Flashcards in Exam 4 Deck (353):
degeneration of articular cartilage with hypertrophy of bone, joint space loss, subchondral cysts, sclerosis and osteophytes
what joints are involved in OA?
DIPs, PIPs, 1st CMC, weight bearing - hips and knees, Spine - cerivical and lumbar, 1st MTP
Predisposing factors to OA
Age, obesity, occupational risks, trauma, or secondary OA due to inflammatory disorders like RA, spondylo, or metabolic disorders
sports and OA
no increased risk, exercise may be protective
avascular and no nerves 1) collage II 2) proteoglycans 3) matrix proteins 4) chondrocyes 5) 70% water
in cartilage - chondroitin and keratin sulfate linked to hyaluronic acid - hydrophilic
Matrix proteins in cartilage
Metalloproteinases - like collagenases, gelatinases, stromeylsins and Tissue inhibitors of metalloproteinases TIMPS
main cell of cartilage that produces the proteins in cartilage
chondroitin and keratin sulfates bound to collagen. Forms a weave that acts like a sponge to hold onto water
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.
Does OA have systemic feaures?
NO - lacks them
Synovial fluid in OA
non-inflammaotry, type I fluid with 200-2000 WMC
Pathophysiology of OA
chondrocytes and synovium produce inflammatory mediators for cartilage destruction - IL1, NO, protsaglandins; they also activate complement and adipokines.
IL-1 release in OA
stimulates MMPs, PGE2, NO, IL6 produciton
NO release in OA
increases MMPs, inhibits protoglycan, induces chondrocyte apoptosis.
Prostaglands in OA
increase production and activation of MMPs
what other cytokines are produces in OA?
TNF, IL6, IL17, IL18
are our own fact cells that make IL6 that go into the liver to make acute phase reactants like CRP. - metabolic aspect of OA.
Radiological findings in OA
Joint space loss, sclerosis, subchondral cysts, osteophytes
Patient will tell about OA
localized pain, worse with use. Stiffness for less than 30 minutes.
Rheumatoid Arthritis - basic
systemic, inflammatory, autoimmune disorder that results in peripheral, symmetric, *synovitis with cartilage and bone destrcution.
Joint involvement in RA
Bilateral and symmetric small joints of hands and feet (sparing DIPs), medium and large too.
X-rays of RA
marginal joint erosions and deformities
Etiology of RA
arthritogenic peptide in host genetically suseptible due to a HLA-DR4 and HLA-DR1 mutation.
mutation in 3rd hypervariable region of the MHC II binding cleft that increases the susceptibility and severity of the RA.
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
anti cyclic citrullinated peptide antiboides that react with synthetic peptides contains citrulline.
modified arginine residue that is commonly seen in RA patients
Sensitivty vs. Specificity of anti-CCP
90% senstivie and 90% specific
RF sensitivity and specificy
80% sensitive, 80% specific
RF and anti-CCP sensitivity and specificity
rare only 40% sensitive and 100% specific
how often do anti_CCP occur
most frequently in those with HLA-DR4 epitope, due to enhanced binding of peptides to cirullination.
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.
Basic one liner of RA
disease of synovium
basic one liner for OA
disease of cartilage
cell types in synovial fluid of RA
where are PMNs in RA?
in synovial fluid, but NOT synovium tissue.
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
Role of cells in RA synovium
CD4 memory cells modify and amplify local immune response through nation recognition.
Extra-articular manifestations of RA
RF-IgG compelx caues induced vasculitis; rhematoid nocules, eye lung, pericardium, peripheral nerves.
Pathophy of RA
unknown antigen is consumed by immune system at diagnosis, but altered proteoglycans, collagen, cirulinated peptides propogate the disease (not the antigen)
what patient experiences in RA
morning stiffness, fatigue, pain that improves with activity, rest makes worse
Lab values in RA
elevated RF, ESR, CRP, anti-CCP antibodies
Imaging of RA
loss of joint space, erosion of marginal distribution, soft tissue swelling, osteopenia
Risk factors of RA
female, any age, smoking
Gout - definition
Tissue deposition of Monosodium urate crystals due to hyeruricemia (MSU supersaturation of extracellular fluid)
Joints in Gout
1st MTP (podagra), Cool peripheral joins of lower and upper extremities.
over production or under excretion of uric acid. (90% are under excretors)
produce of purine metabolism, but humans lack the Uricase enzyme to oxidize uric acid into allegation form.
X-linked conditions for overproduction or uric acid
PRPP synthtase overactivity, and HGPRT deficiency.
Diagnosis of Gout
arthrocentesis - needle biopsy with needle shaped crystals, negatively birefringement.
Increased PRPP synthetase
incrases production of PRPP-glutamine to cause the pathway to form uric acid
inhibits the reaction from going backward to promote more uric acid instead of guanlyic acid or inosinic acid.
inhibited by allopurinol and febuxosat that covers Xanthine into uric acid.
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.
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
Calcium Pyrophosphate Dihydrate deposition
Abnormal pyrophosphate metabolism (PPi) - metabolism of NTPs from chondrocytes., PPi contacts calcium to form crystals.
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.
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
Predisposition to Gout
Men over 30, shelfish, alcohol
Underexcretion of uric acid
activation of URAT1 to decrease excretion
complete deficiency in HGPRT
Axial arthritis of spine, sacroilitis, periphery (small and large), characterized by *enthesitis, mucocutaneous lesions, Uveitis
characterisitc of seronegative spondylarthropaties. - inflammation where ligament, tendon, and fibrossseous junction meet bone.
Systemic effects of Ankylosing Spondylitis
osteoporosis, uveitis, microscopic colitis
lab values of Ankylosing spondylitis
High ESR, negative RF, negative ANA
Genetic predisposition to Spondylarthropaties
HLA-B27 - associated with negative RF and ANA (sero negative).
what is in the synovium of Spondylarthropaties
increased expression of TNFalpha
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 -
Concordance of spondyloarthropties
due to infectious diarrhea or urethritis. Asymmetric, oligoarticular of the lower extremities, dactylitis, hips spared
Triggers of Reactive arhritis
transporttion of bacteria inside by monocytes (chlamydia) via molecular mimicry, arthritogenic peptide, Heavy chain theory, Unfolded protein hypothesis, TH2 response.
systemic effects of Reactive arthritis
inflammatory eye, musculocutaneous lesions, aortas, cardiac conduction defects
Arthritogenic peptide hypothesis
unique presentation of process peptide by HLA-B27
HLA-B27 heavy chain theory
causes NK cell activation
conjunctivitis, urthritis, arthritis
HLA-B27 ER stress response
misfolded HLA-B27 initiates stress response to cuase IL23, IL17 to response to IL-6.
helps trim proteins as they feed into the ER
Systmic Lupus Erythromatses
chronic, autoimmune disease that affects multiple organs - skin, joints, serial, luns, kidneys, CNS
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
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.
Genetics of SLE
Increased risk among relatives, 35% concordance rate, associated with HLA_DR3 and C4A null allel (greatest risk)
Popualtions of SLE
AA, asians, hispanic americans
Environmental factors of SLE
female is 9x more likely, increased risk in childbearing age, sun exposure exacerabates systemic disease
hallmark of abnormala b in SLE, >95% of SLE have ANA. Ab directed to multiple nuclear antignes
SLE and drug induced lupus
Ab to Non-DNA, non Histone
SSA, SSB, Smith, RNP
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
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.
Vasculitis - basic definition
inflammation of vessel
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)
large artery vasculitis
Takayasus (claudication of upper extremities + CNS), Giant Cell (temporal artery + headache)
Medium Artey vasculitis
Classic polyartheritis nodes (skin + joint + peripheral nerves); Kawasaki (acute fever in infants, rash, coronary vasculitis)
small artery vasculitis
Wegener’s granulomatosis (ANCA+, respiratory), microscopic pohylangitis (pulmonary hemorrahge + glomerulonephritis), churg-strauss syndrome (asthma+eos)
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)
Major pathophysiology of Vasculitis - one word
detailed pathophys of vasculitis
inflammation —> platelet activating factors —> increased vascular permeability —> IC deposition; papable purpura.
ANCAS. anti-endothelial ab; T cell mediated endothelial injury,
T cell dependent mediated endothelial cell injury
HLA-DR4 in giant cell arthritis, suggests antigen driven vascular inflammation
Source of immune complexes in vasculitis
Drugs, bugs, CT disease, malignancy
antinuetrophil cytoplasmic antibodies in vasculitis; amplifies inflammatory response - not the cause.
cytoplasmic ANCA, acts on proteinase-3 in primary granules of PMNs; associated with GPA
perinuclear, acts on MPO in primary granules of PMNs associated with MPA
treatment of vasculitis
remove inciting agent, steroids, plasmapheresis, rituximab
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
Systemic effects of PM and DM
GI dysphagia, pulmonary fibrosis, mycocarditis, Ranaud’s phenomenon, Anti-synthetase
PM or DM presenting with **instertitial lung disease, Fever, arthritis, mechanics hands, raynaud’s phenomenon.
anti-aminoacyl-tRNA synthetase in cyto,, Anti-Jo-1 = anti histadyl-tRNA synthetase; not pathologic of myotoxic
PM - lab finding
distribution of inflammatory CD8 cells surrounding and invading muscle fibers
Perivascular and perifascicular inflammation of CD4 cells; complement mediated, vasulopathy
pathophysiology of DM/PM
CTL directly attacks muscles
Immune complex damage skin
MHC class I overexertion on myocytes —> ER stress response and NFkB production
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
increase ab to coxackie B
Anti-Jo1 ab in the spring
Treatment of DM and PM
Corticosteroids, immunosuppressives, PT
Musculocutaneous bleeds are a sign of…
primary hemostasis - disorder of platelet of vWF
Soft tissue or joint bleeds are a sign of…
secondary hemostasis - coagulation disorder
tests the procoagulant activity of intrinsic pathway most often F XI, VIII, IX; NOT VII.
tests the procoagulant activity of the extrinsic pathway and common pathway - sensitive to II, VII, V, X, Vit K, liver disease
tests procoagulant activity of fibrinogen and affect of heparin and fibrin split. Detects heparin contamination and fibrinogen def/dysfunction.
standardized bleeding time test; Collage/Epi and Collagen/ADP;
Abnormal Epi and normal ADP = aspirin effect
Both abnormal: platelet function effect.
chemical added to blood to test the activity of vWF binding to GP1b
vWF Disease - mechanism
qualitative platelet disorder due mut/under production of vWF —> decreased adhesion and unstable VIII
binds to subendothelial collagen and GP1b receptor on platelets for adhesion! stabilizes Factor VIII
receptor on platelets that binds to vWF for adhesion
exposed on surface of platelets with ADP release from dense granules, used as linkage for platelet aggregation
Epidemiology of vWF disease
AD, but can be acquired by autoab
Clinical signs of vWF disease
mild mucosal and skin bleeding - GI bleed, menorrhagia, NO joint or mucosal bleeds.
Types of vWF
Type 1 = partial quantitative deficiency, type 2: qualitative def type 3: near complete absence
Diagnostic lab tests of vWF disease
Normal PT, Long PTT, decrased vWF antigen, decreased F VIII, abnormal ristecetin
Treatment of vWF
DDAVP desmopressin - arginine vasopressin to enhance release of vWF from endothelial stores, or humane P (vWF and Factor VIII)
Qualitative platelet disorder due to GP1b mutation to decrease adhesion; AR; unaffected PT or PTT
Gray Platelet syndrome
qualitative platelet disorder due to reduced/absent alpha granules, AR
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
qualitataive platelet disorder, defective/low GPIIb/IIIa leads to decreased aggregation; AR, PTT and pT are unaffected.
low platelet count due to decreased production, increased destruction, sequestration
Decreased platelet production
BM disorders, aplastic anemia, MDS, leukemia, TB, B12/Folate def, viral infection
Increased platelet destruction
ITP, autoimmune, DIC, TTP, HUS
Thrombocytopenia - clinical characteristics
Mucosal bleeds and skin bleeds - petechiae
immune thrombocytopenia purpura - AutoAb to GPIIb/IIIa to cause removal by macrophages in spleen. Can be acute or chronic
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
occurs in adults with concurrent autoimmune, lymphoma, HIV. requires treatment
Labs for ITP
decreased platelet count, normal PT and PTT, increased megakaryocytes in marrow
Treatment of ITP
Rituximab, steroids, IVIG, splenectomy, Thrombopoetin receptor agonist
Rituximab - ITP treatment
depletes b cells form making autoAb
Steroids in ITP treatment
dampens B-cell clones
IVIG in ITP treatment
blocks Fc receptors to prevent splenic destruction
Thrombopoetin receptor agonists
stimulates platelet production in BM
what should ITP patients avoid?
aspirin and Ibuprofen, contact sports
Thrombotic Thrombocytopenic Purpura - increased platelet consumption due to autoab to ADAMTS13
proteast that cleaves vWF into active monomers
Mutation in ADAMTS13
leaves vWF as inactive multimers that lead to abnormal adhesion and micro thrombi
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
Clinical Signs of TTP and HUS
fever, renal insuff (HUS), microanggiopathic hemolytic anemia, Purpura, mental changes
Lab values for TTP and HUS
low platelets, normal PT and PTT, anemia with schistiocytes, increase megakaryocites in BM, creatinine.
Microangiopathic hemolytic anemis
microthrombi causes shearing of RBC and destruction leading to hemolytic anemia
Treatment of TTP
plasmaphoresis and replacement of ADAMTS13
Factor VIII deficiency (intrinsic), X linked or from new mutations.
Factor IX deficiency, X linked or from new mutations
Hemophilia clinical signs
spontaneous hemorrhage in joints, soft tissue, retroperitoneal space, bleeding after surg/trauma
Lab values in hemophilia
Long PTT, Mix = abnormal after 2 hours, Normal PT, platelet count, BT
Factor XI def, AR; post op delayed bleeding, but rare spontaneous bleeds
Factor VII deficiency (extrinsic), AR, same symptoms as A and B; prolonged PT normal PTT
Liver Disease - bleeding
Decreased Vit K dependent carboxylation of II, VII, IX, X, decreased fibrinogen, increased fibrinolysis, increased platelet consumption.
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
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.
Vitamin K deficiency lab values
Increased PT and PTT (normal to slight increase)
simultaneous bleeding and clothing due to systemic activation of coagulation to cause thrombosis but also platelet depletion to cause bleeding.
DIC is due to
sepsis, trauma, malignancy, obstetric complications, vascular disorders, toxins, immunologic disorders
DIC lab values
Prolonged PT and PTT and TT, delevated FSP and D dimer, low platelets, low fibrinogen, low factors
Treatment of DIC
treat underlying disorder, replace platelets and fibrinogen
lupus anticoagulant (APLA)
IgG ab binds to PL in platelet membranes - causes venous and arterial thrombosis, hepatic vein thrombosis, recurrent miscarriage, headaches
Lupus Anticoagulant lab values
Prolonged PTT (thrombic disorders), Pt mixing - no correcting at time 0
due to high shear stress and vWF, cause aggregated platelets with small amounts of fibrin and RBCs - white in color
Associated conditions of arterial thrombosis
Hypertension, atherosclerosis, endothelial injury
slow blood flow with low shear stress, clots with large amounts of thrombin - red in color.
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.
Swollen, painful, blue leg, (phelegmasia cerulean dozens)
Phelegmasia curelean dolens
signs of DVT - swollen, painful blue leg
Consequences of DVT
Postthrombotic syndrome, intermitten obstruction, PE
chronically swollen, painful extremities that lead to cutaneous ulcers
recurrent bouts of pain due to DVT
Signs of PE
sudden chest pain, dyspnea, anxiety, cough, syncope, cyanosis, hemoptosis
Diagnosis of PE
Ultrasound, D-dimer assay, spiral CT, Ventilation/Perfusion scan
Treatment of DVT
heparin to prevent further clots, fibrinolytic to lyse existing clots.
Arterial thrombosis tx
main goal is anti platelet therapy
Venous thrombosis tx
main goal is inhibition of coagulation.
Inherited thrombotic disorders
Prothrombin G20201A, Protein C def, protein S, anithrombin def,
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
Protein C defiency
2ND most common inherited thrombotic disorder, AD, inability to inactivate Factor V and VIII to inhibit coagulation.
Complication of protein C deficiency
Homozygotes lead to neonatal purport fulminans - fatal
Warfarin induced skin necrosis - increased thrombosis of skin in adults
Protein S deficiency
similar to above, but due to inability to activate Protein C.
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
AD, antithrombin in unable to activate thrombin (as well as factor X, IX, XI, XII)
Tx of Antithrombin Def
1st event 3-6 months; Massive = therapy; prophylaxis for pregnant and surgery
inherited or acquired; enhanced platelet activation and adhesion due to endothelial injury
impaired fibrinolysis is due to..
plasminogen and tPA deficiency
high risk factors for thromosis
increased Factor VIII, oral contraceptives
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
Subtypes of Heparin
Unfractionated, low MW, fondaparinux
long version that can bind to antithrombinthrombin complex to inhibit thrombin directly
produced by depolarization of heparin to 1/2 the size
synthetic version of lmwh
LMWH vs. Fonaparinus vs. unfractionated
LWMH and fona do not bind directly to thrombin, but only antithrombin to inactive factor X
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
Pharmacokinetics of LMWH and fonaparinus
Give SC, better bioavailability than unfractionated and longer half life —> less monitoring. Action in blood and rapid
Clinical use of heparin
Venous thromosis, PE, angina, Acute MI, cardiopulmonary bypass
Adverse effects of heparin use
Bleeding, heparin induced thrombocytpenia, osteoporosis, Drug/drug interactions
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
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.
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
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.
venous thrombosis, systemic embolism, stroke, recurrent infarction
Adverse rxns with warfarin use
Hemorrhage, skin necrosis, food and drug interactions
Hemorrhage due to warfarin
tx with vitamin K or plasma transfusion
Treatment of hemorrhage with heparin
Drugs that increase action of warfarin
Aspirin, antibiotics (decrease vit K synthesis), drugs that displace warfarin from plasma proteins, reduce metabolism
Drugs that decrease action of warfarin
barbituates and rifampin (increase metabolism), decreased GI absorption
advantages of direct thrombin or factor Xa inhibitors
rapid onset, absence of food interactions, do not require monitoring
disadvantages of direct thrombin or factor Xa inhibitors
contraindicated with kidney disease, GI bleeding, short 1/2 life
Inhibitor of thrombin that is used for atrial fibrillation and has lower rates of stroke, systemic embolism and intracranial hemorrhage than warfarin.
inhibitor of Factor Xa that is used for atrial fibrillation, VTE, is better then warfarin at preventing stroke and emboli
Fibrinolytic agents - mechanisms
converts plasminogen to plasmin to degrade fibrin clots
Subtypes of fibrinolytic agents
Tissue plasminogen activator (TPA (Alteplase)) and Urokinase (u-PA) (Abbokinase); Streptokinase
serine protease that binds to fibrin to increase cleavage from plasminogen to plasmin; given via bolus injection
enzyme from renal cells that convert plasminogen to plasmin, but does not bind to fibrin.
non enzymatic protein from beta-hemolytic streptococci that forms a complex with plasminogen to convert to plasmin.
Use of fibrinolytic agnets
Acute MI, stroke, DVT, PE
Adverse effects of fibrinolytic agents
hemorrhage, systemic lytic state, allergic reaction
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
Theinopyridine vs. Ticagrelor
ADP receptor antagonists Theinopyridine binds irreversibly, ticagrelor binds reversibly and has more rapid action
Pharmacokinetics of Thienopyridine
rapidly absorbed but slow onset of action (5-7 days), prodrugs that require liver metabolism; Ticagrelor requires no metabolism
use of ADP receptor antagonists
prevent cardiac events and deaths in patients with atherosclerosis and angina without major bleeding.
Glycoprotein IIb/IIIa inhibitors
block receptor and prevents platelet aggregation.
Glycoprotein IIb/IIIa inhibitor subyptes
Abciximab, eptifibatide, triofiban
GP IIb/IIIa inhibitor; monoclonal ab
GP IIb/IIIa inhibitor; cyclic peptide inhibitor of binding site
GP IIb/IIIa inhibitor; small molecule inhibitor
Pharmacokinetics of GP IIb/IIIa inhibitors
Use of GP IIb/IIIa inhibitors
unstable angina, following coronary angioplasty, MI
Risks of GP IIb/IIIa inhibitors
use of drugs to change the function of the immune system
Biological Response Modifiers
target cytokines or their receptors, or cellular signaling molecules, antagonists or agonists and most are 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!
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.
only CDRs of the V domain are mouse
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
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.
Passive Antibody Therapy
evoke ADCC; antibodies are tagged with poison or radioisotope (modifed antibodies called immunotoxins) that provide highly-targeted delivery of toxic moiety.
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.
decreases DNA syntehsis and mRNA transcription - repalced by mycophenolate mefetil - less toxic - organ trasnplant drug
decreases IL2 production works with steroids to down regulate macrophage function and lessen T-cell stimulation
synergizes with cyclosporin A to decrease IL-2 secretion
binds to FKBP-12 to hinbit target of rapamycin (mTOR) needed for T-cell activation.
prepare BMT recipeints
why can we transplant blood easier than organs
RBCs do not have MHC and antigens they carry are less polymorphic
Blood group antigens
glycolipids on surface of all body cells - including RBCs; lipid backbone spans plasma membrane and terminal sugars confer antigenic specificity.
blood type can be determined by sweat and cigarette buts.
core sugar chain on all RBCs
amorphic - does not code for working transferase - basic core H only
have glycosyl transferase on the 3rd sugar
different sugar on the 3rd sugar.\
lack the transferase gene the puts the final sugar on the core - all blood is foreign!
antibodies arising form natural exposure of IgM class.
proteins coded for at two loci d/D and c/E or e/E (most important is D). Not naturally occurring isohemagglutinins
when you donate blood…
ABO, Rh, syphilus, hep B and C, HIV, west nile; reverse typing
Antiglobulin Coombs test
antibody against human Ig detects human Ig on surface of RBC or plasma
is there antibody on the cells i am interested in?
is there antibody to the red cell antigens in the plasma of the potential recipeint. (red cells, add plasma, rinse, add antiblogulin.
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
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.
cross reactive antibodies
full blown AIDS
CD4 below 200/ul
how many people live with HIV in US?
how many people don’t know they have it
16% of people with HIV
nontransforming retrovirus, reverse trasncriptase -
slow, ultimately fatal illnesses - HIV
Why is HIV antigenically variable?
Rerverse transcripatse is highly error prone - many variants
Long Term survivors of HIV
homozygous for 32 BP deletion in gene for chemokine receptor CCR5, an HIV correcpetor. They never become ill
group in LTS that become infected but do not progress to AIDS due to an HLA-B57 allele. They make effective CTL to HIV
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.
vHIV adherence to lectin on dendritic cells and uses these cells to get to lymph nodes where HIV binds to p120 on Th cells.
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.
9 genes - gag, pol, env (all retroviruses have), and 6 regulate latency and virulence.
how may polypeptides can HIV make?
3 large precurose and by splicing 16 polypeptides
Clearance in early HIV
entire viral population is replaced daily and CD4 cells every 3 days.
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
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)
Common malignancy of AIDS
kaposi sarcoma, burkitt lymphoma
Diagnosis of HIV
antibody measured by ELISA, western blot to conrifm, PCRR
RT inhibitors (nucleosides)
competative inhibitors and chain terminators - HIV drug
Non-nucleside RT inhibitors
bind to hydrophobic bocket and change conformation and activity of RT.
Protease inhbitors in HIV
to inhibit the cleavage of gag, pol, and env proteins
binds to gp41 so membrane cannot fuse
CCR5 antagonst to block viral entry into CD4 *HIV)
integrase inhbiitor in HIV, so HIV cant insert DNA from virus
combines two NRTIs awith an NNRTIs
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)
T-cells are constantly monitoring surface of cells in body to detect abnormal cells before they become mutant.
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
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.
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.
1) elimination 2) equilibrium 3) escape
Elimination in immune editing
malignant clone is recognized by DAMPs to activate innate immunity and cytokine secretion activates T cells and CTLs
Equilibrium in immune editing
When tumor and lymphocytes exist in equilibrium
tumor cells fight back and overpower T cells. CTL inhibitor surface receptors are engaged and down regulate CTL cytotoxic activity.
Tumor escape mechanisms
immunosupression by TGFb, decoy CTLs, reuce expression of MCH Class I
Tumor associated antigens
most often over expressed on tumor
Tumor rejection antigens
subclass of TAA, recognized by t cells that leads to destruction of tumor
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.
Immunotherapy focuses on…
passener mutations —> more mutations = better response.
Microbial Gene products
tumors caused by viruses
normal fetal tissue not found in adults but reexpressed in tumor
lineage specific antigens that are overexposed and represent TAA
expressed uniquely in malignant clone
kill tumor cells by inducing apoptosis via perforin of Fas mediated (transmembrane signaling pathways)
Specific immunization for immunotherapy
a tumor vaccine that is therapeutic but not preventative.
Innocent bystander killing
BCG (TB vaccine) injected into tumor, leads to delayed type hypersensitivity and tumor cells are killed by M1 macrophages.
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.
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.
chimeric antigen receptor that requires small molecule for association and function. To stop working discontinue small molecule
upregualted when T cell engages APC. Binds to CD80 and CD86 for T cell activation
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
later after CTLA-4, PD1 is engaged by PD-L1 ligand to exhaust T-cell and inhibit CTLs.
Nivolumab and Pembrolizumab
blocking monoclonal Abs against PD1
blocking monoclonal ab against CTLA-4; toxic!
ID blood testing
Syphilis, Hep A, B, C, HIV, HTLV, WNV, CMV, (CJD
A allele extra
B allele extra
ABO, Rh, antibody screen for ab other than ABO
Major: serum + donor cells —> agglutination; Coomb’s to lok for IgG and complement
Emergent blood transfusion
O, RhD negative; or O RhD positive for males and non-childbreaing female
Abbreviated (30 min) transfusion
ABO, Rh type, Ab screen negative
if blood is positive for specific alloantibodies
must use blood with negative antigens
if blood has auto antibodies but no alloantibodies
F VIII, vWF ag, fibrinogen, Factor XIII, fibronectin
random donor platlets vs ampheresis platelets
RD is more concentration in smaller volume;
what cannot be stored in blood transfusions
Whole blood is given for
decreased oxygen carrying capacity and volume, must be crossmatched
PRBCs are given for
low oxygen carrying, chronic anemia, acute blood loss, cross matching is a must
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
Cyroprecipitate is given for…
low fibrinogen levels, of vWF disease, must be ABO; infusion over 30-45 min
Platelets are given for..
bleeding due to low or dysfunctional platelets, thrombocytopenia, ABO type , infusion 30-1 hr
Granulocyte concentate is given for..
severe infection with patients with ANC
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.
Tx of Acute hemolytic transfusion rxn
stop trasnfusions, maintain IV fluids, heparin
Delayed hemolytic transfusion rxn
formation of alloantibodes post transfusion to cause extravasualr heomlysis, fewer signs could include jaundice, anemia.
due to leukoagglutinins in recpeient cytokines.
Allergic rxns due to transfusion
result of antibodies to IgA, typcial allergic signs