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1

Chapter

Page

1 Growth, Cells

2

2 Inflammation, Wounds

4

3 Neoplasia

6

4 Hemostasis & related

9

5 RBC disorders

13

6 WBC disorders

17

7 Vascular Pathology

22

8 Cardiac Pathology

25

9 Respiratory Tract Physio

30

10 GI pathology

36

11 Pancrease, Gallbladder, Liver

42

12 Kidney & UG

45

13 Female

49

14 Male

53

15 Endocrine

55

16 Breast Path

60

17 CNS

62

18 NMS

67

19 Skin

71

SSG

Pathoma

Male 53 15 Endocrine 55 16 Breast Path 60 17 CNS 62 18 NMS 67 19

2

Ch 1.1 Growth Adaptations

Hyperplasia

stress on organ → ↑ organ size via

 

&

 

• ↑ cell size = Hypertrophy

Hypertrophy

 

o

protein synth, gene expression, organelle synth

 

• ↑ cell # = Hyperplasia

 
 

o

stem cell divisions

o

stem cells in permanent tissues can only hypertrophy

permanent

Permanent tissues → ∅ stem cells HYPERTROPHY ONLY

tissues

 

1. Cardiac Myocyte

 

2. Skeletal m.m

3. Nerves

 

Pathologic

Pathologic hyperplasia → ↑ risk of dysplasia → ↑ risk of cancer (!) Exception: BPH – ∅ ↑ risk of cancer

Hyperplasia

Atrophy

stress on organ (hormonal stimulation, use, nutrients) atrophy via

 

• ↓ cell size

 
 

o

Ubiquitin-Proteasome Degradation ubiquitin tags proteins to be removed

o

Autophagy –

 
 

cellular componentsvacuolesfuse w/ lysosomes

 

• ↓ # of cells - Apoptosis

 

Metaplasia

stress on organ → ∆ cell type Most commonly involves surface epithelial layers

 
 

Squamous – keratin/non-keratin

 

Columnar – (gut)

 

Transitional – (UG tract)

 

New cells better equipped to handle stress eg: Barrets

 

Normal Esophagus – Squamous

Normal Stomach – Columnar

GERD lower esophagus converts

 

o

columnar non-ciliated mucinous epithelium

(!) Mechanism of Metaplasia = Reprogramming of Stem cells

 

Remove stress REVERSALE of metaplasia

Metaplasia can progress to cancer (eg. Barrets Adenocarcinoma)

(!) Exception: Apocrine Metaplasia (fibrocystic of breast) - ∅ ↑ risk for cancer Vit A deficiency can result in metaplasia

 

Night blindness

immune-system

 

15-17 translocation @ Vit A receptor Promyelocytic Leukemia (PML)

 

o

(Tx: Altra)

 
 

Vit A maintains specialized epithelium (eg: Squamous epithelium lining conjunctiva)

 

o

vit A → ↓ specialization thickening KERATOMALACIA

Mesenchymal Tissues can undergo metaplasia (bone, connective tissues, fat)

 

(!) Myositis Ossificans : trauma skeletal m.m inflammation

 

o

metaplasia@ healing

 

o

Bone produced within skeletal m.m

Dysplasia

Disordered cellular growth refers to proliferation of precancerous cells EG: CIN – cervical intraepithelial neoplasia (I, II, & III) Arises from longstanding pathologically hyperplasia or metaplasia (!) Dysplasia is REVERSIBLE by removing stress

 

If progresses to carcinoma IRREVERSIBLE

Aplasia

Failure of cell production during embryogenesis (eg: unilateral renal agenesis)

 

Hypoplasia

cell production during embryogeneses small organ Eg: streak ovary in Turners

Ch 1.2 – Cellular Injury

Injury

Stress > cells ability to adapt

Factors that

1. Type of Stress - eg. Inflammation vs infarction

determine injury

2. Severity – eg. Atherosclerosis vs embolism

3. Type of Cell effected – neurons are susceptible to hypoxia

Causes of Injury

Inflammation -

Nutritional Deficiency or excess

-

Hypoxia

- Trauma - Genetics

Hypoxia

Low O2 delivery to tissue O2 is final e- acceptor in electron transfer chain → ↓ OxPhos → ↓ ATP Injury

Ischemia

blood flow through an organ via.

Blockage in arterial flow (eg atherosclerosis of coronary angina)

• ↓ venous flow backup & flow across organ bed

 

o

Budd-Chiari – thrombosis of hepatic v liver infarction

Polycythemia Vera is most common cause Lupus anticoagulant hypercoagulable state

 

Shock - perfusion of vital organs

 

o

Cardiogenic

hypovolemic Analphactic

Septic

Hypoxemia

PaO2 < 60 mmHg SaO2 < 90% via

• ↓ FiO2 – eg High altitude

• ↓ PAO2 – eg. Anything that PACO2 – hypoventilation, COPD

Transfer from Aa – interstitial fibrosis of lung

V/Q mismatch

 

O2 carrying capacity

Anemia - RBC mass w normal PaO2 & SaO2 CO poisoning – CO binds Hb more avidly than O2 normal PaO2, SaO2

Smoke, fires, car exhaust, gas heaters

Clinical: (!) CHERRY RED SKIN & HA confusion coma, death

Methemoglobinemia

 

Iron in heme in oxidized Fe +3 form (normal = Fe +2 binds O2)

PaO2 normal, SaO2

Seen w oxidant stress (sulfa & nitrate drugs)

Newborns - amount of reducing “machinery” → ↑ oxidation

Clinical: (!) Chocolate-Colored Blood & Cyanotic

Tx: IV Methylene Blue – reducing agent reduce Fe to Fe +2

Consequences of

OxPhos → ↓ ATP

Hypoxia

• ↓ Na/K pump → ↑ Na in cell H2O follows cell swells

• ↓ Ca +2 pump –

Ca +2 cytosol activate enzymes

 

o

Normal cell – tries to keep Ca +2 in cytosol very low

• ↑Anerobic rxn → ↑ Lactic Acid → ↓ pH DNA & protein precipitation

Initial Phase of Injury

(!) Reversible (!) Cell Swelling = hallmark

 

Loss of microvilli – swelling “covers up” microvilli

membrane blebbilng – cell “blebs” out of cytoskeleton

RER swelling – ER fills w H2O ribosomes pop off → ↓ protein synth

Later phase of Injury

(!) Irreversible (!) Membrane Damage = hallmark

Plasma Membrane damage

 

o

cell products into blood (eg. Troponin)

o

Ca 2 can rush into cell

Mitochondrial Membrane

 

o

ETC in on INNER mitochondrial membrane → ↓ ETC

 

ETC → ↓ ATP irreversible, able to fix

 

o

Cytochrome C leaks into cytoplasm activate apoptosis

Lysosome Membranes

 

o

Enzymes into cytoplasm destroy cell

o

These enzymes futher activated by influx of Ca +2

End result of Injury

Cell Death!

Ch 1.3 – Cell Death

Cell Death

(!) Loss of Nucleus = morphological hallmark of cell death.

1. Pyknosis – nucleus shrinks down into “ink-dot”

2. Karyorrhexis – breakup of nucleus into pieces

3. Karyolysis – pieces broken down into basic building blocks

Mechanisms

Necrosis – “murder” of cells/tissue from outside

Large group of cells affected followed by acute inflammation

Due to underlying pathologic process (never normal physiologic)

Apoptosis – “suicide”, energy dependent, genetic, Single cells or small groups of cells

Eg: endometrial shedding, embryogenesis, CD8+ killing virus infected cells

Dying cell shrinks (becomes eosinophilic)nucleus condenses apoptotic bodies “fall from cell” & are removed by macrophage

• ∅ followed by inflammation

Necrosis types

Coagulative

necrotic tissue that remains film Cellular shape & organ structure remains via coagulation of proteins nucleus in cells Occurs @ ischemic infarction in every organ (except brain) Area of infarction is usually WEDGE shaped & PALE

Necrosis

Tip of wedge points to area of vessel occlusion

Red Infarct

Blood re-enters a loosely organized tissue (eg hemorrhagic infarct)

Liquefactive

Tissue liquefied by enzymatic lysis of cells & proteins

Necrosis

Brain Infarction – bc microglial cell enzymes

Abcess – mediated by PMN enzymes

Pancreatitis – parenchymal destruction via enzymes

Gangrenous

coagulative necrosis that resembles mummified tissue (dry)

Necrosis

(!) Ischemia of Lower limb & GI

If dead tissue becomes infected liquefactive necrosis Wet Gangrene

Caseous

soft friable necrotic tissue with cottage-cheese like appearance

Necrosis

Combination of coagulative & liquefactive necrosis

Characteristic of granulomatous inflammation due to TB or fungus

Fat Necrosis

Necrotic adipose tissues w chalky-white appearance

Calcium deposits on fatty acids saponification chalky appearance

Dystrophic calcification – dead tissue is nidus for Ca deposition

(vs Metastatic calcification - ↑ serum Ca or PO4precipitates) Characteristic @

Trauma to fat (Breast) can present as

o

mass w giant cells

o

calcifications – on mammogram may be benign

Pancreatitis-mediated peripancreatic fat necrosis

Fibrinoid

Necrotic damage to blood vessel wall leaking of proteins from blood vessel into wall BRIGHT PINK staining Characteristic @

Necrosis

Malignant HTN

Vasculitis

Pre-eclampsia placenta

Apoptosis

Mediated by Caspase

Activate proteases (breakdown cytoskeleton)

Activate endonucleases (breakdown DNA) Caspase activated by pathways

1. Intrinsic mitochondrial pathway

o

Cytochrome C mediate in response to… Cellular injury DNA damage, ↓ hormonal s mula on inactivated BCL2

o

Cytochrome C moves from mitocytoactivate caspases

2. Extrinsic Receptor Ligand Pathway

o

FAS-ligand binds FAS-death receptor (CD95) on target cell

3. Cytotoxic CD8+ T-cell Pathways

o

Perforins create pore in membrane of target cell

o

Granzyme enters pore activates caspases

3

Ch 1.4 Free Radical Injury

Free Radical

Chemical speciese w unpaired electron in outer orbit

Physiologic

Occurs normally during Ox Phos Cytochrome C oxidase transfers e- O2 during OxPhos Partial reduction O2, H2O2, & OH radicals

generation

Pathologic

Ionizing Radiation → • OH from splitting up H2O → • OH free radical is most damaging Inflammation – Oxidative burst (NADPH oxidase) Metals (Cu & Fe) – Fe Fenton reaction OH radical (Wilsons & Hemochromatosis) Drugs & Chemicals (acetaminophen hepatotoxicity) & CCl 4

Generation

Free Radical

Peroxidation of Lipids Oxidation of DNA & Proteins

Damage

 

Oxidation of DNA implicated in oncogenesis

Elimiation

Antioxidants

 

of Free

Enzymes

Radicals

 

Super Oxide Dismutase (SOD)– handles O2

Glutathione Peroxidase – handles OH

Catalase – handles H2O2

Metal Carrier Proteins - Transferrin, Ferratin, etc prevent free metals

 

O2

O2• → H2O2 OH H2O

Free Radical

CCl

4 – classically used in DRY CLEANING industry

Injury

converted in body to CCl 3 - in P450 system

initial reversible damage (cell swelling) → ↓ ribosome → ↓ protein synth

fat gets stuck in liver can’t be exported in Lipoprotein FATTY LIVER Reperfusion Injury

 

ischemia cell injury enzymes leak out into blood

blood returned to organ inflammatory cells & O2 & dead tissue free radical production

CH 1.5 Amyloid

Amyloid

Misfolded protein deposited in EXTRAcellular space Results in damaged tissue – tends to deposit around blood vessels Multiple proteins can deposit as amyloid

β pleated sheet configuration

Congo Red staining Apple Green birefringence @ polarized light

Systemic

1° - AL-amyloid - amyloid derived from Ig Light Chain

Amyloid

associated w Plasma Cell Dyscrasia overproduced light chain

2° - AA-Amlyoid – amyloid derived from SAA (Acute phase reactant)

 

inflammatory states (RA, IBD, etc),

malignancy inflammatory states

Family Mediterranean fever – genetic AR dysfunction of PMN

 

o

PMN activated episodes of inflammation

o

Episodes of fever & acute serosal inflammation

Classic Clinical

Nephrotic Syndrome – Kidney is MOST COMMONLY involved organ

Findings

Restrictive Cardiomyopathy Tounge enlargement, malabsorption & hepatosplenomegaly

Dx

Tissue Biopsy required

 

Abdominal fat pad & rectum are easily accessible targets

Tx

Damaged organs must be transplanted amyloid able to be removed

Localized Amyloid

Senile Cardiac

Non-mutated serum Transthyretin deposits in heart

Amyloidosis

Usually asymptomatic Present in 25% > 80 y.o

 

Familial Amyloid

Mutated serum Transthyretin deposits in heart

Cardiomyopathy

Leads to restrictive cardiomyopathy 5% of blacks carry mutated gene

NIDDM Type II

Amylin deposits islets of pancreas

derived from insulin production

Alzeimers dz

Aβ amyloid deposits in brain forms amyloid plaques

derived from β-amyloid precursor protein (Chrm 21)

<downs syndrome patients have early onset alzhemiers>

Dialysis

β2-microglobulin deposits in JOINTS in patients on dialysis

Associated

β2-microgloublin from MHC-I is not well removed from blood

Amyloidosis

 

Medullary

Calcitonin deposits within tumor

carcinoma of

C-cells

thyroid

“Tumor cells in an amyloid background”

4

Ch 2.1 Acute Inflammation Pt 1 – Fluid & Edema

Inflammation

Move PMN & Lymphocyte, plasma protein, fluids from blood interstitial

PMNs = acute

Lymphocyte = chronic

Acute Inflammation

 

Characterized by

 

1) Edema & 2) PMN

Response to

 

1) Infection eliminate pathogen 2) Tissue Necrosis clear necrotic debris

Timing

 

Immediate response limited specificity Innate immunity – epithelium, mucous, complement, mast cells, Mφ, PMN, etc

Ch 2 Acute Inflammation Pt 1 – Fluid & Edema

 

TLR

 

Present on cells innate immune system (Mφ & Dendritic cells) Recognize PAMP (pathogen associated molecular pattern) eg. CD-14 on Mφ recognizes LPS on G- bacteria activates immune system TLR NF-κκκκB turns on acute inflammatory response → ↑ immune mediators TLR also mediate chronic inflammation

Toll-Like

Receptor

Arachidonic Acid

 

Released from phospholipid cell membrane via Phospholipase A2 Acted on by COX or 5-Lipoxygenase

COX path

 

Produces PGs PGI2, PGD2, PGE2

arteriolar vasodilation

post capillary vascular permeability PGE2 also mediates fEEEEver & pain

5-lipooxygenase

 

LTB4 – attracts/activates PMN

(!) (things that attract PMN – LTB4, C5a, IL-8, bacterial products) LTC4, LTD4, LTE4 – contract smooth muscles

mediate vasoconstriction,

bronchospasm,

• ↑ vascular permeability

Mast Cells

 

Widely distributed throughout CT (!) Activated by

Tissue Trauma

Complement (C3a & C5a)

Cross-linking of cell-surface IgE by an antigen

Immediate Response

Release preformed histamine granule

Arterial vasodilation & postcapillary venule vascular perm Delayed Response

Produce arachidonic acid metabolites especially LTs

Complement

 

Proinflammatory serum proteins that “complement” inflammation Circulate as inactive precursors must be activated by various pathways Classic Pathway: C1 binds to IgG or IgM that is bound to antigen

“GM makes classic cars”

Alternative pathway – microbial products directly activate complement Mannose-binding Lectin Pathway(MBL) – MBL binds mannose on microorganism bound MBL activates complement

Result of all 3 pathways

C3 convertase generated : C3 C3a & C3b

C5 convertase generated : C5 C5a & C5b

C5b joints C6-C9 formation of Membrane Attack Complex (MAC) Key Products of complement

C3a & C5a – trigger mast cell degranulation

C5a – chemotactic for PMN

C3b – opsonin for phagocytosis

MAC – lyses microbes by creating holes in cell membrane

Hageman Factor

Inactive Proinflammatory protein, produced in liver

Activated @ exposure to subendothelial or tissue collagen activates

Coagulation & fibrinolytic systems (!) role in G- sepsis & DIC

Complement

Kinnin system – cleave HMWK bradykinin vasodilation, vascular perm, & pain

Cardinal Signs of Inflammation

Redness (rubor) & warmth (calor)

Relax arteriolar smooth m.m Vasodilation ↑ blood flow

 

Mediators: Histamine > PGs (I2,D2,E2) & bradykinin

Swelling (tumor)

Leakage of fluid from postcapillary venule interstitial space

Mediators: Histamine & Tissue Damage

Pain (dolor)

Sensitization of sensory nerve endings

Mediators: Bradykinin & PGE2

Fever

Pyrogens cause Mφ → IL-1 & TNF release hypothalamus

• → ↑ COX ac vity @ perivascular cells of hypothalamus

• → ↑ PGE2 raises temperature set point @ hypothalamus fEEver

Ch 2 Acute Inflammation Pt 2 – PMN arrival & function (~24hr)

Step 1

Vasodilation slows bloodflow in postcapillary venules Cells marginate from center of flow periphery

Margination

Step 2

Endothelial SELECTINs upregulated act as “speedbump” when PMN rolling over

Rolling

P-selectin – from Weibel-Palade bodies

 

o

Mediator: Histamine

o

Weibel-Palade Bodies also have vW factor

E-selectin – induced by TNF & IL-1

Selectins bind Sialyl-Lewis X on WBC interaction slows down WBC

Step 3

Binding of WBC to vessel wall Endothelium: TNF & IL-1 ↑ Cellular Adhesion Molecules (ICAM & VCAM)

Adhesion

WBC: C5a & LTB4 ↑ integrins CAMs & Integrins interact firm adhesion (!) Leukocyte Adhesion Deficiency – AR defect of integrins CD18 subunit

delayed separation of umbilical cord,

↑ circula ng PMN - marginated PMN in lungs ↑ in blood

recurrent infections that lack pus formation

Step 4

WBC transmigrate across endothelium of postcapillary venules Chemotaxis towards IL-8, LTB4, C5a, & bacterial products

Chemotaxis

Step 5

Consumption of pathogens or necrotic tissue Enhanced by opsonins (IgG & C3b) Pseudopods from leukocytes extend form phagosomes Phagosomes internalized merge w lysosomes form phagolysosomes Chediak-Higashi Syndrome – AR

protein trafficking defect (microtubules for movement)

Phagocytosis

↑ risk of pyogenic infec on, neutropenia, giant granules in leukocytes

Defective primary hemostatsis, albinism, peripheral neuropathy

Step 6

O2-depended killing – MOST effective

Detruction

Phagocytosed

material

HOCl generated by oxidative burst in phagolysosome

Chronic Granulomatous Disease

• ↓ O2 depended killing due to NADPH oxidase (X-linked or AR)

Cat+ organisms –

 

o

S.aureus,

(!) Pseudomonas cepacia

o

S marcescens,

Nocardia,

Aspergillus

Nitroblue Tetrazolium Test – (NBT Test) - tests NAPDH oxidase

 

o

If reaction is intact dye will turn blue

o

If reaction (CGD) dye will stay clear

MPO deficiency – usually asymptomatic, but ↑ risk Candida infec ons, normal NBT O2 – independent killing – less effect

Occur via enzymes in leukocyte 2ndary granules

Lysozyme

Major Basic Protein

Step 7

PMN undergo APOPTOSIS within 24 hrs after resolution of inflammatory stimulus

Resolution

Stage 3 of inflammation

Mφ stage Days 2-3 after inflammation begins

Mφ

Monocyte in blood arrive via margination/rolling/adhesion/transmigration Ingest via phagocytosis destroy using enzymes in 2ndary granules

Lysozyme is (!) enzyme

Manage the next step of inflammation

Resolution & Healing IL-10 & TGF-β → ↓ inflammatory process

Continue acute inflammation IL-8 Mφ recruit more PMN

Abscess formation – area of fibrosis around area of infection

Chronic Inflammation

Ch 2.2 Chronic Inflammation

General

Lymphocytes & Plasma cell in tissue Delayed response but ↑ specific (adaptive)

 

Stimuli

Persistent infection – most common cause Viral, mycobacterial, parasites, fungi, autoimmune dz, foreign material, some cancers

T-lymphocytes

Produce in marrow as “Progenitor T-cell” Thymus for education

TCR (T-cell Receptor) undergoes rearrangement

 

Become CD4+ helper or CD8+ cytotoxic

TCR-complex used to survey antigens presented on MHC (TCR & CD3)

CD4+ MHC Class II

CD8+ MHC Class I

Activation of T-Cell requires 1. Binding of Ag/MHC complex & 2. Additional 2 nd signal

CD4+ activation

APC take extracellular Ag phagocytosedprocessedpresent on MHC II APC B7 CD28 on CD4+ T cell (mnemonic: 28/7 = 4)

Activated CD4+ T-cells secrete cytokines help B-cells or CD8+ T-cells

Th1 – help CD8+

 
 

o

IL-2 – T-cell growth factor & CD8+ T cell activator

o

IFN-y – Mφ activator

 

Th2 – helps B-cells

 
 

o

IL-4 – class switching to IgG & IgE

 

o

IL-5 – eosinophil chemotaxis & activation/maturation of

 

B-cell plasma cell & class switching to IgA

 

o

IL-10 – inhibits Th1 phenotype

 

CD8+ activation

INTRACELLULAR antigens processed & presented on MHC-I IL-2 from CD4+ Th1 cells provides 2ndary activation signal Activated CD8+ kill cells with Ag of choice of MHC

 

Secretion of Perforins & Granzymes induce Apoptosis (caspase)

Expression of FasL bind Fas on target cells activated apoptosis

B-lymphocytes

Immature B-cell produced in marrow undergo Ig rearrangement to become naïve B-cell w IgM & IgD

 

B-cell Activation

1.Ag binds surface IgM (or IgD) become IgM secreting plasma cell 2.B-cell Ag presentation to CD4+ via MHC II

CD40-r on B-cell binds CD40L on helper T-cell 2 nd activation signal

IL-4 & IL-5 from T-cell B-cell isotype switch, mutation, & maturation

 

o

Now produces IgM, IgD, IgG, IgA

 

Granulomatous

Subtype of chronic inflammation Granuloma

 

Inflammation

(!) Epitheloid histiocytes – Mφ w abundant pink cytoplasm = DEFINING

Other optional features Surrounded by giant cells & rim of lymphocytes

Subtypes Caseating & Non-caseating

 

Noncaseating

central necrosis

granuloma

rxn to foreign material

Sarcoidosis

Beryllium

Crohns dz

Cat Scratch Dz – stellate shaped

Caseating

Central Necrosis

Granuloma

(!) TB & Fungal infection AFB stain for TB & GMS (silver) stain for fungi

Granuloma

Mφ → present Ag via MHC-II to CD4+ Mφ secreted IL-12 induce CD4+ into Th1 subtype Th1 cells secrete IFN-y converts Mφ to Epithelioid Histiocytes

 

formation

(both types)

5

Ch 2.4 Primary Immunodeficiency

Name

Desc

Cause

Clinical

 

Patho & Pics

Dx/Tx & Notes

DiGeorge

Failure of development of 3 rd & 4 th pharyngeal pouch

22q11 microdeletion

T-cell deficiency ( thymus) → ↓ immune to virus Hypocalcemia (parathyroids) Abnormal heart, great vessels & face

∅ parathyroids) Abnormal heart, great vessels & face   C ardiac Abnormality (especially tetralogy of Fallot)
 

Cardiac Abnormality (especially tetralogy of Fallot) Abnormal facies

Thymic aplasia

Chromosome 22

 

Cleft palate

Hypocalcemia.

SCID

Defective cell-mediated & humoral immunity

CK-receptor defects (!) Adenosine deaminase deficiency

↑ susceptibility to fungal, viral, bacterial & protozoal infection

to fungal, viral, bacterial & protozoal infection   Sterile isolation – Bubble Boy Stem cell transplant
 

Sterile isolation – Bubble Boy Stem cell transplant

 

“severe combined”

 

Build up adenosinetoxic to lymphocyte

↑ opportunis c infec ons

 

Generate normal T & B cells

MHC Class II deficiency

give live vaccines

 
 

CD4+ able to activate → ↓ B-cell & T-cell function

 

X-linked

Lack of immunoglobulins Disordered B-cell maturation Naïve B-cell able to mature to Plasma Cell

X-linked mutation @ BTK

presenta on a er 6 months of life (a er moms Abs gone)

<The Brute Tyrant on the X chromosome takes away your Ab’s>

 

agammaglobulinemia

 

Bruton Tyrosine Kinase

(!) ↑ recurrent bacterial, enterovirus & Giardia infections

 

Avoid Live vaccines

   

CVID

immunoglobulin bc B-cell or helper T cell defect

 

Present late in childhood

     

“common variable”

bacterial, enterovirus & Giardia infections

(!) ↑ risk for autoimmune dz & lymphoma

IgA deficiency

Low serum & mucosal IgA

 

risk for mucosal infec ons (esp viral)

<IgA in musosA>

   

Hyper-IgM syndrome

Elevated IgM ↓↓ IgA, IgG, IgE

Mutated CD40L or CD40-receptor

Recurrent pyogenic infections Mucosal infections

     
 

IL-4 or IL-5→ ∅ class switching of B-cell

Wiskott Aldrich

 

X-liked mutation in WASP

Thrombocytopenia – bleeding, petechiae Eczema Recurrent infections (humoral & cellular immunity)

   

Complement

   

C5b-C8 ↑ risk for Neisseria infec on

   

<you better complement neiserria 5 to 9 times, or it will infect you> <C1- – if you see (some) one w periorbit edema>

Deficiency

C1 inhibitor – hereditary angioedema of skin & mucosa

 

Periorbital edema is classic finding

Ch 2.5 Autoimmune Disorders General

 

Loss of self-tolerance

in women, esp @ childbearing age

     

• ∅ apoptosis of self-reactive lymphocyte

Environmental triggers in genetically susceptible individual

Self-reactive lymphocytes anergic

incidence in twins & association w certain HLA subtypes

Name

Desc

Cause

Clinical

 

Patho

Dx/Tx

SLE

Systemic autoimmune dz Antibodies vs host damage multiple tissue

Systemic autoimmune dz Antibodies vs host → damage multiple tissue

Type II (Cytotoxic) hypersensitivity Type III (Ag-Ab complex) Hypersensitivity

Fever & weight loss

 

ANA

ANA – sensitivity test - screening Anti-dsDNA – specific test

 

Malar “butterfly” rash w photosensitivity

Anti-dsDNA

 

Arthritis

Pleuritis & pericarditis

CNS psychosis

Anti-Smith core protein of snRNPs Antiphospholipid Syndrome – associated w SLE -antibody against proteins bound to phospholipids -anticardiolipin false+ for syphilis -lupus anticoagulant – falsely elevated PTT

 

Renal damage – common cause of death in SLE

 

(!) Diffuse Proliferative GN = most common

(Note:

Can have other lesions Heart – can affect any layers

 

AntiHISTONE Ab = drug-induced SLE Drugs: Hydralazine, procainamide, INH

 
 

Endocarditis, Myocarditis, Pericarditis

Ptnt is actually hypercoagulable

Tx: remove drug

Libman-Sacks endocarditis – vegetations on both sides of valves <”Leaflet stacks” on both sides> Anemia, TCP, Leukopenia – blood products

DVT

Stroke

Hepatic Vein thrombosis – budd chairi

Placental thrombosis loose babies

   

Infections – common cause of death

Tx: Lifelong anticoagulation

Sjogren Snydrome

Autoimmune destruction of lacrimal & salivary gland

 

Dry eyes “dirt in my eyes” Dry mouth “can’t chew a cracker” Recurrent dental carries Associated w other AI dz – esp RA (!) ↑ risk for B-cell lymphoma – UNILATERAL enlargement of parotid late in disease course

ANA Anti-Ribonucleoprotein antibody

<Sjogren = “Stoner”

UNILATERAL enlargement of parotid late in disease course ANA Anti-Ribonucleoprotein antibody <Sjogren = “Stoner”

Anti-SS-Α

Anti-SS-B

Dry eyes, cotton mouth

 

Dental carries – from junk food

Anti Studying Stuff to get an A or B

B-lymphoma – Bowl, Brownies>

Scleroderma

Autoimmune activation of fibroblasts Collagen deposition into skin

 

Diffuse – skin & visceral involvement

 

Diffuse - Anti-DNA topoisomerase I antibody (Scl-70) Localized Anti-centromere antibody

 
   

Esophagus commonly affected dysphagia Localized Scleroderma CREST syndrome

   

Calcinosis & anti-Centromere

Raynaud’s

 

Esophageal dysmotility

Sclerodactyly

Telangiectasias of skin

Mixed CT disease

Mixed – features of SLE, scleroderma, polymyositis

   

U1-ribonucleoprotein antibody

 

6

Ch 2.6 Wound Healing

 

General

Healing is initiated when inflammation begins Combination of Regeneration & Repair (scar)

 

Regeneration

Replace damaged tissue with native tissue Depends on regenerative capacity of tissue 3 types of capacity 1.Labile Tissues – constantly cycle tissues, stem cells in tissue

Bowel/crypts, skin/basal layer, marrow/hematopoietic stem cell (CD34) 2.Stable Tissues – quiescent but can renter cell cycle

Liver – compensatory hyperplasia after partial resection

Proximal Renal Tubule –

 

3.Permanent Tissues – lack significant regenerative potential repair w fibrous scar

Myocardium

Skeletal m.m

Neurons

Repair

permanent tissues & trauma/lesion that removes stem cells Granulation Tissues = initial phase of repair Eventually Type III collagen replaced w Type I collagen

(!) Collagenase removes Type III collagen & requires Zn co-factor

Mediated by paracrine signaling via growth factors

Factors bind receptors → ∆ gene expression & cellular growth

TGFα – epithelial & fibroblast growth factor

TGFβ – fibroblast growth factor, inhibit inflammation

Platelet Derived GF – endothelium , smooth m.m, & fibroblast growth

Fibroblast GF – angiogenesis, skeletal development

VEGF – angiogenesis

 

Granulation

Fibroblasts deposit Type III collagen Capillaries – provide nutrients Myofibroblast – contract wound

 

Tissues

Cutaneous

Primary Intention – wound edges brought together minimal scar

Healing

Secondary intention – edges approximated granulation tissue fills in defect

Myofibroblast can cause retraction of wound/scar

Delayed Wound

Infection – most common cause Vit C - hydroxylation of Proline or Lycine → ∅ pro-collagen cross-linking Cu - Lysyl oxidase → ∅ crosslinking of collagens Zn deficiency - Collagenase → ∅ able replace Type III Type I Other: foreign body, ischemia, DM, malnutrition

Healing

Dehiscence

Rupture of wound Most commonly seen @ abdominal surgery

 

Hypertrophic Scar

Scar is in excess of the wound Type I

 

Keloid

Excess scar tissue way out of proportion to wound Type III collagen

↑ in African Americans

 

↑ @ earlobes, face & upper extremity +6

 

Ch 3.1 Neoplasia

General Neoplasia - New tissue growth that is unregulated, irreversible & monoclonal • Monoclonal =
General
Neoplasia - New tissue growth that is unregulated, irreversible & monoclonal
Monoclonal = neoplastic cells are derived from a single mother cell
Clonality
(!) Can be determined by G6P-DH enzyme isoforms
• Multiple isoforms exist (G6PD A ,G6PD B , G6PD C , etc)
• 1 isoform inherited from each parent onto X- chromosome
o
In females → 1 isoform is inactivated by Lyonization
• Normal ratio of active forms is 1:1 (50% of each isoform)
o
Hyperplasia is Polyclonal → 1:1 ratio maintained
o
Neoplasia is monoclonal → ∆ ratio of isoforms
Clonality can also be determined by adregen-r isoforms (also on X chromosome)
(!) Clonality of B-lymphocyte determined by immunoglobulin (Ig) light chain phenotype
• Each B cell has light chain→ either • κappa or • lambda
• Normal κappa::lambda ratio = 3:1
o
Reactive Hyperplasia (Polyclonal) → ratio maintained
o
(!) Lymphoma (monoclonal) → ratio reverses & is 6:1
κappa::lambda ratio = 1:6 → lambda:: κappa ratio = 6:1
Neoplastic
Tumor
Remember: both types are monoclonal!
Benign Tumors – remain locations → ∅ mets
Malignant Tumors (cancer)– invade locally & have potential to mets
Tumor
Lineage
Malignant
Nomenclature
Epithelium
Mesencyhme
Lymphocyte
Melanocyte
Benign
Adenoma - glands
Papilloma – fingerlike
Lipoma, Osteoma, etc
∅ exist
Nevus (mole)
Adenocarinoma – glands
Papillary Carcinoma – fingerlike (Epithelium, CT core, vessel)
Liposarcoma, Osteosarcoma, etc
Lymphoma/Leukemia
Melanoma – mass of cells
Epidemiology
Cancer is #2 cause of death in both adult & children
• Adults
1) Cardiovascular Dz
2) Cancer
3) Cerebrovascular Dz
• Children
1) Accidents
2) Cancers
3) Congenital Defect
Most common cancers in adults (excluding skin)
Most common (by Incidence)
Mortality (# deaths)
1. Breast/Prostate
1. Lung – ∅ really good screen
2. Lung
2. Breast/Prostate – mammogram, PSA
3. Colorectal
3. Colorectal - colonscopy
Screening
Cancer starts as single cell
(!) 30 divisions needed before earliest symptoms arise
• Every division → increased mutations
• Cancers that are detected late have a poorer prognosis
Goal of Screening
• Catch dysplasia before it becomes carcinoma
• Detect carcinoma before clinical symptoms arise
Pap smear – identify cervical dysplasia (Cervical Intraepithelial Neoplasia or CIN) before it becomes carcinoma
Mammography – detect breast cancer before clinical symtpoms
• Ductal Carcinoma in Situ – pick it up before tissue invades → Look for calcifications
• Average size when detected by patient 2 cm
Average size when detected by mammography = 1 cm
PSA & DRE
• Prostate cancer tends to grow @ posterior peripheral prostate
(∅ urinary symptoms till late)
• (remember BPH is periurethral→ urinary symptoms)
Hemoccult Test & Colonoscopy → Colonic adenoma before it becomes carcinoma or carcinoma before it spreads

7

3.2 Carcinogenesis -

Chemicals

Carcinogenic Agent

Associated Cancer

Comments

Aflatoxin

Hepatocellular Carcinoma

Derive from Aspergillus contaminates grains

Alkylating Agents

Leukemia/Lymphoma

Side effect of chemotherapy

Alcohol

Squamous Cell carcinoma of oropharynx Squamous Cell carcinoma of upper esophagus Pancreatic carcinoma Hepatocellular carcinoma

 

Arsenic

Squamous Cell Carcinoma of Skin Lung Cancer Angiosarcoma of Live

Arsenic also present in cig smoke

Asbestos

Lung Cancer

(!) more likely to get lung cancer than

Mesothelima

mesothelioma

Cig Smoke

Carcinoma of Oropharynx & Esophagus Lung Cancer (Squamous Cell & Small Cell) Kidney & Bladder cancer

Most common carcinogen worldwide (!) Polycyclic hydrocarbon – most important carcinogen in cig smoke

Nitrosamines

Stomach carcinoma (intestinal type)

in smoked food → ↑ in Japan

Naphthylamine

Urothelial Carcinoma of bladder

Derived from cig smoke

Vinyl Chloride

Angiosarcoma of Liver

Occupational Exposure Used to make PVC pipes

Nickel, Chromium,

Lung cancer

Occupational exposures

Beryllium, Silica

Oncogenic Viruses

Bug

Associated Cancer

Comments

EBV

Nasopharyngeal Carcinoma – Asians, male Burkitt Lymphoma – in Africa CNS lymphoma in AIDS

Presents as neck mass mets to regional LN

HHV-8

Kaposi Sarcoma

-Eastern Europeans Maleexcise to treat

Tumor of endothelial cells

-AIDS patients Anti-Retroviral (HAART) -Transplants → ↓ immunosuppressive drugs

HBV & HCV

Hepatocellular Carcinoma

 

HTLV-1

Adult T-cell leukemia/lymphoma

 

HPV 16, 18, 31,33

SCC of vulva vagina, anus, cervix Adenocarcinoma of Cervix

 

Radiation

   

Type

Associated Cancer

Comments

Ionizing

Papillary Carcinoma of Tyroid

Radiation Hydroxyl free radicals

(Nuclear Reactors)

AML

CML

Non-Ionizing

Basal Cell Carcinoma of skin SCC of skin Melanoma of skin

Form pyrimidine dimers in DNA Normally excised by restriction endonuclease

(UVB sunlight)

Xeroderma Pigmentosum

3.2 – part 2 Carcinogenesis 2

Carcinogens DNA mutations

 

DNA mutations disruptied regulatory systems

   

1.Protoncogenes

 
 

2. Tumor Surpressor Genes 3.Regulators of Apoptosis

Proto-oncogenes

Essential for cell growth & differentiations

 

Mutation of proto-oncogene Onco-gene unregulated growth Categories of proto- oncogenes

 
 

Growth Factors

Growth Factor Receptors

 

Signal Transducers

Nuclear Regulator

Cell Cycle Regulator

Genes

 

Function

 

Mechanism

 

Tumor

Growth Factors

PDGFB

Platelet-Derived Growth Factor

PDGF expression → ↑ astrocyte divisions

Astrocytoma

 

Autocrine loop (cell signals self)

 

Growth Factor Receptors

 

Her2/neu

Epidermal Growth Factor Receptor

Ampliation

 

Subset of breast cancers

ERBB2

 

trastuzumab

 

RET

Neural Growth factor receptor

Point mutation

 

Medullary Carcinoma of Thyroid

   

MEN 2A & 2B

KIT

Stem cell growth factor receptor

Point Mutation

 

Gastrointestinal Stromal Tumor

Signal Transducers

RAS gene family

GTP-binding protein RAS-GTP work @ nucleus

Point mutation . RAS can normally inactivate GTP

Carcinoma,

 

melanoma,

 

GAS

lymphoma

ABL

Tyrosine Kinase

t(9:22) with BCR

 

CML

& some types of ALL (adult ALL)

Philadelphia chromosome (Ph + )

Nuclear Regulators

c-MYC

Transcription factor

t(8:14) involving IgH

 

Burkitt lymphoma

 

Immunoglobulin heavy chain coded on Chrm 14

 

N-MYC

Transcription factor

Amplification

 

Neuroblastoma

 

L-MYC

Transcription factor

Amplification

 

Lung

Small Cell Carcinoma

Cell Cycle Regulator

CCND1 (cyclin D1)

Cyclin

 

t(11:14) involving IgH

 

Mantle cell lymphoma

G1 phase S phase

   

Expansion of LN mantle

CDK4

Cyclin-Dependent Kinase

Ampliation

 

Melanoma

 

8

3.2 – part 3 – Carcinogenesis (Part 3)

Tumor

Regulate cell growth

 

Suppressor

 

P53

Genes

Rb

p53

Regulates G1 S phase

 

p53 examines DNA

DNA injured p53 triggers DNA repair mechanism ↑↑↑ mutations p53 triggers BAX BAX destroys BCL2

 

BCL2 normally stabilizes mitochondrial membrane

• ↓ BCL2 Cytochrome C release Caspases Apoptosis

Both copies of p53 must be knocked out for tumor formation

 

“Knudson’s Two-Hit Hypothesis”

Loss is seen in >50% of cancer

Li-Fraumeni Syndrome – germline mutation 1 bad copy of p53

risk of carcinomas & sarcomas

Rb

Regulates G1S

 

(retinoblastoma)

 

Rb normally binds E2F

Phosphorylate Rb release E2F cell cycle progression

 

o

Phos by CyclinD/CD4 complex

Rb → ↑ free E2F uncontrolled progression of cell cycle Both Rb must be damaged (Two Hit Hypothesis)

 

Sporadic mutation Unilateral Retinoblastoma

Germline Mutation Bilateral Retinoblastoma + Osteosarcoma

Regulators of

Prevent apoptosis in normal cell, promote apoptosis in mutated cells

Apoptosis

BCL2

BCL2

Stabilizes mitochondrial membrane prevent cytochrome c Overexpressed in Follicular Lymphoma

t(14,18) moves BCL (18) IgH locus (14)

BCL2 expression in B-cell → ∅ apoptosis in B-cell in follicle

Other important regulators

 

Telomerase

Necessary enzyme for cell immortality Normal: telomere shortening w cell divisions senescence Cancers – upregulated telomerase preserves telomeres

Angiogenesis

FGF & VEGF – commonly produces by tumor cells

Avoiding

Tumor cells evade immune response by expression of MHC I

Immune

Immunodeficiency → ↑ cancer risk

Surveillance

 

3.3 Tumor Progression

 

Tumor Invasion

Accumulate mutations

 

Invasion

spread

Characteristics to

regulation of E-cadherin

 

spread

E-cadherin

Normally: keep epithelial cells attached to each other Tumors need to be able to dissociate from neighbors

regulated E-cadherin

 

dissociated Tumor cell will bind to Laminin in BM

Eventually destroy BM via Collagenase IVspread to ECM

In ECM bind to Fibronectin local spread lymph or blood

Lymph Spread

(!) Carcinoma Lymphatic Spread

 

(Carcinoma)

Initial Spread: Regional draining lymph nodes

Heme spread

(!) Sarcomas Hematogenous Spread

(and some carcinomas)

(Sarcomas)

Characteristic spread to lungs

Hematogenous spreading Carcinomas

 

Renal Cell Carcinoma Renal Vein mets

Hepatocellular Carcinoma Hepatic vein mets

Follicular Carcinoma of Thyroid

 

Choriocarcinoma (placenta, Trophoblast)

Seeding of Body Cavities

(!) Ovarian Carcinoma

 

Seed to omentum “Omental Caking”

3.4 Clinical Characterisics of Cancer

Tumor

Benign

Malignant Rapid growing Poorly circumscribed Infiltrative Fixed to surrounding tissue

Characteristics

Slow Growing

Well Circumscribed

Distinct

Mobile

Biopsy/Excision

Required to classify a tumor w certainty

Histo Features

Benign Differentiated Organized Growth Uniform Nuclei Low Nuclear/Cytoplasm ratio Minimal mitotic activity

Malignant differentiation Disorganized growth Nuclear pleomorphism w hyperchromasia High nuclear to cytoplasmic ratio High mitotic activity

invasion

Invasion

metastatic potential

(!) Metastatic potential = hallmark

Immuno-Histo-

Useful to characterize malignant tumors that are difficult to classify histologically

Chemistry

Intermediate Filaments

 

Keratin

Epithelium carcinoma

 

Vimentin

Mesenchyme sarcoma

 

Desmin

Muscle Cell

 

GFAP

Neuroglia

 

Neurofilament

Neurons

 

Other

PSA

Prostate

 

Estrogen R

Breast epithelium

 

Thyroglobulin

Tyroid Follicular cell

 

Chromogranin

Neuroendocrine cells

 
 

Small cell carcinoma of Lung – worst differentiated neuroendocrine

Carcinoid Tumor – best differentiated neuroendocrine

S-100

Melanoma

 

Serum Tumor

Proteins released by tumor

 

Markers

 

1.screening,

2.monitors Tx response,

3.monitor recurrence

used for diagnosis Tissue Biopsy needed for dx

Grading of

Look @ architectural & nuclear features Well differentiated -resembles parent tissuebetter prognosis Poorly differentiated - resemble parent tissue worse prognosis

Cancer

Staging of

Based on Size & Spread (!) Staging is key prognostic factor (more important than Grading) Final staging is determined after resection of tumor TNM

Tumor – size & depth of invasions (tubular organs)

Cancer

 

Nodes – spread to regional lymph nodes - #2 prognostic factor

Metastasis – (!) most important prognostic factor

9

Ch 4.1 – Primary Hemostasis

Intro Blood vessels Hemostasis = Repair to damage wall of vessel Primary Hemostasis – goal
Intro
Blood vessels
Hemostasis = Repair to damage wall of vessel
Primary Hemostasis – goal is to form a weak Platelet Plug
Endothelial cells on a BM
Forms a Thrombus/Clot
2ndary Hemostasis – goal is to stabilize platelet
Mediated by coagulation cascade
Mediated by endothelium/platelet
1° Hemostasis
1. Transient
caused by:
2. vWF binds
3.Platelet
4 Platelet
Vasoconstriction
Neural stimulation/reflex
subendothelial
Platelet Adhesion: Platelet - GPIb –binds to→ vWF
vWF comes from
Degranulation
Adhesion to vWF → platelet shape change → dumping of mediators
Mediators
Aggregation
of damaged
Endothelial cells release Endothelin →
vasoconstriction
collagen → vWF
links to platelets
• endothelial cells → Weibel-Palade bodies
• ADP – induces platelets to express GP2II/IIIa
Aggregation via GP2b3a
(!) Fribinogen = linking molecule
End Result – Weak Platelet Plug
vessels
• Platelet α granules
o
GP2II/IIIa is important for aggregation (step 4)
Weibel-Palade bodies - in endothelial cells hold vWF Factor
• vWF factor
both stored in WP bodies
• Thromboxane A2 – derived from platelet cox
promotes aggregation
• P-selectin
Name
Desc
Cause
Clinical
Labs/Dx
Tx & Notes
Disorders of 1°
hemostasis (general)
Abnormality in platelet
Mucosal Bleed
Labs
o
• quantitative
• (!) Epistaxis
• Hemoptysis
• Platelet Count (Normal: 150k-
• Qualitative
• GI Bleed
400k)
• Hematuria
• Menorrhagia
• Bleeding Time (Normal 2-7 min)
• (!) complication @ severe TCP → Intracranial bleed
• Blood Smear
Skin Bleed
o
# of platelets
• Petechiae – sign of TCP (↓ quantity)
o
Size of plateles
o
∅ seen w qualitative disorder
• • Purpura
Ecchymoses
Bone Marrow Biopsy
Megakarytocytes
• Easy Bruising
ITP
(!) most common cause of TCP in childrens & adult
Acute Form – Children
Autoimmune IgG → platelet antigens
Thrombocytopenia
Corticosteroid
eg. IgG against Gp2b3a
Platelets <50k/uL
• Children respond well
TCP weeks after vial infection or immunization
(!) self-lmiting – resolves in few weeks
Chronic Form – Adults
Spleen → Plasma Cells → Antibodies
Ab-covered platelets travel to spleen
→ consumed by splenic macrophages
Normal PT
Normal PTT
Hyperplasia of Megakarytocytes @ Biospy
• Adults – respond but often relapse
IVIG - can raise platelet count in symptomatic
bleeding
• ↑ in women of childbearing age
o
IgG can cross placenta and cause short
period of TCP in offspring
Slpeenic Mφ focuses on consuming
IVIG
Short period of ↑ platelets
• Primary – cause unknown
Splenectomy
• 2ndary – associated w SLE, others
• (!) Elimate site of Antibody
• (!) Eliminate site of destruction
Microangiopathic
RBC crossing across Platelet Microtrhombi gets sheared
Hemloytic Anemia
Pathological formation of platelets microthrombi in small
vessels
Hemolysis → Schistocytes
<pic of schistocyte>
2 points at both end
Causing Hemolytic Anemia
Platelets are consumed in formation of microthrombi
Look like “helmet cell”
2 classic disorders → TTP& HUS
Thrombotic
Microthrombi due to ↓ ADAMSTS13
Thrombocytopenic
• Genetic Deficiency
Plasmapharesis – remove autoAb against ADAMS
Corticosteroid - ↓ autoAb production
Pupura
• Autoantibody to ADAMSTS13 in adult female
ADAMSTS13 normally chop up polymeric vWF precursor
TCP w ↑ bleeding time
Normal PT/PTT
platelet adhesion
Hemolytic
Skin & Mucosal Bleeding
Microangiopathic Hemolytic Anemia
Fever
Renal Insufficiency – predominant in HUS
CNS Abnormalities – predominant in TTP
Anemia w Schedistocytes
↑ megakaryocytes @ bone marrow biopsy
Uremic
endothelial damage by drugs or infection
Platelet microthrombi formed
Syndrome
• E Coli 0157:H7 (EHEC)→ Verotoxin
• Verotoxin damages endothelial cell
• Undercooked beef → Dysentery
Bernard-Soulier
Genetic GP1b deficiency → ↓ platelet adhesion
Bleed
(Big Suckers (platelets) in Bernard Soulier)
Syndrome
Mild TCP – platelets destroyed earlier
Enlarged Platelet
Glanzmann
Genetic GpIIb/IIIa deficiency
Glands often come in two or 3s
Thrombasthenia
↓ platelet aggregation
Gp 2 or 3
ASA
ASA irreversibly inactivates COX
↓ TXA2 → impaired platelet aggregation
Uremia
↓ kidney → buildup of nitrogenous waste products
∆ platelet Adhesion & Aggregation

10

4.2 2ndary Hemostasis – goal is strengthen plug w Coagulation Cascade

Name Desc Cause Clinical Labs/Dx Tx & Notes 2ndary Hemostasis Stabilizes weak plug via Coagulation
Name
Desc
Cause
Clinical
Labs/Dx
Tx & Notes
2ndary Hemostasis
Stabilizes weak plug via Coagulation Cascade
Factors of Cascade are produced by Liver→ produced in an Inactive state
<Coagulation Cascade>
12 – activated by subendothelial collagen
11 Intrinsic
PT – extrinsic & common pathway
Coagulation cascade → thrombin →
fibrinogen2fibrin → fibrin cross linked
Activation of Factors requires
Best for monitoring wafrain dose
Exposure to Activating Substance –
PTT – intrinsic & common pathway
o
Tissue Thromboplastin
9
• The side with more numbers
activate Factor VII (extrinsic)
8
7 – activated by tissue thromboplastin
Extrinsic
• Best for monitoring HEParin dose
o
Subendothelial Collage
o
X
activate Factor XII (intrinsic)
<“HEP” is clinic slang for heparin
and has 3 letters, like PTT>
5 → 2 → 1
• Phospholipid Surface of Platelet
• Calcium
Disorder of 2ndary
Hemostasis
usually due to Factor Abnormalities
Deep Tissue Bleeding → into muscle & joints
Rebleeding after Sx procedures
PT – extrinsic & common pathway
PTT – intrinsic & common pathway
Hemophilia A
Factor VIII Deficiency <call it Hemophilia 8>
Xlinked-Rec → ↑ in Males
Can arise from de novo mutation without family hx
Deep tissue, Joint bleeding
Postsurgical Bleed
PTT
Recombinant Factor VIII
Normal PT
Factor VIII
Normal Platelet Count & Bleeding Time
Normal PTT @ mixing study (vs Factor Inhibitor)
Hemophilia B
<B for Bear
Factor IX deficiency
“Christmas Dz”
• Santa bear → Christmas
Deep tissue, Joint bleeding
Postsurgical Bleed
PTT
Normal PT
• Deep bleeds from bear
bites
Factor IX
Normal Platelet Count & Bleeding Time
Coagulation Factor
Antibody against coagulation factor
Inhibitor
Anti-Factor VIII is most common → similar to hemophilia A
Deep tissue, Joint bleeding
Postsurgical Bleed
Same as Hemophilia A except…
(!) ↑ PTT in Mixing Study (vs Hemophelia A)
vonWillibrand Dz
Most common inherited coagulation disorder
Genetic vWF deficiency - many reasons exist (qualitative & quantitate)
Autosomal Dominat w ↓ vWF - Most common type
Mild mucosal & skin bleeding
↑ bleeding time – poor platelet adhesion
(!) Demopressin
↑ PTT – vWF needed to stabilize factor VIII
Not severe enough for clinical signs
Normal PT
(!) Abnormal Ristocetin test – platelets ∅ aggregate
↑ vWF release from
Weibel-Palade bodes of
endothelium
Vit K Deficiency
Dirupts multiple coagulation factors
<Vit K epoxide normally activates Vit K in liver
Vit K → Gamma Carboylate 2, 7, 9, 10, C, S>
Deficiency in ↓ gut flora
• Newborns
• Long-term antibiotic
• Malaborption – Vit A,E,D, & K are fat soluble
Liver Failure
↓ coagulation factors
Measure liver failure effect by monitoring
↓ activation of Vit K by epoxide reductase
PT
Large Volume
Dilutes coagulation factors → relative deficiency
Transfusion
4.3
Other Hemostatic Disorders
Heparin-Induced TCP
Heparin forms complex w Platlet Factor 4 (PF4)
IgG antibody against Heparin-PF4 complex
Complication – platelet fragments
→ activate more platelets → thrombosis
∅ give coumadin → ↑ risk of skin necrosis
Protamine Sulfate?
DIC
Widespread microthrombi → ischemia & infarction
Exhaustion of platelets & factors → bleed
Pathologic activation of coagulation cascade
Microthrombi in vessel → ischemia & infarction
Ischemia & Infarction
Bleed
↓ platelet coutn
↑ PT & PTT
Tx underlying cause
Tx patient supportively
Consumption of platelets & factors → ↑ bleed @ IV sites & mucosa
Almost always 2ndary to some other dz
↓ Fibrinogen
• Blood products
Microangiopathic Hemolytic Anemia
• Cryoprecipitate
• OB complication – aminiotic fluid w Thromboplasin
Thrombi sheer RBC → schitocytes
• Sepsis – endotoxin or Mφ → IL-1 & TNF
(!) ↑ Fibrin Split Products (D-Dimer)
• Adenocarcinoma → mucin actiates
Best screening test for DIC
• Acute Promyelocytic Leukemia – granules/auer rod
• Rattlesnake Bite
Disorders of
Plasmin overactivity → excessive cleavage of fibrinogen
Resembles DIC
↑ PT & PTT
Aminocaproic Acid
Fibrinolysis
↓ coag factors, ↓ fibrinogen, ↓ platelet function
↑ Bleeding Time – w normal platelet coutn
Blocks Plasminogen activation
Plasmin
↑ fibrinogen split products
• cleaves linked fibrin AND cleaves serum fibrinogen
• without D-dimer
• cleave factors
• ∅ fibrin to split → only fibrinogen
• block platelet aggregation
α2-antiplasmin – normally inactivates plasmin
Examples
• Radical Prostatectomy – urokinase released→activate plasmin
• Cirrhosis of Liver - ↓ production of α2-antiplasmin

11

4.4 – Thrombosis

Thrombosis

Pathologic formation of an intravascular blood clot

 

(!) 3 risk factors for thrombosis (Virchows Triad)

Disruption in Blood Flow Endothelial Cell Damage Hypercoagulable State Optional #4 – Iatrogenic – Dr Siew – “The Siew Quatrad”

Basic Principles

In artery or vein

Most common location – Deep Vein of leg ((DVT) BELOW THE KNEE

Thrombus

1. lines of Zahn – alternating layers of RBC platelet fibrin RBC Fibrin

Disruption in Normal Blood Flow

Stasis or turbulence Examples

 

Characteristics

2. Attachment to Vessel Wall – Mural Thrombi

Characteristics 2. Attachment to Vessel Wall – Mural Thrombi
   

Immobilization – post-op

 

**remember to distinguish b/t post-mortem clot → ∅ lines of zahn or attachment

Cardiac Wall Dysfunction –

o

a-fib

 

o

MI

Aneurysm – stasis & turbulent flow in aneurysm

Name

Desc

Cause

Clinical

Endothelial Cell

Endothelium is normally protective against thrombosis

 

Examples:

Damage

blocks exposure of subendothelial collagen

produces PGI 2

produces NO

.Atherosclerosis, .Vasculitis, .Homocysteine

 

secretes Heparin-Like molecules activate AntiThrombin-III → ↓ thrombin & coagulation factors

secretes tPA converts Plasminogen Plasmin

 
 

o

Plasmin works @ 1. Fibrin 2. Fibrinogen 3. Platelet Aggregation 4.Destroy Coag Factors

b12/folate deficiency

 

Thrombomodulin – modulates Thrombin activity

 

CBS deficiency

 

o

Normally: Thrombin ( Factor II) coverts Fibrinogen Fibrin

   

o

@ Thrombomodulin: Thrombin modulated Activates Protein C

Protein Cinactivate Factor V & VIII

B12 or Folate deficiency

homocysteine

 

Mildly elevated homocysteine levels

able to convert homocysteine methionine

Cystathionine β

able to convert homocysteine cystathionine

 

homocysteine Homocystinuria

Synthase (CBS)

Vessel Thrombosis

Synthase (CBS) • Vessel Thrombosis

Deficiency

Mental Retardation

Lens Dislocation

Long Slender Features

Hypercoagulable State

 

Procoagulants and/or Anticoagulant Proteins Inherited or Acquired

Recurent DVT or DVT @ young age Other sites – Hepatic & Cerebral

 

Protein C or S deficiency

Normal : Protein C & S Inactivate Factor V & VIII Protein C & S → ↑ coagulation risk

 

(!) risk for Wafarin Skin Necrosis

 

Warfarin blocks Epoxide Reductase in Liver → ↓ activated Vit K

   

• ↓ 2,7,9,10,C,S activations

Old factors start to degrade C & S degrade first → ↑ risk of thrombus formation

Factor V Leiden

Normal: C & S inactivate Factor V by cleaving it Mutated form → ∅ able to be cleaved by C & S Most common inherited cause of hypercoabule state

Mutated form of Factor V

 

Prothrombin 20210A

 

Inherited point mutation in Prothrombin

 

gene expression → ↑ thrombus formation

AntiThrombin III

protective effect of heparin-like molecules from endothelium → ↑ thrombus risk formation

 

Heparin @ standard does will have increased PTT

Deficiency

antithrombin III to bind

 

Use high does of heparin will bind what it can .Coumadin given to maintain anticoagulated state wean off heparin

OC

E→ ↑ production of coagulation factors

OC – Estrogen → ↑ production of coagulation factors