Maturing Granulation Tissue 

Test q: The principal cells of

• Vessels decreasing granulation tissue are: fibroblasts
• Fibrocytes decreasing and endothelial cells,
• Type III replaced by Type I collagen
• Inflammation resolved
• Epithelium restored

Wound Strength
Primary intention:
• 10% when sutures removed (4-10 days)
• Rapid increase 4 weeks
– Granulation tissue remodeling
• 70-80% strength plateau 3 months
– Synthesis > degradation first 2 months
– Collagen III replaced by collagen I
– Cross- binding and increase in fiber size strengthen
Secondary intention:
– Wound contraction up to 95% at 6 weeks
– Myofibroblasts and Elastin remodeling participate

Scars never have the same tensile strength, even when healed back by primary intention.

Remodeling Scar 
By the end of 3 months:
• Vessels absent
• Fibrocytes few
• Type III replaced by Type I
collagen
• Contraction complete
• Inflammation resolved
• Epithelium restored

Test q: A 22y/o female succumbs

to peer pressure and has her ears
pierced. Two months later, the
sites of piercing develop firm
nodules that are the same color as
the surrounding skin. There is no
evidence of infection. You would
expect the histopathology to show:
Broad bands of collagen.
Test q: A well-healed scar that is Above: FIGURE 3–26 Repair, regeneration, and fibrosis after
6mo old contains primarily injury and inflammation.
collagen type: I

FIGURE 3–20A Healing of skin ulcers. A, Pressure ulcer

of the skin, commonly found in diabetic patients. The
histologic slides show: B, a skin ulcer with a large gap
between the edges of the lesion; C, a thin layer of
epidermal re-epithelialization and extensive granulation
tissue formation in the dermis; and D, continuing re-
epithelialization of the epidermis and wound contraction.
FIGURE 3–21B A, Granulation tissue showing numerous
blood vessels, edema, and a loose ECM containing
occasional inflammatory cells. Collagen is stained blue by
the trichrome stain; minimal mature collagen can be seen
at this point. B, Trichrome stain of mature scar, showing
dense collagen, with only scattered vascular channels.
  FIGURE 3–2 Role of the extracellular matrix
in regeneration and repair. Liver regeneration
with restoration of normal tissue after injury
requires an intact cellular matrix. If the matrix
is damaged, the injury is repaired by
fibrous tissue deposition and scar
formation.
Test q: A 50y/o female develops lobar pneumonia
secondary to Streptococcus pneumoniae infection.
Neutrophils are numerous and the ECM is
destroyed locally. The patient recovers after
antibiotic treatment. The involved area of the lung
will exhibit: Fibrosis.

Test q: A 45y/o female is hospitalized for

Pathologic Wound Healing
• Deficient scar
– Dehiscence resulting from tension or infection
– Nonhealing ulcer
» In diabetes or peripheral vascular disease
• Excessive repair
– Granulation tissue excess
» Pyogenic granuloma, “proud flesh”
– Keloid (mostly Af Am)
– Fibromatoses
» Desmoid, aggressive fibromatosis
» Uncertain whether neoplastic
• Contracture at flexor surfaces
– Palms, soles, anterior chest wall
Pneumococcal pneumonia (caused by
Streptococcus pneumoniae). The isolated bacteria
is resistant to penicillin and the pneumonia persists
for several weeks, but she recovers. At discharge,
many of the alveoli in the patient’s lung would
exhibit: Granulation tissue and fibrosis.
Test q: What is the most frequent reason acute
inflammation may result in replacement of the
tissue by collagen scar: Damage to ECM.
REPEATED TWICE.
Test q: An 18y/o man lacerated his left hand and required sutures. The
sutures were removed 1 wk later. Wound healing continued, but the site
became disfigured by a prominent raised, nodular scar that developed over
the next 2 months. Which of the following terms best describes the process
that occurred during this 2mo period? Keloid formation.

Keloid and Contracture 

FIGURE 3–23A Keloid. A, Excess collagen deposition in the skin forming
a raised scar known as keloid. B, Note the thick connective tissue
deposition in the dermis.
FIGURE 3–24 Wound contracture. Severe contracture of a wound after
deep burn injury.

Learning Objectives (w/answers):

1. Regeneration versus replacement
– Stable or labile cells, BM & ECM preserved
2. 3 Surface receptor types
– IK – mitogenic, CK – cytokines, GPCR – hormones
3. Cell cycle, 4 cyclins, 2 checkpoints
– G0G1SG2M; Cyclins DEAB; midG1(Rb) G2M(p53)
4. 2 unique basement membrane molecules
– Collagen IV, Laminin
5. Collagen synthesis & structure
– Pro→OHPro→Glycos→Select3α→LysOx→/
C,N peptidase to tropocollagen→LysOx→agg
6. 5 Growth factors
– EGF Ep mitogenic, PDGF MpEn mito/tactic, FGF En angio SkmsLung maturing, VEGF En angio, TGFβ
Ep inhibits Fb collagen synthesis-collagenase inhib.
7. Wound healing & maturation, zinc function
– Angiogenesis, Fibroblast invasion/mitosis, ECM synthesis, Remodeling (Zn metalloproteinase)
Hemodynamics Fri. 08/27/10

• Topics:
– Homeostasis - Water/Compartments
• Edema
• Congestive Heart Failure
• Congestion/Hyperemia
– Hemostasis:
• Hemostasis - Normal
• Hemostasis - Thrombosis
– Atherosclerosis
– Thrombosis/Embolism
– Infarct
– Shock

Vascular Fluid Hemodynamics

• Body Compartments: Body Water (60% of body weight)
• Intravascular Space: 5%
• Cellular Space: 40%
• Interstitial (Extracellular) Space: ~ 15%
• Lymphatic Space: small %
• Blood Flow: Blood Pressure Maintenance
– Cardiac Output
– Vascular Perfusion Pressure - Vascular Tone
– Vascular Resistance - Organs

 Increased Hydrostatic Pressure

• Impaired Venous Return
– Congestive Heart Failure
– Constrictive Pericarditis
– Ascites (liver cirrhosis)
– Venous Obstruction
• Thrombosis
• External pressure – mass
• Lower extremity inactivity
Congestive Heart Failure: Below: Congestive Heart Failure - Vascular Pressures
• Left Sided CHF: Decreased Cardiac Output
– Etiology: Myocardial dysfunction -
Atherosclerosis, Infarcts, Hypertension,
Aortic/Mitral valve diseases, Myocarditis,
Constrictive Pericarditis
– Findings:
 Decreased Cardiac Output - Decreased
tissue perfusion
 Reactive vasoconstriction (increased
vascular tone)
 Peripheral and Pulmonary Edema
 Organ Congestion: Liver, Spleen,
Kidneys, GI, etc.
 Effusions: Pleural, Peritoneal (ascites)
• Symptoms/Findings:
– Dyspnea, decreased activity level
– PND (paroxysmal nocturnal dyspnea)
Test q: A 74y/o woman w/left heart failure develops pulmonary edema. This
– Orthopnea accumulation of fluid is best explained by which of the following mechanisms?
– Jugular-venous distention Increased hydrostatic pressure.
– Increased BNP (B type nutriuretic peptide –
produced by distended ventricle) Test q: The most common cause of right-sided congestive heart failure is:
left-sided heart failure.
– Peripheral edema
– Pulmonary rales Test q: Which of the following is seen predominantly in acute left heart
failure? Pulmonary edema.
• Right Sided CHF:
Test q: A 50y/o male w/a history of previous MI develops shortness of breath
– Etiology: Left sided failure most common and dies after 2wk in the hospital. At autopsy the patient exhibits necrosis of
cause, pulmonary hypertension, hepatocytes surrounding the central veins. The most likely cause is:
pulmonary/tricuspid valve disease, myocarditis congestive heart failure.
– Findings: Similar to Left Sided except no
pulmonary edema

Congestive Heart Failure Mechanisms: Myocardial Infarction:

Decreased Cardiac Output

Constrictive Pericarditis:
Decreased Cardiac Output

Above: fibrous bands constrict

the pericardium to heart
surface.
Sodium Retention: Increased Plasma Volume
Pulmonary Congestion and Edema:
Pulmonary edema: fluid/transudate
w/few RBCs
Test q: On day 3 after an acute MI, the patient developed congestive heart failure and died. The lungs would show: congested capillaries and
transudate in alveoli.
Peripheral Edema:
Above: pitting edema.
Discoloration = chronic
venous stasis.
Congestive Heart Failure:
Exaggeration of pulmonary
vasculature. Filling of air spaces
w/fluid.
Reduced Osmotic/Oncotic Pressure:
Test q: A 48y/o man w/alcoholic cirrhosis has ascites
and dependent pitting edema in the lower legs. Fluid
accumulation in the peritoneal cavity and legs occur by
which of the following mechanisms? Decreased
plasma oncotic pressure.
Test q: Choose the best answer concerning
congestive heart failure (CHF): May result in
increased sodium retention from increased
aldosterone action. (Other choices-
Peripheral edema seen w/CHF is the result of
decreased osmotic/oncotic vascular pressure;
Pulmonary edema seen w/CHF is the result of
increased right ventricular pressure; Left
ventricular failure is commonly the result of
pulmonary embolisms; Is most often a
complication of portal hypertension.)
Pulmonary Edema:
Frothy/blood-tinged edema fluid
Reduced Osmotic/Oncotic Pressure:
• Reduced Plasma Colloid Osmotic/Oncotic
Pressure
– Protein losing states: nephrotic
syndrome (glomerulonephritis),
protein losing enteropathies
– Cirrhosis/Malnutrition: decrease
albumin production (protein has
strong effect of pulling H2O back into
vascular system)
– Effect:
• Peripheral edema
• Non-dependent edema,
periorbital/facial
• Effusions: Ascites (Peritoneal),
Pleural
• Sodium and H2O Retention: Increased
Plasma Volume
– Acute/Chronic Renal Failure
– Abnormal Renin-Aldosterone
Test q: The mechanism for the production of anasarca is: extensive loss of albumin in the urine. (Anasarca = extreme generalized edema)
REPEATED TWICE

Lymphatic Obstruction Reduced Lymphatic Flow:

• Lymphatic Obstruction
– Neoplasms, Infections, Post-surgery, Post-Rad Tx
– Lymphomas - neoplasms
– Filarisis - infection
– Mastectomy - post surgery
– Abdominal lymph node obstruction - Rad Tx
• Localized Edema
– –Inflammation, vessicle/bullae, injury, etc

Lymphatic Obstruction: Filarial Infection Local Edema: Inflammation

Cerebral Edema Cerebral Edema: Localized from Trauma:

• Localized or Diffuse:
– Localized - Trauma, Infections/abscess
– Diffuse - Hypertensive Crisis, Venous obstruction, CSF
Obstruction, Trauma
• Effects:
– Decreased Mental Status
– Tissue destruction, infarct, paralysis
– Brain stem herniation - death

Cerebral Edema: Diffuse Swelling – Herniation: Hyperemia/Congestion: Active vs Passive:

Inflammation –
Active
Exercise – Active
Heat – Active

Above: herniation of cerebellum.

Compresses midbrain/spinal cord. Congestive Heart
Failure – Passive

Venous Obstruction
– Passive
Congestion:
• Increased amount of blood in capillaries, venules Pulmonary Congestion:
– Active Hyperemia: Increased blood flow to
area due to inflammation or vascular control
• Inflammation: Vasodilatation, increased
vascular permeability
• Exercise: Increase muscle tissue blood flow
• Heat: Increase skin blood flow
– Passive Congestion: Reduced venous
return/obstruction, Edema, Common with
CHF
• Lung Congestion: Edema, extravasated
RBC’s, interstitial thickening (chronic), “heart
failure cells” = hemosiderin laden
macrophages
• Liver Congestion: Centrilobular congestion,
centrilobular necrosis/fibrosis (chronic, i.e.
cardiac cirrhosis)
• Spleen Congestion: Splenomegaly, fibrosis
(chronic)
• Localized, venous thrombosis
Test q: A 62y/o male is found dead at home. At autopsy, the alveolar wall capillaries are congested w/RBCs and alveoli contain macrophages that
exhibit brown, granular material. This patient most likely has a history of: Left heart failure.

Hepatic Congestion: Centro-lobular Congestion/Atrophy

Test q: “Nutmeg liver” is a descriptive term for liver changes due to: chronic passive congestion.

Hemostasis: Coagulation/Fibrinolytic Pathways

• Bleeding/Hemorrhage vs Hemostasis/Clotting Hemostasis – Vascular Injury:
– Dynamic Equilibrium: bleeding vs clotting
– Vascular Endothelium/Platelets/Coagulation
Factors/Fibrinolytic Factors
• Primary Hemostasis - Vascular Seal = Platelets
– Vasoconstriction
– Platelet Adhesion
– Platelet Aggregation
• Secondary Hemostasis - Coagulation Pathway
– Endothelial/Platelet Activation
– Coagulation Cascade
• Thrombolytic/Fibrinolytic Elements
– Regulatory Factors for Clotting vs Clot Lysis
Primary Hemostasis Hemostasis - Platelet Adhesion/Aggregation:
• Clotting: Platelets
– Platelet adhesion (Von Willebrand Factor (vWF),
collagen)
– Platelet shape change (discoid)
– Platelet release of aggregation factors: ADP, Thromboxane A2
• Aspirin inhibits production of Thromoboxane A2
– Platelet recruitment/aggregation
• New anti-platelet drugs inhibit aggregation
– Platelet hemostatic plug
• Anti-platelet aggregation/adhesion
– Prostaglandin I2, nitric oxide, ADPase (derived from
endothelium) Platelet Adhesion Mechanism: (Gp1b receptor)
Test q: A 35y/o woman takes acetylsalicylic acid (aspirin) for arthritis.
Although her joint pain is reduced w/this therapy, the inflammatory process
continues. The aspirin therapy alleviates her pain mainly through reduction
in the synthesis of which of the following mediators? Prostaglandins.
REPEATED TWICE.

Test q: A 59y/o obese woman w/a history of diabetes mellitus had an MI

3mo ago. She is now taking a low dose of aspirin to reduce the risk of
arterial thrombosis. On which of the following steps in hemostasis does
aspirin have its greatest effect? Aggregation of platelets. REPEATED
TWICE.

Inadequate Platelet Function or #:

• Platelet - Inadequate Primary Hemostasis:
– Petechiae - pinpoint loss of blood into tissues, ex. Skin
– Purpura - larger loss of blood into tissues, ex. Skin
– Hemorrhage - severe bleed (Brain, GI, etc)

Inadequate Platelet #/Function: Petechiae Congestion/Hemorrhage: Bowel, Brain:

less than 2 mm hemorrhage:

Purpura: Platelets and Coag Factors Ecchymosis: Subcutaneous Secondary Hemostasis -

> 3 mm hemorrhage: Hemorrhage Platelets/Coag Coagulation System
Factors > 1-2 cm hemorrhages

Above: Tissue factor is primary driving

factor.
Coagulation Cascade:

 The function of the extrinsic pathway

is measured by PT.

Vascular injury activates Factor VIIa +

TF, which activate the conversion of
Factor X to Factor Xa. Factor Xa is the
central area within the clotting cascade.

Coagulation Pathway - Platelet Surface: Fibrin Generation:

Hemostasis Equilibrium: Coagulation Control

• Clotting Stimulating Factors (Pro-coagulants):
• Exposed collagen, vWF = Platelet activation
• Platelet aggregation factors = ADP, Thromboxane
A2
– Tissue Factor (Thromboplastin) = tissue injury
– Activated Factors = XIIa, XIa, IXa, Xa, VIIa, IIa
• Plasminogen Activator Inhibitor (PAI) = anti-
fibrinolytic
• Alpha-2-antiplasmin = anti-fibrinolytic
• Anti-coagulation Factors:
– Antithrombin III (ATIII) : Inactivates Xa, IXa, IIa
– Protein C (+Protein S): Inactivates Va, VIIIa
– Thrombomodulin: activates Protein C
– Tissue Factor Pathway Inhibitor (inactivates VIIa+Xa)
• Clot Lysis Factors:
– Tissue Plasminogen Activator (tPA)
– Plasminogen = Plasmin: Degrades Fibrin

ATIII is a key anti-coagulant. 

Anti-coagulants:
Test q: The clotting factors that are produced in the liver and
• Anti-coagulants use in blood tubes to yield whole blood or plasma: are vitamin K dependent are: II, VII, IX, X.
– EDTA (lavender top) binds Ca++, used for hematology tests Test q: A 33y/o female presents to the ER w/a deep vein
– Citrate (blue top) binds Ca++, used for coagulation testing thrombosis in her left leg. She is treated w/heparin until
– Oxalate (grey top) binds Ca++, used for some whole blood stable. On discharge, you wish to change her anticoagulant
to Coumadin (Warfarin). What lab test should you order to
testing monitor drug effectiveness after discharge? PT.
– Heparin (green top) inhibits AT III
• Therapeutic Anticoagulants:
– Heparin, Unfractionated: Binds to Anti-thrombin III and inhibits Thrombin (II) and Factor Xa; Monitor with Partial
Thromboplastin time aPTT or activated clotting time
– Heparin, Low molecular weight: Binds to Anti-thrombin III and inhibits Factor Xa mostly; Monitor with Anti-Xa
assay
– Warfarin (coumadin): Decreases factors II, VII, IX, X, production (Vitamin K factors); Monitor with Prothrombin
Time (PT, INR)
– Direct Factor Xa Inhibitors; effects PT, aPTT, and Anti-Xa
assay
– Direct Thrombin Inhibitors

Thrombin – Equilibrium Thrombosis vs Anti-thrombosis:

• Thrombin effect on thrombosis:
– Fibrinogen to Fibrin reaction
– Activates XIII to cross-link
fibrin
– Activates VIII, V
– Stimulates Platelet
Aggregation and Secretion
– Endothelial leukocyte
adhesion molecules
• Thrombin effect on anti-thrombosis =
Fibrinolytic Process Stimulation:
– Tissue Plasminogen Activator
(tPA)
– Vasoactive - NO, PGI2
(inhibits Platelet aggregation)
– Cytokines
• Heparin + Antithrombin III – inhibits Thrombin Test q: Lysis of a thrombus is
enhanced by which of the following
mechanisms? Thrombin
Thrombolysis/Fibrinolysis stimulation of tPA release.
• Tissue Plasminogen Activator (tPA) released from adjacent normal endothelium:
– Activates Plasminogen to Plasmin Test q: A 66y/o woman comes to
– Plasmin lyses fibrinogen with release of d-dimers (d-dimer assay used to rule- the ER 30 min after the onset of
chest pain that radiates to her neck
out DVT or Pulmonary Embolus) and left arm. She is diaphoretic and
– Fibrinogen breakdown products inhibits coagulation hypotensive; the serum troponin I
• Thrombomodulin released from endothelial cells inhibits coagulation by inaction with level is elevated. Thrombolytic
thrombin in activating Protein C therapy is begun. Which of the
following drugs is most likely to be
• Anti-fibrinolysis actions administered? Tissue plasminogen
– Alpha2-Anti-plasmins activator.
– Plasminogen Activator Inhibitors

Fibrinolytic System: Activation and Regulation

Hemodynamics/Hemostasis – Lecture # 2
– Thrombosis/Embolism
– Atherosclerosis Thrombosis Formation:
– Infarcts
– Shock

Pathologic Causes of Thrombosis:

• Genetic Disorders: Hyper-coagulable States
– Mutations in Factor V (Leiden Mutation):
• 2-15% of whites; reduced degradation of Factor V by Protein C
(decreased aPC)
– Antithrombin III Deficiency: Autosomal dominant (1:2-5000); or
acquired (i.e. nephrotic syndrome or DIC)
– Protein C or S Deficiency: Anti-coagulant
– Allelic Variations in Prothrombin:
• 1-2% Population; Increased Levels (3 x’s risk) – but not
structural change.
– D5, 10 Methylenetetrahydrofolate reductase mutation (C677T
– homozygous) – increased homocysteine
– Fibrinolysis defects
– Homocysteinemia - genetic disorder or folate deficiency
• Acquired: Hyper-coagulable States
– Tissue damage (release of activating factors)
– Cancer (pro-coagulant factor release)
• Trousseau’s Syndrome: Pancreatic Ca, Thrombi 
– Disseminated Intravascular Coagulation (DIC):
• Diffuse endothelial injury (sepsis, toxins)
– Anti-Phospholipid Syndrome (Lupus Anticoagulant)
• Systemic Lupus Erthyematous, Pregnancy (causes
miscarriages and stillbirths), Viral Infections
• Antibodies to cardiolipin, beta-2 glycoprotein I,
phosphotidylserine
– Heparin induced thrombocytopenia (HIT)
• 10 % of patients; Antibodies to heparin bound to platelet
factor 4 results in platelet activation and initiation of
thrombus formation
Test q: An athletic, 51y/o man w/a
Endothelial Cell Injury history of diabetes mellitus goes to the
ER because he has had left-sided chest
• Necrotic Tissue - Infarct pain that radiates to the arm for the past
• Valve Disease - Rheumatic 5 hr. Serial measurements of serum
Fever creatine kinase-MB levels show an
• Atherosclerosis - Plaques elevated level 24hr after the onset of
pain. Partial thromboplastin time and
• Traumatic Injury prothrombin time are normal. Coronary
• Vasculitis - Autoimmune angiography shows occlusion of the left
Disorders anterior descending artery. Which of the
• Infections - Endotoxins following mechanisms is the most likely
cause of thrombosis in this patient?
• Other Damage to endothelium.
Test q: An elderly man presents w/multiple deep
vein thromboses over the past several months with
one episode of pulmonary embolism. Which of the
following is the most likely underlying condition?
Adenocarcinoma of the pancreas. (Not cirrhosis,
Von Willebrand’s disease, FH, or renal cell
carcinoma w/lung metastases)
Test q: A 55y/o former baseball player presents to
his doctor w/a small thrombus in his lower leg and
1mo later is hospitalized for a pulmonary embolus.
Further workup reveals a malignancy. Which is
most likely? Adenocarcinoma, pancreas.
Test q: A 45y/o present w/multiple venous
thromboses in his legs and also in the mesentery of
his intestinal tract. He most likely has a history of:
Pancreatic cancer.
Test q: A 45y/o white male is mildly overweight, but
otherwise healthy. During the past year he has
developed thromboemboli in his lower extremities.
The most likely cause is Leiden mutation.
REPEATED TWICE.
Test q: The Leiden mutation of the gene for Factor
V is commonly seen in persons who: have history
of thombosis of the deep veins. REPEATED
TWICE.
Test q: A 25y/o woman has had multiple episodes
of deep venous thrombosis during the past 10 years
and one episode of pulmonary thromboembolism
during the past year. Prothrombin time, partial
thromboplastin time, platelet count, and platelet
function studies are all normal. Which of the
following risk factors has most likely contributed to
the patient’s condition? Factor V mutation.

Disseminated Intravascular Coagulopathy DIC - Small Vessel Thrombi:

• Etiology: Diffuse activation of Thrombin/Coagulation System, example:
Diffuse endotoxin injury of endothelium
• Findings:
– Diffuse clotting in small vessels
– Ischemic injury to organs, especially brain, lung, heart, kidneys
– Consumption of clotting factors (Platelets, Factor VIII, V, etc) –
bleeding can result (increased aPTT and decreased platelet
count)
– Activation of Fibrinolytic System = dissolution of clots and
subsequent bleeding (fibrinolytic products inhibit clotting);
increased d-dimers
Test q: Choose the best answer concerning Disseminated Intravascular Coagulation (DIC): It is often seen with septicemia and endotoxin release.
(Other choices- It is commonly assoc’d w/an increased platelet count, Fibrin split products are increased which enhance clotting, Thrombi in small
vessels commonly result in pulmonary emboli.)
Test q: A 32y/o female gives birth to a 10lb male infant at 42 weeks gestation after induction and stressful delivery. She develops multiple clots as well
as large hematomas and hematuria. Lab studies would show: Elevated D-dimer.
Test q: A 13mo old male presents to the ER w/a swollen right knee. The family reports that the child bruises easily. There is no family history of
bleeding disorders. Lab results: PT: 12s (10-14s). APTT: 43s (21-35s). Bleeding time: 5min (3-6min). Platelet count: 300,000 (150-450,000). Mixing
studies: APTT corrected to normal. What is the diagnosis? Factor VIII deficiency. (Did not specifically discuss this?)

Hemodynamics: Abnormal Blood Flow

• Turbulence - Arterial/Cardiac Thrombosis Atherosclerotic Plaque:
– Abnormal Valves - Abnormal surface, Stasis with Mitral Stenosis
– Atherosclerosis - Plaques/Nodules
• Ulcerated Plaques
• Aneurysms (stasis and abnormal surfaces)
– Atrial Fibrillation - irregular atrial contraction
– Turbulence can directly injure endothelial cells
• Stasis - Venous Thrombosis
– Reduced circulation: CHF, Obstructions, Varicose Veins, immobility, etc
• Failure to dilute out activated clotting factors
• Failure to bring fresh anti-coagulant factors
– Promotes endothelial cell activation
– Sickle Cell Anemia, Hyperviscosity States, polycythemia rubra vera

Genetic and acquired etiologies:

Above: Top aorta is severe

atherosclerosis. There is a large
ulcer overlying the atherosclerotic
plaque. The middle aorta represents
moderate atherosclerosis. The
bottom aorta is smooth and normal.
Plaque Formation:

Atherosclerotic Plaque:

Fate of Atherosclerotic Plaques: Atherosclerosis:

* = thrombus overlying plaque

Coronary Artery

Coronary Artery
Thrombosis 
Ulcerated Plaque - Coronary Artery Ulcerated Plaque: Coronary Artery - Thrombus Aorta – Mural Thrombus

Blood
clot, a Can break off
cause of  embolus 
MI. tissue
infarction.

Test q: A 50y/o male presents to the ER w/crushing chest pain. A stress test 2 months ago was suspicious. Cardiac catheterization one month ago
showed 25% occlusion of the left circumflex artery. The patient was given a prescription for Atorvastatin (Lipitor) and told to take 81mg of aspirin daily.
He did neither. What is the likely cause of his MI? Acute thrombus over an ulcerated plaque.

Atherosclerosis Consequences Thrombi - Organized/New Channel

Blood going
through
channel (but
not enough!)

Test q: A 76y/o woman is hospitalized after falling and fracturing

Deep Vein Thrombosis and Pulmonary Emboli her left femoral trochanter. 2wk later, the left leg is swollen,
Predisposing Factors: particularly below the knee. She experiences pain on movement
• Venous Stasis/Immobilization especially of lower of the leg; on palpation, there is tenderness. Which of the
following complications is most likely to occur after these events?
extremities Pulmonary thromboembolism. Another year- same story, diff
• Hypercoagulable States question: What is the diagnosis for her current problem? Deep
• Surgery or Trauma, especially orthopedic and pelvic vein thrombosis.
surgery
Test q: A 42y/o obese male suffers a compound fracture of his
• Pregnancy tibia playing soccer. He is placed in traction and bed rest. He is at
• Oral Contraceptive Pills – 3 fold (higher with cigarette use) high risk for: Pulmonary embolus.
• Malignancy – Identified in 17% of thrombo-embolism
Test q: A 75y/o woman has had discomfort and swelling of the left
leg for the past week. A venogram shows thrombosis of deep left
leg veins. Which of the following mechanisms is most likely to
cause this condition? Long-term bedrest.

Emboli Venous Thrombus: Fate

• 20-25/100,000 hospital patients = 200-600,000 deaths/year
(third most common cause of hospital death)
• Most from dislodged thrombus (Thrombo-embolism)
• Pulmonary Embolus (venous thrombi) - common
– Most are small and clinically silent (may lead to
pulmonary hypertension over time)
– Large emboli  infarct or cardiac collapse/death
– Commonly arise in large veins in legs or pelvic area
i.e. DVT (60-80% will have emboli)
• Systemic/Arterial Emboli: Infarction
– Most from mural thrombus in heart: due to MI or Mitral
Stenosis, atrial fibrillation, endocarditis, Aneurysms,
ulcerated plaques, valve diseases
– Result = Organ Injury: Lower Extremities, Brain, GI,
Kidneys, Spleen
• Rare forms: Fat, Air/Nitrogen, Atherosclerotic debris
(angioplasty), amniotic fluid, bone marrow
Pulmonary Emboli Pulmonary Embolus: “Saddle Embolus”:
• Symptoms:
– May not have any symptoms if small
– Dyspnea, pleuritic chest pain
– Hemoptysis especially with infarction
– Cardiac decompensation
– Sudden death

Thromboembolus:

deposition Above: Saddle

of fibrin embolus crossing
where the pulmonary
artery branches to
go to two lungs.

Thrombus - Lines of Zahn (alternating bands of fibrin) Organizing Thrombus:

Organizing Thrombus:

Post-Mortem
Clot 
Not organized;
not adherant
(gel-like).
Can see fibroblasts “Currant jelly”
growing into thrombus Passive
settling out of
RBCs and
plasma. No
Lines of Zahn.

Test q: Features consistent w/a post-mortem clot are:

Test q: A pathologist is asked to perform an exam of a diabetic woman who died
Jelly-like.
suddenly w/a history of thrombophlebitis of the left lower leg. He finds a clot in the
pulmonary artery. Which of the following findings would indicate that this clot is a
thromboembolus? Presence of Lines of Zahn. REPEATED x3!!
Hemodynamics: Infarcts Post-mortem Clot:
• Infarct Determinates:
– Nature of vascular system (alternative blood supply)
– Rate of occlusion
– Vulnerability to hypoxia (cell type)
– Oxygen content of blood/cardiac output
– Use of thrombolytic therapy (tPA – tissue plasmingen activator
or streptokinase)
• “Red” Infarct:
– Loose tissues (lung) and/or 2 vascular systems (lung, liver)
– Venous infarcts (ovarian torsion)
– Previously congested organs (spleen)
– Re- establishment of blood flow (lysis of thrombus in MI after
angioplasty or thrombolytic treatment)
• “White” Infarct:
– Solid Organs with single vascular system (kidney, heart, spleen (later))
Test q: A 60y/o hospitalized woman has sudden onset of dyspnea, pleural pain, and cough productive of frothy, blood-tinged sputum. Ventilation-
perfusion scintigraphy indicates a perfusion defect in the left lung. Which of the following would most likely be present in section of the lung?
Hemorrhagic (red) infarct.

Coronary Artery Occlusion – MI Infarct Course:

Biochemical Markers
• Myoglobin – increased at 2-4 hours;
non-specific – skeletal muscle injury also
increases myoglobin
• Cardiac Troponin I or Troponin T –
increased at 4-6 hours; primary criteria
for myocardial infarct
– elevated for > 3 days
• Creatine Kinase (MB) – increased at 6
hours, not as sensitive as troponin I or T
for MI
– Elevated for 1-2 days
• Lactate Dehydrogenase (LDH),
especially isoenzyme 1 – increased at 6
hours+; not commonly used today
– Elevated for > 3 days
Test q: The main disadvantage of the serum
Myocardial Infarct: 6 – 18 hours MI: Inflammation –
myoglobin test for acute MI is its: poor
Can see contraction bands (arrow) Coag Necrosis 24-48hr specificity.

Test q: A 57y/o man has just returned from an

overseas trip and reports having had severe
substernal chest pain 3 days ago. Which of the
following is the most appropriate lab test to order
for this patient? Troponin I.

 Complete loss of nuclear and

See some loss of nuclei. cytoplasmic detail.
Myocardial Infarct: 1-2 days –
Loss of nuclei and PMNs: Congestion at edge of infarct: MI: Complete loss of nuclei (48hr)

Myocardial Infarct: Recent (several days old) Below: MI: 2-3 weeks
Infarct: softening; pale, hyperemic border MI: Myocardial Rupture 1-2 wks Macrophages and fibroblasts

Myocardial Infarct: months/years

Lung Infarct: (wedge-shaped) Pulmonary Infarct - Coagulative Necrosis w/tissue

congestion/hemorrhage; loss of alveolar septae

Extravasated blood in
damaged area.

Test q: An organ from a 70y/o woman at the time of autopsy showed a focal, wedge-shaped area that was firm and accompanied by extensive
hemorrhage, giving it a red appearance. Choose the best answer w/the organ and the situation that resulted in this lesion: Lung with pulmonary
embolism. (Other choices: heart w/coronary thrombosis, liver w/hypovolemic shock, kidney w/septic emboli, and brain w/hypertensive stroke.)
Kidney Infarct Kidney Infarct – Coagulative Necrosis Kidney Infarct

Wedge-shaped. Loss of cellular

More tan/white in detail in
character. infarcted area.

Renal Infarct: Healed Extremity Infarct: Brain Infarct

(organized w/fibrous scar) Infarct of foot (from embolus or thrombus) Liquefactive necrosis

Can be from systemic arterial emboli.

Shock: Hypotension/Diffuse Organ Damage

• Cardiogenic: High Mortality
– MI, Ventricular Rupture, Arrhythmia, Tamponade,
Pulmonary Embolism
– Hypovolemic: Hemorrhage, Fluid Loss (burns,
vomiting/GI, trauma)
• Septic: 100,000 deaths/year; High Mortality
– Overwhelming Infections (septicemia)
– Endotoxic Shock: Release of bacterial cell wall = lipopolysaccharide
components (LPS)
• Neurogenic: anesthesia Septic Shock:
• Anaphylactic: IgE mediated hypersensitivity

Test q: Platelets are: Created from whole blood donations or

collected from donors using apheresis machines.
Other choices:
– Stored for 14 days on a rotator at room temp
– Treated w/multiple antibiotics to prevent the growth of bact
and fungi
– Are the first line therapy for patients the TTP (what?? typo?)
– Frozen at -70*C for later use

Test q: Disorders of primary hemostasis include all of the following

except: hypofibrinogenemia. (Other choices: Aspirin or Plavix
(acquired); Von Willebrand’s disease; Hereditary platelet defects)

(Not sure that these q’s were covered… maybe the tests
are outdated compared to our ppts…or maybe I skipped
over these while reading?)