Pathoma_Husain

Pathoma_Husain. Growth Adaptations, Cellular Injury, and Cell Death I. BASIC PRINCIPLES A. An organ is in homeostasis with the physiologic stress placed on it. B. An increase, decrease, or change in stress on an organ can result in growth adaptations. II. HYPERPLASIA AND HYPERTROPHY A. An increase in stress leads to an increase in organ size. 1. Occurs via an increase in the size (hypertrophy) and/or the number (hyperplasia) of cells B. Hypertrophy involves gene activation, protein synthesis, and production of organelles. C. Hyperplasia involves the production of new cells from stem cells. D. Hyperplasia and hypertrophy generally occur together (e.g., uterus during pregnancy). 1. Permanent tissues (e.g., cardiac muscle, skeletal muscle, and nerve), however, cannot make new cells and undergo hypertrophy only. 2. For example, cardiac myocytes undergo hypertrophy, not hyperplasia, in response to systemic hypertension (Fig. 1.1).


Pathoma_Husain

Pathoma_Husain. 2. For example, cardiac myocytes undergo hypertrophy, not hyperplasia, in response to systemic hypertension (Fig. 1.1). E. Pathologic hyperplasia (e.g., endometrial hyperplasia) can progress to dysplasia and, eventually, cancer. 1. A notable exception is benign prostatic hyperplasia (BPH), which does not increase the risk for prostate cancer. III. ATROPHY A. A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) leads to a decrease in organ size (atrophy). 1. Occurs via a decrease in the size and number of cells B. Decrease in cell number occurs via apoptosis. C. Decrease in cell size occurs via ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components. 1. In ubiquitin-proteosome degradation, intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteosomes. 2.


Pathoma_Husain

Pathoma_Husain. 1. In ubiquitin-proteosome degradation, intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteosomes. 2. Autophagy of cellular components involves generation of autophagic vacuoles. These vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components. IV. METAPLASIA A. A change in stress on an organ leads to a change in cell type (metaplasia). 1. Most commonly involves change of one type of surface epithelium (squamous, columnar, or urothelial) to another 2. Metaplastic cells are better able to handle the new stress. B. Barrett esophagus is a classic example. pathoma.com 1. Esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle friction of a food bolus). 2. Acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells (better able to handle the stress of acid, Fig. 1.2).


Pathoma_Husain

Pathoma_Husain. 2. Acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells (better able to handle the stress of acid, Fig. 1.2). C. Metaplasia occurs via reprogramming ofstem cells, which then produce the new cell type. 1. Metaplasia is reversible, in theory, with removal of the driving stressor. 2. For example, treatment of gastroesophageal reflux may reverse Barrett esophagus. D. Under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer. 1. For example, Barrett esophagus may progress to adenocarcinoma of the esophagus. 2. A notable exception is apocrine metaplasia of breast, which carries no increased risk for cancer. E. Vitamin A deficiency can also result in metaplasia. 1. Vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. 2.


Pathoma_Husain

Pathoma_Husain. E. Vitamin A deficiency can also result in metaplasia. 1. Vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. 2. In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium. This change is called keratomalacia (Fig. 1.3). F. Mesenchymal (connective) tissues can also undergo metaplasia. 1. A classic example is myositis ossificans in which connective tissue within muscle changes to bone during healing after trauma (Fig. 1.4). V. DYSPLASIA A. Disordered cellular growth B. Most often refers to proliferation of precancerous cells 1. For example, cervical intraepithelial neoplasia (CIN) represents dysplasia and is a precursor to cervical cancer. C. Often arises from longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus)


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Pathoma_Husain. C. Often arises from longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus) D. Dysplasia is reversible, in theory, with alleviation of inciting stress. 1. Ifstress persists, dysplasia progresses to carcinoma (irreversible). VI. APLASIA AND HYPOPLASIA A. Aplasia is failure of cell production during embryogenesis (e.g., unilateral renal a genesis). B. Hypoplasia is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome). Fig. 1.1 Left ventricular hypertrophy. (Courtesy of Fig. 1.2 Barrett esophagus. Aliya Husa in, MD) ------Growth Adaptations, Cellular Injury, and Cell Death I. BASIC PRINCIPLES A. Cellular injury occurs when a stress exceeds the cell's ability to adapt. B. The likelihood ofinjury depends on the type of stress, its severity, and the type of cell affected. 1.


Pathoma_Husain

Pathoma_Husain. A. Cellular injury occurs when a stress exceeds the cell's ability to adapt. B. The likelihood ofinjury depends on the type of stress, its severity, and the type of cell affected. 1. Neurons are highly susceptible to ischemic injury; whereas, skeletal muscle is relatively more resistant. 2. Slowly developing ischemia (e.g., renal artery atherosclerosis) results in atrophy; whereas, acute ischemia (e.g., renal artery embolus) results in injury. C. Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations. II. HYPOXIA A. Low oxygen delivery to tissue; important cause ofcellular injury 1. Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation. 2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. 3. Lack of ATP (essential energy source) leads to cellular injury.


Pathoma_Husain

Pathoma_Husain. 2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. 3. Lack of ATP (essential energy source) leads to cellular injury. B. Causes of hypoxia include ischemia, hypoxemia, and decreased 0 2-carrying capacity of blood. C. Ischemia is decreased blood flow through an organ. Arises with 1. Decreased arterial perfusion (e.g., atherosclerosis) 2. Decreased venous drainage (e.g., Budd-Chiari syndrome) 3. D. Hypoxemia is a low partial pressure ofoxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%). Arises with 1. 2. 3. Diffusion defect-PAo2 not able to push as much 0 2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis) 4. V/Q mismatch-Blood bypasses oxygenated lung (circulation problem, e.g., right-to-left shunt), or oxygenated air cannot reach blood (ventilation problem, e.g., atelectasis). E. Decreased 0 -carrying capacity arises with hemoglobin (Hb) loss or dysfunction. 1. 2.


Pathoma_Husain

Pathoma_Husain. E. Decreased 0 -carrying capacity arises with hemoglobin (Hb) loss or dysfunction. 1. 2. Fig.1.3 Keratomalacia. (Courtesy of Fig. 1.4 Myositis Ossificans. (Reprinted with motherchildnutrition.org) permission from orthopaedia.com) i. CO binds hemoglobin more avidly than oxygen-Pao2 normal; Sao2 decreased ii. Exposures include smoke from fires and exhaust from cars or gas heaters. iii. Classic finding is cherry-red appearance of skin. iv. Early sign of exposure is headache; significant exposure leads to coma and death. 3. Methemoglobinemia i. Iron in heme is oxidized to FeH, which cannot bind oxygen-Pao normal; 11. Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns 111. Classic finding is cyanosis with chocolate-colored blood. iv. Treatment is intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state. III. REVERSIBLE AND IRREVERSIBLE CELLULAR INJURY A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP.


Pathoma_Husain

Pathoma_Husain. III. REVERSIBLE AND IRREVERSIBLE CELLULAR INJURY A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP. B. Low ATP disrupts key cellular functions including 1. Na+-K+ pump, resulting in sodium and water buildup in the cell 2. Ca2+ pump, resulting in Ca2+ buildup in the cytosol of the cell 3. Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA. C. The initial phase of injury is reversible. The hallmark of reversible injury is cellular swelling. 1. Cytosol swelling results in loss of microvilli and membrane blebbing. 2. Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis. D. Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage.


Pathoma_Husain

Pathoma_Husain. D. Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage. 1. Plasma membrane damage results in i. Cytosolic enzymes leaking into the serum (e.g., cardiac troponin) ii. Additional calcium entering into the cell 2. Mitochondrial membrane damage results in i. Loss of the electron transport chain (inner mitochondrial membrane) ii. Cytochrome c leaking into cytosol (activates apoptosis) 3. Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by the high intracellular calcium. E. The end result of irreversible injury is cell death. Fig. 1.5 Coagulative necrosis of kidney. A, Gross appearance. B, Microscopic appearance. C, Normal kidney histology for comparison. {A, Courtesy of Aliya Husain, MD) Growth Adaptations, Cellular Injury, and Cell Death I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. Growth Adaptations, Cellular Injury, and Cell Death I. BASIC PRINCIPLES A. The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis). B. The two mechanisms of cell death are necrosis and apoptosis. II. NECROSIS A. Death oflarge groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features III. GROSS PATTERNS OF NECROSIS A. Coagulative necrosis 1. Necrotic tissue that remains firm (Fig. l.SA); cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears (Fig. l.SB). 2. Characteristic of ischemic infarction of any organ except the brain 3. Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale. 4.


Pathoma_Husain

Pathoma_Husain. 2. Characteristic of ischemic infarction of any organ except the brain 3. Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale. 4. Red infarction arises if blood re-enters a loosely organized tissue (e.g., pulmonary or testicular infarction, Fig. 1.6). B. Liquefactive necrosis 1. Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction. 2. Characteristic of i. Brain infarction-Proteolytic enzymes from microglial cells liquefy the brain. ii. Abscess-Proteolytic enzymes from neutrophils liquefy tissue. u1. Pancreatitis-Proteolytic enzymes from pancreas liquefy parenchyma. C. Gangrenous necrosis 1. Coagulative necrosis that resembles mummified tissue (dry gangrene, Fig. 1.7) 2. Characteristic of ischemia of lower limb and GI tract 3. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene). D. Caseous necrosis 1.


Pathoma_Husain

Pathoma_Husain. Characteristic of ischemia of lower limb and GI tract 3. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene). D. Caseous necrosis 1. Soft and friable necrotic tissue with "cottage cheese-like" appearance (Fig. 1.8) 2. Combination of coagulative and liquefactive necrosis 3. Characteristic of granulomatous inflammation due to tuberculous or fungal infection Fig. 1.8 Caseous necrosis of lung. (Courtesy of Fig. 1 .6 Hemorrhagic infarction of testicle. Fig. 1.7 Dry gangrene. Yale Rosen, MD) (Courtesy of humpath.com) E. Fat necrosis 1. Necrotic adipose tissue with chalky-white appearance due to deposition of calcium (Fig. 1.9) 2. Characteristic of trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat 3. Fatty acids released by trauma (e.g., to breast) or lipase (e.g., pancreatitis) join with calcium via a process called saponification.


Pathoma_Husain

Pathoma_Husain. Fatty acids released by trauma (e.g., to breast) or lipase (e.g., pancreatitis) join with calcium via a process called saponification. i. Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate. ii. Metastatic calcification, as opposed to dystrophic calcification, occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis). F. Fibrinoid necrosis 1. Necrotic damage to blood vessel wall 2. Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically (Fig. 1.10). 3. Characteristic of malignant hypertension and vasculitis IV. APOPTOSIS


Pathoma_Husain

Pathoma_Husain. 3. Characteristic of malignant hypertension and vasculitis IV. APOPTOSIS A. Energy (ATP) -dependent, genetically programmed cell death involving single cells or small groups of cells. Examples include 1. 2. Removal of cells during embryogenesis 3. CDs+ T cell-mediated killing of virally infected cells B. Morphology 1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink, Fig. l.ll). 2. Nucleus condenses and fragments in an organized manner. 3. Apoptotic bodies fa ll from the cell and are removed by macrophages; apoptosis is not followed by inflammation. C. Apoptosis is mediated by caspases that activate proteases and endonucleases. 1. Proteases break down the cytoskeleton. 2. Endonucleases break down DNA. D. Caspases are activated by multiple pathways. 1. Intrinsic mitochondrial pathway i. Cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2.


Pathoma_Husain

Pathoma_Husain. D. Caspases are activated by multiple pathways. 1. Intrinsic mitochondrial pathway i. Cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2. ii. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases. Fig. 1.9 Fat necrosis of peri-pancreatic adipose Fig. 1.10 Fibrinoid necrosis of vessel. Fig. 1.11 Apoptosis. tissue. (Courtesy of humpath.com) Growth Adaptations, Cellular Injury, and Cell Death 2. Extrinsic receptor-ligand pathway i. FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). ii. Tumor necrosis factor (TNF) binds TNF receptor on the target cell, activating caspases. 3. Cytotoxic CDs+ T cell-mediated pathway i. Perforins secreted by CDs+ T cell create pores in membrane of target cell. ii. Granzyme from CDS+ T cell enters pores and activates caspases.


Pathoma_Husain

Pathoma_Husain. 3. Cytotoxic CDs+ T cell-mediated pathway i. Perforins secreted by CDs+ T cell create pores in membrane of target cell. ii. Granzyme from CDS+ T cell enters pores and activates caspases. iii. CDs+ T-cell killing ofvirally infected cells is an example. I. BASIC PRINCIPLES A. Free radicals are chemical species with an unpaired electron in their outer orbit. B. Physiologic generation of free radicals occurs during oxidative phosphorylation. 1. Cytochrome c oxidase (complex IV) transfers electrons to oxygen. 2. Partial reduction of 0 2 yields superoxide (0:), hydrogen peroxide (H2O), and hydroxyl radicals ("OH). C. Pathologic generation of free radicals arises with 1. Ionizing radiation-water hydrolyzed to hydroxyl free radical 2. Inflammation-NADPH oxidase generates superoxide ions during oxygendependent killing by neutrophils. 3. Metals (e.g., copper and iron)-Fe2+ generates hydroxyl free radicals (Fenton reaction). 4.


Pathoma_Husain

Pathoma_Husain. Inflammation-NADPH oxidase generates superoxide ions during oxygendependent killing by neutrophils. 3. Metals (e.g., copper and iron)-Fe2+ generates hydroxyl free radicals (Fenton reaction). 4. Drugs and chemicals-P450 system of liver metabolizes drugs (e.g., acetaminophen), generating free radicals. D. Free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis. E. Elimination of free radicals occurs via multiple mechanisms. 1. Antioxidants (e.g., glutathione and vitamins A , C, and E) 2. i. Superoxide dismutase (in mitochondria)-Superoxide co:) ➔ HP2 ii. Glutathione peroxidase (in mitochondria)-2GSH + free radical ➔ GS-SG and H2O iii. Catalase (in peroxisomes)-H2O2 ➔ 0 2and H2O 3. Metal carrier proteins (e.g., transferrin and ceruloplasmin) II. EXAMPLES OF FREE RADICAL INJURY A. Carbon tetrachloride (CC1) 1. Organic solvent used in the dry cleaning industry 2.


Pathoma_Husain

Pathoma_Husain. Metal carrier proteins (e.g., transferrin and ceruloplasmin) II. EXAMPLES OF FREE RADICAL INJURY A. Carbon tetrachloride (CC1) 1. Organic solvent used in the dry cleaning industry 2. Converted to CC13 free radical by P450 system of hepatocytes 3. Results in cell injury with swelling of RER; consequently, ribosomes detach, impairing protein synthesis. 4. Decreased apolipoproteins lead to fatty change in the liver (Fig. 1.12). B. Reperfusion injury 1. Return of blood to ischemic tissue results in production ofO2-derived free radicals, which further damage tissue. 2. Leads to a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of infarcted myocardial tissue I. BASIC PRINCIPLES A. Amyloid is a misfolded protein that deposits in the extracellular space, thereby damaging tissues. B. Multiple proteins can deposit as amyloid. Shared features include 1. 2.


Pathoma_Husain

Pathoma_Husain. A. Amyloid is a misfolded protein that deposits in the extracellular space, thereby damaging tissues. B. Multiple proteins can deposit as amyloid. Shared features include 1. 2. Congo red staining and apple-green birefringence when viewed microscopically under polarized light (Fig. 1.13) C. Deposition can be systemic or localized. II. SYSTEMIC AMYLOIDOSIS A. Amyloid deposition in multiple organs; divided into primary and secondary amyloidosis B. Primary amyloidosis is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain. 1. Associated with plasma cell dyscrasias (e.g., multiple myeloma) C. Secondary amyloidosis is systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA). 1. SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever (FMF). 2.


Pathoma_Husain

Pathoma_Husain. 1. SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever (FMF). 2. FMF is due to a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin. i. Presents with episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction) ii. High SAA during attacks deposits as AA amyloid in tissues. D. Clinical findings of systemic amyloidosis are diverse since almost any tissue can be involved. Classic findings include 1. Nephrotic syndrome; kidney is the most common organ involved. 2. 3. Tongue enlargement, malabsorption, and hepatosplenomegaly E. Diagnosis requires tissue biopsy. Abdominal fat pad and rectum are easily accessible biopsy targets. F. Damaged organs must be transplanted. Amyloid cannot be removed. III. LOCALIZED AMYLOIDOSIS A. Amyloid deposition usually localized to a single organ. B. Senile cardiac amyloidosis 1.


Pathoma_Husain

Pathoma_Husain. F. Damaged organs must be transplanted. Amyloid cannot be removed. III. LOCALIZED AMYLOIDOSIS A. Amyloid deposition usually localized to a single organ. B. Senile cardiac amyloidosis 1. Non-mutated serum transthyretin deposits in the heart. 2. Usually asymptomatic; present in 25% of individuals > 80 years of age C. Familial amyloid cardiomyopathy Fig. 1.12 Fatty change of liver. Fig. 1.13 Amyloid. A, Congo red. B, Apple-green birefringence. (Courtesy of Ed Uthman, MD) Growth Adaptations, Cellular Injury, and Cell Death 1. Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy. 2. 5% of African Americans carry the mutated gene. D. Non-insulin-dependent diabetes mellitus (type II) 1. Amylin (derived from insulin) deposits in the islets of the pancreas. E. Alzheimer disease 1. AP amyloid (derived from P-amyloid precursor protein) deposits in the brain forming amyloid plaques. 2.


Pathoma_Husain

Pathoma_Husain. E. Alzheimer disease 1. AP amyloid (derived from P-amyloid precursor protein) deposits in the brain forming amyloid plaques. 2. Gene for P-APP is present on chromosome 21. Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset). F. Dialysis-associated amyloidosis 1. P2-microglobulin deposits in joints. G. Medullary carcinoma of the thyroid 1. Calcitonin (produced by tumor cells) deposits within the tumor ('tumor cells in an amyloid background').


Pathoma_Husain

Pathoma_Husain. G. Medullary carcinoma of the thyroid 1. Calcitonin (produced by tumor cells) deposits within the tumor ('tumor cells in an amyloid background'). Thank you for choosing Pathoma for your studies. We strive to provide the highest quality educational materials while keeping affordability in mind. A tremendous amount of time and effort has gone into developing these materials, so we appreciate your legitimate use of this program. It speaks to your integrity as a future physician and the high ethical standards that we all set forth for ourselves when taking the Hippocratic oath. Unauthorized use of Pathoma materials is contrary to the ethical standards of a training physician and is a violation of copyright. Pathoma videos are updated on a regular basis and the most current version, as well as a complete list of errata, can be accessed through your account at Pathoma.com. Sincerely, Dr. Sattar, MD Inflammation, Inflammatory Disorders, and Wound Healing I. INFLAMMATION


Pathoma_Husain

Pathoma_Husain. Sincerely, Dr. Sattar, MD Inflammation, Inflammatory Disorders, and Wound Healing I. INFLAMMATION A. Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit blood vessels and enter the interstitial space B. Divided into acute and chronic inflammation I. BASIC PRINCIPLES A. Characterized by the presence of edema and neutrophils in tissue (Fig. 2.lA) B. Arises in response to infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris) C. Immediate response with limited specificity (innate immunity) II. MEDIATORS OF ACUTE INFLAMMATION A. Toll-like receptors (TLRs) 1. Present on cells of the innate immune system (e.g., macrophages and dendritic cells) 2. Activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes i. CD14 (a co-receptor for TLR4) on macrophages recognizes lipopolysaccharide (a PAMP) on the outer membrane of gram-negative bacteria. 3.


Pathoma_Husain

Pathoma_Husain. 3. TLR activation results in upregulation of NF-KB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators. 4. TLRs are also present on cells of adaptive immunity (e.g., lymphocytes) and, hence, play an important role in mediating chronic inflammation. B. Arachidonic acid (AA) metabolites 1. AA is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase. i. Cyclooxygenase produces prostaglandins (PG). a. PGI2, PGD2, and PGE2 mediate vasodilation and increased vascular permeability. b. PGE also mediates pain and fever. ii. 5-lipoxygenase produces leukotrienes (LT). a. LTB4 attracts and activates neutrophils. b. LTC , LTD , and LTE (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability. C. Mast cells 1. 2.


Pathoma_Husain

Pathoma_Husain. b. LTC , LTD , and LTE (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability. C. Mast cells 1. 2. Activated by (1) tissue trauma, (2) complement proteins C3a and CSa, or (3) cross-linking of cell-surface IgE by antigen pathoma.com i. Immediate response involves release of preformed histamine granules, which mediate vasodilation of arterioles and increased vascular permeability. ii. Delayed response involves production of arachidonic acid metabolites, particularly leukotrienes. D. Complement 1. 2. Circulate as inactive precursors; activation occurs via i. Classical pathway-Cl binds IgG or IgM that is bound to antigen. ii. Alternative pathway-Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway-MEL binds to mannose on microorganisms and activates complement. 3.


Pathoma_Husain

Pathoma_Husain. ii. Alternative pathway-Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway-MEL binds to mannose on microorganisms and activates complement. 3. All pathways result in production of C3 convertase (mediates C3 ➔ C3a and C3b), which, in turn, produces CS convertase (mediates CS ➔ CSa and CSb). CSb complexes with C6-C9 to form the membrane attack complex (MAC). 1. C3a and CSa (anaphylatoxins)-trigger mast cell degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability ii. CSa-chemotactic for neutrophils iii. C3b-opsonin for phagocytosis iv. MAC-lyses microbes by creating a hole in the cell membrane E. Hageman factor (Factor XII) 1. 2.


Pathoma_Husain

Pathoma_Husain. E. Hageman factor (Factor XII) 1. 2. Activated upon exposure to subendothelial or tissue collagen; in turn, activates i. Coagulation and fibrinolytic systems ii. Complement iii. Kin in system-Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine), as well as pain. III. CARDINAL SIGNS OF INFLAMMATION A. Redness (rubor) and warmth (calor) 1. Due to vasodilation, which results in increased blood flow 2. Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradykinin. B. Swelling (tumor) 1. Due to leakage of fluid from postcapillary venules into the interstitial space (exudate) 2. Key mediators are (1) histamine, which causes endothelial cell contraction and (2) tissue damage, resulting in endothelial cell disruption. C. Pain (dolor) 1. Bradykinin and PGE sensitize sensory nerve endings.


Pathoma_Husain

Pathoma_Husain. C. Pain (dolor) 1. Bradykinin and PGE sensitize sensory nerve endings. Fig. 2.1 Inflammation. A, Acute inflammation with neutrophils. B, Chronic inflammation with lymphocytes and plasma cells. Inflammation, Inflammatory Disorders, and Wound Healing D. Fever 1. Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus. 2. Increased PGE2 raises temperature set point. IV. NEUTROPHIL ARRIVAL AND FUNCTION A. Step 1-Margination 1. Vasodilation slows blood flow in postcapillary venules. 2. Cells marginate from center of flow to the periphery. B. Step 2-Rolling 1. Selectin "speed bumps" are upregulated on endothelial cells. i. P-selectin release from Weibel-Palade bodies is mediated by histamine. ii. E-selectin is induced by TNF and IL-1. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall. C. Step 3-Adhesion 1.


Pathoma_Husain

Pathoma_Husain. ii. E-selectin is induced by TNF and IL-1. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall. C. Step 3-Adhesion 1. Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1. 2. Integrins are upregulated on leukocytes by C5a and LTB4 • 3. Interaction between CA Ms and integrins results in firm adhesion ofleukocytes to the vessel wall. 4. Leukocyte adhesion deficiency is most commonly due to an autosomal recessive defect of integrins (CD18 subunit). i. Clinical features include delayed separation of the umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation. D. Step 4-Transmigration and Chemotaxis 1. Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis). 2.


Pathoma_Husain

Pathoma_Husain. D. Step 4-Transmigration and Chemotaxis 1. Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis). 2. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB • E. Step 5-Phagocytosis 1. Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3b). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes. 3. Chediak-Higashi syndrome is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation. Clinical features include i. Increased risk of pyogenic infections ii. Neutropenia (due to intramedullary death of neutrophils) iii. Giant granules in leukocytes (due to fusion of granules arising from the Golgi apparatus) iv. Defective primary hemostasis (due to abnormal dense granules in platelets) v. vi. Peripheral neuropathy


Pathoma_Husain

Pathoma_Husain. Defective primary hemostasis (due to abnormal dense granules in platelets) v. vi. Peripheral neuropathy F. Step 6-Destruction of phagocytosed material 1. 0 2-dependent killing is the most effective mechanism. 2. HOC! generated by oxidative burst in phagolysosomes destroys phagocytosed microbes. 1. 0 2 is converted too; by NADPH oxidase (oxidative burst). ii. o ; is converted to H 0 by superoxide dismutase (SOD). iii. Hp2 is converted to HOC! (bleach) by myeloperoxidase (MPO). 3. Chronic granulomatous disease (CGD) is characterized by poor 0 -dependent killing.


Pathoma_Husain

Pathoma_Husain. iii. Hp2 is converted to HOC! (bleach) by myeloperoxidase (MPO). 3. Chronic granulomatous disease (CGD) is characterized by poor 0 -dependent killing. i. Due to NADPH oxidase defect (X-linked or autosomal recessive) ii. Leads to recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus iii. Nitroblue tetrazolium test is used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue ifNADPH oxidase can convert 0 too;, but remains colorless ifNADPH oxidase is defective. 4. MPO deficiency results in defective conversion ofH 0 to HOCL i. Increased risk for Candida infections; however, most patients are asymptomatic. ii. NBT is normal; respiratory burst (02 to Hp2) is intact.


Pathoma_Husain

Pathoma_Husain. ii. NBT is normal; respiratory burst (02 to Hp2) is intact. 5. 0 2-independent killing is less effective than 0 2 -dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils). G. Step ?-Resolution 1. Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus. V. MACROPHAGES A. Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins. 1. Derived from monocytes in blood B. Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence C. Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules (02independent killing) D. Manage the next step of the inflammatory process. Outcomes include 1. Resolution and healing-Anti-inflammatory cytokines (e.g., IL-10 and TGF-~) are produced by macrophages. 2.


Pathoma_Husain

Pathoma_Husain. D. Manage the next step of the inflammatory process. Outcomes include 1. Resolution and healing-Anti-inflammatory cytokines (e.g., IL-10 and TGF-~) are produced by macrophages. 2. Continued acute inflammation-marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess-acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation-Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation. I. BASIC PRINCIPLES A. Characterized by the presence oflymphocytes and plasma cells in tissue (Fig. 2.lB) B. Delayed response, but more specific (adaptive immunity) than acute inflammation C. Stimuli include (1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers. II. T LYMPHOCYTES


Pathoma_Husain

Pathoma_Husain. II. T LYMPHOCYTES A. Produced in bone marrow as progenitor T cells B. Further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4+ helper T cells or CDs+ cytotoxic T cells 1. T cells use TCR complex (TCR and CD3) for antigen surveillance. Inflammation, Inflammatory Disorders, and Wound Healing 2. TCR complex recognizes antigen presented on MHC molecules. i. CD4+ T cells-MHC class II ii. CDS+ T cells-MHC class I 3. Activation ofT cells requires (1) binding of antigen/MHC complex and (2) an additional 2nd signal. C. CD4 + helper T-cell activation 1. Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (APCs). 2. B7 on APC binds CD2S on CD4+ helper T cells providing 2nd activation signal. 3. Activated CD4 + helper T cells secrete cytokines that "help" inflammation and are divided into two subsets.


Pathoma_Husain

Pathoma_Husain. 2. B7 on APC binds CD2S on CD4+ helper T cells providing 2nd activation signal. 3. Activated CD4 + helper T cells secrete cytokines that "help" inflammation and are divided into two subsets. i. T Hl subset secretes IFN-y (activates macrophage, promotes B-cell class switching from IgM to IgG, promotes T1) phenotype and inhibits TH2 phenotype). ii. TH2 subset secretes IL-4 (facilitates B-cell class switching to IgE), IL-5 (eosinophil chemotaxis and activation, and class switching to IgA), and IL-13 (function similar to IL-4). D. CDs+ cytotoxic T-cell activation 1. Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets. 2. IL-2 from CD4+ THl cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. 1. Secretion of perforin and granzyme; perforin creates pores that allow granzyme to enter the target cell, activating apoptosis.


Pathoma_Husain

Pathoma_Husain. 3. Cytotoxic T cells are activated for killing. 4. 1. Secretion of perforin and granzyme; perforin creates pores that allow granzyme to enter the target cell, activating apoptosis. ii. Expression of FasL, which binds Fas on target cells, activating apoptosis III. B LYMPHOCYTES A. Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become na'ive B cells that express surface IgM and IgD. B. B-cell activation occurs via 1. Antigen binding by surface IgM or IgD; results in maturation to IgM-or IgDsecreting plasma cells 2. B-cell antigen presentation to CD4+ helper T cells via MHC class II. i. CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells). IV. GRANULOMATOUS INFLAMMATION A. Subtype of chronic inflammation


Pathoma_Husain

Pathoma_Husain. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells). IV. GRANULOMATOUS INFLAMMATION A. Subtype of chronic inflammation B. Characterized by granuloma, which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm), usually surrounded by giant cells and a rim of lymphocytes C. Divided into noncaseating and caseating subtypes 1. Noncaseating granulomas lack central necrosis (Fig. 2.2A). Common etiologies include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease. 2. Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections (Fig. 2.2B). D. Steps involved in granuloma formation 1. Macrophages process and present antigen via MHC class II to CD4+ helper T cells. 2. Interaction leads macrophages to secrete IL-12, inducing CD4+ helper T cells to differentiate into TH 1 subtype.


Pathoma_Husain

Pathoma_Husain. Macrophages process and present antigen via MHC class II to CD4+ helper T cells. 2. Interaction leads macrophages to secrete IL-12, inducing CD4+ helper T cells to differentiate into TH 1 subtype. 3. TH 1 cells secrete IFN-y, which converts macrophages to epithelioid histiocytes and giant cells. I. DIGEORGE SYNDROME A. Developmental failure of the third and fourth pharyngeal pouches 1. Due to 22qll microdeletion B. Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack of parathyroids); and abnormalities of heart, great vessels, and face II. SEVERE COMBINED IMMUNODEFICIENCY (SCIO) A. Defective cell-mediated and humoral immunity B. Etiologies include 1. Cytokine receptor defects-Cytokine signaling is necessary for proliferation and maturation of B and T cells. 2. Adenosine deaminase (ADA) deficiency-ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste products; buildup of adenosine and deoxyadenosine is toxic to lymphocytes. 3.


Pathoma_Husain

Pathoma_Husain. Adenosine deaminase (ADA) deficiency-ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste products; buildup of adenosine and deoxyadenosine is toxic to lymphocytes. 3. MHC class II deficiency-MHC class II is necessary for CD4+ helper T cell activation and cytokine production. C. Characterized by susceptibility to fungal, viral, bacterial, and protozoa! infections, including opportunistic infections and live vaccines D. Treatment is sterile isolation ('bubble baby') and stem cell transplantation. III. X-LINKED AGAMMAGLOBULINEMIA A. Complete lack of immunoglobulin due to disordered B-cell maturation 1. Pre-and pro-B cells cannot mature. B. Due to mutated Bruton tyrosine kinase; X-linked C. Presents after 6 months of life with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies present during the first 6 months oflife are protective. D. Live vaccines (e.g., polio) must be avoided.


Pathoma_Husain

Pathoma_Husain. D. Live vaccines (e.g., polio) must be avoided. IV. COMMON VARIABLE IMMUNODEFICIENCY (CVID) A. Low immunoglobulin due to B-cell or helper T-cell defects Fig. 2.2 Granuloma. A, Noncaseating. B, Caseating. Fig. 2.3 Angioedema. (Courtesy of James Heilman, MD, Wikipedia) Inflammation, Inflammatory Disorders, and Wound Healing B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood C. Increased risk for autoimmune disease and lymphoma V. IgA DEFICIENCY A. Low serum and mucosa! IgA; most common immunoglobulin deficiency B. Increased risk for mucosa! infection, especially viral; however, most patients are asymptomatic. VI. HYPER-IgM SYNDROME A. Characterized by elevated IgM B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells) 1. Second signal cannot be delivered to helper T cells during B-cell activation. 2. Consequently, cytokines necessary for immunoglobulin class switching are not produced.


Pathoma_Husain

Pathoma_Husain. Second signal cannot be delivered to helper T cells during B-cell activation. 2. Consequently, cytokines necessary for immunoglobulin class switching are not produced. C. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosa! sites. VII. WISKOTT-ALDRICH SYNDROME A. Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death B. Due to mutation in the WASP gene; X-linked VIII. COMPLEMENT DEFICIENCIES A. C5-C9 deficiencies-increased risk for Neisseria infection (N gonorrhoeae and N meningitidis) B. Cl inhibitor deficiency-results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital, Fig. 2.3) and mucosa! surfaces I. BASIC PRINCIPLES A. Characterized by immune-mediated damage of self tissues 1. US prevalence is 1%-2%. B. Involves loss of self-tolerance 1.


Pathoma_Husain

Pathoma_Husain. I. BASIC PRINCIPLES A. Characterized by immune-mediated damage of self tissues 1. US prevalence is 1%-2%. B. Involves loss of self-tolerance 1. Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance. 2. Central tolerance in thymus leads to T-cell (thymocyte) apoptosis or generation of regulatory T cells. i. AIRE mutations result in autoimmune polyendocrine syndrome. 3. Central tolerance in bone marrow leads to receptor editing or B-cell apoptosis. 4. Peripheral tolerance leads to anergy or apoptosis ofT and B cells. 1. Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS). 5. Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-~). i. CD25 polymorphisms are associated with autoimmunity (MS and type 1 DM).


Pathoma_Husain

Pathoma_Husain. i. CD25 polymorphisms are associated with autoimmunity (MS and type 1 DM). ii. FOXP3 mutations lead to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). C. More common in women; classically affects women ofchildbearing age 1. Estrogen may reduce apoptosis of self-reactive B cells. D. Etiology is likely an environmental trigger in genetically-susceptible individuals. 1. Increased incidence in twins 2. Association with certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms 3. Environmental triggers lead to bystander activation or molecular mimicry. E. Autoimmune disorders are clinically progressive with relapses and remissions and often show overlapping features; partially explained by epitope spreading II. SYSTEMIC LUPUS ERYTHEMATOSUS A. Chronic, systemic autoimmune disease 1. Flares and remissions are common.


Pathoma_Husain

Pathoma_Husain. II. SYSTEMIC LUPUS ERYTHEMATOSUS A. Chronic, systemic autoimmune disease 1. Flares and remissions are common. B. Classically arises in middle-aged females, especially African American and Hispanic women 1. May also arise in children and older adults (less dramatic gender bias) C. Antigen-antibody complexes damage multiple tissues (type III HSR). 1. Poorly-cleared apoptotic debris (e.g., from UV damage) activates self-reactive lymphocytes, which then produce antibodies to host nuclear antigens. 2. Antigen-antibody complexes are generated at low levels and taken up by dendritic cells. 3. DNA antigens activate TLRs, amplifying immune response (IFN-a). 4. Antigen-antibody complexes are subsequently generated at higher levels and deposit in multiple tissues causing disease. 5. Deficiency of early complement proteins (Clq, C4, and C2) is associated with SLE. D. Almost any tissue can be involved. Classic findings include 1.


Pathoma_Husain

Pathoma_Husain. 5. Deficiency of early complement proteins (Clq, C4, and C2) is associated with SLE. D. Almost any tissue can be involved. Classic findings include 1. Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon 2. Malar 'butterfly' rash (Fig. 2.4A) or discoid rash (Fig. 2.4B), especially upon exposure to sunlight 3. 4. Arthritis (usually involving ?. 2 joints) 5. 6. 7. i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury. ii. Other patterns of injury (e.g., membranous glomerulonephritis) also occur. 8. Anemia, thrombocytopenia, or leukopenia (type II HSR) 9. 10. Antinuclear antibody (ANA; sensitive, but not specific) 11. E. Antiphospholipid antibody is associated with SLE (one-third of patients). 1. Autoantibody directed against proteins bound to phospholipids Fig. 2.4A Malar 'butterfly' rash, SLE. Fig. 2.4B Discoid rash, SLE.


Pathoma_Husain

Pathoma_Husain. 1. Autoantibody directed against proteins bound to phospholipids Fig. 2.4A Malar 'butterfly' rash, SLE. Fig. 2.4B Discoid rash, SLE. Inflammation, Inflammatory Disorders, and Wound Healing 2. Important antiphospholipid antibodies include anticardiolipin (false-positive VDRL and RPR syphilis screening tests), anti-02-glycoprotein I, and lupus anticoagulant (falsely-elevated PTT). F. Antiphospholipid antibody syndrome is characterized by hypercoagulable state due to antiphospholipid antibodies (especially lupus anticoagulant). 1. Results in arterial and venous thrombosis including deep venous, hepatic vein, placental (recurrent pregnancy loss), and cerebral (stroke) thrombosis 2. 3. Associated with SLE; however, more commonly occurs as a primary disorder G. Antihistone antibody is characteristic of drug-induced lupus. 1. Procainamide, hydralazine, and isoniazid are common causes. 2. ANA is positive by definition. 3. CNS and renal involvement are rare. 4.


Pathoma_Husain

Pathoma_Husain. 1. Procainamide, hydralazine, and isoniazid are common causes. 2. ANA is positive by definition. 3. CNS and renal involvement are rare. 4. Removal of drug usually results in remission. H. First-line treatment includes avoiding exposure to direct sunlight and glucocorticoids for flares; other immunosuppressive agents are useful in severe or refractory disease. I. 5-year survival is > 90%; renal failure, infection, and accelerated coronary atherosclerosis (occurs late) are common causes of death. III. SJOGREN SYNDROME A. Autoimmune destruction of lacrimal and salivary glands 1. Lymphocyte-mediated damage (type IV HSR) with fibrosis B. Classically presents as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and recurrent dental caries in an older woman (50-60 years)-"Can't chew a cracker, dirt in my eyes" 1. May progress to ulceration of corneal epithelium and oral mucosa


Pathoma_Husain

Pathoma_Husain. C. Can be primary (sicca syndrome) or associated with another autoimmune disorder, especially rheumatoid arthritis 1. Rheumatoid factor is often present even when rheumatoid arthritis is absent. D. Characterized by ANA and anti-ribonucleoprotein antibodies (anti-SSA/Ro and anti-SSB/La) 1. Anti-SSA and anti-SSB are associated with extraglandular manifestations (e.g., neuropathy). 2. Pregnant women with anti-SSA are at risk for delivering babies with neonatal lupus and congenital heart block. 3. Anti-SSA and anti-SSB are also seen in a subset of patients with SLE (screen pregnant patients) E. Lymphocytic sialadenitis on lip biopsy (minor salivary glands) is an additional diagnostic criterion (Fig. 2.4C). F. Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral enlargement of the parotid gland late in disease course IV. SYSTEMIC SCLEROSIS (SCLERODERMA)


Pathoma_Husain

Pathoma_Husain. F. Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral enlargement of the parotid gland late in disease course IV. SYSTEMIC SCLEROSIS (SCLERODERMA) A. Autoimmune disorder characterized by sclerosis of skin and visceral organs 1. Classically presents in middle-aged females (30-50 years) B. Fibroblast activation leads to deposition of collagen. 1. Autoimmune damage to mesenchyme is possible initiating event. 2. Endothelial dysfunction leads to inflammation (increased adhesion molecules), vasoconstriction (increased endothelin and decreased NO), and secretion of growth factors (TGF-0 and PDGF). 3. Fibrosis, initially perivascular, progresses and causes organ damage. V. I. II. C. Limited type-Skin involvement is limited (hands and face) with late visceral involvement. 1. Prototype is CREST syndrome: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (Fig. 2.4D), and Telangiectasias of the skin.


Pathoma_Husain

Pathoma_Husain. 1. Prototype is CREST syndrome: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (Fig. 2.4D), and Telangiectasias of the skin. D. Diffuse type-Skin involvement is diffuse with early visceral involvement. 1. Any organ can be involved. 2. i. Vessels (Raynaud phenomenon) ii. GI tract (esophageal dysmotility and reflux) iii. Lungs (interstitial fibrosis and pulmonary hypertension) iv. Kidneys (scleroderma renal crisis) 3. Highly associated with antibodies to DNA topoisomerase I (anti-Scl-70). A. Autoimmune-mediated tissue damage with mixed features ofSLE, systemic sclerosis, and polymyositis B. Characterized by ANA along with serum antibodies to Ul ribonucleoprotein A. Healing is initiated when inflammation begins. B. Occurs via a combination of regeneration and repair A. Replacement of damaged tissue with native tissue; dependent on regenerative capacity of tissue


Pathoma_Husain

Pathoma_Husain. B. Occurs via a combination of regeneration and repair A. Replacement of damaged tissue with native tissue; dependent on regenerative capacity of tissue B. Tissues are divided into three types based on regenerative capacity: labile, stable, and permanent. C. Labile tissues possess stem cells that continuously cycle to regenerate the tissue. 1. Small and large bowel (stem cells in mucosa] crypts, Fig. 2.5) 2. Skin (stem cells in basal layer, Fig. 2.6) 3. D. Stable tissues are comprised of cells that are quiescent (G ), but can reenter the cell cycle to regenerate tissue when necessary. 1. Classic example is regeneration of liver by compensatory hyperplasia after partial resection. Each hepatocyte produces additional cells and then reenters quiescence. Fig. 2.4C Lymphocytic sialadenitis, Sjogren Fig. 2.4D Sclerodactyly, scleroderma. Fig. 2.5 Intestinal crypts. syndrome. Inflammation, Inflammatory Disorders, and Wound Healing


Pathoma_Husain

Pathoma_Husain. Fig. 2.4C Lymphocytic sialadenitis, Sjogren Fig. 2.4D Sclerodactyly, scleroderma. Fig. 2.5 Intestinal crypts. syndrome. Inflammation, Inflammatory Disorders, and Wound Healing E. Permanent tissues lack significant regenerative potential (e.g., myocardium, skeletal muscle, and neurons). III. REPAIR A. Replacement of damaged tissue with fibrous scar B. Occurs when regenerative stem cells are lost (e.g., deep skin cut) or when a tissue lacks regenerative capacity (e.g., healing after a myocardial infarction, Fig. 2.7) C. Granulation tissue formation is the initial phase of repair (Fig. 2.8). 1. Consists of fibroblasts (deposit type III collagen), capillaries (provide nutrients), and myofibroblasts (contract wound) D. Eventually results in scar formation, in which type III collagen is replaced with type I collagen 1. Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids. 2.


Pathoma_Husain

Pathoma_Husain. Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids. 2. Type I collagen has high tensile strength and is present in skin, bone, tendons, and most organs. 3. Collagenase removes type III collagen and requires zinc as a cofactor. IV. A. Mediated by paracrine signaling via growth factors (e.g., macrophages secrete growth factors that target fibroblasts) B. Interaction of growth factors with receptors (e.g., epidermal growth factor with growth factor receptor) results in gene expression and cellular growth. C. Examples of mediators include 1. 2. 3. Platelet-derived growth factor-growth factor for endothelium, smooth muscle, and fibroblasts 4. 5. V. A. Cutaneous healing occurs via primary or secondary intention. 1. Primary intention-Wound edges are brought together (e.g., suturing of a surgical incision); leads to minimal scar formation 2.


Pathoma_Husain

Pathoma_Husain. A. Cutaneous healing occurs via primary or secondary intention. 1. Primary intention-Wound edges are brought together (e.g., suturing of a surgical incision); leads to minimal scar formation 2. Secondary intention-Edges are not approximated. Granulation tissue fills the defect; myofibroblasts then contract the wound, forming a scar. B. Delayed wound healing occurs in 1. Infection (most common cause; S aureus is the most common offender) Fig. 2.6 Basal layer of skin. Fig. 2.7 Myocardial scarring. (Courtesy of Aliya Fig. 2.8 Granulation tissue. Husa in, MD) 2. Vitamin C, copper, or zinc deficiency i. Vitamin C is an important cofactor in the hydroxylation of proline and lysine procollagen residues; hydroxylation is necessary for eventual collagen cross-linking. ii. Copper is a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen.


Pathoma_Husain

Pathoma_Husain. ii. Copper is a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen. iii. Zinc is a cofactor for collagenase, which replaces the type III collagen of granulation tissue with stronger type I collagen. 3. Other causes include foreign body, ischemia, diabetes, and malnutrition. C. Dehiscence is rupture of a wound; most commonly seen after abdominal surgery D. Hypertrophic scar is excess production of scar tissue that is localized to the wound (Fig. 2.9). E. Keloid is excess production of scar tissue that is out of proportion to the wound (Fig. 2.10). 1. 2. 3. Classically affects earlobes, face, and upper extremities Fig. 2.9 Hypertrophic scar. (Reprinted with Fig . 2.10 Keloid. permission, http://emedicine.medscape.com/ article/ 1128404-overview) Principles of Neoplasia I. BASIC PRINCIPLES A. Neoplasia is new tissue growth that is unregulated, irreversible, and monoclonal; these features distinguish it from hyperplasia and repair.


Pathoma_Husain

Pathoma_Husain. Principles of Neoplasia I. BASIC PRINCIPLES A. Neoplasia is new tissue growth that is unregulated, irreversible, and monoclonal; these features distinguish it from hyperplasia and repair. B. Monoclonal means that the neoplastic cells are derived from a single mother cell. C. Clonality was historically determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms. 1. Multiple isoforms (e.g., G6PDA, G6PDB, and G6PDc) exist; only one isoform is inherited from each parent. 2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome). 3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PDA, and 50% of cells have G6PD8) . 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). 5. Only one isoform is present in neoplasia, which is monoclonal. 6.


Pathoma_Husain

Pathoma_Husain. 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). 5. Only one isoform is present in neoplasia, which is monoclonal. 6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome. D. Clonality ofB lymphocytes is determined by immunoglobulin (Ig) light chain phenotype. 1. lg is comprised of heavy and light chains. 2. Each B cell expresses light chain that is either kappa or lambda. 3. Normal kappa to lambda light chain ratio is 3:1. 4. This ratio is maintained in hyperplasia, which is polyclonal. 5. Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio= 1:3) in lymphoma, which is monoclonal. E. Neoplastic tumors are benign or malignant. 1. Benign tumors remain localized and do not metastasize. 2. Malignant tumors (cancer) invade locally and have the potential to metastasize.


Pathoma_Husain

Pathoma_Husain. E. Neoplastic tumors are benign or malignant. 1. Benign tumors remain localized and do not metastasize. 2. Malignant tumors (cancer) invade locally and have the potential to metastasize. F. Tumor nomenclature is based on lineage of differentiation (type of tissue produced) and whether the tumor is benign or malignant (Table 3.1). Table 3.1: Examples of Tumor Nomenclature pathoma.com II. EPIDEMIOLOGY A. Cancer is the 2nd leading cause of death in both adults and children. 1. The leading causes of death in adults are (1) cardiovascular disease, (2) cancer, and (3) chronic respiratory disease. 2. The leading causes of death in children are (1) accidents, (2) cancer, and (3) congenital defects. B. The most common cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal. C. The most common causes of cancer mortality in adults are (1) lung, (2) breast/ prostate, and (3) colorectal. III. ROLE OF SCREENING A. Cancer begins as a single mutated cell.


Pathoma_Husain

Pathoma_Husain. C. The most common causes of cancer mortality in adults are (1) lung, (2) breast/ prostate, and (3) colorectal. III. ROLE OF SCREENING A. Cancer begins as a single mutated cell. B. Approximately 30 divisions occur before the earliest clinical symptoms arise. C. Each division (doubling time) results in increased mutations. 1. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and, hence, additional mutations. 2. Cancers that are detected late tend to have a poor prognosis. 3. Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise; efficacy of screening, however, requires a decrease in cancer-specific mortality. D. Common screening methods include 1. 2. Mammography-detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable 3. 4. I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. 2. Mammography-detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable 3. 4. I. BASIC PRINCIPLES A. Cancer formation is initiated by damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal. 1. Carcinogens are agents that damage DNA, increasing the risk for cancer. Important carcinogens include chemicals, oncogenic viruses, and radiation (Table 3.2). B. DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread). 1. Disrupted systems include proto-oncogenes, tumor suppressor genes, and regulators of apoptosis. II. ONCOGENES A. Proto-oncogenes are essential for cell growth and differentiation; mutations of proto-oncogenes form oncogenes that lead to unregulated cellular growth.


Pathoma_Husain

Pathoma_Husain. II. ONCOGENES A. Proto-oncogenes are essential for cell growth and differentiation; mutations of proto-oncogenes form oncogenes that lead to unregulated cellular growth. B. Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators (Table 3.3). 1. Growth factors induce cellular growth (e.g., PDGFB in astrocytoma). 2. Growth factor receptors mediate signals from growth factors (e.g., ERBB2 [HER2/neu] in breast cancer). 3. Signal transducers relay receptor activation to the nucleus (e.g., ras). Principles of Neoplasia Table 3.2: Important Carcinogens and Associated Cancers Nitrosamines Naphthylamine Vinyl chloride Nickel, chromium, beryllium, or silica HBVandHCV HTLV-1 High-risk HPV (e.g., subtypes 16, 18, 31, 33) sunlight is most common source) Squamous cell carcinoma of oropharynx and upper esophagus, and hepatocellular carcinoma


Pathoma_Husain

Pathoma_Husain. HBVandHCV HTLV-1 High-risk HPV (e.g., subtypes 16, 18, 31, 33) sunlight is most common source) Squamous cell carcinoma of oropharynx and upper esophagus, and hepatocellular carcinoma Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver Carcinoma of oropharynx, esophagus, lung, kidney, bladder, and pancreas Urothelial carcinoma of bladder Angiosarcoma of liver Nasopharyngeal carcinoma, Burkitt lymphoma, and CNS lymphoma in AIDS Squamous cell carcinoma ofvulva, vagina, anus, and cervix; adenocarcinoma of cervix AML, CML, and papillary carcinoma of the thyroid Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin Derived from Aspergillus, which can contaminate stored rice and grains Side effect of chemotherapy Arsenic is present in cigarette smoke. Exposure to asbestos is more likely to lead to lung cancer than mesothelioma. Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogen ic.


Pathoma_Husain

Pathoma_Husain. Exposure to asbestos is more likely to lead to lung cancer than mesothelioma. Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogen ic. Found in smoked foods; responsible for high rate of stomach carcinoma in Japan Occupational exposure; used to make polyvinyl chloride (PVC) for use in pipes Results in formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease -,--~---------FUNDAMENTALS OF PA_T_H_O_L_O_G_Y_______ 1. Ras is associated with growth factor receptors in an inactive GDP-bound state. ii. Receptor binding causes GDP to be replaced with GTP, activating ras. iii. Activated ras sends growth signals to the nucleus. iv. Ras inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein. v. Mutated ras inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals.


Pathoma_Husain

Pathoma_Husain. v. Mutated ras inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals. 4. Cell cycle regulators mediate progression through the cell cycle (e.g., cyclin and cyclin-dependent kinase). i. Cyclins and cyclin-dependent kinases (CDKs) form a complex which phosphorylates proteins that drive the cell through the cell cycle. ii. For example, the cyclinD/CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G/ S checkpoint. III. TUMOR SUPPRESSOR GENES A. Regulate cell growth and, hence, decrease ("suppress") the risk of tumor formation; p53 and Rb (retinoblastoma) are classic examples. B. p53 regulates progression of the cell cycle from G to S phase. Table 3.3: Important Oncogenes and Associated Tumors PDGFB Platelet-derived growth factor Overexpression, autocrine loop Astrocytoma


Pathoma_Husain

Pathoma_Husain. Table 3.3: Important Oncogenes and Associated Tumors PDGFB Platelet-derived growth factor Overexpression, autocrine loop Astrocytoma Amplification Subset of breast carcinomas neu] receptor MEN 2A, MEN 2B and sporadic RET Neural growth factor receptor Point mutation medullary carcinoma of thyroid Carcinomas, melanoma, and ABL Tyrosine kinase t(9;22) with BCR CML and some types of ALL Principles of Neoplasia 1. In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes. 2. IfDNA repair is not possible, p53 induces apoptosis. 1. p53 upregulates BAX, which disrupts Bcl2. ii. Cytochrome c leaks from the mitochondria activating apoptosis. 3. Both copies of the p53 gene must be knocked out for tumor formation (Knudson two-hit hypothesis). i. Loss is seen in > 50% of cancers. ii. Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas.


Pathoma_Husain

Pathoma_Husain. ii. Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas. C. Rb also regulates progression from G1 to S phase. 1. Rb "holds" the E2F transcription factor, which is necessary for transition to the S phase. 2. E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex. 3. Rb mutation results in constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells. 4. Both copies of Rb gene must be knocked out for tumor formation (Knudson twohit hypothesis). i. Sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma (Fig. 3.1). 11. Germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma. IV. REGULATORS OF APOPTOSIS


Pathoma_Husain

Pathoma_Husain. 11. Germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma. IV. REGULATORS OF APOPTOSIS A. Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g., Bcl2) l. Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cytochrome c. 2. Disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate apoptosis. B. Bcl2 is overexpressed in follicular lymphoma. 1. t(l4;18) moves Bcl2 (chromosome 18) to the lg heavy chain locus (chromosome 14), resulting in increased Bcl2. 2. Mitochondrial membrane is further stabilized, prohibiting apoptosis. 3. B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma.


Pathoma_Husain

Pathoma_Husain. 3. B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma. Fig. 3.1 Retinoblastoma. (Courtesy of Jerome Fig. 3.2 Carcinoma involving lymph node. Fig. 3.3 Seeding of the omentum by carcinoma. Taxy, MD) (Courtesy of Jerome Taxy, MD) V. OTHER IMPORTANT FEATURES OF TUMOR DEVELOPMENT A. Telomerase is necessary for cell immortality. 1. Normally, telomeres shorten with serial cell divisions, eventually resulting in cellular senescence. 2. Cancers often have upregulated telomerase, which preserves telomeres. B. Angiogenesis (production of new blood vessels) is necessary for tumor survival and growth. 1. FGF and VEGF (angiogenic factors) are commonly produced by tumor cells. C. Avoiding immune surveillance is necessary for tumor survival. 1. Mutations often result in production of abnormal proteins, which are expressed on MHC class I. 2. CDS+ T cells detect and destroy such mutated cells. 3.


Pathoma_Husain

Pathoma_Husain. 1. Mutations often result in production of abnormal proteins, which are expressed on MHC class I. 2. CDS+ T cells detect and destroy such mutated cells. 3. Tumor cells can evade immune surveillance by downregulating expression of MHC class I. 4. Immunodeficiency (both primary and secondary) increases risk for cancer. I. TUMOR INVASION AND SPREAD A. Accumulation of mutations eventually results in tumor invasion and spread. 1. Epithelial tumor cells are normally attached to one another by cellular adhesion molecules (e.g., E-cadherin). 2. Downregulation of E-cadherin leads to dissociation of attached cells. 3. Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase. 4. Cells attach to fibronectin in the extracellular matrix and spread locally. 5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread). II. ROUTES OF METASTASIS A. Lymphatic spread is characteristic of carcinomas.


Pathoma_Husain

Pathoma_Husain. 5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread). II. ROUTES OF METASTASIS A. Lymphatic spread is characteristic of carcinomas. 1. Initial spread is to regional draining lymph nodes (Fig. 3.2). B. Hematogenous spread is characteristic of sarcomas and some carcinomas. 1. 2. 3. Follicular carcinoma of the thyroid 4. C. Seeding of body cavities is characteristic of ovarian carcinoma, which often involves the peritoneum ('omental caking', Fig. 3.3). Fig. 3.4 Histologic features of neoplasia. A, Well differentiated, follicular adenoma of thyroid. B, Fig. 3.5 lmmunohistochemical stain for keratin Poorly differentiated, anaplastic carcinoma of thyroid. marking epithelial cells (in brown). I. CLINICAL FEATURES A. Benign tumors tend to be slow growing, well circumscribed, distinct, and mobile. B. Malignant tumors are usually rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures.


Pathoma_Husain

Pathoma_Husain. B. Malignant tumors are usually rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures. C. Biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty. 1. Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion. A. Benign tumors are usually well differentiated (Fig. 3.4A). Characteristics include 1. 2. 3. Low nuclear to cytoplasmic ratio 4. 5. Lack of invasion (of basement membrane or local tissue) 6. B. Malignant tumors are classically poorly differentiated (anaplastic, Fig. 3.4B). Characteristics include 1. Disorganized growth (loss of polarity) 2. 3. High nuclear to cytoplasmic ratio 4. High mitotic activity with atypical mitosis 5. C. Metastatic potential is the hallmark of malignancy-benign tumors never metastasize. Table 3.4: Common lmmunohistochemical Stains and Target Cell Types


Pathoma_Husain

Pathoma_Husain. C. Metastatic potential is the hallmark of malignancy-benign tumors never metastasize. Table 3.4: Common lmmunohistochemical Stains and Target Cell Types Neuroendocrine cells (e.g., small cell Melanoma, Schwannoma and Langerhans cell histiocytosis IBll, ______________ F_U_N_D_A_M_E_N_T_A_L_S_O_F_P_A_T_H_O_L_O_G_Y_______ D. Immunohistochemistry is used to characterize tumors that are difficult to classify on histology (Fig. 3.5, Table 3.4). III. SERUM TUMOR MARKERS A. Proteins released by tumor into serum (e.g., PSA) B. Useful for screening, monitoring response to treatment, and monitoring recurrence C. Elevated levels require tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA). IV. A. Microscopic assessment of differentiation (i.e., how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features 1. 2.


Pathoma_Husain

Pathoma_Husain. IV. A. Microscopic assessment of differentiation (i.e., how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features 1. 2. B. Important for determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers. V. A. Assessment of size and spread of a cancer B. Key prognostic factor; more important than grade C. Determined after final surgical resection ofthe tumor D. Utilizes TNM staging system 1. T-tumor (size and/or depth of invasion) 2. N-spread to regional lymph nodes; second most important prognostic factor 3. I. HEMOSTASIS A. Integrity of the blood vessel is necessary to carry blood to tissues. 1. Damage to the wall is repaired by hemostasis, which involves formation of a thrombus (clot) at the site of vessel injury. B. Hemostasis occurs in two stages: primary and secondary. 1.


Pathoma_Husain

Pathoma_Husain. 1. Damage to the wall is repaired by hemostasis, which involves formation of a thrombus (clot) at the site of vessel injury. B. Hemostasis occurs in two stages: primary and secondary. 1. Primary hemostasis forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall. 2. Secondary hemostasis stabilizes the platelet plug and is mediated by the coagulation cascade. I. PRIMARY HEMOSTASIS A. Step 1-Transient vasoconstriction of damaged vessel 1. Mediated by reflex neural stimulation and endothelin release from endothelial cells B. Step 2-Platelet adhesion to the surface of disrupted vessel 1. Von Willebrand factor (vWF) binds exposed subendothelial collagen. 2. Platelets bind vWF using the GPib receptor. 3. vWF is derived from the Weibel-Palade bodies of endothelial cells and a-granules of platelets. C. Step 3-Platelet degranulation 1. Adhesion induces shape change in platelets and degranulation with release of multiple mediators.


Pathoma_Husain

Pathoma_Husain. C. Step 3-Platelet degranulation 1. Adhesion induces shape change in platelets and degranulation with release of multiple mediators. i. ADP is released from platelet dense granules; promotes exposure of GPilb/ Illa receptor on platelets. 11. TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation D. Step 4-Platelet aggregation 1. Platelets aggregate at the site of injury via GPIIb/llla using fibrinogen (from plasma) as a linking molecule; results in formation of platelet plug 2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it. II. DISORDERS OF PRIMARY HEMOSTASIS A. Usually due to abnormalities in platelets; divided into quantitative or qualitative disorders B. Clinical features include mucosa! and skin bleeding. 1. Symptoms of mucosa! bleeding include epistaxis (most common overall symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.


Pathoma_Husain

Pathoma_Husain. 1. Symptoms of mucosa! bleeding include epistaxis (most common overall symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia. 2. Symptoms of skin bleeding include petechiae (1-2 mm, Fig. 4.1), purpura (> 3 mm), ecchymoses (> 1 cm), and easy bruising; petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders. pathoma.com C. Useful laboratory studies include 1. Platelet count-normal 150-400 K/µL; < 50 K/µL leads to symptoms. 2. Bleeding time-normal 2-7 minutes; prolonged with quantitative and qualitative platelet disorders 3. Blood smear-used to assess number and size of platelets 4. Bone marrow biopsy-used to assess megakaryocytes, which produce platelets III. IMMUNE THROMBOCYTOPENIC PURPURA (ITP) A. Autoimmune production oflgG against platelet antigens (e.g., GPIIb/IIIa) 1. Most common cause of thrombocytopenia in children and adults


Pathoma_Husain

Pathoma_Husain. III. IMMUNE THROMBOCYTOPENIC PURPURA (ITP) A. Autoimmune production oflgG against platelet antigens (e.g., GPIIb/IIIa) 1. Most common cause of thrombocytopenia in children and adults B. Autoantibodies are produced by plasma cells in the spleen. C. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia. D. Divided into acute and chronic forms 1. Acute form arises in children weeks after a viral infection or immunization; selflimited, usually resolving within weeks of presentation 2. Chronic form arises in adults, usually women of childbearing age. May be primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta. E. Laboratory findings include 1. ..J.. platelet count, often < 50 K/µL 2. Normal PT/PTT-Coagulation factors are not affected. 3. F. Initial treatment is corticosteroids. Children respond well; adults may show early response, but often relapse. 1.


Pathoma_Husain

Pathoma_Husain. Normal PT/PTT-Coagulation factors are not affected. 3. F. Initial treatment is corticosteroids. Children respond well; adults may show early response, but often relapse. 1. IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is short-lived. 2. Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases). IV. MICROANGIOPATHIC HEMOLYTIC ANEMIA A. Pathologic formation of platelet microthrombi in small vessels 1. Platelets are consumed in the formation of microthrombi. 2. RBCs are "sheared" as they cross microthrombi, resulting in hemolytic anemia with schistocytes (Fig. 4.2). B. Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) C. TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation. Fig. 4.1 Petechiae involving skin. Fig. 4.2 Schistocyte. 1.


Pathoma_Husain

Pathoma_Husain. C. TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation. Fig. 4.1 Petechiae involving skin. Fig. 4.2 Schistocyte. 1. Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi. 2. Decreased ADAMTS13 is usually due to an acquired autoantibody; most commonly seen in adult females D. HUS is due to endothelial damage by drugs or infection. 1. Classically seen in children with E coli 0157:H? dysentery, which results from exposure to undercooked beef 2. E coli verotoxin damages endothelial cells resulting in platelet microthrombi. E. Clinical findings (HUS and TTP) include 1. 2. 3. 4. Renal insufficiency (more common in HUS)-Thrombi involve vessels of the kidney. 5. CNS abnormalities (more common in TTP)-Thrombi involve vessels of the CNS. F. Laboratory findings include 1. Thrombocytopenia with t bleeding time 2. Normal PT/PTT (coagulation cascade is not activated) 3.


Pathoma_Husain

Pathoma_Husain. F. Laboratory findings include 1. Thrombocytopenia with t bleeding time 2. Normal PT/PTT (coagulation cascade is not activated) 3. Anemia with schistocytes 4. G. Treatment involves plasmapheresis and corticosteroids, particularly in TTP. V. QUALITATIVE PLATELET DISORDERS A. Bernard-Soulier syndrome is due to a genetic GPib deficiency; platelet adhesion is impaired. 1. Blood smear shows mild thrombocytopenia with enlarged platelets. B. Glanzmann thrombasthenia is due to a genetic GPIIb/IIIa deficiency; platelet aggregation is impaired. C. Aspirin irreversibly inactivates cyclooxygenase; lack of TXA impairs aggregation. D. Uremia disrupts platelet function; both adhesion and aggregation are impaired. I. SECONDARY HEMOSTASIS A. Stabilizes the weak platelet plug via the coagulation cascade 1. Coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrin. 2. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus.


Pathoma_Husain

Pathoma_Husain. Coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrin. 2. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus. B. Factors of the coagulation cascade are produced by the liver in an inactive state. Activation requires 1. Exposure to an activating substance i. Tissue thromboplastin activates factor VII (extrinsic pathway). ii. Subendothelial collagen activates factor XII (intrinsic pathway). 2. Phospholipid surface of platelets 3. II. DISORDERS OF SECONDARY HEMOSTASIS A. Usually due to factor abnormalities B. Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures (e.g., circumcision and wisdom tooth extraction). C. Laboratory studies include 1. Prothrombin time (PT)-measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade 2.


Pathoma_Husain

Pathoma_Husain. C. Laboratory studies include 1. Prothrombin time (PT)-measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade 2. Partial thromboplastin time (PTT)-measures intrinsic (factors XII, XI, IX, VIII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade III. HEMOPHILIA A A. Genetic factor VIII (FVIII) deficiency 1. 2. B. Presents with deep tissue, joint, and postsurgical bleeding 1. Clinical severity depends on the degree of deficiency. C. Laboratory findings include 1. 2. ,I, FVIII 3. D. Treatment involves recombinant FVIII. IV. A. Genetic factor IX deficiency 1. Resembles hemophilia A, except FIX levels are decreased instead of FVIII V. A. Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common. 1. Clinical and lab findings are similar to hemophilia A. 2.


Pathoma_Husain

Pathoma_Husain. V. A. Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common. 1. Clinical and lab findings are similar to hemophilia A. 2. PTT does not correct upon mixing normal plasma with patient's plasma (mixing study) due to inhibitor; PTT does correct in hemophilia A. VI. VON WILLEBRAND DISEASE A. Genetic vWF deficiency 1. Most common inherited coagulation disorder B. Multiple subtypes exist, causing quantitative and qualitative defects; the most common type is autosomal dominant with decreased vWF levels. C. Presents with mild mucosa! and skin bleeding; low vWF impairs platelet adhesion. D. Laboratory findings include 1. 2. t PTT; normal PT-Decreased FVIII half-life (vWF normally stabilizes FVIII); however, deep tissue, joint, and postsurgical bleeding are usually not seen. 3.


Pathoma_Husain

Pathoma_Husain. D. Laboratory findings include 1. 2. t PTT; normal PT-Decreased FVIII half-life (vWF normally stabilizes FVIII); however, deep tissue, joint, and postsurgical bleeding are usually not seen. 3. Abnormal ristocetin test-Ristocetin induces platelet agglutination by causing vWF to bind platelet GPib; lack of vWF ➔ impaired agglutination ➔ abnormal test. E. Treatment is desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells. VII. VITAMIN K DEFICIENCY A. Disrupts function of multiple coagulation factors 1. Vitamin K is activated by epoxide reductase in the liver. 2. Activated vitamin K gamma carboxylates factors II, VII, IX, X, and proteins C and S; gamma carboxylation is necessary for factor function. B. Deficiency occurs in 1. Newborns-due to lack of GI colonization by bacteria that normally synthesize vitamin K; vitamin K injection is given prophylactically to all newborns at birth to prevent hemorrhagic disease of the newborn.


Pathoma_Husain

Pathoma_Husain. 2. Long-term antibiotic therapy-disrupts vitamin K-producing bacteria in the GI tract 3. Malabsorption-leads to deficiency of fat-soluble vitamins, including vitamin K VIII. OTHER CAUSES OF ABNORMAL SECONDARY HEMOSTASIS A. Liver failure-decreased production of coagulation factors and decreased activation ofvitamin K by epoxide reductase; effect of liver failure on coagulation is followed using PT. B. Large-volume transfusion-dilutes coagulation factors, resulting in a relative deficiency I. HEPARIN-INDUCED THROMBOCYTOPENIA A. Platelet destruction that arises secondary to heparin therapy B. Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis. II. DISSEMINATED INTRAVASCULAR COAGULATION A. Pathologic activation of the coagulation cascade 1. Widespread microthrombi result in ischemia and infarction. 2. Consumption of platelets and factors results in bleeding, especially from IV sites and mucosa! surfaces (bleeding from body orifices).


Pathoma_Husain

Pathoma_Husain. Widespread microthrombi result in ischemia and infarction. 2. Consumption of platelets and factors results in bleeding, especially from IV sites and mucosa! surfaces (bleeding from body orifices). B. Almost always secondary to another disease process 1. Obstetric complications-Tissue thromboplastin in the amniotic fluid activates coagulation. 2. Sepsis (especially with E Coli or N meningitidis)-Endotoxins from the bacterial wall and cytokines (e.g., TNF and IL-1) induce endothelial cells to make tissue factor. 3. Adenocarcinoma-Mucin activates coagulation. 4. Acute promyelocytic leukemia-Primary granules activate coagulation. 5. Rattlesnake bite-Venom activates coagulation. C. Laboratory findings include 1. j,. platelet count 2. 3. j,. fibrinogen 4. 5. Elevated fibrin split products, particularly D-dimer i. Elevated D-dimer is the best screening test for DIC. ii. Derived from splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen.


Pathoma_Husain

Pathoma_Husain. ii. Derived from splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen. D. Treatment involves addressing the underlying cause and transfusing blood products and cryoprecipitate (contains coagulation factors), as necessary. III. DISORDERS OF FIBRINOLYSIS A. Normal fibrinolysis removes thrombus after damaged vessel heals. 1. Tissue plasminogen activator (tPA) converts plasminogen to plasmin. 2. Plasmin cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation. 3. a2-antiplasmin inactivates plasmin. B. Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen. Examples include 1. Radical prostatectomy-Release of urokinase activates plasmin. 2. Cirrhosis ofliver-reduced production of a2-antiplasmin C. Presents with increased bleeding (resembles DIC) D. Laboratory findings include 1. t PT/PTT-Plasmin destroys coagulation factors. 2.


Pathoma_Husain

Pathoma_Husain. 2. Cirrhosis ofliver-reduced production of a2-antiplasmin C. Presents with increased bleeding (resembles DIC) D. Laboratory findings include 1. t PT/PTT-Plasmin destroys coagulation factors. 2. t bleeding time with normal platelet count-Plasmin blocks platelet aggregation. 3. Increased fibrinogen split products without D-dimers-Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent. E. Treatment is aminocaproic acid, which blocks activation of plasminogen. I. BASIC PRINCIPLES A. Pathologic formation of an intravascular blood clot (thrombus) 1. 2. Most common location is the deep veins (DVT) of the leg below the knee. B. Characterized by (1) lines of Zahn (alternating layers of platelets/fibrin and RBCs, Fig. 4.3) and (2) attachment to vessel wall 1. Both features distinguish thrombus from postmortem clot.


Pathoma_Husain

Pathoma_Husain. B. Characterized by (1) lines of Zahn (alternating layers of platelets/fibrin and RBCs, Fig. 4.3) and (2) attachment to vessel wall 1. Both features distinguish thrombus from postmortem clot. C. Three major risk factors for thrombosis are disruption in blood flow, endothelial cell damage, and hypercoagulable state (Virchow triad). II. DISRUPTION IN NORMAL BLOOD FLOW A. Stasis and turbulence of blood flow increases risk for thrombosis. 1. Blood flow is normally continuous and laminar; keeps platelets and factors dispersed and inactivated B. Examples include 1. 2. Cardiac wall dysfunction (e.g., arrhythmia or myocardial infarction) 3. III. ENDOTHELIAL CELL DAMAGE A. Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis. B. Endothelial cells prevent thrombosis by several mechanisms. 1. Block exposure to subendothelial collagen and underlying tissue factor 2.


Pathoma_Husain

Pathoma_Husain. B. Endothelial cells prevent thrombosis by several mechanisms. 1. Block exposure to subendothelial collagen and underlying tissue factor 2. Produce prostacyclin (PGI ) and NO-vasodilation and inhibition of platelet Fig, 4.3 Lines of Zahn characterized by alternating layers of platelets/fibrin and RBCs. 3. Secrete heparin-like molecules-augment antithrombin III (ATIII), which inactivates thrombin and coagulation factors 4. Secrete tissue plasminogen activator (tPA)-converts plasminogen to plasmin, which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation 5. Secrete thrombomodulin-redirects thrombin to activate protein C, which inactivates factors V and VIII C. Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine. 1. Vitamin Bl2 and folate deficiency result in mildly elevated homocysteine levels, increasing the risk for thrombosis.


Pathoma_Husain

Pathoma_Husain. 1. Vitamin Bl2 and folate deficiency result in mildly elevated homocysteine levels, increasing the risk for thrombosis. i. Folic acid (tetrahydrofolate, THF) circulates as methyl-THF in the serum. 11. Methyl is transferred to cobalamin (vitamin Bl2), allowing THF to participate in the synthesis of DNA precursors. iii. Cobalamin transfers methyl to homocysteine resulting in methionine. iv. Lack ofvitamin Bl2 or folate leads to decreased conversion of homocysteine to methionine resulting in buildup of homocysteine. 2. Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels with homocystinuria. 1. CBS converts homocysteine to cystathionine; enzyme deficiency leads to homocysteine buildup. ii. Characterized by vessel thrombosis, mental retardation, lens dislocation, and long slender fingers. A. Due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired


Pathoma_Husain

Pathoma_Husain. A. Due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired B. Classic presentation is recurrent DVTs or DVT at a young age. 1. Usually occurs in the deep veins of the leg; other sites include hepatic and cerebral veins. C. Protein C or S deficiency (autosomal dominant) decreases negative feedback on the coagulation cascade. 1. Proteins C and S normally inactivate factors V and VIII. 2. i. Initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X ii. In preexisting C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing risk for thrombosis, especially in the skin. D. Factor V Leiden is a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S. 1. Most common inherited cause of hypercoagulable state


Pathoma_Husain

Pathoma_Husain. D. Factor V Leiden is a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S. 1. Most common inherited cause of hypercoagulable state E. Prothrombin 20210A is an inherited point mutation in prothrombin that results in increased gene expression. 1. Increased prothrombin results in increased thrombin, promoting thrombus formation. F. A TIII deficiency decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus. 1. Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors. 2. In ATIII deficiency, PTT does not rise with standard heparin dosing. 1. Pharmacologic heparin works by binding and activating ATIII. 11. High doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state. I. II. G. Oral contraceptives are associated with a hypercoagulable state.


Pathoma_Husain

Pathoma_Husain. 11. High doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state. I. II. G. Oral contraceptives are associated with a hypercoagulable state. 1. Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis. A. Intravascular mass that travels and occludes downstream vessels; symptoms depend on the vessel involved. B. Thromboembolus is due to a thrombus that dislodges; most common type of embolus (>95%) C. Atherosclerotic embolus is due to an atherosclerotic plaque that dislodges. 1. Characterized by the presence of cholesterol clefts in the embolus (Fig. 4.4A) D. Fat embolus is associated with bone fractures, particularly long bones, and soft tissue trauma. 1. Develops while fracture is still present or shortly after repair 2. Characterized by dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels, Fig. 4.4B) and petechiae on the skin overlying the chest


Pathoma_Husain

Pathoma_Husain. Characterized by dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels, Fig. 4.4B) and petechiae on the skin overlying the chest E. Gas embolus is classically seen in decompression sickness. 1. Nitrogen gas precipitates out of blood due to rapid ascent by a diver. 2. Presents with joint and muscle pain ('bends') and respiratory symptoms ('chokes'). 3. Chronic form (Caisson disease) is characterized by multifocal ischemic necrosis of bone. 4. Gas embolus may also occur during laparoscopic surgery (air is pumped into the abdomen). F. Amniotic fluid embolus enters maternal circulation during labor or delivery 1. Presents with shortness of breath, neurologic symptoms, and DIC (due to the thrombogenic nature of amniotic fluid) 2. Characterized by squamous cells and keratin debris, from fetal skin, in embolus (Fig. 4.4C)


Pathoma_Husain

Pathoma_Husain. Characterized by squamous cells and keratin debris, from fetal skin, in embolus (Fig. 4.4C) A. Usually due to thromboembolus; the most common source is deep venous thrombus (DVT) of the lower extremity, usually involving the femoral, iliac, or popliteal veins. B. Most often clinically silent because (1) the lung has a dual blood supply (via pulmonary and bronchial arteries) and (2) the embolus is usually small (selfresolves) Fig. 4.4 Emboli. A, Atherosclerotic em bolus characterized by cholesterol clefts. B, Fat embolus with bone marrow elements. C, Amniotic fluid em bolus with squamous cells and keratin debris from fetal skin. (A, Courtesy of Professor A. Garfia. C, Courtesy of Shakuntala Teas, MD) C. Pulmonary infarction occurs if a large-or medium-sized artery is obstructed in patients with pre-existing cardiopulmonary compromise; only 10% of PEs cause infarction. 1. Presents with shortness of breath, hemoptysis, pleuritic chest pain, and pleural effusion 2.


Pathoma_Husain

Pathoma_Husain. 1. Presents with shortness of breath, hemoptysis, pleuritic chest pain, and pleural effusion 2. V/Q lung scan shows mismatch; perfusion is abnormal. 3. Spiral CT shows a vascular filling defect in the lung. 4. Lower extremity Doppler ultrasound is useful to detect DVT. 5. D-dimer is elevated. 6. Gross examination reveals a hemorrhagic, wedge-shaped infarct. D. Sudden death occurs with a large saddle embolus that blocks both left and right pulmonary arteries or with significant occlusion of a large pulmonary artery (Fig. 4.5); death is due to electromechanical dissociation. E. Pulmonary hypertension may arise with chronic emboli that are reorganized over time. III. SYSTEMIC EMBOLISM A. Usually due to thromboembolus B. Most commonly arise in the left heart C. Travel down systemic circulation to occlude flow to organs, most commonly the lower extremities Fig. 4.5 Saddle em bolus involving pulmonary artery. (Courtesy of Yale Rosen, MD) I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. Fig. 4.5 Saddle em bolus involving pulmonary artery. (Courtesy of Yale Rosen, MD) I. BASIC PRINCIPLES A. Reduction in circulating red blood cell (RBC) mass B. Presents with signs and symptoms of hypoxia 1. Weakness, fatigue, and dyspnea 2. 3. 4. Angina, especially with preexisting coronary artery disease C. Hemoglobin (Hb), hematocrit (Hct), and RBC count are used as surrogates for RBC mass, which is difficult to measure. 1. Anemia is defined as Hb < 13.5 g/dL in males and < 12.5 g/dL in females (normal Hb is 13.5-17.5 g/dL in males and 12.5-16.0 g/dL in females). D. Based on mean corpuscular volume (MCV), anemia can be classified as microcytic (MCV < 80 µm3), normocytic (MCV = 80-100 µm 3), or macrocytic (MCV > 100 µm 3). I. BASIC PRINCIPLES A. Anemia with MCV < 80 µm 3 B. Microcytic anemias are due to decreased production of hemoglobin. 1.


Pathoma_Husain

Pathoma_Husain. I. BASIC PRINCIPLES A. Anemia with MCV < 80 µm 3 B. Microcytic anemias are due to decreased production of hemoglobin. 1. RBC progenitor cells in the bone marrow are large and normally divide multiple times to produce smaller mature cells (MCV = 80-100 µm 3). 2. Microcytosis is due to an "extra" division which occurs to maintain hemoglobin concentration. C. Hemoglobin is made of heme and globin; heme is composed of iron and protoporphyrin. A decrease in any of these components leads to microcytic anemia. D. Microcytic anemias include (1) iron deficiency anemia, (2) anemia of chronic disease, (3) sideroblastic anemia, and (4) thalassemia. II. IRON DEFICIENCY ANEMIA A. Due to decreased levels of iron 1. ..I.-iron ➔ ..I.-heme ➔ ..I.-hemoglobin ➔ microcytic anemia B. Most common type of anemia 1. Lack of iron is the most common nutritional deficiency in the world, affecting roughly 1/3 of world's population.


Pathoma_Husain

Pathoma_Husain. B. Most common type of anemia 1. Lack of iron is the most common nutritional deficiency in the world, affecting roughly 1/3 of world's population. C. Iron is consumed in heme (meat-derived) and non-heme (vegetable-derived) forms. 1. Absorption occurs in the duodenum. Enterocytes have heme and non-heme (DMTl) transporters; the heme form is more readily absorbed. 2. Enterocytes transport iron across the cell membrane into blood via ferroportin. 3. Transferrin transports iron in the blood and delivers it to liver and bone marrow macrophages for storage. 4. Stored intracellular iron is bound to ferritin, which prevents iron from forming free radicals via the Fenton reaction. pathoma.com D. Laboratory measurements of iron status 1. Serum iron-measure of iron in the blood 2. Total iron-binding capacity (TIBC)-measure of transferrin molecules in the blood 3. % saturation-percentage of transferrin molecules that are bound by iron (normal is 33%) 4.