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Antithrombogenic substances

Prostacyclin (PGI2),
nitric oxide,
tissue plasminogen activator,
thrombomodulin

Steps in hemostasis

1. Endothelial injury relases tissue factor (activates factor VII, extrinsic pathway); exposure of thrombogenic subendothelial collagen activates factor XII (intrinsic pathway), release of vWF; decreased synthesis of antithrombogenic substances; 2. Platelet adhesion to vWF through glycoprotein Ib; 3. Platelet activation with degranulation and synhesis of TXA2 and ADP (aggregators); 4. Aggregation mediated by TXA2 and ADP and fibrinogen/Gp IIb-IIIa

Bernard Soulier syndrome

Autosomal recessive. Deficiency of platelet GPIb. Defective platelet adhesion

Glanzman thrombastenia

Deficiency of Gp IIB-IIIa; defective platelet aggregation

Immune thrombocytopenic pupura

Antiplatelet antibodies and destruction in spleen by macrophages (bing IgG coated platelets via Fc receptor). Thrombocytopenia, prolonged bleeding time, normal PT and PTT. Petechiae, ecchymoses, menorrhagia, nosebleeds. Present in Wiskot-Aldrich

Thrombotic thrombocytopenic purpura

Platelet thrombi with scant fibrin with no activation of coagulation system. Fever, thrombocytopenia, hemolytic anemia, neurologic symptoms, renal failure. Increased bleeding time, normal PT/PTT, schistocytes

Hemolytic uremic syndrome

Gastroenteritis with bloody diarrhea, fever, thrombocytopenia, renal failure, hemolytic anemia. Produced by verotixin-producing E. coli 0157

Activation of coagulation system

Intrinsic pathway (Factor XII): exposure to subendothelial collagen; Extrinsic pathway (factor VII): tissue thromboplastin by endothelium

Kinin cascade

Hageman factor converts prekallikrein into kallikrein. HMWK is converted to bradykinin by kallikrein

Fibrinolytic system cascade

Kallikrein activates plasminogen into plasmin which inhibits fibrin from coagulation cascade

Vitamin K-dependant factors

Factors II, VII, IX, X. Both intrinsic and extrinsic paths need vitamin k-dependant gamma carboxylation

Prothrombin time (PT)

Tests extrinsic and common paths. Factors V, VII, X, prothrombin and fbrinogen. Used to monitor warfarin therapy

MOA of warfarin

Blocks epoxide reductase (activates vitamin K). Takes 3-4 days for effect due to long half life of previously carboxylated factors which are still circulating

Partial thromboplastin time (PTT)

Tests intrinsic and common paths. Factors XII, XI, IX, VIII, X, V, prothrombin, fibrinogen. Used to monitor heparin

DIC

Thrombocytopenia, prolonged PT/PTT, decreased fibrinogen, elevated D-dimers

Hemophilia

Deficiency of factor VIII or IX. X-linked recessive (affects males). Bleeding at circumcision, hemarthrosis, easy bruising and hematomas. No petechiae or ecchymoses. Normal platelets and bleeding time, normal PT, prolonged PTT (intrinsic path coagulopathy)

Increased PT and PTT

Vitamin K deficiency, liver disease

Von Willenbrand disease

bleeding from mucous membranes, prolonged bleeding time, normal PT/PTT, abnormal response to ristocetin

Auto mechanics

Carbon monoxide poisoning. Decreased SaO2, cherry red color of skin, headache. Rx.: 100% O2

Firefighters

Carbon monoxide poisoning. Decreased SaO2, cherry red color of skin, headache. Rx.: 100% O2

Wood stoves and space heaters

Carbon monoxide poisoning. Decreased SaO2, cherry red color of skin, headache. Rx.: 100% O2

Pesticide industry

Organophosphate poisoning (acetylcholinesterase inhibitors) and arsenic. Lacrimation, salivation, miosis, weakness. Rx.: atropine

Meat packing industry

Plyvinyl chloride (PVC). Hepatic angiosarcoma

Coal workers

Anthracosis. Pulmonary fibrosis and respiratory distress

Insulation workers

Asbestosis. Interstitial lung fibrosis, fibrous pleural plaques, brnchogenic CA, mesotheliomas, recurrent pleural effusions, dyspnea, pleuritic chest pain

Demolition workers

Asbestosis. Interstitial lung fibrosis, fibrous pleural plaques, brnchogenic CA, mesotheliomas, recurrent pleural effusions, dyspnea, pleuritic chest pain

Construction workers

Asbestosis. Interstitial lung fibrosis, fibrous pleural plaques, brnchogenic CA, mesotheliomas, recurrent pleural effusions, dyspnea, pleuritic chest pain

Shipyard workers

Asbestosis. Interstitial lung fibrosis, fibrous pleural plaques, bronchogenic CA, mesotheliomas, recurrent pleural effusions, dyspnea, pleuritic chest pain

Dry cleaners

Carbon tetrachloride (CCL4). Liver centrilobular necrosis

Rubber/chemical workers

Benzene. Aplastic anemia, leukemia

Battery factory workers

Lead poisoning. MOA: denatures ferrochelatase, (microcytic anemia with ringed sideroblasts), denatures ALA dehydrase. Clinical features: depositis in epiphysis, lethargy, cognitive impairment, cerebral edema, lead colic, basophilic stipling. Dx.: blood lead levels

Plumbers

Lead poisoning. MOA: denatures ferrochelatase, (microcytic anemia with ringed sideroblasts), denatures ALA dehydrase. Clinical features: depositis in epiphysis, lethargy, cognitive impairment, cerebral edema, lead colic, basophilic stipling. Dx.: blood le

Pottery paint

Lead poisoning. MOA: denatures ferrochelatase, (microcytic anemia with ringed sideroblasts), denatures ALA dehydrase. Clinical features: depositis in epiphysis, lethargy, cognitive impairment, cerebral edema, lead colic, basophilic stipling. Dx.: blood le

Combustion of polyurethane foam during fires

Cyanide poisoning. Blocks cytochrome oxidase. Hypoxia. Rx.: nitrites (form methhemoglobin which binds cyanide before it reaches tissues), thiosulfate bind cyanide forming thiocyanate

Dental amalgams

Mercury poisoning. Intention tremors, dementia, delirium

Insecticides

Mercury poisoning. Intention tremors, dementia, delirium

Hat-making industry

Mercury poisoning. Intention tremors, dementia, delirium

Cancers produced by cigarette smoke

Lung, oral cavitiy, pharynx, larynx, esophagus, pancreas, kidney

Cardiovascular disease due to cigarette smoke

Atherosclerosis (major risk factor), CAD, AMI, Buerger disease

Respiratory disease due to cigarette smoke

Chronic bronchitis, emphysema, asthma

Diseases associated with alcohol

Thiamine deficiency (Wernicke-Korsakoff), macrocytic anemia (folate deficiency), Mallory-Wiess, Boerhaave's syndrome, cirrhosis, esophageal varices, acute pancreatitis, congestive cardiomyopathy, hyperlipidemia

Down syndrome

Trisomy 21 due to meiotic nondisjunction (95%) or robertsonian translocation (4%); Severe mental retardation, mongoloid features, brushfeld spots, simian crease, heart defects, duodenal atresia, Hirchsprung, ALL, Alzheimer's by age 40

Edward syndrome

Trisomy 18. Mental retardation, low set ears, micrognathia, heart defects, overlapping flexed fingers, rocker-bottom feet

Patau syndrome

Trisomy 13. Mental retardation, cleft lip or palate, cardiac defects, renal defects, microcephaly, polydactyly

Cri du chat

5p deletion. Cat-like cry, mental retardation, heart defects, microcephaly

Klinefelter syndrome

47XXY. Male hypogonadism, testicular atrophy, infertility, female distribution of hair, gynecomastia, elevated FSH/LH ratio, low levels of testosterone

Turner syndrome

45X0. Female hypogonadism, no barr body, no secondary sex characteristics, short stature, widely spaced niples, gonadal dysgenesis, amenorrhea, infertility, hypothyroidism, preductal coarctation of the aorta, bicuspid aortic valve

Female hermaphrodite

46XX. Female internal organs, virilized external genitalia. Cause: congenital adrenal hyperplasia, androgen-producing tumor

Male hermaphrodite

46XY. Testes present, female genitalia, testicular feminization. Cause: androgen insensitivity syndrome

CCystic Phibrosis

Chloride Channel protein defect, DP508 on chromosome 7. Recurrent pseudomona/staph infections, chronic bronchitis, bronchiectasis, atrophy of pancreatic ducts, pancreatic insuficiency, fat malabsorbtion, steatorrhea, infertility, meconium ileum, elevated NaCl sweat test

PKU

Deficiency of phenylalanine hydroxylase. Mental retardation by 6 months, light-colored hair and skin, musty odor. Avoid aspartame, monitor pregnancy

Alkaptonuria

"Black Homo" homogentisic acid oxidase deficiency. Black urine, black cartilage

Albinism

Tyrosinase deficiency. Increased risk of squamous carcinoma, no melanin

Von Gierke disease

Glucose 6 phosphatase deficiency. Hepatomegaly, fasting hypoglycemia, hyperuricemia

Pompe disease

Lysosomal alpha 1-4 glucosidase deficiency. Hepatomegaly, muscle hypotonia, cardiomegaly

McArdle disease

Myophosphorylase deficiency. Excersice-induced muscle cramps

Tay SaX

Hexosaminidase A deficiency with acumulation of glangliocerebroside GM2. Mutation of HEXA gene on chromoseme 15. Cherry-red spot on retina

Nieman PickS

Sphingomyelinase deficiency. Cherry-red spot on retina, hepatosplenomegaly, zebra bodie on EM

Gaucher disease

Glucocerebrosidase deficiency. In adulthood, hepatosplnomegaly, hypersplenism, lymphadenopathy, osteoporosis

Mucopolysaccharidosis

Glycosaminoglycans acumulation. Mental retardation, cloudy cornea, coarse facial features, hepatosplenomegaly, skeletal deformities

Familial hypercholesterolemia

Mutation on LDL receptor gene on chromosome 19. Xanthomas, xanthelasmas, atherosclerosis

Marfan syndrome

Mutation of fibrillin gene on 15q. Tall, thin with big extremities, hyperextensible joints, pectus excavatum, ectopia lentis, disecting aortic aneurysm, aortic insuficiency, mitral prolapse

Ehlers-Danlos

Hyperxtensible skin and joints. Collagen gene defects

Menkes disease

Mutation in Cu+ efflux protein gene. High concentration of Cu+ that cant be released. Associated with Ehlers-Danlos type 9

Neurofibromatosis type 1

Von Recklinghousen disease (has 17 letters). NF-1 tumor suppressor gene mutation on chromosome 17. Normal gene product neurofibromim inhibits p21 ras oncoprotein. Neurofibromas, café-au-lait spots, Lisch nodules (pigmented iris hamartomas)

Neurofibromatosis type 2

NF-2 tumor suppressor gene mutation on chromosome 22. Bilateral acoustic neuromas, café-au-lait spots, pheochromocytoma

Von Hippel Lindau disease

Mutation on VPL tumor suppressor gene on chromosome 3p. Retinal hemangioblastoma, hemangioblastoma of cerebellum, brainstem and spinal cord, cysts of the liver, pancreas and kidneys, bilateral renal carcinomas

Fragile X syndrome

X-linked dominant mutations on FMR-1 gene. CGG triplet repeats. Retardation elongated face with large jaws, large everted ears, macroorchidism

Huntington disease

CAG triplet repeats of huntington gene produces neurotoxic protein. Progressive dementia, choreiform movements

Prader-Willi syndrome

Deletion of paternal 15q. Mental retardation, obesity, hypogonadism, hypotonia

Angelman syndrome

deletion of maternal 15q. Retardation, seizures, ataxia, inapropriate happy-puppet laughter

Homocystinuria

Cysthathione synthase deficiency. Resembles Marfan. Ectopic lens, arachnodactyly, eunuchoid proportions osteoporosis, atherosclerosis, DVT

Classic 21B-Ohase deficiency

Hypovolemia, hyponatremia, female pseudohermaphrodite, hirsutism (increased 17 KS), skin hyperpigmentation (high ACTH increases melanin). Labs: increased serum 17OH-progesterone, hyperkalemia, metabolic acidosis, increased 17KS, decreased 17OHCS, hypocortisolism

Non-classic 21B-Ohase deficiency

Increase in 17 KS, hirsutism, no salt loss, acne in females, secondary amenorrhea. Labs: increased 17OH pregenterone

Classic 11OHase deficiency

Salt retention/hypertension (11-deoxycorticosterone), increased 17KS (virilization), skin hyperpigmentation

17OHase deficiency

Salt retention, hypertension, (aldosterone), female hypogonadism (decreased 17KS), male pseudohermaphrodite (low 17KS). Labs: low 17KS, 17OHCS, hypocortisolism, increased ACTH

Clinical features of SLE

Type II and III hypersensitivity reactions. Pancytopenia, arthritis, butterfly rash, diffuse proliferative glomerulonephritis, Libman-Sacks endocarditis. ANA, anti-DNA, anti-Sm, anti-histone (drug-induced lupus). Rx.: steroids

Sjogren syndrome

Autoantibodies against lacrimal and salivary glands. Keratoconjunctivitis, corneal ulcers (dry eyes), xerostomia (dry mouth). Anti-Ro (SS-A), anti-La (SS-B). 15% of rheumatoid arthritis patients have Sjogren.

Mikulicz syndrome

Enlargement of the salivary and lacrimal glands associated with Sjogren syndrome

Diffuse scleroderma

Fibroblast stimulation and deposition of collagen in the skin and internal organs. Anti-DNA topoisomarease I (Scl-70) (helicase). Skin involvement, dysphagia, malabsorption, pulmonary fibrosis (dyspnea), cardiac fibrosis (arrhythmias), kidney fibrosis (renal failure)

Localized scleroderma (CREST)

Fibroblast stimulation and deposition of collagen. Anti-centromere antibodies. Calcinosis, Raynaud, esophageal dysmoility, sclerodactyly, telangiectasia.

Bruton's agammaglobulinemia

X-linked recessive. No B cells, No Igs. Recurrent staph, haemophilus and strep infections after 6 months. Increased pre-B cells. Mutation of B-cell Bruton tyrosine kinase (btK).

Common variable immunodeficiency

B-cell maturation defect. Hypogammaglubulinemia, recurrent bacterial infections, giardia lamblia.

DiGeorge syndrome

Failure to develop 3rd and 4th pharyngeal puches results in absence of parathyroid and thymus glands, hypocalcemia, tetany, T-cell deficiency, recurrent viral infections, heart defects, chronic candidiasis

SCID

B and T cell deficiency due to mutation of IL-2 receptor (x-linked), adenosine deaminase deficiency (AR) or failure to make MHC II. Recurrent infections and susceptibility to candida, CMV and p. carinii

Wiskot-Aldrich syndrome

X-linked recessive. "WIPE": recurrent infections, thrombocytopenic purpura, eczema, risk of lymphomas, low IgM

Ataxia-Telangiectasia

Ataxia, spider angiomas, low IgA, defect of DNA repair enzyme

Chronic granulomatous disease

Low NADPH oxidase. Recurrent catalase+ infections, negative nitroblue tetrazolium test.

Leukocyte adhesion deficiency

Defect of CD-18 (LFA-1 beta chain), no pus formation, failure of umbilical cord to detach

Chediak-Higashi

Defect in microtubules with no phagocytosis by lysosome. Partial albinism, peripheral neuropahty, recurrent infections

Hereditary angioedema

Edema at mucosal surfaces. Defect of C1-INH (esterase inhibitor). Decreased C1, C2, C4

Hyper IgM

Defect of CD-40L on T-lymphocytes. No isotype switching, increased IgM

MHC-I deficiency

Normal CD4, no CD8. Failure of TAP-1 to transport peptides to MHC-I groove

Amyloid stains

Stains red with Congo-red stain then apple green birefringence under polarized light

Signs and symptoms of amyloidosis

Nephrotic syndrome, renal failure, arrythmias, CHF, hepatosplenomegaly, macroglosia

Mediators of leukocyte margination

Selectins mediate margination. P and E selectins on endothelium bind Sialyl-Lewis on leukocyte; GlyCAM/CD34 on endothelium binds L-selectin on leukocyte

Mediators of leukocyte adhesion

Integrins mediate adhesion. ICAM, VCAM on endothelium bind LFA-1 and VLA on leukocyte

Regulators of leukocyte margination and adhesion

Histamine upregulates P-selectin. IL-1 and TNF induce E-selectin, ICAM and VCAM. Chemotactic agents cause conformational change of LFA-1

Leukocyte adhesion deficiency

Defect of CD18 (beta chain subunit of LFA-1 integrin on leukocytes). Recurrent infections, no pus formation, failure of umbilical cord to detach

Chemotactic factors

N-formyl methionine, leukotriene B4, C5a, IL-8

Opsonins

Fc portion of IgG, c3b, C reactive protein

Chediak-Higashi syndrome

Defect of microtubule polymerization causes defect in chemotaxix and degranulation. Partial albinism, peropheral neuropathy

CGD

NADPH oxidase deficiency. No production of superoxide for respiratory burst. Recurrent catalase+ infections, negative nitroblue tetrazolium test

Arachidonic acid products

AA produced by phospholipase A2 (inhibited by steroids). Produces leukotrienes, prostaglandins and thromboxane A2

Lypoxigenase pathway

Arachidonic acid is converted to leukotrienes by 5-lypoxigenase. LTB4 --> chemotaxis. LTC4, D4, E4 --> bronchoconstriction

Cycloxigenase pathway

Arachidonic acid is converted to TXA2 and prostaglandins (NSAIDs block). TXA2 --> vasoconstriction, platelet aggregator. PGI2, PGE2, PGF2

Mediators of vasodilation

Histamine , bradikinin, PGI2, PGD2, E2, F2

Mediators of pain

Bradikinin, PGE2

Mediators of increased permeability

Histamine, Bradikinin

Mediators of vasoconstriction

TXA2, LTC4, D4, E4

Mediators of bronchoconstriction

LTC4, D4, E4, bradikinin

Mediators of fever

IL-1, PGD2, E2, F2

Anaphilotoxins

C3a, C5a. Directly stimulate histamine release from basophils, mast cells and platelets

C3b

Opsonin; neutrophils, macrophages and monocytes have C3b receptros

Bradikinin synthesis and actions

Synthesized from activation of prekalikrein by factor XII (Hageman). Kalikrein cleaves HMWK into bradikinin. Vasodilator, increased permeability, brnchoconstrictor, pain

PGE2

Vasodilation in kidneys, increases renal blood flow, increases gastric mucosal blood flow (mucoprotection), activates osteoclasts, fever, pain, maintains ductus arteriosus

Prostacyclin (PGI2)

Vasodilation and inhibits platelet aggregation

IL-1

Stimulates PGE2 synthesis in hypothalamus --> fever; B-cell stimulation to synthesize Ig; osteoclast activation (released by osteoblasts under PTH stimulation); lytic bone lessions of multiple myeloma; increases adhesion molecules in endothelium; increases acute phase reactants

Hageman factor

Activates intrinsic coagulation system, kinin cascade and fibrinolytic system

PGF

Uterine muscle contraction (cause pf primary amenorrhea)

gamma interferon

Produced by CD4 TH1 cells and NK cells. Activates macrophages; antiviral properties; class I and class II antigens; increases IL-2, IL-12 production by CD4 cells

IL-2

Produced by CD4 cells. T cell growth factor. Promotes B cell and NK cell proliferation

IL-6

Synthesis of acute phase reactants

Factors that increase adhesion molecule synthesis

C5a, LTB4, IL-1, TNF

Key cells in acute and chronic inflamation

Acute: neutrophil has IgG and C3b receptros; Chronic: macrophage has receptors for IgG and C3b, process antigen and secrete IL-1, IL-12 and TNF

Chronic granulomatous inflamation

Epitheloid cells and multinucleated giant cells surrounded by a rim of lymphocytes with central caseous necrosis

Type I collagen

skin, bones, tendons and most organs

Type II collagen

Cartilage and vitreous humor

Type III collagen

granulation tissue

Type IV collagen

basement membranes

Composition of basement membranes

Has negative charge. Collagen type IV, proteoglycans (heparan sulfate), laminin, fibronectin

Nitrosamines

Gastric CA, Esophagus

Cigarette smoke

Larynx, ling, renal cell carcinoma, transitional cell carcinoma

Polycyclic aromatic hydrocarbons

Bronchogenic CA

Asbestos

Bronchogenic CA, mesothelioma

Chromium and nickel

Bronchogenic CA

Arsenic

Squamous cell CA of skin and lung, angiosarcoma of liver

Vinyl chloride (PVC)

Liver angiosarcoma

Alkylating agents

Leukemia, lymphoma

Benzene

Leukemia, lymphoma

Napthalene

Bladder CA

CCL4

Liver centrilobular necrosis

HTLV-1

Adult T-cell leukemia

HBV, HCV

Hepatocellular CA

EBV

Burkitt's lymphoma, nasopharyngeal CA

HPV

Cervical CA (16, 18)

HHV-8

Kaposi sarcoma

hst-1 & int-2

Cancer of stomach, breast, bladder and melanoma; produces growth factors; overexpression

sis

Astrocytoma; produces PDGF; overexpression

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