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Flashcards in Exam 4 Deck (353):
1

Osteoarthritis

degeneration of articular cartilage with hypertrophy of bone, joint space loss, subchondral cysts, sclerosis and osteophytes

2

what joints are involved in OA?

DIPs, PIPs, 1st CMC, weight bearing - hips and knees, Spine - cerivical and lumbar, 1st MTP

3

Heberden’s

DIPs

4

Bouchard’s

PIPs

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Predisposing factors to OA

Age, obesity, occupational risks, trauma, or secondary OA due to inflammatory disorders like RA, spondylo, or metabolic disorders

6

sports and OA

no increased risk, exercise may be protective

7

Cartilage components

avascular and no nerves 1) collage II 2) proteoglycans 3) matrix proteins 4) chondrocyes 5) 70% water

8

Proteoglycans

in cartilage - chondroitin and keratin sulfate linked to hyaluronic acid - hydrophilic

9

Matrix proteins in cartilage

Metalloproteinases - like collagenases, gelatinases, stromeylsins and Tissue inhibitors of metalloproteinases TIMPS

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Chondrocytes

main cell of cartilage that produces the proteins in cartilage

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aggrecans

chondroitin and keratin sulfates bound to collagen. Forms a weave that acts like a sponge to hold onto water

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changes to cartilage in OA

increase chondrocytes, increase MMPs, decrease TIMP, proteglycans, Increase water. This is due to a mechanical injury, inflammation, metabolic hit of cartilage. Looses the weave and forms a dish rag instead of a sponge.

13

Does OA have systemic feaures?

NO - lacks them

14

Synovial fluid in OA

non-inflammaotry, type I fluid with 200-2000 WMC

15

Pathophysiology of OA

chondrocytes and synovium produce inflammatory mediators for cartilage destruction - IL1, NO, protsaglandins; they also activate complement and adipokines.

16

IL-1 release in OA

stimulates MMPs, PGE2, NO, IL6 produciton

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NO release in OA

increases MMPs, inhibits protoglycan, induces chondrocyte apoptosis.

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Prostaglands in OA

increase production and activation of MMPs

19

what other cytokines are produces in OA?

TNF, IL6, IL17, IL18

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Adipokines

are our own fact cells that make IL6 that go into the liver to make acute phase reactants like CRP. - metabolic aspect of OA.

21

Radiological findings in OA

Joint space loss, sclerosis, subchondral cysts, osteophytes

22

Patient will tell about OA

localized pain, worse with use. Stiffness for less than 30 minutes.

23

Rheumatoid Arthritis - basic

systemic, inflammatory, autoimmune disorder that results in peripheral, symmetric, *synovitis with cartilage and bone destrcution.

24

Joint involvement in RA

Bilateral and symmetric small joints of hands and feet (sparing DIPs), medium and large too.

25

X-rays of RA

marginal joint erosions and deformities

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Etiology of RA

arthritogenic peptide in host genetically suseptible due to a HLA-DR4 and HLA-DR1 mutation.

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HLA-DR4

mutation in 3rd hypervariable region of the MHC II binding cleft that increases the susceptibility and severity of the RA.

28

RF

antibody that detects Fc profession of IgG. usually composed of IgM, but can be IgG and IgA. Not a very sensitive marker of RA (85%). Produced in synovial tissue by plasma cells. RF-IgG immune complexes are pathogenic and form rheumatoid nodules over extensor system and lungs

29

Anti CCP

anti cyclic citrullinated peptide antiboides that react with synthetic peptides contains citrulline.

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Cirulline

modified arginine residue that is commonly seen in RA patients

31

Sensitivty vs. Specificity of anti-CCP

90% senstivie and 90% specific

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RF sensitivity and specificy

80% sensitive, 80% specific

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RF and anti-CCP sensitivity and specificity

rare only 40% sensitive and 100% specific

34

how often do anti_CCP occur

most frequently in those with HLA-DR4 epitope, due to enhanced binding of peptides to cirullination.

35

Pannus

characteristic of RA, containing major T lymphocytes, macrophages, and some fibroblasts, plasma cells, DCs. Located adjacent to bone and cartilage that chews away the erosions at margins of the joint.

36

Basic one liner of RA

disease of synovium

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basic one liner for OA

disease of cartilage

38

cell types in synovial fluid of RA

PMNs

39

where are PMNs in RA?

in synovial fluid, but NOT synovium tissue.

40

Synovium tissue in RA contains…

contains CD4 lymphocytes and Th17; more often than B-cells and plasma cells; IL2 and IFNgamma are sparse. no PMNs

41

Role of cells in RA synovium

CD4 memory cells modify and amplify local immune response through nation recognition.

42

Extra-articular manifestations of RA

RF-IgG compelx caues induced vasculitis; rhematoid nocules, eye lung, pericardium, peripheral nerves.

43

Pathophy of RA

unknown antigen is consumed by immune system at diagnosis, but altered proteoglycans, collagen, cirulinated peptides propogate the disease (not the antigen)

44

what patient experiences in RA

morning stiffness, fatigue, pain that improves with activity, rest makes worse

45

Lab values in RA

elevated RF, ESR, CRP, anti-CCP antibodies

46

Imaging of RA

loss of joint space, erosion of marginal distribution, soft tissue swelling, osteopenia

47

Risk factors of RA

female, any age, smoking

48

Gout - definition

Tissue deposition of Monosodium urate crystals due to hyeruricemia (MSU supersaturation of extracellular fluid)

49

Joints in Gout

1st MTP (podagra), Cool peripheral joins of lower and upper extremities.

50

Hyperuricemia

over production or under excretion of uric acid. (90% are under excretors)

51

Uric Acid

produce of purine metabolism, but humans lack the Uricase enzyme to oxidize uric acid into allegation form.

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X-linked conditions for overproduction or uric acid

PRPP synthtase overactivity, and HGPRT deficiency.

53

Diagnosis of Gout

arthrocentesis - needle biopsy with needle shaped crystals, negatively birefringement.

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Increased PRPP synthetase

incrases production of PRPP-glutamine to cause the pathway to form uric acid

55

decreased HGPRT

inhibits the reaction from going backward to promote more uric acid instead of guanlyic acid or inosinic acid.

56

Xanthione oxidase

inhibited by allopurinol and febuxosat that covers Xanthine into uric acid.

57

Inflammation induced Gout

Endogenous MUS crystals trigger TLR2/4 of inflammatory response. These are on monocytes, macrophages, synovial cells and activate NFkB to pour out inflammaotry cytokiesn and attract PMNs. 2) MSU crystals are internalized to activate NLRP3 inflammation via activation of Caspase 1 to results in IL-1 cleavage and release.

58

Self limiting nature of Gout

Cellular response due to protein coatings: gig coating promotes phagocytosis by PMNs. As time goes on you switch to ApoB coating that inhibits phagocytosis and the immune response.
2) phagocytosis decreases crystal concentrations
3) heat of inflammation, increases solubility
4) ACTH secretion supresses inflammation
5) IL1 and TNF anti antibodies are produced to modulate the inflammation

59

Calcium Pyrophosphate Dihydrate deposition

Abnormal pyrophosphate metabolism (PPi) - metabolism of NTPs from chondrocytes., PPi contacts calcium to form crystals.

60

PPi generation on chondrocytes

NTP pyrophosphohydrolase NTPPPH hydrolyzes phosphodiester1 bond to make NMP and PPI.
2) mutations in ank gene (ANKH) case transmembrane PPi transporter to all egression of excess PPi.

61

Visualization of Ca Pyrophospahte dehydrate deposition

PPi precipitates with Ca to form crystals in midzonal cartilage layers - shedding, strip mining. Rhomboid shape with positive birefringement

62

Predisposition to Gout

Men over 30, shelfish, alcohol

63

Underexcretion of uric acid

activation of URAT1 to decrease excretion

64

Lesch-Nyhan

complete deficiency in HGPRT

65

Seronegative spondylarthropaties

Axial arthritis of spine, sacroilitis, periphery (small and large), characterized by *enthesitis, mucocutaneous lesions, Uveitis

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Enthesitis

characterisitc of seronegative spondylarthropaties. - inflammation where ligament, tendon, and fibrossseous junction meet bone.

67

Systemic effects of Ankylosing Spondylitis

osteoporosis, uveitis, microscopic colitis

68

lab values of Ankylosing spondylitis

High ESR, negative RF, negative ANA

69

Genetic predisposition to Spondylarthropaties

HLA-B27 - associated with negative RF and ANA (sero negative).

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what is in the synovium of Spondylarthropaties

increased expression of TNFalpha

71

HLA-B27

Increased prevalence in Caucasians (6-9%), but relative low incidence of sponylarthropaties (0.1-0.2%. Thus there is low chance of having Spondyloarthropaties, and a 20% if you have the mutation and first degree relative. Only accounts for 40% of genetic risk -

72

Concordance of spondyloarthropties

60%

73

Reative Arthritis

due to infectious diarrhea or urethritis. Asymmetric, oligoarticular of the lower extremities, dactylitis, hips spared

74

Triggers of Reactive arhritis

transporttion of bacteria inside by monocytes (chlamydia) via molecular mimicry, arthritogenic peptide, Heavy chain theory, Unfolded protein hypothesis, TH2 response.

75

systemic effects of Reactive arthritis

inflammatory eye, musculocutaneous lesions, aortas, cardiac conduction defects

76

Arthritogenic peptide hypothesis

unique presentation of process peptide by HLA-B27

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HLA-B27 heavy chain theory

causes NK cell activation

78

Reiter’s syndrome

conjunctivitis, urthritis, arthritis

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HLA-B27 ER stress response

misfolded HLA-B27 initiates stress response to cuase IL23, IL17 to response to IL-6.

80

ERAp1

helps trim proteins as they feed into the ER

81

Systmic Lupus Erythromatses

chronic, autoimmune disease that affects multiple organs - skin, joints, serial, luns, kidneys, CNS

82

What causes SLE?

disdirectied recognition of self as foreign; requires both the T and B cell lectures; misdirected recognition of self as foreign.Antibody response requires antigen driven CD4 cells.
loss of t and b cells can happen

83

Pathophysiology of SLE

1) auto reactive B and T cells; Nucleic acids stimualte TLR receptors on DC cells to pump out IFN-alpha to represent to auto reactive Tcells. This leads to B cell stimulation and autoantibody creation. 2) NETOSIS - when apoptosis occurs of PMNs, they spew their nucleus out and trap bacterial pathogens. They trap, but the trap is made of DNA —> more autoAb.

84

Genetics of SLE

Increased risk among relatives, 35% concordance rate, associated with HLA_DR3 and C4A null allel (greatest risk)

85

Popualtions of SLE

AA, asians, hispanic americans

86

Environmental factors of SLE

female is 9x more likely, increased risk in childbearing age, sun exposure exacerabates systemic disease

87

Antinulcear Antiboides

hallmark of abnormala b in SLE, >95% of SLE have ANA. Ab directed to multiple nuclear antignes

88

ANA -dsDNA

renal disease

89

ANA anti-histone

SLE and drug induced lupus

90

Ab to Non-DNA, non Histone

SSA, SSB, Smith, RNP

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SLE diagnostic criterai

4/11: Malar rash, discoid rash, photo sensitivity, oral ulcer, Arthritis, serositis, renal invomvement, CNS - seizures, psychosis, hematologic disease, immunologic disorders, ANA

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SLE pathophysiolgy

1) Type III specific antibodies mediated to cause HM, neurophenia, thrombopenia, anti phospholipid ab to block prothrombin activation of clotting. Immune complex form with anti-dsDNA and DNA immune complex that can cause the lump and bumpy IF.

93

Vasculitis - basic definition

inflammation of vessel

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Pathology of vasculitis

varying degress of lymphs, monocytes, histiocytes, eosinophils, PMNs. Granulmonas or giant cells form in some types
large vessels: disruption of elastic lamina + intimal thickening
small vessels: fibroid necrosis (leukocutclastic vasulitis)

95

large artery vasculitis

Takayasus (claudication of upper extremities + CNS), Giant Cell (temporal artery + headache)

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Medium Artey vasculitis

Classic polyartheritis nodes (skin + joint + peripheral nerves); Kawasaki (acute fever in infants, rash, coronary vasculitis)

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small artery vasculitis

Wegener’s granulomatosis (ANCA+, respiratory), microscopic pohylangitis (pulmonary hemorrahge + glomerulonephritis), churg-strauss syndrome (asthma+eos)

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Arteriole/capillary venule vasculitis

Cryoglobinemia (RF ab and Hep C ab), Cutaneous leukoclastic vasculitis (palpablr purpuric lesions + althralgia), Henoch-schonlein purpura (palpable purpra + abdominal pian + IgA)

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Major pathophysiology of Vasculitis - one word

immune complexes

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detailed pathophys of vasculitis

inflammation —> platelet activating factors —> increased vascular permeability —> IC deposition; papable purpura.
ANCAS. anti-endothelial ab; T cell mediated endothelial injury,

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T cell dependent mediated endothelial cell injury

HLA-DR4 in giant cell arthritis, suggests antigen driven vascular inflammation

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Source of immune complexes in vasculitis

Drugs, bugs, CT disease, malignancy

103

ANCA

antinuetrophil cytoplasmic antibodies in vasculitis; amplifies inflammatory response - not the cause.

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c-ANCA

cytoplasmic ANCA, acts on proteinase-3 in primary granules of PMNs; associated with GPA

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p-ANCA

perinuclear, acts on MPO in primary granules of PMNs associated with MPA

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treatment of vasculitis

remove inciting agent, steroids, plasmapheresis, rituximab

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Polymyositis and Dermatomyositis

Inflammatory myopathies with muscle weakness, low endurance, idiopathic, but may overlap with CTDs or neoplastic disease. DM has skin rashes - Guttron’s papules, heliotrope rash, V sign, shawl-sign, mechanics hands, periungual changes/erythema

108

Systemic effects of PM and DM

GI dysphagia, pulmonary fibrosis, mycocarditis, Ranaud’s phenomenon, Anti-synthetase

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Anti-synthetase syndrome

PM or DM presenting with **instertitial lung disease, Fever, arthritis, mechanics hands, raynaud’s phenomenon.

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Anti-synthetase antibodies

anti-aminoacyl-tRNA synthetase in cyto,, Anti-Jo-1 = anti histadyl-tRNA synthetase; not pathologic of myotoxic

111

PM - lab finding

distribution of inflammatory CD8 cells surrounding and invading muscle fibers

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DM

Perivascular and perifascicular inflammation of CD4 cells; complement mediated, vasulopathy

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pathophysiology of DM/PM

CTL directly attacks muscles
Immune complex damage skin
MHC class I overexertion on myocytes —> ER stress response and NFkB production
Viral infections

114

Etiology of PM and DM

Virus! Flu and HIV —> viral particles are detected, but not live virus.; DM microarray of mRNA shows interferon responsive pathways

115

Juvenile DM

increase ab to coxackie B

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Seasonal DM

Anti-Jo1 ab in the spring

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Treatment of DM and PM

Corticosteroids, immunosuppressives, PT

118

Musculocutaneous bleeds are a sign of…

primary hemostasis - disorder of platelet of vWF

119

Soft tissue or joint bleeds are a sign of…

secondary hemostasis - coagulation disorder

120

aPTT

tests the procoagulant activity of intrinsic pathway most often F XI, VIII, IX; NOT VII.

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PT

tests the procoagulant activity of the extrinsic pathway and common pathway - sensitive to II, VII, V, X, Vit K, liver disease

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TT

tests procoagulant activity of fibrinogen and affect of heparin and fibrin split. Detects heparin contamination and fibrinogen def/dysfunction.

123

PFA-100

standardized bleeding time test; Collage/Epi and Collagen/ADP;
Abnormal Epi and normal ADP = aspirin effect
Both abnormal: platelet function effect.

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Ristocetin

chemical added to blood to test the activity of vWF binding to GP1b

125

vWF Disease - mechanism

qualitative platelet disorder due mut/under production of vWF —> decreased adhesion and unstable VIII

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vWF

binds to subendothelial collagen and GP1b receptor on platelets for adhesion! stabilizes Factor VIII

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GP1b

receptor on platelets that binds to vWF for adhesion

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GPIIb/IIIa

exposed on surface of platelets with ADP release from dense granules, used as linkage for platelet aggregation

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Epidemiology of vWF disease

AD, but can be acquired by autoab

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Clinical signs of vWF disease

mild mucosal and skin bleeding - GI bleed, menorrhagia, NO joint or mucosal bleeds.

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Types of vWF

Type 1 = partial quantitative deficiency, type 2: qualitative def type 3: near complete absence

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Diagnostic lab tests of vWF disease

Normal PT, Long PTT, decrased vWF antigen, decreased F VIII, abnormal ristecetin

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Treatment of vWF

DDAVP desmopressin - arginine vasopressin to enhance release of vWF from endothelial stores, or humane P (vWF and Factor VIII)

134

Bernard-Soulier Syndrome

Qualitative platelet disorder due to GP1b mutation to decrease adhesion; AR; unaffected PT or PTT

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Gray Platelet syndrome

qualitative platelet disorder due to reduced/absent alpha granules, AR

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Afibrogenemia

qualitative platelet disorder due to lack of fibrinogen —> no platelet aggregation due to lack of GPIIb/IIIa-fibrinogen binding and no GPIIb/IIIa cross linking; AR; has both mucosal and deep muscle bleeds; prolonged PT and PTT

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Ganzman Thrombasthenia

qualitataive platelet disorder, defective/low GPIIb/IIIa leads to decreased aggregation; AR, PTT and pT are unaffected.

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Abciximab

GPIIb-IIIa antagonists

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Thrombocyopenia

low platelet count due to decreased production, increased destruction, sequestration

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Decreased platelet production

BM disorders, aplastic anemia, MDS, leukemia, TB, B12/Folate def, viral infection

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Increased platelet destruction

ITP, autoimmune, DIC, TTP, HUS

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Thrombocytopenia - clinical characteristics

Mucosal bleeds and skin bleeds - petechiae

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ITP

immune thrombocytopenia purpura - AutoAb to GPIIb/IIIa to cause removal by macrophages in spleen. Can be acute or chronic

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Acute ITP

occurs in children and is proceeded by a virus. Sudden severe onset, but no treatment require. Presents with petichiase and nosebleeds, risk of Intracranial hemorrhage

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Chronic ITP

occurs in adults with concurrent autoimmune, lymphoma, HIV. requires treatment

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Labs for ITP

decreased platelet count, normal PT and PTT, increased megakaryocytes in marrow

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Treatment of ITP

Rituximab, steroids, IVIG, splenectomy, Thrombopoetin receptor agonist

148

Rituximab - ITP treatment

depletes b cells form making autoAb

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Steroids in ITP treatment

dampens B-cell clones

150

IVIG in ITP treatment

blocks Fc receptors to prevent splenic destruction

151

Thrombopoetin receptor agonists

stimulates platelet production in BM

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what should ITP patients avoid?

aspirin and Ibuprofen, contact sports

153

TTP

Thrombotic Thrombocytopenic Purpura - increased platelet consumption due to autoab to ADAMTS13

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ADAMTS13

proteast that cleaves vWF into active monomers

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Mutation in ADAMTS13

leaves vWF as inactive multimers that lead to abnormal adhesion and micro thrombi

156

HUS

hemolytic uremic syndrome - increase platelet consumption due to bacterial toxin or drug that damages endothelium and leads to increased adhesion and activation —> microthrombi; often seen in childen with E. coli

157

Clinical Signs of TTP and HUS

fever, renal insuff (HUS), microanggiopathic hemolytic anemia, Purpura, mental changes

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Lab values for TTP and HUS

low platelets, normal PT and PTT, anemia with schistiocytes, increase megakaryocites in BM, creatinine.

159

Microangiopathic hemolytic anemis

microthrombi causes shearing of RBC and destruction leading to hemolytic anemia

160

Treatment of TTP

plasmaphoresis and replacement of ADAMTS13

161

Hemophilia A

Factor VIII deficiency (intrinsic), X linked or from new mutations.

162

Hemophilia B

Factor IX deficiency, X linked or from new mutations

163

Hemophilia clinical signs

spontaneous hemorrhage in joints, soft tissue, retroperitoneal space, bleeding after surg/trauma

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Lab values in hemophilia

Long PTT, Mix = abnormal after 2 hours, Normal PT, platelet count, BT

165

HemophiliaC

Factor XI def, AR; post op delayed bleeding, but rare spontaneous bleeds

166

Acquired hemophilia

Factor VII deficiency (extrinsic), AR, same symptoms as A and B; prolonged PT normal PTT

167

Liver Disease - bleeding

Decreased Vit K dependent carboxylation of II, VII, IX, X, decreased fibrinogen, increased fibrinolysis, increased platelet consumption.

168

Liver disease - lab testing

Prolonged PT and pTT and TT, decreased fibrinogen, presence of FSP and D dimers, decreased platelet count, defects in protein S and C

169

Vitamin K deficiency

cannot make II, VII, IX and X - common in newborns because the lack GI bacteria to synthesize Vit K, or with long term antibiotic use, malabsorption.

170

Vitamin K deficiency lab values

Increased PT and PTT (normal to slight increase)

171

DIC

simultaneous bleeding and clothing due to systemic activation of coagulation to cause thrombosis but also platelet depletion to cause bleeding.

172

DIC is due to

sepsis, trauma, malignancy, obstetric complications, vascular disorders, toxins, immunologic disorders

173

DIC lab values

Prolonged PT and PTT and TT, delevated FSP and D dimer, low platelets, low fibrinogen, low factors

174

Treatment of DIC

treat underlying disorder, replace platelets and fibrinogen

175

lupus anticoagulant (APLA)

IgG ab binds to PL in platelet membranes - causes venous and arterial thrombosis, hepatic vein thrombosis, recurrent miscarriage, headaches

176

Lupus Anticoagulant lab values

Prolonged PTT (thrombic disorders), Pt mixing - no correcting at time 0

177

Arterial Thrombosis

due to high shear stress and vWF, cause aggregated platelets with small amounts of fibrin and RBCs - white in color

178

Associated conditions of arterial thrombosis

Hypertension, atherosclerosis, endothelial injury

179

Venous Thromobsis

slow blood flow with low shear stress, clots with large amounts of thrombin - red in color.

180

Associated conditions of venous thrombosis

Stasis - right heart failure, tumor with extrinsic vascular compression, obesity, chronic venous insufficiency, surgery, altered coagulability, defect in fibrinolysis, contraceptives, pregnancy.

181

DVT symptoms

Swollen, painful, blue leg, (phelegmasia cerulean dozens)

182

Phelegmasia curelean dolens

signs of DVT - swollen, painful blue leg

183

Consequences of DVT

Postthrombotic syndrome, intermitten obstruction, PE

184

Postthrombotic syndrome

chronically swollen, painful extremities that lead to cutaneous ulcers

185

Intermittent obstruction

recurrent bouts of pain due to DVT

186

Signs of PE

sudden chest pain, dyspnea, anxiety, cough, syncope, cyanosis, hemoptosis

187

Diagnosis of PE

Ultrasound, D-dimer assay, spiral CT, Ventilation/Perfusion scan

188

Treatment of DVT

heparin to prevent further clots, fibrinolytic to lyse existing clots.

189

Arterial thrombosis tx

main goal is anti platelet therapy

190

Venous thrombosis tx

main goal is inhibition of coagulation.

191

Inherited thrombotic disorders

Prothrombin G20201A, Protein C def, protein S, anithrombin def,

192

Prothrombin G20210A

Highest prevalence of inherited thrombotic disorders; AD, cause elevated plasma prothrombin and thrombin levels. long term treatment is not necessary for heterozygotes, asymptomatic is not treated

193

Protein C defiency

2ND most common inherited thrombotic disorder, AD, inability to inactivate Factor V and VIII to inhibit coagulation.

194

Complication of protein C deficiency

Homozygotes lead to neonatal purport fulminans - fatal
Warfarin induced skin necrosis - increased thrombosis of skin in adults

195

Protein S deficiency

similar to above, but due to inability to activate Protein C.

196

Treatment of Protein C and S deficiency

NO treatment of asymptomatic, but with 1st Thrombotic event 6-12 months therapy; >1 is long term terapy

197

Anithrombin deficiency

AD, antithrombin in unable to activate thrombin (as well as factor X, IX, XI, XII)

198

Tx of Antithrombin Def

1st event 3-6 months; Massive = therapy; prophylaxis for pregnant and surgery

199

Hyperhomocytenemia

inherited or acquired; enhanced platelet activation and adhesion due to endothelial injury

200

impaired fibrinolysis is due to..

plasminogen and tPA deficiency

201

high risk factors for thromosis

increased Factor VIII, oral contraceptives

202

Heparin mechanism

activates antithrombin II to increase rate of thromin inactivation and accelerated rate of decay for factors IX, X,XII; prevents conversion of fibrinogen to fibrin

203

Subtypes of Heparin

Unfractionated, low MW, fondaparinux

204

Unfractionated heparin

long version that can bind to antithrombinthrombin complex to inhibit thrombin directly

205

LMWH

produced by depolarization of heparin to 1/2 the size

206

Fondaparinus

synthetic version of lmwh

207

LMWH vs. Fonaparinus vs. unfractionated

LWMH and fona do not bind directly to thrombin, but only antithrombin to inactive factor X

208

Pharmacokinetics of unfractionated heparin

IV or SC, short half life of 1-5 hours, acts in the blood rapidly. Must be administered in hospital; does not cross placenta

209

Pharmacokinetics of LMWH and fonaparinus

Give SC, better bioavailability than unfractionated and longer half life —> less monitoring. Action in blood and rapid

210

Clinical use of heparin

Venous thromosis, PE, angina, Acute MI, cardiopulmonary bypass

211

Adverse effects of heparin use

Bleeding, heparin induced thrombocytpenia, osteoporosis, Drug/drug interactions

212

heparin induced thrombocytopenia

development of ab to heparin bound platelet factor IV to cause thrombosis and cytosine about 5-10 days after use. Tx with direct thrombin inhibitors like argatroban or lepirudin

213

Warfarin - mechanism

a vitamin K analoge that inhibits gamma carboxylation of of II, VII, IX, X and C and S. It also acts on VKORC1 (activator of vitamin K) a vitamin K epoxide reductase that develops polymorphisms.

214

Pharmacokinetics of warfarin

oral anticoag with 90 min absoprtion, T1/2 is 36-48 hours; acts in the liver with a very slow onset of action. Duration of action days/chronic. IT CROSSES the placenta

215

Warfarin vs. Heprin

Heparin is only for acute cases and administered IV or SC; acts in the blood and with rapid onset of action; short half life. Does not cross placenta
Warfarin is for chronic use and is administered orally, acts in liver with very slow onset and long half life; crosses the placenta.

216

warfarin uses

venous thrombosis, systemic embolism, stroke, recurrent infarction

217

Adverse rxns with warfarin use

Hemorrhage, skin necrosis, food and drug interactions

218

Hemorrhage due to warfarin

tx with vitamin K or plasma transfusion

219

Treatment of hemorrhage with heparin

protamine sulfate

220

Drugs that increase action of warfarin

Aspirin, antibiotics (decrease vit K synthesis), drugs that displace warfarin from plasma proteins, reduce metabolism

221

Drugs that decrease action of warfarin

barbituates and rifampin (increase metabolism), decreased GI absorption

222

advantages of direct thrombin or factor Xa inhibitors

rapid onset, absence of food interactions, do not require monitoring

223

disadvantages of direct thrombin or factor Xa inhibitors

contraindicated with kidney disease, GI bleeding, short 1/2 life

224

Dabigatran, Etexilate

Inhibitor of thrombin that is used for atrial fibrillation and has lower rates of stroke, systemic embolism and intracranial hemorrhage than warfarin.

225

Rivaroxaban

inhibitor of Factor Xa that is used for atrial fibrillation, VTE, is better then warfarin at preventing stroke and emboli

226

Fibrinolytic agents - mechanisms

converts plasminogen to plasmin to degrade fibrin clots

227

Subtypes of fibrinolytic agents

Tissue plasminogen activator (TPA (Alteplase)) and Urokinase (u-PA) (Abbokinase); Streptokinase

228

T-PA

serine protease that binds to fibrin to increase cleavage from plasminogen to plasmin; given via bolus injection

229

U-Pa

enzyme from renal cells that convert plasminogen to plasmin, but does not bind to fibrin.

230

Streptokinase

non enzymatic protein from beta-hemolytic streptococci that forms a complex with plasminogen to convert to plasmin.

231

Use of fibrinolytic agnets

Acute MI, stroke, DVT, PE

232

Adverse effects of fibrinolytic agents

hemorrhage, systemic lytic state, allergic reaction

233

ADP receptor antagonists

binds to ADP receptor P2Y12 to block activation of ADP to inhibit secretion of alpha granules and block GPIIb/IIIa adhesion proteins

234

Theinopyridine vs. Ticagrelor

ADP receptor antagonists Theinopyridine binds irreversibly, ticagrelor binds reversibly and has more rapid action

235

Pharmacokinetics of Thienopyridine

rapidly absorbed but slow onset of action (5-7 days), prodrugs that require liver metabolism; Ticagrelor requires no metabolism

236

use of ADP receptor antagonists

prevent cardiac events and deaths in patients with atherosclerosis and angina without major bleeding.

237

Glycoprotein IIb/IIIa inhibitors

block receptor and prevents platelet aggregation.

238

Glycoprotein IIb/IIIa inhibitor subyptes

Abciximab, eptifibatide, triofiban

239

Amciximab

GP IIb/IIIa inhibitor; monoclonal ab

240

Eptifibatide

GP IIb/IIIa inhibitor; cyclic peptide inhibitor of binding site

241

Tirofiban

GP IIb/IIIa inhibitor; small molecule inhibitor

242

Pharmacokinetics of GP IIb/IIIa inhibitors

IV

243

Use of GP IIb/IIIa inhibitors

unstable angina, following coronary angioplasty, MI

244

Risks of GP IIb/IIIa inhibitors

bleeding thrombocytopenia

245

Immunomodoulation

use of drugs to change the function of the immune system

246

Biological Response Modifiers

target cytokines or their receptors, or cellular signaling molecules, antagonists or agonists and most are antibodies.

247

Monoclonal Antibodies

Biological response modifier - derived from single B cell that has been fused with multiple myeloma tumor cells to result in hybrid that can grow forever in tumor. — very costly!

248

Chimeric antibiodes

enginerred to have different strain of variable domains (ie mouse) and human constant domains -making them less likely to be recognized by own immune system.

249

Humanized antibodies

only CDRs of the V domain are mouse

250

NK cells

natural killer cells that are large granular lymphocytes in the blood (5-10% of lymphocytic cells); have killer mechanism like CTL but no V(D)J genes or thymic derived. Recognize DAMPS - innate immune system

251

Antibodie dependent cell mediated cytotoxicity

ADCC - NK cells have receptor for Fc end of IgG; IgG binds to target cell and NK cell binds to Fc end of antibody. Cell dies of apoptosis.

252

Passive Antibody Therapy

evoke ADCC; antibodies are tagged with poison or radioisotope (modifed antibodies called immunotoxins) that provide highly-targeted delivery of toxic moiety.

253

BiTE

Bispecific T-cell Engager - two single chained antibodies are coupled together one against CD19 and on against CD3 (on T-cell) for tumor cell death.

254

Azathioprine

decreases DNA syntehsis and mRNA transcription - repalced by mycophenolate mefetil - less toxic - organ trasnplant drug

255

Cyclosporin A

decreases IL2 production works with steroids to down regulate macrophage function and lessen T-cell stimulation

256

Tacrolimus

synergizes with cyclosporin A to decrease IL-2 secretion

257

Sirolimus (rapamycin)

binds to FKBP-12 to hinbit target of rapamycin (mTOR) needed for T-cell activation.

258

Anti-thymocyte globulin

prepare BMT recipeints

259

why can we transplant blood easier than organs

RBCs do not have MHC and antigens they carry are less polymorphic

260

Blood group antigens

glycolipids on surface of all body cells - including RBCs; lipid backbone spans plasma membrane and terminal sugars confer antigenic specificity.

261

Secretor phenotype

blood type can be determined by sweat and cigarette buts.

262

H Antigen

core sugar chain on all RBCs

263

O allele

amorphic - does not code for working transferase - basic core H only

264

A allele

have glycosyl transferase on the 3rd sugar

265

B allele

different sugar on the 3rd sugar.\

266

Bombay Phenotype

lack the transferase gene the puts the final sugar on the core - all blood is foreign!

267

isohemagglutinins

antibodies arising form natural exposure of IgM class.

268

Rh.

proteins coded for at two loci d/D and c/E or e/E (most important is D). Not naturally occurring isohemagglutinins

269

when you donate blood…

ABO, Rh, syphilus, hep B and C, HIV, west nile; reverse typing

270

Antiglobulin Coombs test

antibody against human Ig detects human Ig on surface of RBC or plasma

271

DAT asks?

is there antibody on the cells i am interested in?

272

IAT

is there antibody to the red cell antigens in the plasma of the potential recipeint. (red cells, add plasma, rinse, add antiblogulin.

273

hemolytic disease of newborns

erythroblastosis fetalis - RhD+ babies of RhD- mothers. Baby’s RBC enter mothers circulation, mother makes anti RhD antibodes. In subsequent pregnancy, if fetus if RhD+, ab attach fetus’s RBC and fetus is jaundiced and cause damage basal ganglia —> cerebral palsy, fetal death

274

Prevention of Hemolytic disease of newborns

given IgG to Rh(D) after first baby, these ab combine with fetal red cells, opsonizing them and destroying them before they can a chance to immunize her.

275

Heterophile antibodies

cross reactive antibodies

276

full blown AIDS

CD4 below 200/ul

277

how many people live with HIV in US?

1.1 million

278

how many people don’t know they have it

16% of people with HIV

279

HIV-1

nontransforming retrovirus, reverse trasncriptase -

280

Lentiviruses

slow, ultimately fatal illnesses - HIV

281

Why is HIV antigenically variable?

Rerverse transcripatse is highly error prone - many variants

282

Long Term survivors of HIV

homozygous for 32 BP deletion in gene for chemokine receptor CCR5, an HIV correcpetor. They never become ill

283

Elite controllers

group in LTS that become infected but do not progress to AIDS due to an HLA-B57 allele. They make effective CTL to HIV

284

Pathogenesis of HIV

single exposure —> high blood virus at 6 weeks —> loss of CD4 in gut mucosa and increased gut permeability. HIV spreads systemically. HIV peaks at 9 weeks and virus level falls for about 9.5 year.

285

DC sign

vHIV adherence to lectin on dendritic cells and uses these cells to get to lymph nodes where HIV binds to p120 on Th cells.

286

gp120

binding site of HIV in lymph nodes, binding triggers conformational change to allow binding to corrector CCR5; this binding changes conformation of GP41 glycoprotein to expose hydrophobic region and melt away T-cell membrane - cell and viral fusion where dsDNA issued and inserted via integrase into random breaks in DNA.

287

HIV genome

9 genes - gag, pol, env (all retroviruses have), and 6 regulate latency and virulence.

288

how may polypeptides can HIV make?

3 large precurose and by splicing 16 polypeptides

289

Clearance in early HIV

entire viral population is replaced daily and CD4 cells every 3 days.

290

what is unique about HIV spread

not extracellular - gp120/gp41 is made early and virus is inserted into plasma mebrane. This allow fusion of infected cell to nearby uninfected CD4. Thus antibody is useless

291

Steps in HIV clinical symptoms

serpositive without symptoms —> opportunistic infection (candida, fevers, night sweatws, weight loss, fatigue —> major opportunistic infections like TB, malignancy, CD4 below 200 (AIDS dementia)

292

Common malignancy of AIDS

kaposi sarcoma, burkitt lymphoma

293

Diagnosis of HIV

antibody measured by ELISA, western blot to conrifm, PCRR

294

RT inhibitors (nucleosides)

competative inhibitors and chain terminators - HIV drug

295

Non-nucleside RT inhibitors

bind to hydrophobic bocket and change conformation and activity of RT.

296

Protease inhbitors in HIV

to inhibit the cleavage of gag, pol, and env proteins

297

Enfuvirtide

binds to gp41 so membrane cannot fuse

298

Maraviroc

CCR5 antagonst to block viral entry into CD4 *HIV)

299

Raltegravir

integrase inhbiitor in HIV, so HIV cant insert DNA from virus

300

Art

combines two NRTIs awith an NNRTIs

301

Vaccine problems with HIV

difficult betcuase we need a vaccine to preferentially stimulate Th1 and CTL - not antibody response. Key epitope of HIV is concealed in p120 and p41 and is invisible to B cells. but 20% HIV positiv apple make a broadly neutralizing antibody that blocks infection by almost all HIV strains and mutant forms. (but rare)

302

Immune survelliance

T-cells are constantly monitoring surface of cells in body to detect abnormal cells before they become mutant.

303

Evidnece of immune survelliance

1) immunodefienct peole have higher tumor incidences 2) activated T cells that recognize Tumor antigens are easily identified 3) some tumors spontaneously regress 4) paraneoplastic syndrome

304

Paraneoplastic syndrome

symptoms at a distant organ that do not contain tumor cells due to rxn of antibodies or T cells to another organ that expresses that anigen.

305

Nude Mice

have no thymus and get tumors readily, but spontaenous tumors are rare. These mice don’t have Tcells, but they have NK cells that kil the cancer.

306

Immunoediting proces

1) elimination 2) equilibrium 3) escape

307

Elimination in immune editing

malignant clone is recognized by DAMPs to activate innate immunity and cytokine secretion activates T cells and CTLs

308

Equilibrium in immune editing

When tumor and lymphocytes exist in equilibrium

309

Escape

tumor cells fight back and overpower T cells. CTL inhibitor surface receptors are engaged and down regulate CTL cytotoxic activity.

310

Tumor escape mechanisms

immunosupression by TGFb, decoy CTLs, reuce expression of MCH Class I

311

Tumor associated antigens

most often over expressed on tumor

312

Tumor rejection antigens

subclass of TAA, recognized by t cells that leads to destruction of tumor

313

Driver vs passengers

Driver: activate oncogenes and inactive tumor suppressor genes; passenger genes have numerous other mutations that dont’ affect growth rate, but make mutated proteins.

314

Immunotherapy focuses on…

passener mutations —> more mutations = better response.

315

Microbial Gene products

tumors caused by viruses

316

Oncofetal antignes

normal fetal tissue not found in adults but reexpressed in tumor

317

Differntiation anitgens

lineage specific antigens that are overexposed and represent TAA

318

Clonal Antigens

expressed uniquely in malignant clone

319

CTL

kill tumor cells by inducing apoptosis via perforin of Fas mediated (transmembrane signaling pathways)

320

Specific immunization for immunotherapy

a tumor vaccine that is therapeutic but not preventative.

321

Innocent bystander killing

BCG (TB vaccine) injected into tumor, leads to delayed type hypersensitivity and tumor cells are killed by M1 macrophages.

322

Tumor-Infiltrating lymphocytes

autologous cell therapy where Tcells are expanded in culture using IL2; patients immune system is partially depleted by irradiation and T-cells are reintroduced to kill tumor cells.

323

Chimeric Antigen Receptors

rearmed CTLs with antibody/TCR chimeric receptors. Stitched together High affinity antibody linked to transmembrane region and t-cell intracellular tumor agent with high affinity and chosen specificy. (CD3) This allows CTL to bind to tumor with high affinity and chosen specificity with no MHC restriction.

324

Split car

chimeric antigen receptor that requires small molecule for association and function. To stop working discontinue small molecule

325

CD28

upregualted when T cell engages APC. Binds to CD80 and CD86 for T cell activation

326

CTLA-4

after a few days of CD28 upregualtion, it is down regulated and CTLA-4 appears on T-cell surface and binds to CD80/86 to be inhibitory of T-cell activation

327

PD-1

later after CTLA-4, PD1 is engaged by PD-L1 ligand to exhaust T-cell and inhibit CTLs.

328

Nivolumab and Pembrolizumab

blocking monoclonal Abs against PD1

329

ipilimumab

blocking monoclonal ab against CTLA-4; toxic!

330

ID blood testing

Syphilis, Hep A, B, C, HIV, HTLV, WNV, CMV, (CJD

331

A allele extra

N-acetylgalactosamine

332

B allele extra

D-galactose

333

pretransfusion testing

ABO, Rh, antibody screen for ab other than ABO

334

Crossmatch

Major: serum + donor cells —> agglutination; Coomb’s to lok for IgG and complement

335

Emergent blood transfusion

O, RhD negative; or O RhD positive for males and non-childbreaing female

336

Abbreviated (30 min) transfusion

ABO, Rh type, Ab screen negative

337

if blood is positive for specific alloantibodies

must use blood with negative antigens

338

if blood has auto antibodies but no alloantibodies

re-evaulate transfusion

339

cyroprecipiates

F VIII, vWF ag, fibrinogen, Factor XIII, fibronectin

340

random donor platlets vs ampheresis platelets

RD is more concentration in smaller volume;

341

what cannot be stored in blood transfusions

granulocyte concetnration

342

Whole blood is given for

decreased oxygen carrying capacity and volume, must be crossmatched

343

PRBCs are given for

low oxygen carrying, chronic anemia, acute blood loss, cross matching is a must

344

FFPs are given for

coagulopathy related to DIC, liver failure, Vit K def, can use specific clotting factors, must be ABO specific but no crossmatch. Given under 4 hours

345

Cyroprecipitate is given for…

low fibrinogen levels, of vWF disease, must be ABO; infusion over 30-45 min

346

Platelets are given for..

bleeding due to low or dysfunctional platelets, thrombocytopenia, ABO type , infusion 30-1 hr

347

Granulocyte concentate is given for..

severe infection with patients with ANC

348

Acute hemolytic transfusion rxn.

preformed alloantibodes (ABO) cause intravascualr hemolysis and activation of DIC, inflammatory mediators and renal failure. fever, nasuea, chills, hypotension, dyspnea, dark urine.

349

Tx of Acute hemolytic transfusion rxn

stop trasnfusions, maintain IV fluids, heparin

350

Delayed hemolytic transfusion rxn

formation of alloantibodes post transfusion to cause extravasualr heomlysis, fewer signs could include jaundice, anemia.

351

Febrile reactions

due to leukoagglutinins in recpeient cytokines.

352

Allergic rxns due to transfusion

result of antibodies to IgA, typcial allergic signs

353

Transfusion acute lung injury

4 hours post, due to infection, surgery, cytokine therapy, lipids, antibodies, cytokines.