CHAPTER 4

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HEMODYNAMIC DISORDERS, THROMBOEMBOLIC DISEASE,
AND SHOCK

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EDEMA
• Extravascular fluid collection +/- involvement of body cavities
• Increased capillary pressure or decreased osmotic pressure can equal increased interstitial fluid
• Transudate: protein poor fluid caused by increased hydrostatic pressure or reduced plasma protein ex.
Heart failure, renal failure, hepatic failure and malnutrition
• Exudate: protein rich from increased vascular permeability

Pathophysiologic categories of edema

Increased hydrostatic Reduced plasma osmotic Lymphatic obstruction Sodium retention Inflammation
pressure pressure
Impaired venous return Nephrotic syndrome -Inflammatory -Excess sodium intake -Acute inflammation
• CHF Liver cirrhosis -Neoplastic -Increased tubular -Chronic inflammation
• Constrictive Malnutrition -Post surgical reabsorption -Angiogenesis
pericarditis Protein losing -Post irradiation
• Ascites gastroenteropathy

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• Venous obstruction

Arteriolar dilatation
• Heat
• Neurohumoral
dysregulation

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HYPEREMIA AND CONGESTION
• Hyperemia (active process) - arteriolar dilatation
• Congestion (passive process) - reduced outflow of blood from tissues
• Local increase in blood volume
• Ex. Acute and chronic pulmonary congestion
• Acute and chronic hepatic congestion
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HEMORRHAGE
• Hemorrhage: extravasated blood into extravascular spaces
• Hematoma---accumulated blood that is either external or within tissue
• Increased tendency to hemorrhage - hemorrhagic diatheses
• Patterns of tissue hemorrhage:
• Petechiae - 1 to 2mm
• Usually associated with locally increased intravascular pressures, low platelets or
defective platelet function
• Purpura - >3mm
• Similar associations as petechiae, but also seen in trauma, vasculitis and increased
vascular fragility
• Ecchymoses (subcutaneous hematoma) - >1 to 2cm
• Presence of RBCs that are degraded and phagocytized by macrophages
• Enzymatic conversion of hemoglobin
• Within body cavities - hemothorax, hemopericardium, hemoperitoneum, hemoarthrosis
!
• Clinical significance of hemorrhage is dependent on the volume and rate of loss
• Ex. > losses than 20% of the blood volume may lead to hemorrhagic shock
• Site of hemorrhage is important
• Chronic hemorrhages - consider iron deficiency
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HEMOSTASIS AND THROMBOSIS

NORMAL HEMOSTASIS
• Vasoconstriction Local  activation  of  coagulation  cascade  
• Primary hemostasis → hemostatic plug (involving  TF  and  platelets  phospholipid)  →  
fibrin  polymerization,  “cementing”  the  
• Secondary hemostasis → tissue factor activates coagulation platelets  into  a  definitive  secondary  
cascade with activation of thrombin hemostatic  plug

• Thrombus and antithrombotic events → permanent plug and

tPA
!! Vascular  injury  →  local  neurohumoral  
factors  induce  transient  vasoconstriction
Endothelium
• Endothelial cells are key players in regulation of
homeostasis, as the balance between the anti- and
prothrombotic activities of endothelium determines whether Platelets  bing  via  glyoprotein  Ib  (GpIb)  
thrombus formation, propagation, or dissolution occurs. receptors  to  vWF  on  exposed  ECM  and  are  
activated,  undergoing  a  shape  change  and  
• Normally, endothelial cells exhibit antiplatelet, granule  release  (ADP  and  TxA2)  →  induce  
additional  pot  aggregation  through  GpIIb-­‐
anticoagulant, and fibrinolytic properties; however, after IIIa  receptor  bindings  to  fibrinogen  →  
injury or activation they acquire numerous procoagulant primary  hemostatic  plug.

activities
• Besides trauma, endothelium can be activated by infectious
agents, hemodynamic forces, plasma mediators, and Counter-­‐regulatory  mechanis,ms,  
mediated  by  t-­‐PA,  a  fibrinolytic  product)  
cytokines.
! and  thrombomopdulin,  confine  the  
hemostatic  process  to  site  of  injury

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 Table 2 Endothelial antithrombotic and prothrombotic properties

Antithrombotic properties Thrombotic properties

Antiplatelet - NO and PGI2 Platelet effect - vWF products
Anticoagulation - heparin like molecules with a Procoagulant - tissue factor, synthesis induction
antithrombin III, thrombomodulin, and protein C/S
Fibrinolytic effect - produce tPA Antifibrinolytic - secrete plasminogen activator

Platelets
• Platelets---anuclear cell fragments from megakaryocytes that have an important role in hemostasis
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Coagulation Cascase
• Vitamin K dependent factors (II, VII, IX, X)
• Note some overlap in the pathways since the do end up having a common pathway at the end of the
cascade

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 Comparison of extrinsic and intrinsic pathways in coagulation

Extrinsic Intrinsic
Activated by tissue injury and Factor VII Activated in vitro with Hagemann factor (XII)
Physiologically more relevant
Prothrombin time (PT) assesses VII, X, II, V and fibrinogen Partial thromboplastin time (PTT) assesses XII, XI, IX, VIII, X, V, II
and fibrinogen

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Conversion of factor X to factor Xa via extrinsic pathway:

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• After coagulation cascade is activated, it also activates the fibrinolytic cascade
• Fibrinolysis mainly determined by plasmin
• Plasminogen (inactive) - plasmin (converted by factor XII dependent path or by
plasminogen activator (PA))
• Most important PA is t-PA produced by the endothelium
• As a result, fibrin split products (FSPs) occur
• FSPs can be weak anticoagulants
• One important one is fibrin derived D-dimers
• Elevated FSPs can be used to determine abnormal thrombotic states:
• Disseminated intravascular coagulation (DIC)
• Deep venous thrombosis
• Pulmonary thrombosis
!
• Role of thrombin in hemostasis and cellular activation:

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THROMBOSIS
• Virchow’s Triad (abnormal blood flow, endothelial injury, hypercoagulability)
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Abnormal blood flow
• Normal flow is laminar - platelets flow centrally in the vessel, separated from endothelium by plasma
• Turbulence (important in arterial and cardiac thrombus formation) and stasis (important in venous
thrombus formation)
• Promotes endothelial activation
• Contact between platelets and endothelium
• Prevents washout/dilution of activated clotting factors
• Clinically, thrombus formation by turbulence and stasis is seen in the following examples:
• Ulcerated atherosclerotic plaques - create turbulence
• Aneurysms - create local stasis
• Myocardial infarctions - noncontractile areas which lead to stasis
• Rheumatic mitral valve stenosis - left atrial dilatation with atrial fibrillation can cause
stasis
• Polycythemia vera - hyperviscosity which can increase resistance to flow and lead to
stasis in small vessels
• Sickle cell anemia - vascular occlusions with stasis
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Endothelial injury
• Important in thrombi that occur in the heart and arterial system
• Results from a disruption in the endothelium or dysfunction in the endothelial cell
• Disruption - physical injury
• Endothelial dysfunction - hypertension, turbulent blood flow, bacterial endotoxins, radiation,
metabolic abnormalities, smoking
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Hypercoagulability
• Aka thrombophilia
• Less frequent contributor to thrombosis but important one
• If a patient is <50 years of age with thrombosis, inherited hypercoagulability should be considered
• May have primary and secondary disorders (refer to Table 4)
• Most important inherited one is point mutation in Factor V gene and prothrombin gene:
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• Factor V or Leiden mutation
• in 2-15% of Caucasians
• Recurrent DVTs, up to 60% of patients have this mutation
• Glutamine → arginine substitution at 506 position
• Heterozygotes have a five fold relative risk of venous thrombosis
• Homozygotes have a 50-fold relative risk increase in venous thrombosis
!
• Prothrombin gene mutation - is a single nucleotide change in the 3prime untranslated
region
• Seen in 1-2% of the population
• Elevated prothrombin levels
• 3 fold increased risk of venous thrombosis
!
• Homocystinuria
• elevated levels of homocysteine which may occur because of an inherited
deficiency in cystathione beta-synthetase
• A more mild homocysteinemia may occur with the variant form of 5,10-
methylenetetrahydrofolate reductase which can be seen in 5-15% of Caucasians
and eastern Asians
• May develop arterial and venous thrombi
• Also important in the development of atherosclerosis

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 • Folic acid, pyridoxine and vitamin b12 supplements have been found to elevate
homocysteine concentrations but the risk of thrombosis is the same
!
• Antithrombin III, Protein C/S deficiencies
• will result in venous thrombosis and recurrent thromboemboli may be seen
• Early onset
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• Heparin induced thrombocytopenia syndrome
• Acquired hypercoagulable states
• Occurs after receiving unfractionated heparin → possible antibodies produced
against complexes of heparin and platelet factors
• Antibodies result in activation aggregation and consumption leading to a
prothrombotic state
• Low molecular weight heparin preparations are less likely to cause HIT
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• Antiphospholipid antibody syndrome
• Aka lupus anticoagulant syndrome
• Clinically present with recurrent thromboses, repeated miscarriages, cardiac
valve vegetations, and thrombocytopenia
• Antibodies bind to plasma proteins creating a hypercoagulable state in vivo
• In vitro antibodies act with phospholipids and inhibit coagulation
• May be primary or secondary:
• Primary - only hypercoagulable state without any autoimmune disorder
• Drugs or infection may be the cause
• Secondary - seen in individuals with an autoimmune disease like SLE
• An aggressive form called catastrophic antiphospholipid syndrome exists
• 50% mortality
• Clinically relevant since surgery more difficult
• Increased complications
• Diagnosis both by measuring for these antibodies and clinical presentation
• 5-15% of individuals may have antibodies but are asymptomatic
• Treatment for the syndrome includes anticoagulation and immunosuppression

Classification of hypercoaguable states (highlighted ones are discussed above)

Primary (genetic) Secondary (acquired)

Common High risk for thrombosis
• Factor V mutation • immobilization
• Prothrombin mutation • myocardial infarction
• 5,10-methylenetetrahydorfolatereductase homozygous mutation • atrial fibrillation
• increased levels of factors VIII, IX, XI, fibrinogen • tissue injury
• cancer
• prosthetic cardiac valves
• disseminated intravascular coagulation
• heparin induced thrombocytopenia
• antiphospholipid antibody syndrome

Rare Lower risk for thrombosis

• antithrombin III deficiency • cardiomyopathy
• Protein C deficiency • nephrotic syndrome
• Protein S deficiency • hyperestrogenic states
• oral contraceptive use
• sickle cell anemia
• smoking

Very rare
• Fibrinolysis defects
• homozygous homocystinuria

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Pathology of thrombi
• Thrombi develop anywhere in the CV system
• Size and shape of thrombus dependent on site of origin and the etiology
• Thrombi will adhere to vascular surface
• Arterial thrombi:
• grow retrograde
• Usually occur at sites of endothelial injury or turbulence (same with cardiac thrombi)
• Usually occlusive
• Known as mural thrombi
• Most common sites include coronary, cerebral and femoral arteries
• Typically superimposed on ruptured atherosclerotic plaque
• trauma and vasculitis are other important etiologies in the aortic thrombi while
abnormal myocardial contraction, endomyocardial injury can cause cardiac
mural thrombi
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• Venous thrombi (phlebothrombosis):
• grow in direction of flow (leads to embolus)
• Usually occur at sites of stasis
• Also typically occlusive
• Known as “stasis thrombi” since they have a lot of RBCs in them compared to arterial
thrombi
• Most common sites are lower extremities followed by upper extremities, periprostatic
plexus, and ovarian and periuterine veins
• Sometimes can also be seen in the dural sinuses, portal vein and hepatic vein
!
• Postmortem clots
• Confused with antemortem venous thrombi
• More gelatinous with dark red dependent portion due to gravity and yellow upper
portion “chicken fat”
• Not attached to the vessel wall
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• Thrombi on heart valves
• Infective endocarditis
• Bacteria or fungi adhere to damaged valves and cause damage
• Endothelial injury and abnormal blood flow result in large thrombotic vegetations
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• Non bacterial thrombotic endocarditis
• Sterile vegatations on noninfected valves
• Hypercoagulable state
• Less common more verrucous endocarditis---Libman-Sacks endocarditis in SLE
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• Thrombi can be seen to have laminations “Lines of Zahn” both macro- and microscopically
• Layers of fibrin, platelets and RBC
• Significance is that thrombus has been formed in flowing blood
• Important in distinguishing an antemortem thrombosis from a post-mortem clot
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Fate of thrombi
1. Propagation - accumulation of additional platelets and fibrin
2. Embolization - dislodgement of thrombus and travel to other sites
3. Dissolution - result of fibrinolysis, better on new and recent thrombi as opposed to old thrombi with
extensive fibrin deposition
4. Organization and Recanalization - older thrombi develop ingrowth of endothelial cells, smooth muscle
cells and fibroblasts which can lead to capillary channel formation
5. Overtime some flow may be restored to the vessel, however the vessel wall in the area of the thrombus
might be affected by infections and become seeded forming mycotic aneurysms

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Clinical significance of thrombi
• Occlusion of vessels
• Embolization
• Venous thrombi - congestion and edema distal to obstruction
o Most common area is the superficial or deep veins of the leg
o Usually because of hypercoagulable state
• Superficial thrombi—in saphenous vein with varicosities
• Rare to embolize
• Varicose ulcers may occur
• Deep venous thrombosis (above or at knee)
• Tend to embolize to lungs → PE
• May be asx since collateral channels may occur.
• Other important thrombotic states occur in pregnancy - hypercoagulable
• Cancer → tumour associated inflammation and coagulation factors from the cancer cells can cause
thromboemboli
• Migratory thrombophlebitis or Trosseau syndrome
• Arterial and cardiac thrombi - may cause infarctions
• Atherosclerosis is important in the development of these thrombi
• Embolization to the peripheral vasculature may occur
• Important targets include brain, kidneys and spleen
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DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
• Sudden onset of widespread fibrin in microcirculation
• Microscopically apparent in the tissues
• Causes platelet and coagulation protein consumption which further activates the fibrinolytic system
• It is not a primary condition but a complication of conditions associated with widespread activation of
thrombin
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EMBOLISM
• Detached intravascular solid, liquid, or gaseous mass that is carried to a distant site from the point of
origin/entry
• Emboli can occur anywhere in the vascular system
• Most common type of emboli is thrombotic
• Occlusion of the vessel can lead to ischemic necrosis—infarction
!
• Examples of emboli:
1. Pulmonary embolism
• Cause of sudden death
• Usually arise from DVTs
• DVT → larger veins → R heart → pulmonary arterial system
• Size of embolus determines what structure is occluded
• Main pulmonary artery
• Pulmonary artery bifurcation → saddle embolus
• Smaller branching channels
• Frequently multiple emboli - may be sequential or a shower from a larger one
• Patient with one PE at risk for another one
• Clinically asymptomatic in 60-80% (small arteries)
• If 60% of more of the pulmonary circulation is compromised than sudden death,
right heart failure or cardiovascular collapse may occur
• Medium sized artery involvement with vascular rupture → pulmonary hemorrhage
• Pulmonary infarction rare since the lungs have a dual supply
• Small arteries may get some pulmonary hemorrhage and infarction
• Recurrent multiple emboli may lead to pulmonary hypertension and right ventricular failure
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 !
2. Systemic thromboembolism
• Emboli in the arterial circulation
• 80% arise from intracardial mural thrombi (2/3 from left ventricular wall infarcts and ¼ from
left atrial dilatation and fibrillation)
• The remaining systemic TE arise from aortic aneurysms, thrombi from ulcerated
atherosclerotic plaques, valvular vegetation fragments and paradoxical emboli or unknown
origin
• (Rarely the embolus may pass throw an interarterial or interventricular defect and go to the
systemic circulation (paradoxical embolism))
• Arterial emboli can travel widely and lodge in many sites
• Lower extremities> brain> intestines> kidneys>spleen> upper extremities
• Results of systemic TE are dependent on tissue vulnerability to ischemia, caliber of vessel,
presence of collateral blood flow
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3. Fat and Bone Marrow Embolism
• Fat globules +/- marrow elements may be seen in the circulation after long bone fractures,
soft tissue trauma and burns, CPR
• The entrance into the vasculature is due to the disruption of marrow vascular sinusoids or
venules
• Fat embolism syndrome: patients who are symptomatic
• Clinically - pulmonary insufficiency, neurologic symptoms, anemia,
thrombocytopenia and death
• Presentation is typically 1-3 days after the injury - tachypnea, dyspnea, tachycardia,
irritability and restlessness, delirium, coma, petechial rash
• Pathogenesis of the syndrome is both mechanical obstruction and biochemical
injury
• Fat microemboli
• Release of free fatty acids - local toxic insult to endothelium
• Diagnosis on histology usually requires special techniques of frozen sections and
stains for fat

4. Air embolism
• Coalescence of air bubbles that can cause an obstruction
• 100cc of air needed
• Iatrogenic introduction during obstetric or laproscopic procedures or chest wall injury
• Decompression sickness - one type of gas embolism
• Sudden decrease in atmospheric pressure
• Scuba divers
• Under water construction
• Unpressurized aircraft with rapid ascent
• Pathogenesis: air at high pressure is dissolved more rapidly in the blood and with
ascent this air (nitrogen) dissolves out
• Clinically, patients will have the bends
• Pain in muscle and joints since the gas bubbles accumulate there
• The chokes
• Respiratory distress
• Caisson disease
• Chronic form of decompression sickness
• Persistence of gas bubbles in skeletal system can lead to multiple foci of
ischemic necrosis
• Treatment requires placement of patient into a high pressure chamber with
slow decompression
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 5. Amniotic fluid embolism
• Complication of labour and immediate postpartum period
• 1/40000 deliveries with mortality of 80%
• 10% of maternal deaths in the US
• 85% have permanent neurologic deficits in survivors
• Clinically patients present with sudden dyspnea, cyanosis, shock with neurologic
impairments (headaches, seizures or coma), pulmonary edema, DIC
• Pathogenesis of the embolism is amniotic fluid enters the maternal circulation from a tear in
the placental membranes or uterine veins
• Histology of embolus may show squamous cells, lanugo hair, fat from vernix caseoa and
mucin from fetus respiratory or GI tract in the maternal pulmonary microcirculation
!!
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INFARCTION
• Infarction: Area of ischemic necrosis from occlusion of arterial supply or venous drainage
• Common and clinically important
• 40% of deaths in US from cardiovascular disease - usually a myocardial or cerebral infarction
• Pulmonary infarction
• Bowel infarction
• Ischemic necrosis of extremities (gangrene)
!
• Pathogenesis: result of occlusion by thrombi or emboli in the arteries
• Other causes include, vasospasm, hemorrhage into a plaque, vessel compression, traumatic rupture,
torsion, vascular compromise by edema, or entrapment in a hernia sac
• Venous thrombosis can also cause infarction - usually congestion occurs
• More common in organs with a single efferent vein (ovary and testis)
!
• Factors that effect development of infarcts:
• Nature of the vascular supply:
• Alternate blood supply will determine what kind of damage may occur
• Rate at which the occlusion occurs:
• If slowly developing, less likely to infarct
• Vulnerability to hypoxia
• Cell type: neurons only have minutes without O2, myocytes 20-30 minutes while
fibroblasts have hours
• O2 content of the blood:
• Anemia or cyanotic patient more likely to develop an infarct
!
• Gross and microscopic appearance of infarcts:
• Classify by colour, presence of infection:
• Red infarcts
• With venous occlusions and in loose tissues that allow for the accumulation of
blood, tissues with dual circulations, tissues previously congested by slow
venous flow, or in areas of flow that is re-established after and arterial necrosis
• White infarcts
• Arterial occlusion in solid organs with end arterial circulation and tissue that is
dense
• Overall infarcts are wedge shaped (occluded vessel at apex and peripherary of organ at base)
• Acute - poorly defined and hemorrhagic
• Chronic - better defined
• Arterial infarcts overtime get more paler
• Lung infarcts are hemorrhagic
• Septic infarcts - embolization of infective vegetations or seeding of tissue
• An abscess may develop

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!
• Histology demonstrates ischemic coagulative necrosis (exception is the brain - liquefactive
necrosis)
• Recent - sometimes no changes appreciated
• 4-12 hours needed to show necrosis - presence of acute inflammation
• Overtime reparative response - scar
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SHOCK
• Final common pathway for several clinical events
• Characterized by severe hypotension from reduced cardiac output or reduced effective circulating blood
volume- impaired tissue perfusion and cellular hypoxia
• At first may be reversible but prolonged turns irreversible → death

Main Causes of Shock

Cardiogenic Hypovolemic Septic

Myocardial infarction Fluid loss Overwhelming microbial infection
Ventricular rupture -hemorrhage Superantigens
Arrhythmia -vomiting
Cardiac tamponade -diarrhea
Pulmonary embolism -burns
-trauma
Myocardial pump failure Inadequate blood/plasma volume Peripheral vasodilation
Pooling of blood
Endothelial activation
Leukocyte induced damage
DIC
Activation of cytokine cascade

• Less common forms of shock include:

• Neurogenic shock: anesthetic accidents or spinal cord injury
• Vascular tone lost and peripheral pooling of blood
• Anaphylactic shock
• vasodilation - tissue hypoperfusion and hypoxia
• increased vascular permeability
!!
• Septic Shock
• Severe hemodynamic and hemostatic abnormalities
• Mortality rate of 20%, increasing incidence
!
• Pathogenesis from gram positive bacteria> gram negative> fungi
• Microorganisms activate the immune system
• Immune system mediators will activate complement and coagulation pathways
• Sometimes toxic shock syndrome confused with septic shock
• Similar but different with the cause being secreted bacterial proteins (superantigens)
• Superantigens are T cell activators with production of cytokines
• Severity and extent of infection are determined by the virulence, immune status of host, presence
of comorbid conditions, and pattern and level of mediator production
!!
• Important factors:
• Inflammatory mediators:
• Toll like receptors (TLRs) activation
• Inflammatory cells release TNF, IL-1, IFNgamma, IL-12 and IL-18 and HMGB1
• Reactive oxygen species and prostaglandins and platelet activating factor release
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 • Complement cascade activated
• Endothelial cell activation and injury
• Thrombosis
• Increased vascular permeability
• Vasodilation
• DIC occurs in 50% of patients
• Metabolic abnormalities
• Insulin resistance
• hyperglycemia
• Immune suppression
• Activation of counter regulatory immunosuppression mechanisms
• Organ dysfunction
• Multiple organ failure
!
• Stages of shock
• Progressive disorder
• Full mechanism is still unclear with septic shock
• Hypovolemic and cardiogenic shock better understood:
• Nonprogressive phase - reflex compensatory mechanisms activated
• Neurohumoral mechanisms (barorecptors, catcholamine release, renin angiotensin
activation, ADH release and sympathetic stimulation)
• Clinical signs of tachycardia, peripheral vasoconstriction and renal conservation,
coolness, pallor
• Progressive stage - tissue hypoperfusion, circulatory and metabolic imbalances including
acidosis
• Aerobic respiration - anaerobic glycolysis - lactic acid → decreases vasomotor response
• Irreversible stage - severe injury that is incompatible with life
• Gross and histologic features are of hypoxic injury
• Brain - DIC
• Heart - DIC
• Kidneys - acute tubular necrosis, DIC
• Lungs - not much if hypovolemic; if septic diffuses alveolar damage, DIC
• Adrenals - DIC, cortical cell depletion
• Gastrointestinal tract - DIC
• Clinically
• Cardiogenic and Hypovolemic - hypotensive, tachypnea, weak, tachycardia, cool and
clammy and cyantic skin
• Septic-warm, flushed
• Prognosis is better for hypovolemic in young, healthy patients but worse for septic or cardiogenic
shock

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! QUESTIONS
What are the pathophysiologic categories of edema? List 5 and give an example of each.
What is the difference between a transudate and an exudate? Give an example of each.
What is the main difference between hyperemia and congestion?
What are the clinical consequences of edema?

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 What is the end product of the common pathway in the coagulation cascade?
Which of the coagulation cascade pathways (extrinsic or intrinsic) is more physiologically relevant?
What is the laboratory test called to assess this pathway?
What are the events of normal hemostasis?
List all the vitamin K dependent factors.
What is edema?
What are examples of antithrombotic and thrombotic properties of the endothelium. Name 3.
What is thrombosis?
What is Virchow’s triad?
What are the fates of a thrombus? List 4.
What is disseminated intravascular coagulation? Give 3 clinical situations when this occurs.
What is the definition of an embolism? List 5 types of emboli.
What is shock?
What are the 3 stages of shock?
What are the 3 main types of shock?
Provide 6 pathologic changes in any organ during shock.
What is an infarction? List 3 causes of an infarction.
What are the causes of a red and white infarction?
What is the dominant histologic correlate of an infarction? What is the exception?
How do septic infarctions occur?
What are the factors that affect the development of an infarct? List 4.

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