Exam 4 Flashcards
1
Q
Osteoarthritis
A
degeneration of articular cartilage with hypertrophy of bone, joint space loss, subchondral cysts, sclerosis and osteophytes
2
Q
what joints are involved in OA?
A
DIPs, PIPs, 1st CMC, weight bearing - hips and knees, Spine - cerivical and lumbar, 1st MTP
3
Q
Heberden’s
A
DIPs
4
Q
Bouchard’s
A
PIPs
5
Q
Predisposing factors to OA
A
Age, obesity, occupational risks, trauma, or secondary OA due to inflammatory disorders like RA, spondylo, or metabolic disorders
6
Q
sports and OA
A
no increased risk, exercise may be protective
7
Q
Cartilage components
A
avascular and no nerves 1) collage II 2) proteoglycans 3) matrix proteins 4) chondrocyes 5) 70% water
8
Q
Proteoglycans
A
in cartilage - chondroitin and keratin sulfate linked to hyaluronic acid - hydrophilic
9
Q
Matrix proteins in cartilage
A
Metalloproteinases - like collagenases, gelatinases, stromeylsins and Tissue inhibitors of metalloproteinases TIMPS
10
Q
Chondrocytes
A
main cell of cartilage that produces the proteins in cartilage
11
Q
aggrecans
A
chondroitin and keratin sulfates bound to collagen. Forms a weave that acts like a sponge to hold onto water
12
Q
changes to cartilage in OA
A
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
Q
Does OA have systemic feaures?
A
NO - lacks them
14
Q
Synovial fluid in OA
A
non-inflammaotry, type I fluid with 200-2000 WMC
15
Q
Pathophysiology of OA
A
chondrocytes and synovium produce inflammatory mediators for cartilage destruction - IL1, NO, protsaglandins; they also activate complement and adipokines.
16
Q
IL-1 release in OA
A
stimulates MMPs, PGE2, NO, IL6 produciton
17
Q
NO release in OA
A
increases MMPs, inhibits protoglycan, induces chondrocyte apoptosis.
18
Q
Prostaglands in OA
A
increase production and activation of MMPs
19
Q
what other cytokines are produces in OA?
A
TNF, IL6, IL17, IL18
20
Q
Adipokines
A
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
Q
Radiological findings in OA
A
Joint space loss, sclerosis, subchondral cysts, osteophytes
22
Q
Patient will tell about OA
A
localized pain, worse with use. Stiffness for less than 30 minutes.
23
Q
Rheumatoid Arthritis - basic
A
systemic, inflammatory, autoimmune disorder that results in peripheral, symmetric, *synovitis with cartilage and bone destrcution.
24
Q
Joint involvement in RA
A
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
26
Etiology of RA
arthritogenic peptide in host genetically suseptible due to a HLA-DR4 and HLA-DR1 mutation.
27
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.
30
Cirulline
modified arginine residue that is commonly seen in RA patients
31
Sensitivty vs. Specificity of anti-CCP
90% senstivie and 90% specific
32
RF sensitivity and specificy
80% sensitive, 80% specific
33
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
37
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.
52
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.
54
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
66
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).
70
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
77
HLA-B27 heavy chain theory
causes NK cell activation
78
Reiter’s syndrome
conjunctivitis, urthritis, arthritis
79
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
91
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
92
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
94
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)
96
Medium Artey vasculitis
Classic polyartheritis nodes (skin + joint + peripheral nerves); Kawasaki (acute fever in infants, rash, coronary vasculitis)
97
small artery vasculitis
Wegener’s granulomatosis (ANCA+, respiratory), microscopic pohylangitis (pulmonary hemorrahge + glomerulonephritis), churg-strauss syndrome (asthma+eos)
98
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)
99
Major pathophysiology of Vasculitis - one word
immune complexes
100
detailed pathophys of vasculitis
inflammation —> platelet activating factors —> increased vascular permeability —> IC deposition; papable purpura.
ANCAS. anti-endothelial ab; T cell mediated endothelial injury,
101
T cell dependent mediated endothelial cell injury
HLA-DR4 in giant cell arthritis, suggests antigen driven vascular inflammation
102
Source of immune complexes in vasculitis
Drugs, bugs, CT disease, malignancy
103
ANCA
antinuetrophil cytoplasmic antibodies in vasculitis; amplifies inflammatory response - not the cause.
104
c-ANCA
cytoplasmic ANCA, acts on proteinase-3 in primary granules of PMNs; associated with GPA
105
p-ANCA
perinuclear, acts on MPO in primary granules of PMNs associated with MPA
106
treatment of vasculitis
remove inciting agent, steroids, plasmapheresis, rituximab
107
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
109
Anti-synthetase syndrome
PM or DM presenting with **instertitial lung disease, Fever, arthritis, mechanics hands, raynaud’s phenomenon.
110
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
112
DM
Perivascular and perifascicular inflammation of CD4 cells; complement mediated, vasulopathy
113
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
116
Seasonal DM
Anti-Jo1 ab in the spring
117
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.
121
PT
tests the procoagulant activity of the extrinsic pathway and common pathway - sensitive to II, VII, V, X, Vit K, liver disease
122
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.
124
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
126
vWF
binds to subendothelial collagen and GP1b receptor on platelets for adhesion! stabilizes Factor VIII
127
GP1b
receptor on platelets that binds to vWF for adhesion
128
GPIIb/IIIa
exposed on surface of platelets with ADP release from dense granules, used as linkage for platelet aggregation
129
Epidemiology of vWF disease
AD, but can be acquired by autoab
130
Clinical signs of vWF disease
mild mucosal and skin bleeding - GI bleed, menorrhagia, NO joint or mucosal bleeds.
131
Types of vWF
Type 1 = partial quantitative deficiency, type 2: qualitative def type 3: near complete absence
132
Diagnostic lab tests of vWF disease
Normal PT, Long PTT, decrased vWF antigen, decreased F VIII, abnormal ristecetin
133
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
135
Gray Platelet syndrome
qualitative platelet disorder due to reduced/absent alpha granules, AR
136
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
137
Ganzman Thrombasthenia
qualitataive platelet disorder, defective/low GPIIb/IIIa leads to decreased aggregation; AR, PTT and pT are unaffected.
138
Abciximab
GPIIb-IIIa antagonists
139
Thrombocyopenia
low platelet count due to decreased production, increased destruction, sequestration
140
Decreased platelet production
BM disorders, aplastic anemia, MDS, leukemia, TB, B12/Folate def, viral infection
141
Increased platelet destruction
ITP, autoimmune, DIC, TTP, HUS
142
Thrombocytopenia - clinical characteristics
Mucosal bleeds and skin bleeds - petechiae
143
ITP
immune thrombocytopenia purpura - AutoAb to GPIIb/IIIa to cause removal by macrophages in spleen. Can be acute or chronic
144
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
145
Chronic ITP
occurs in adults with concurrent autoimmune, lymphoma, HIV. requires treatment
146
Labs for ITP
decreased platelet count, normal PT and PTT, increased megakaryocytes in marrow
147
Treatment of ITP
Rituximab, steroids, IVIG, splenectomy, Thrombopoetin receptor agonist
148
Rituximab - ITP treatment
depletes b cells form making autoAb
149
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
152
what should ITP patients avoid?
aspirin and Ibuprofen, contact sports
153
TTP
Thrombotic Thrombocytopenic Purpura - increased platelet consumption due to autoab to ADAMTS13
154
ADAMTS13
proteast that cleaves vWF into active monomers
155
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
158
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
164
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.
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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.
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H Antigen
core sugar chain on all RBCs
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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.
