis of pleura & alveolar septa
o most commonly seen with chronic cardiac failure and o Types of hyperemia:
accompanying pulmonary congestion a. Physiologic Hyperemia
o Masson trichome staining stains fibrous connective tissues - eg. ↑blood flow to stomach and intestines during
green digestion
CEREBRAL EDEMA: Edema of the Brain ↑blood flow in the muscles during exercise
Causes o trauma (head injury) ↑blood flow in skin to dissipate heat
o obstruction of venous outflow ↑neurovascular hyperemia (blushing)
o intracranial infections (eg. meningitis, b. Pathologic Hyperemia
encephalitis) - result of an underlying pathologic process (usu.
Gross o brain heavier than normal inflammation)
appearance o sulci are narrow: due to swollen brain - arteriolar dilation is a response to inflammatory
constricted by the bony cranium stimuli/ mediators
o gyri swollen and flattened - Red coloration is a cardinal sign of inflammation =
o When severe, can see: “Hyperemia of Inflammation”
1. Cerebellar coning: herniation of cerebellum - Often see associated edema.
through the foramen magnum 2. Congestion - passive
2. Cerebral herniation: herniation of caudal o Passive engorgement of a vascular bed generally caused by a
cerebral cortex beneath the tentorium decreased outflow of blood
cerebelli Gross appearance o Tissues: dark red to blue/black (cyanotic),
Tentorium cerebelli: portion of dura mater depending on degree of stagnation
that separates cerebellum from the inferior (deoxygenated blood)
portion of the occipital lobes o Cut surfaces ooze blood & often wet (due to
Histopathology o Expansion of perivascular (Virchow-Robin) accompanying edema from increased
spaces (result of fluid leakage through BBB) hydrostatic pressure).
DEHYDRATION Histologic o Acute: 1. Capillaries engorged with blood
o Deficiency of water resulting from imbalance bw uptake and loss appearance 2. Usually some edema
of water from the body o Chronic: engorgement by poorly
o Causes: deoxygenated venous blood → chronic local
1. Uncontrolled diarrhea hypoxia (↓O2) →
2. Vomiting 1. Atrophy
3. Renal failure 2. Degeneration or even necrosis of
4. Diabetes parenchymal cells
5. Heat-stroke
6. Water deprivation
o Mechanisms of dehydration
1. A decrease in total body water → deficit of water shared
among plasma –cells-interstitium.
2. Renal perfusion reduced
3. When severe see hypovolemic shock (plasma water drawin
into interstitium and cells)
Gross o Folds of skin pulled out from the body hesitate
before returning to their normal position:
“tenting” o Two factors in defining the types of congestion
o Eyes are sunken, mucous membranes and subQ a. DURATION
tissues are dry and sticky - Acute: implies abrupt onset w/ rapid development
- Chronic: slowly developing or present for a long
time
b. EXTENT
ALTERATIONS IN BLOOD FLOW AND PERFUSION
- Localized: change confined to a discrete area (eg.
1. HYPEREMIA
isolated venous obstruction)
2. CONGESTION
- Generalized: indicates a systemic change (eg.
Both terms indicate a local increase in blood within a tissue
cardiac failure)
1. HYPEREMIA - active
o Examples of Congestion
o Active engorgement of vascular beds due to increased
a. Localized Congestion
arteriolar airflow
 - Local obstruction to venous drainage (eg. intestinal
volvulus (torsion)/ intussusception/ strangulation
→ congestion of segments of s.i.
- Blood backs up into microvascular bed → passive
venous engorgement of the drainage area
b. Acute Generalized Congestion
- Sudden death due to heart failure/ eauthanasia
with barbiturates
- Blood accumulates in lung, spleen, liver
c. Congestion associated with pathology of heart or lung
- With left-sided heart failure: congestion of lungs
- With right sided heart failure: systemic congestion
(esp. liver) and edema (eg. ascites, subcutis,
hydrothorax)
- With certain types of primary pulmonary disease
→ progressive loss of pulmonary vascular bed →
pulmonary hypertension → right heart failure
secondary to pulmonary disease = Cor Pulmonale
- Lungs can be congested but still be red because
oxygenated blood in lungs wasn’t drained out;
therefore it is difficult to differentiate bw
hyperemia and congestion in the lungs.
Left-sided heart failure: congestion (& edema) of lungs
Right-sided heart failure: systemic congestion (esp. liver) + edema
d. Pulmonary Congestion
- Usu. due to left heart failure
- When acute: lungs are red (congestion), wet (edema) and
heavy
- Certain types of lung disease → progressive damage of
pulmonary vascular bed → increased resistance/ pulmonary
hypertension → right heart failure
Gross appearance o When acute: lungs are red (congestion), wet
(edema) and heavy
o When chronic: lungs can be lightly tan in
color (due to hemosiderin accumulation in
“heart failure cells”)
Histologic o Blood accumulated in capillaries/ on top of
appearance alveoli
Consequences of Chronic Pulmonary Congestion
- Chronic left ventricular failure → impedes forward flow of
blood from lungs → chronic passive congestion of lungs →
alveolar capillaries become engorged with blood (↑psi in
alveolar capillaries).
Intra-alveolar o Small capillaries rupture → focal hemorrhage
hemorrage into alveolar spaces → red cells are
phagocytized by alveolar macrophages → iron
from RBCs is stored as hemosiderin pigment
→ “heart failure cells”
o Heart failure cells: alveolar macrophages with
abundant hemosiderin can be stained with
H&E and also stains positive for iron with
Prussian blue staining
Pulmonary o Causes interference with gaseous exchange
edema
Interstitial o Fibroblasts secrete excess collagen in
fibrosis response to increased pressure in alveolar
capillaries & chronic edema in alveolar
interstitium (↑capillary pressure)
Pulmonary o Increased pressure in alveolar capillaries → inc
hypertension pressure in pulmonary arteries (cor
pulmonale) → pulmonary hypertension
o Cor pulmonale = right heart failure resulting
from pulmonary disease
e. Hepatic Congestion
Causes o most commonly due to right heart failure, eg.
valvular disease, myocardial damage on right side
of the heart, etc.
o occasionally secondary to pulmonary hypertension
(cor pulmonale)
Gross o Liver: enlarged with rounded edges and dark red-
appearance brown
o On cut surface has reticular appearance (ie regular
red and tan zonal pattern) = “nutmeg liver”
o Dark red areas correspond to congested zones
 around the central veins (zone 3) and yellow-brown
areas correspond to less affected/normal
parenchyma around the portal/ midzonal areas
(zone 1 & 2)
o Acutely: overall increase in liver size due to inc
volume of added blood
o Chronically: low-grade hypoxia & ↑psi → atrophy
& death of centrolobular hepatocytes & fibrosis
- Centrolobular necrosis: necrosis around
centrolobular vein
Histologic o Acute:
appearance 1. Central vein & sinusoids in zone 3 are distended
with RBC (congested). (redder around the
central vein, + pink in the lumen due to
edema)
2. Zone 3 (Central hepatocyte): congested sinusoids
& hepatocyte degeneration/ necrosis/ loss
due to hypoxia in stagnant blood.
3. Zone 2 (midzonal hepatocyte): fatty change due
to partial hypoxia.
4. Zone 1 (periportal hepatocytes): mostly normal
o Chronic:
1. Hemosiderin-filled macrophages (Kupffer cells)
due to erythrocyte phagocytosis.
2. Central (zone 3) dilation of sinusoids → atrophy
&/or loss (following necrosis) of centrolobular
hepatocytes
3. Low-grade hypoxia & increased pressure in zone
3 → increase fibrous CT (hepatic fibrosis) around
central veins(“Cardiac Cirrhosis”)
- Fibrosis: evidence of chronicity
o SUMMARY
Hyperemia Congestion
↑blood inflow ↓blood outflow
Oxygenated blood (red) Deoxygenated blood (blue)
Exercise, inflammation Obstruction
Active engorgement of Passive engorgement of vascular
vascular beds due to bed due to ↓blood outflow
↑arteriolar inflow
Gross: tissue red Gross: dark red to blue/black, ooze
(oxygenated Hb) & warm blood & wet
Eg. physiologic: exercise, Eg. gastric volvulus → twisting bvv
dissipate heart, blushing → obstructs gastric portion of portal
(neurovascular); pathologic, venous system → severe necrosis
parvovirus infection ingestion → ischemia (necrosis) →
loss of endothelial structure→
hemorrhage → shock →death
o HYPEREMIA/CONGESTION vs. HEMORRHAGE
- Hyperemia/congestion: blood inside of vessel wall (ie.
Intravascular)
- Hemorrhage: blood outside vessel wall (ie. Extravascular)
- Vs. edema: usu. only associated with fluid accumulation,
not blood
HEMORRHAGE
o Escape from blood from the cardiovascular system
(extravasation).
o May be external: discharge of blood from vascular compartment
to the exterior of the body
o Or internal: enclosed within a tissue
o Capillary bleeding can occur under conditions of chronic
congestion.
o Causes of Hemorrhage
1. Trauma → subQ, body cavity, intramuscular, or tissue
hemorrhage
2. Septicemia, viremia, or toxic conditions → widespread
petechiae and ecchymoses
3. Abdominal neoplasia → hemoperitoneum
4. Coagulation disorders → often large hemorrhages
5. Thrombocytopenia (dec. numbers of platelets) → often
small mucosal hemorrhages
a. Platelets: blood coagulating cells
b. In PH, associated with Dengue
c. In dogs, associated with elichiasis & epistaxis
o Significance of Hemorrhage
1. Location: two critical sites – CNS and HEART
- Subdural (or epidural) hematomas
a. Blood accumulation beneath (or above) the
dura; can compress brain
- Cardiac Tamponade due to Hemopericardium
a. Acute right heart failure due to massive blood
accumulation w/in the pericardial sac
b. Compresses atrium and ventricles (restriction of
cardiac filling)
c. Hemopericardium: blood present w/in
pericardial sac
2. Rate and Volume of Blood Loss
a. Severe blood loss → Hemorrhagic shock (most
common cause of hypovolemic shock)
o Terminologies of Hemorrhage
1. Hemorrhage by Rhexis
- Hemorrhage due to a substantial tear (rip/ rent) in a
blood vessel or heart
- Moderate to marked flow of blood out of
cardiovascular system
2. Hemorrhage by Diapedesis
- Bleeding from a small defect
- RBCs passing through vessel wall in hyperemia or
inflammation
- Eg. RBCs entering alveoli with chronic passive
congestion of lung
3. Hemorrhagic Diathesis
- Increased tendency to hemorrhage from usually
insignificant injuries
- In wide variety of clinical disorders
a. Platelet disorder
b. Coagulation deficiency
- Hemophilia: a type of coagulation disorder; includes
several hereditary disorders in which the blood fails to
clot normally because of a deficiency or abnormality
of clotting factors.
4. Hematoma
- Extravascular, 3-D blood clot, enclosed within a
tissue; may be small or very large
5. Hemopericardium
- Blood in the pericardial sac
6. Hemothorax
- Blood in the pleural cavity
7. Hemoperitoneum
- Blood in the peritoneal cavity
8. Hemarthrosis
- Blood present in joint spaces
9. Hemoptysis
- Coughing up of blood from the lungs/ airways
10. Epistaxis
- Bleeding from the nose
 11. Petechia (pl. petechiae)
- Small, up to 1-2 mm, hemorrhages; esp. on skin,
mucosal/ serosal surfaces
12. Purpura
- Hemorrhages 3mm – 1 cm, often scattered on skin &
mucus membranes
- Often seen with diseases that cause petechiae
(vascular inflammation/ damage).
13. Ecchymosis (pl. ecchymoses)
- Hemorrhages larger than petechiae (>1 or 2 cm).
- Often blotchy or irregular; as seen in bruise
(contusion) or small hematoma
14. Agonal Hemorrhages 2. Primary hemostasis – PLATELET
- Small hemorrhages (petechiae & ecchymoses) - damage to endothelium exposes the subendothelial
associated with the death struggle (ie terminal ECM
hypoxia) - Causes platelets to:
15. Suffusive Hemorrhage i. Adhere to ECM (adhesion)
- Affected areas of hemorrhage are larger than ii. Shape change (from round discs to flat plates)
ecchymosis and contiguous iii. Release granules (components to promote
16. Paint Brush Hemorrhages hemostasis)
- Hemorrhages which look as though red paint was iv. Recruit other platelets to site (aggregation)
hastily applied w/ a paint brush - Forms a primary hemostatic (platelet) plug → covers &
- most commonly found on serosal or mucosal seals small area of vascular damage
surfaces. - If minimal injury, platelet plug may be adequate; if more
o Resolution of Hemorrhage severe injury → secondary hemostasis
1. Resoprtion
- Dependent on amount: small amount can be
reabsorbed
- Larger areas: require breakdown & removal of RBCs
2. Organization
- Larger amounts of hemorrhage requires phagocytosis
and degradation by macrophages
- Hemoglobin (red-blue) → Bilirubin (blue-green) →
Hemosiderin (yellow-brown)
3. Organizing Hematoma
- Center: mass of fibrin & RBCs surrounded by vascular
CT → phagyocytosed and degraded by macrophages
→ see pigments from degraded hemoglobin
3. Secondary hemostasis – COAGULATION (formation of
- Outside: vascularized fibrous tissue (supplies
fibrin)
nutrients & support)
a. Tissue factor (TF) release
HEMOSTASIS - A membrane-bound procoagulant factor is
o Refers to the arrest of bleeding exposed at the site of injury (esp damaged
o Normally is a well-regulated process to: endothelium)
1. Keep blood fluid (clot free) within a normal vessel - Acts in conjuction with material secreted by
2. Rapid clot formation (hemostatic plug) occurs when vessel platelets to activate the coagulation cascade
is injured (generates thrombin)
o Hemostatic clot: normal in cases of vessel injury b. Platelets
o Thrombosis: refers to an inappropriate activation of the - Expose phospholipid complexes (provide sites
hemostatic process for coagulation reactions).
o Three general components required for hemostasis and c. Thrombin activation
thrombosis: - Formation of thrombin induces more platelet
1. Endothelial cells (vascular wall) recruitment & granule release
2. Platelets - Converts fibrinogen to fibrin monomers (soluble)
3. Coagulation Cascade d. Fibrin polymerization/ stabilization
o Sequence of events following vascular injury (Normal - Local fibrin deposition cements & anchors
Hemostasis): primary platelet aggregate, ie secondary
1. Arteriolar vasoconstriction – VASCULAR WALL (transient hemostatic plug
effect)
due to:
a. reflex neurogenic mechanism
b. local secretion of endothelin (from endothelium)
 4. Antithrombotic Counter-Regulation
- release of components to limit the size of hemostatic
plug

2. Prothrombotic (Procoagulant) Properties of Endothelial

Cells
- Endothelial cells may be injured directly or activated
by infectious agents (eg. bacterial endotoxin),
hemodynamic factors, plasma mediators & cytokines
(eg. TNF, or IL-1)
o Endothelial Factors a. Von Willebrand factor (vWF)
- Injury ot the endothelium: major initiating event for - Endothelial cells synthesize, store & release;
thrombosis & coagulation essential cofactor for platelet binding to collagen
- Normal endothelium: meodulates many aspects of normal & other surfaces
hemostasis. b. Tissue Factor (TF = Factor III = thromboplastin)
- Endothelium: modulates many aspects of normal - Injured endothelial cells are induced to secrete
hemostasis TF which activates the extrinsic clotting pathway.
- Antithrombotic: Provides a surface that promotes the c. Plasminogen activator inhibitors (PAIs)
smooth, nonturbulent flow of blood - Endothelial cells secrete PAI’s which suppresses
- Prothrombotic: when necessary, produces and fibrinolysis (via counteracting PA’s).
responds to substances to form a thrombus/ clot
- When required it can also enhance vasodilation and inhibit
platelet adhesion, aggregation and coagulation
1. Antithrombotic Properties of Endothelial Cells
a. Antiplatelet
i. Barrier: prevent platelets & plasma factors from
being exposed to subendothelial matrix
ii. Prostacyclin and nitric oxide (NO): inhibit platelet
adhesion/ aggregation and maintains vascular
relaxation
iii. Adenosine diphosphatase (ADPase): expressed to
degrade ADP (ADP promotes platelets
aggregation).
b. Anticoagulant properties
i. Heparin-like molecules: membrane-binding sites
for antithrobmbin III → inactivate thrombin +
factor Xa + other factors
ii. Thrombomodulin: binds to thrombin converting it
to an anticoagulant which can activate protein C →
active Protein C (with Protein S) → inhibits clotting
by cleaving factors Va and VIIIa
iii. Tissue factor pathway inhibitor (TFPI): synthesized
and express on membrane → complexes and
inactivates TF-VIIa and Xa.
c. Fibrinolytic properties
3. Vascular Repair
i. Plasminogen activators (PA’s): synthesize tissue PA
Numerous growth factors are secreted by endothelial
(tPA) → activates plasmin (fibrinolytic) → removes
cells:
fibrin from endothelial surfaces
 a. Platelet Derived Growth Factor (PDGF): stimulates
smooth muscle and fibroblasts proliferation
b. Fibroblast Growth Factor (FGF): stimulates
angiogenesis & fibroblasts in wound healing.
c. Transforming Growth Factor-β (TFG-β) modulates
vascular repair.
o Platelets
- Derived from megakaryocytes; circulate as round, smooth
discs
- Play central role in hemostasis → contain mostly
procoagulants (& few anticoagulants)
- Major role: form the primary hemostatic plug → covers
and seals a small damaged area
a. Platelet Response
- Vascular injury → exposes ECM (esp collagen);
normally hidden by endothelium
- Platelets + ECM → 3 reactions:
Adhesion and o Adhesion mediated via interactions with vWF
shape change → acts as bridge for platelet surface receptors
& ECM
Secretion o Release of dense granules is important bc Ca2+
(release is required for coagulation cascade and ADP is
reaction) of an important mediator of platelet aggregation
granules o Leads to surface expression of phospholipid
complexes (binding site for Ca2+ & coagulation
factors)
Aggregation o Thromboxane A2 (TxA2) secreted by platelets
→ induces vasoconstriction & platelet
aggregation
o ADP + TxA2 start reaction → enlarged platelet
aggregation → 10 hemostatic plug
b. Thrombocytopenia
Definition o Platelet numbers are low when compared to
normal reference ranges
o <100 x 109/L is a thrombocytopenia in many
species
Diagnosis o History of bleeding
o Low platelet counts
Mechanisms o Deficient formation of platelets (eg. estrogen
toxicity suppresses marrow production in dogs)
o Excessive utilization (eg. consumptive
coagulopathies)
o Premature destruction (eg. antibodies to
platelets)
c. Thrombocytopathy
Definition o Defective platelet function
Mechanisms o Defect in adhesion (eg. von Willebard’s disease)
o Defect in aggregation
o Defect in release of granules
o Coagulation Cascade
- Third arm of hemostasis → an enzymatic cascade
- A reaction pathway: enzyme (previously activated
coagulation factor) + substrate (next non-activated
coagulation factor) → activated coagulation factor
- Reaction typically occurs on platelet phospholipid complex
held together by Ca2+
- Culmination of cascade: production of thrombin (bound to
platelet surface) → thrombin converts soluble fibrinogen
to fibrin → stabilizes the hemostatic plug
- Generation of thormbin: most important factor in the
progression & stabilization of the clot (thrombus).
- Thrombin can be generated at the site of injury by either
the intrinsic or extrinsic coagulation pathway which
converge where factor X is activated.
1. Intrinsic Pathway
- All factors present in normal plasma
- Cascade is activated by contact of factor XII (Hageman
factor) with subendothelial collagen (ie ECM)
2. Extrinsic Pathway
- Tissue factor (Factor III/ thromboplastin) is a cell
surface protein (esp on injured endothelial cells) that
interacts with circulating factor VII to initiate the
extrinsic pathway
3. Common Pathway: fibrin formation
a. Proteolysis of Factor X at terminus of both intrinsic &
extrinsic coagulation pathways → Activated factor X
(Xa)
b. Xa converts prothrombin to thrombin
c. Calcium and platelet surface phospholipids also
necessary for factor Xa to be activated
d. Thrombin cleaves peptides from plasma fibrinogen
(soluble) → fibrin monomers
e. Monomers self-polymerize → larger fibrin polymers
(insoluble) → cross-linked/stabilized by factor XIII a
f. Results:
→ Contraction of fibrin-platelet thrombus
→ Reduces size of thrombus (restore blood flow)
→ Draws damaged vessel edges closer (for healing).
4. Anticoagulation/Fibrinolytic System
a. Fibrinolytic cascade limits the size &/or dissolves
thrombus (temporary patch)
b. Primarily by the generation of plasmin (from inactive
circulating precursor plasminogen)
c. Plasminogen activated by tPA’s &/or intrinsic
coagulation (XIIa-kallirein)
d. Fibrin degradation products FDPs have anticoagulant
activity & used as measure of thrombotic states
PLASMINOGEN (in plasma)
↓
↓ PLASMINOGEN ACTIVATOR (counteracted by PAI’s)
↓
PLASMIN
 ↓ o Artherosclerosis: foam cells (manifestation); almost always the
↓ cause of endothelial damage leading to thrombus in coronary
FIBRIN→→→ BREAKDOWN PRODUCTS (Fibrin Degradation
Products)
5. Coagulation Disorders
2. In general, large hematomas suggest a coagulation
disorder whereas chronic bleeding (petechial/ecchymotic
hemorrhage) from a mucosal surface is may indicate a
platelet deficiency or abnormality
a. Inherited Deficiensies of Coagulation
b. Acquired Deficiencies of Coagulation
- Can be due to decreased production or
increased use (overconsumption)
i. Accompany many severe diseases
- Transitory depression of factor synthesis
- Excessive utilization (consumption) of
factors
ii. Acquired disorders may be general/ specific
- Severe trauma or deep burns
- Snake venoms and plant toxins
- Vitamin K deficiency (required for factors
II, VII, IX, X, and proteins C and S)
iii. Liver failure
- Site of synthesis of many coagulation
factors
- Acute destruction of hepatocytes or
chronic liver disease may result in
coagulopathy
THROMBOSIS
o inappropriate activation of hemostatic process in uninjured or
slightly injured vessels
o Formation or presence of a solid mass (thrombus) within CV
system – blood vessels or heart.
THROMBUS (pl. thrombi)
o Histopathology: Aggregate of platelets and fibrin with entrapment
of rbc’s/wbc’s
o Can lead to vascular obstruction (±complete) and embolism
o Often adherent to vascular wall (differentiating feature from a
simple post-mortem blood clot)
o May develop anywhere in CV system, valves, artieries, veins,
capillaries.
o Grow in direction of blood flow (eg. arterial thombi grow away
from heart while venous thrombi grow toward the heart)
o Pieces can break off forming emboli
o Growth of thrombus is downstream
o Normal blood vessel: no fibrin
o Fibrin: formed during vascular damage
o Fibrin amongst RBC in blood vessel = clotting; thrombus
o Thrombus can cause: heart attack (heart) or stroke (brain)
o Areas of obstruction → necrosis
artery
PATHOGENESIS OF THROMBOSIS
o Three primary influences = Virchow’s triad
1. Endothelial injury
- Dominant influence = can lead to thrombosis by itself
- Eg. inflammation of heart valves (endocarditis) →
exposure of subendothelial ECM → platelet
adherence/ release of tissue factor → primary and
secondary hemostatic plug formation
- Attempts to repair, but w/o nutrients (eg. Vit C
deficiency) fats are used to patch up the blood vessels
- Eg. Mouth sore treatment: vit C (synthesis of
collagen)
2. Alterations in normal blood flow
- Normal blod flow is laminar: cellular elements in the
middle, surrounded by plasma
- Turbulence or stasis → disrupts normal laminar flow
allowing platelets to contact endothelium:
a. Tubulence: promotes endothelial cell
injury/activation
b. Stasis: prevents dilution of activated clotting
factors by flesh-flowing blood → build up of
thombi
- Aspirin: a blood thinner, given to people with risk of
blood coagulation (decreases chances of stroke and
heart attack)
3. Hypercoagulability
- Any alteration of the coagulation pathways that
predisposes to thrombosis
- Generally due to
a. ↑increased coagulation factors (eg. with sepsis)
b. ↓inhibitory factors (eg. loss of antithrombin III
with glomerular disease)
o Location in Cardiovascular System
1. Valves: Thrombi on the heart valves is often associated
with a infection / inflammation of the valves (ie septic
thrombi of bacterial endocarditis, eg. Erysipelothrix
rhusiopathiae or diamond skin disease; dislodged in lungs
→ multifocal coagulation)
2. Arterial thrombi: grow away from the heart
3. Venous thrombi: grow toward the heart
TERMINOLOGIES
o Arterial thrombi
- Usually form at sites of endothelial injury
- Often paler & “meatier” than a venous thrombi
- Composed mainly of platelets & fibrin, bc rapid blood flow
tends to exclude rbc’s
 - Can have alternating dark and pale lamination (lines of - Both of the above aid in the reflow of blood
Zahn): reflects continued waves of thrombosis, ie pale - Not competely resolved
layers (mostly fibrin/ platelets) alternating with dark red
layers (more entrapped rbc’s) EMBOLISM
o Venous thrombi o Passage through the venous or arterial circulation of any material
- Usually form in static (slow flow) movements, with more capable of lodging in a blood vessel and thereby obstructing the
entrapped rbc’s lumen
- Fibrin strands with entrapped rbc’s → more uniformly dark o Most common embolism: thromboembolism, ie from piece/s
red colored broken off of a thrombus
- Sometimes difficult to differentiate from post-mortem EMBOLUS (pl. emboli)
blood clot (can look similar) o Detached intravascular material (solid, liquid, or gaseous) carried
o Blood clot via blood to a site distant from its origin
- Clotted blood within a blood vessel THROMBOEMBOLISM
- can refer to thrombus or post-mortem blood clot (so be o Occlusion of a blood vessel by an embolus that has broken away
specific) from a thrombus
- Post-mortem blood clots are not associated with o Localizes at point where it can no longer “fit” through
pathological change & usu. not attached to wall COMPOSITION OF EMBOLI
o Chicken-Fat Clot o Remember most emboli are thromboemboli, however many other
- Gelatinous, yellow, post-mortem blood clot types exist, eg:
- Due to rapid erythrocyte sedimentation in animals with 1. Parasites
high fibrinogen a. Nematodes: Dirofilaria immitis (heartworm)
- Yellow areas: represent fibrin and plasma b. Nematode larvae: Ascarid or Strongylus vulgaris
- Dark red areas at margins: represent sedimented RBCs (affecting cranial mesenteric artery in horses)
- Mostly horses, pigs 2. Fibrocartilaginous emboli
- Yellow color may be bc of diet (corn, soy meal GMO) a. Originate from intervertebral disk material (traumatic
- Post-mortem blood clot means it is not a lesion implantation into spinal vessels)
- Erythrocytes settle due to gravity in a post-mortem blood b. Causes necrotizing myelopathy (spinal cord infarction)
clot similar to blood in a test tube; giving “chicken fat” c. Alcian blue stain: stains cartilage (recall Prussian blue
appearance to the upper part of the clot. stains iron, Rodanine stains copper, PAS stains
o Morphological Differentiation of Thrombi vs PM Clots glycogen)
Arterial Venous Post-Mortem 3. Fat
Thrombus Thrombus Clot a. Bone fractures
Colour Pale to dark Red Yellow = b. Surgery
red chicken fat c. Osteomyelitis
Lamination Yes Not frequent No d. Hyperlipidemia
Attachment Yes Often No 4. Other
Size & Location Often small Often fill lumen Fill lumen a. Foreign material (eg. hair, air bubbles, etc.)
o Outcome of thrombi b. Tumor cell clusters (“tumor emboli”)
c. Amniotic fluid
d. When injecting, ensure no air bubbles are trapped in
the syringe as this can cause embolus
Infectious causes of thrombosis or thromboembolism
o Infectious agents can damage endothelium, thereby causing
thrombosis and/or thromboembolism, eg:
- Many bacteria can cause valvular endocarditis →
thrombosis and thromboembolism
- Histophilus somni in cattle: cause thrombotic
meningoencephalitis
- Several viral agents (eg. hog cholera, equine viral arteritis)
can damage endothelium → thrombosis
- Erysipelothrix rhusiopathiae, Streptococcus suis
- Bacterial endocarditis in cattle often involves the right AV
1. Lysis (resolution) valves. They often give rise to septic thromboemboli which
- esp. when small and in early phase due to potent shower and implant in small branches of the pulmonary
thrombolytic/ fibrinolytic activity of blood artery, resulting in scattered inflammatory foci (ie embolic
2. Propagation pneumonia)
- Increase in size, which may eventually obstruct the Disseminated Intravascular Coagulation (DIC)
vessel o sudden onset of fibrin thrombi in microcirculation (not visible
3. Embolization grossly)
- Can occur if piece/s break off (floating around) o Can cause diffuse circulatory insufficiency, particularly in:
4. Organization and Recanalization 1. Brain
- Presence of thrombi: induces inflammation & fibrosis 2. Lungs
(organization); latter reduces size 3. Heart
- New small bvv can penetrate/ grow within the 4. Kidneys
organizing thrombus (recanalization)
o Development of multiple thrombi → rapid concurrent
consumption of platelets & coagulation proteins + fibrinolytic
mechanisms activated → initial thombotic disorder can evolve
into a serious bleeding disorder → consumption coagulopathy
o Note: DIC is not a primary disease but a potential complication of
any condition associated with widespread activation of thrombin
o Some causes:
1. Severe burns
2. Heatstroke
3. Systemic viral disease
4. Shock (toxemia / septicemia)
5. Widespread metastatic tumors
6. Heartworm disease (dogs)
INFARCTION
o An area of ischemic necrosis resulting from occlusion of either
arterial supply or venous drainage
o Most due to thrombosis, embolism or vascular occlusion due to
compressed/ twisted vessels (eg. Intestinal volvulus, testicular
torsion, etc.)
o ~40% of human deaths in north america result of cv disease,
mostly from myocardial or cerebral infarction (heart & brain)
o Pulmonary, intestinal and renal infarction most common in
domestic animals
o Factors that Incluence Development of an Infarct
1. Nature of the vascular supply: end artery (eg. kidney) vs.
availability of collateral blood supply (eg. lung)
2. Rate of development of occlusion: if slow, allows collateral
supply to fully open
3. Vulnerability to hypoxia: eg. differential vulnerability of
certain cell types to ischemia (esp. brain and heart)
4. O2 content of blood at time of infarct: eg. underlying
anemia would increase severity of infarct
Gross o Often wedge-shaped with base at periphery and
appearance occluded vessel at the apex
o Early: ill-defined (+/- irregular margins) and often
hyperemic
o by 48 hours (later) most become paler.
>Red Infarct = o Due to blood in infarct
hemorrhagic o Some acute renal infarcts due to rbcs leaking in
infarct from adjacent arteries and veins (eventual rbc
lysis →pale
o In venous occlusions (no drainage), ie preventing
blood from draining (eg volvulus, strangulations)
→ venous infarct
o Also in organs with dual (multiple) blood supply
(eg. lung, liver) or where blood collects in loose
tissue (usu. at margin of lungs)
o Pulmonary infarct: typical dark areas (mostly deox
blood) at margins of lobes
>White infarct o Lack of blood in infarct
=pale/anemic o Mostly with arterial occlusions in solid organs
infarct with end arterial circulation (eg. heart, kidney)
o Usu. has a red zone at periphery bc the capillaries
at the border of infarct undergo dissolution and
blood seeps into this marginal area.
o Eg. pale infarct in kidney: pyramidal-shaped,
bulge above capsular surface indicative of cell
swelling
Histopatholog o Ischemic necrosis of affected parenchyma tissues
y (coagulative necrosis in all tissues, except brain)
o Infarcts arising from septic (bacterially infected)
emboli may be converted to an abscess.
Repair of Infarcts
o Fibrous CT (scar tissue) replaces parenchyma
o parenchymal loss + fibrous tissue contraction = depression/ indent
on organ surface
Septic Infarct
o Develop from a bacterially infected thromboembolus (eg. valvular
endocarditis)
o Or when necrotic tissue of an infarct is seeded by opportunistic
bacteria.
Venous Obstruction/ Venous Infarction
o Severe venous obstruction can cause venous infarction
o Mostly due to twisting of vessels (eg. intestinal volvulus/ torsion/
strangulation) → shock/ death
o Also seen with obstruction (eg. thrombosis or tumor invasion) of
anterior/ posterior vena cava; often incomplete obstruction
causing slowly developing stasis w/ engorgement of tributary
veins
o Acute Blockage of the Portal Venous System
- Mostly with twists in portions of GIT/ portal venous system
→ venous infarction of stomach/ intestine; twisted vessels
are compressed, but bc arterial > venous pressure → blood
gets into tissue, but not out
- Sequelae: shock and death w/o surgery
- Eg. gastric torsions (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 Posterior Vena Cava
Etiologies o Eg. severe dirofilariasis or adrenal tumors in dogs
o Rupture of hepatic abscesses into caudal vena cava in
ruminants
Result o Acute, complete occlusion → death
o Chronic → possibility of collateral circulation
developing from azygous vein
Pulmonary Artery Thrombosis
Etiologies o Eg. pneumonia
o parasities (eg heartworm)
o hypercoagulability (eg nephrotic syndrome,
hyperadrenocorticism, ie Cushing’s disease)
o liver abscess rupture into vena cava (ruminants)
o deep vein thromboembolism (eg humans, downer
cows)
Result o If sudden and large branch of artery → death
o If incomplete and smaller branches → variably altered
circulation or possible pulmonary infarcts (usu. red)
SHOCK
o Systemic hypotension due to reduced cardiac output or reduced
blood volume
o Final common pathway for many potentially lethal clinical events,
eg:
1. Microbial sepsis
2. Severe hemorrhage
3. Extensive trauma or burns
4. Myocardial damage
5. Severe pulmonary embolism
o Results in impaired tissue perfusion and cellular hypoxia
o Brain and heart are organs most susceptible to ischemic damage
from shock
o Three General Categories of Shock
1. Cardiogenic Shock
- Results from failure of heart to adequately pump
blood, ie cardiac output is decreased
- Can occur w/ a variety of heart disesaes, eg.
 a. Myocardial infarction 6. Brain: neuronal cell death
b. Ventricular tachycardia 7. Adrenal glands: hemorrhage
c. Arrhythmias 8. Gastrointestinal tract: mucosal congestion + necrosis
d. Cardiomyopathy 9. Skeletal muscle: pallor (probably due to peripheral
e. Obstruction of flow of blood from the heart vasoconstriction)
2. Hypovolemic Shock
- Results from decreased circulating blood volume
- Can be due to blood loss form hemorrhage or fluid
loss (dehydration) secondary to vomiting, diarrhea, or
burns
3. Blood Maldistribution (Vasogenic Shock)
- See a decrease in peripheral vascular resistance →
pooling of blood in peripheral tissues
- Many causes, including:
a. Neural or cytokine induced vasodilation
b. Trauma
c. Systemic hypersensitivity to allergens
(anaphylaxis)
d. Endotoxemia
- Especially vasodilation due to:
a. Anaphylactic shock: vasodilation due to release
of vasoactive amines (histamine)
b. Neurogenic shock: vasodilation due to loss of
ANS signals to smooth mm. in vessel walls
c. Septic shock: vasodilation due to overwhelming
infections (esp. gram-negative)
Pathogenesis of Septic Shock
Microbial substances (eg LPS/endotoxin from gram- bacteria,
peptidoglycan from gram+ bacteria) are released from bacteria
↓
Bind to TLRs: activation/ injury of endothelial cells + stimulates
WBC’s to release cytokines (eg. TNF, IL-1)
↓
Vasodilation, prothrombotic (DIC), complement activation, etc.

o Note: all of the cellular & hemodynamic effects of septic schock

can be produced with LPS injection alone.
Three Stages of Shock
1. Nonprogressive (compensated) shock
o Reflex compensatory mechanisms are activated and
perfusion of vital organs is maintained
2. Progressive Shock
o Characterized by: tissue hypoperfusion and onset of
worsening circulatory + metabolic imbalances, including
acidosis
3. Irreversible Shock
o Sets in after body has incurred cellular & tissue injury so
severe that even if the hemodynamic defects are corrected,
survival is not possible
Eg. In hypovolemic shock, there is initially compensation
characterized by increased cardiac rate and output, vasoconstriction
of nonessential vascular beds, and predominantly oxidative
metabolism by morphologically normal cells(1). With progression,
cardiac output falls as peripheral vasodilation occurs and cell
metabolism shifts to glycolysis with progressive morphological
changes in cells (2 → 3).
Lesions of Shock
o Shock is characterized by failure of multiple organ systems:
1. Pulmonary edema: prominent shock organ of cattle and
horses
2. Liver congestion: prominent shock organ of dogs
3. Kidneys: acute tubular necrosis
4. Heart: subendocardial hemorrhage + myocardial necrosis
5. Blood vessels: endothelial damage w/ possible
thrombosis/ DIC