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223 Cards in this Set

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1c is in Yellow - hemostasis thrombosis
1C is in Yellow - hemostasis thrombosis
What distinguishes normal from pathologic hemostasis
Pathologic is not temporally nor geographically restricted
How is coagulation initiated
Exposure of constitutively synthesized TF to plasma via endothelial cell damage
list five stages of clot formation
1. platelet deposition (weak) 2. fibrin production 3. control of fibrin production 4. fibrinolysis 5. control of fibrinolysis
What are two ways platelets accelerate coagulation
1. platelets provide binding sites for clotting proteins 2. anionic phospholipids relocate to outside of platelets causing this
what phenotype might you see in pts with depleted platelets
menorrghagia epistaxis- petechiae soon after trauma
what two mechanisms might produce TF and which is the shorter one
de-encryptation is fast route- postulate constitutively available and go from inactive dimer to active monomer on vascular injury or itassociates with phospholipids giving it anticoag activity. Synthesis is the other route and takes 1-3 hours but is not longlasting without outside stimulus beyond trauma
Which five proteins are direct members of the extrinsic pathway
TF- 7- 10- 2-->thrombin- fibrinogen-->fibrin are members of this pathway
how is factor 7 activated
TF binds to this factor and activtes it
What two proteins are activated by TF-7a
X and 9 are activated by this - X is believed to be the main pathway
What's required for optimal Xa (prothrombinase) activity
activated platelets bind to Xa- secrete Ca- express phospholipids- and bind FVa in order to optimize THIS enzyme's activity
What does Xa cleave
Prothrombin (2) into thrombin is done by this enzyme
what does thrombin cleave
Fibrinogen to fibrin is made by this
what are four functions of thrombin
1. to cleave a and b peptides off fibrinogen to produce the fibrin monomer 2. it increases TF production 3. It activates platelets 4. it activates V to Va which in turn helps stabilize Xa to make more thrombin
why do you need 9 and 10?
because there usually isn't enough TF-7a to sustain production of Xa. 9a is also activated by TF7a which ALSO makes more Xa from X
what factor are hemophelia B patients defective in and how does this explain their phenotype
these pts are deficient in 9 and suffer from delayed bleeding in joint spaces or elsewhere that TF is low signaling the importance of 9 in production of addtl 10a
what are two "chairs" activated by thrombin and what do they do?
factors V and VIII are both activated by this. factor Va helps produce more thrombin and factor 8a assists 9a in making more Xa
which two proteins in the extrinsic pathway amplify their own production?
Xa (acts on 7) and thrombin (acts on 5- 8- and indirectly on 9 via 11)
why is factor 11 (XI) deficiency usually mild
this factor deficiency is mild because factor 9a production usually depends more on activated factor 7a than on help from 11a
if you have prolonged aPTT only and pt asymptomatic what 4 factors could be deficient
HK- PK- XI or XII
if you have prolonged aPTT only and pt symptomatic what factors could be deficient
8- 9- XI
what is a normal PTT
22-32 seconds
what are three required components for PT measurement
citrated plasma containing all coagulation proteins- TF- and Ca++ (activates)
what does the PT time measure
function of 7- 5- 8- prothrombin (ii) and fibrinogen tested by this one
why do you add a LOT of TF in a PT test
because there is no tissue to regenerate it
what are the contact factors
clinically unimportant to clotting but they are prekallikrein-->kallikrein- 12- and the enzyme HMK. they show up in the aPTT
what is lacking when you do an aPTT
no TF- use partial thromboplastin instead in this test
what protein is NOT tested by an aPTT
7 not tested in this one
what if you only have long pT and aPTT normal
7 is abnormal showing these results
what if BOTH aPTT and PT are abnormal
5- 10- prothrombin- fibrinogen abnormalities produce this
what protein is affected in hempphelia A
XIII
What protein is affected in hemophelia B
9a
how do hemphelias manifest differently from platelet disorders
hemophelias often result in delayed internal bleeding rather than mucocutaneous due to weak clot formation
How can you identify an inhibitor vs. a deficiency?
Incubate with normal plasma missing any factor but the one that is deficient- and the PTT should correct
which factors are vitmain K dependent
2- 7- 9- 10- C and S proteins require this for posttranslational y-carboxylation
post-translational y-carboxylation occuring in the liver mediated by vitamin K allows..
2-7-9-10 localize to the membrane of the platelets once they have these
How does coumadin affect clottin
when coumadin is present- this stops regeneration of active vitamin K- causing decreased activation of these clotting proteins
what does TFPI do>
This protein associates with excess Xa- then with Xa-VIIa- inhibiting VIIa-TF activity
which protein might be expected to step up when there is a lot of TFPI activity
Factor 9a activated by factor 8
what generates activated protein C
thrombin and vitamin K are required to make this- along with a thrombomodulin substrate
what might deficiencies in protein C or S cause?
increased thrombosis due to decreased inactivation of V- 8 by C and S
What does APC do?
inactivate factors V and 8
what does Anti-thrombin III do and where is it made
This protein is made in the liver and competitively binds to serine residues on activated coagulation proteins which stops clotting
what does heparin do
this dug prevents AT3 from interacting with its targets
what if there were no AT3
lifethreatening risk of thrombosis
what are three steps in fibrinolysis
initation- propagation- and control of this process stop clots from getting too big
what is plasmin produced from
plasminogen activated by tissue plasminogen activator (tPA)
where is tPA stored and when is it released
this is stored in endothelial cless and released under hypoxia or mechanical stress
which domains of tPA mediate its binding?
The 2nd kringle and finger domains allow tPA to bind to fibrin- allowing this protein to cleave plasminogen to plasmin
what does plasmin do?
this protein cleaves fibrin into FDPs to stop clot formation (helped form by tPA)
what are five ways to stop fibrinolysis
1. loss of fibrin surface ( down tPA) 2. genereation of 13a which is a glue holding clot together preventing entry of plasmin and TAFI 4. generate plasminogen activator inhibitors 5. generate an inhibitor of plasmin (a2 antiplasmin)
what does 13a do
this protein crosslinks fibrin preventing physical access by plasmin
what does TAFI do?
thrombin activates this protein causing it to remove binding sites for plasminogen on the endothelium
what does PAI do?
binds up tPA preventing it from interacting with plasminogen to make plasmin
what does a2 anti-plasmin do?
duh it prevents interaction of plasmin with fibrin (kind of like how factor 13 physically prevented plasmin from getting to fibrin)
1D phatology of thrombi
1D pathology of thrombi
What are two food related terms describing postmortem clots but NOT thrombi?
red currant jelly and chicken fat are characteristic of clots that form at these times
Which types of clots are gelatinous- not friable
Post mortem clots' texture may be described this way
What two main features identify thrombi as opposed to post-mortem clots
Lines of Zahn and a site of attachemnet to the vessel wall are signs of this
What composes the pink layer of line of zahn
platelets and fibrin
What's a mural thrombus
a thrombus that forms on the inside wall fo the heart
1e Pathology of cell injury
1e pathology of cell injury
List a few ways in which cells are injured
mech- temp trauma- virus- nutritional- genetic can do this
Identify the major cell organelles that are injured
mitochondria- any membrane bound organelle as Ca breaks them open
How are free radicals generated (four)
UV light- Xray- CCl4- iron- normal redox rxns
How are free radicals controlled?
antioxidants (A and E)- superoxide dismutase & cataase- as well as GSSG
What can result from free radical damage
DNA damage- modification of proteins- modification of lipids
What is the main difference between hypoxia and ischemia
ischemia deprives tissues of glucose in addition to oxygen (stops blood flow entirely whereas CO poisoning or something)
What are four ways that cells can adapt to non-lethal stimuli
hyperplasia hypertrophy atrophy metaplasia
name the adaptation that results in increased cell number and the adaptation that results in expression of a different cell type than normal
hyperplasia and metaplasia
What are a few differences between apoptosis and necrosis
How does the bulding of colloid lakes in the thyroid of Graves' disease illustrate an adaptation
There is hyperplasia in Graves' disease die to continual stim of TSH resulting in too many cells impingining on the lakes
What two muscle types commonly show hypertrphy
skeletal and heart muscle show this because they are non-dividing
Which cell type adaptations are reversble
all ____ are reversible
What is SMA and associated denervation an example of
Atrophy of babies' muscles - due to denervation
describe an adaptive cell response to smoking that is a metaplasia
transformation of pseudo columnar ciliated epithelium into squamus in smokers
Which cell types are most susceptible to ischemia? Least?
most-neurons least-skin (epidermis fibroblast- skeletal muscle)
Why does the heart stop contracting in 60s after ischemic onset
depletion of ATP leads to slowdown of oxphos due to no pump- [cell swells] rapid depletion of glycogen stores- protein synthesis decreases
membrane blebs signal what
these signal prolonged ischemia
What does Ca influz into cell signal
irreversible process of cell death is triggered by this
How does acetaminophen and CCl4 cause toxicity
both interact with the cytochrome P450 system in the liver
What's a lewy body
misformed aggregates of a synuclein protein that aggregate to cause degeneration of the substantia negra
mutations in the E3 protein (parkin) can cause PD how?
by preventing ubiquitnation and misfolded a synuclein accumulates
List the trhee main patterns of necrosis
caseous- liquefactive- coagulative
what is coagulative necrosis
ischemia as with a clot- MAINTAINS tissue architecture are characteristic fo this type of necrosis
what is liqufactive necrosis
example of cardiac abcess (near valve- drug user infetion)- predominant hydrolytic enzymes- pus and neutrophil infiltrate with secondarry inflammation
what type of necrosis predominates in the brain
liquefactive is most common in this organ
what are two histologic signs of apoptosis
shrink away from neighbors and chromatin condense
What does hyperactivation of PARP cause and what process does it favor
This compound is hyperactivated to rapidly deplete ATP and thus tends to favor necrosis
IN which type of cell death do you see only small cell groups and cell shrinkage
apoptosis displays these histo findings (also no inflammation)
what are BCL2 proteins
antiapoptotic- their ratio to the BH3 and Bak- Bax are important
What does BH3-only BCl2 proteins do
proapoptotic
What do Bax and Bak do
pro-apoptotic- multimerize to puncture mitochondial membrane
What does cytochrome C play in apoptosis
this protein is part of the apoptosome and also requires APAF1 and ADP
ROle of apaf1 in apoptosis
this protein is part of the apoptosome and also requires cytochrome C
What are initiator caspases
receive signals form the apoptosome and activate the iexecutor caspases
what are executioner caspases
they cause the morphological changes seen in apoptosis eg chromatin condense- membrane bleb
what is the difference between the intrinsic and extrinsic apoptotic pathways
intrinsic is from mitochondrial explosion while extrinsic can be from death signals or lack of GFs- but both meet at initiator caspases
where is bcl2 found and what does this mean for its function
it's found in the outer mitochondrial membrane so it is antiapoptotic
which mitochondrial membrane must be permeable for apoptosis and why
The outer membrane in order to release cyt c
Name two diseases associated with too much apoptosis
PD- AD- lots of neurodegen
Name two diseases associated with too little apoptosis
p53 mutation cancers- lupus- herpesvirsus- estrogen dependent carcinoma- follicular lymphoma
would you expect follicular lymphoma to express too much or too little BCl2
too much
What does the Fenton rxn produce and what disease is associated
Friedrich's ataxia is a neurodegen disease that kills neurons due to oxidative radicals produced in the iron fenton reaction
If you increase mitochondrial mutations what happens to mouse age
mice age prematurely if you screw this up
Pink1 is another mitochondrial protein which may link WHAT to parkin and alpha synuclein folding
Pink1 may associate mitochondrial error with this pathology in parkinson's
1E platelets
1E platelets
How do activated and resting platelets differ in morphology?
Activated are all spiky looking
What three compounds keep platelets flowing
PGI2 NO and CD39 from endothelium (especially PGI2 does this)
What causes tumbling- adhesion and activation of platelets
exposure of collagen and VWF due to endothelial injury stimulate this
What usually activates platelets?
collagen thrombin TxA2 ADP
How do platelets encourage clotting reactions?
Platelets usually support factor five and eight (phospholipids and Calcium)
How does aspirin affect platelets
Aspirin inhibits COX2 in platelets which prevents formation of TxA2 which platelets normally need to be recruited into a plug
what two hormones regulate platelet count
TPO and MPL (the latter is competed for by platelets and megakaryocytes to
how long do platelets normally survive
10days and then either cleared in clot or spleen
14.0 - 17.5
Male hemoglobin
12.3 - 15.3
Female hemoglobin
42-50%
hematocrit
36-45%
hematorcrit
4-11000
white cell count
150-400k
platelet normal
what is an ecchymosis
bruise
what are petechiae
littler brusises
why don't you see hemearthrosis in thrombocytopenia
it's more of a hemophelia thing- slow vs fast
What Which bleed type is characterized by delayed bleeding into retroperioneum- joints
hemophelia (defects in clotting factors)
name two diseases resultings from inappropriatesly activated platelets
heart attack and stroke- can be consequences of too many of these
what are bleed thresholds for any and gross bleeding
100k any gross 15k
name three ways thrombocytopenia may develop
increased destruction (- decreased production- or MALdistribution including spleomegaly due to portal hypertension)
list a few causes of thrombocytopenia from decreased produciton
low megakaryocytes=chloramphenical- leukemia or aplastic anemia- b12 and folate deficiency
what are four immune causes of thrombocytopenia
ITP PTP CVD HEP: ITP (immune or idiopathic) post-transfusion- collagen-vascular disease (lupus)- quinidine and heparin
what are four non-immune causes of thrombocytopenia
DIC sepsis TTP and bypass pumps
kid with ITP preceded by several weeks of viral illness. rest of CBC normal. think?
ITP is diagnosed by these clinical features and exclusion
Why are steroids and rituxan appropriate therapy for ITP? What about Nplate? Why might splenectomy be a last resort
steroid immunosuppress. rituxan suppress CD20 B cell- Nplate is TPO to increase production- and splenectomy
are drug induced cytopenias more likely to result in damage to megakaryocyte or platelet?
platelet because drug may bind to platelet glycoprotein and then trigger antibody removal (so more potent the next time)
how can liver disease resilt in thrombocytopenia
portal hypertension leading to splenomegaly and 80-100k platelets
how is thrombocytosis different from thrombocytothemia
thrombocytothemia is neoplastic and results in increased but abnormal platelet count- still leading to bleeds. thrombocytosis is often secondary to iron deficiency or splenectomy put is udually asymptomatic.
what might you expect to see in a pt with CML
thrombocytothemia may result in this type of marrow cancer
polycythemia vera - what is it and how might it lead to increaed bleeds
increases in number of all marrow output but not cancer- bluish skin with red spots- it can perturb bone marrow so much that platelet counts actually drop (termed myelofibrosis)
what is TTP
immune reaction to platelets in transfused blood. a wait and see.
What effects does heparin induced thrombocytopenia have
Actually this causes THROMBOSIS not bleeds because pts generate antibodies to heparin plus platelet. plus remains longer
what are a few usually asymptomatic causes of thrombocytosis/thrombocythemia?
osetomyelitis- splenectomy. these are REACTIVE to another insult.
1T Anticoag and antiplatelet therapy
1T Anticoag and antiplatelet therapy
Which agent inhibits thrombin or the conversion of 2 into thrombin (Xa inhib)
heparin!
What do antiplatelet agents do as opposed to fibrinolytic agents
antiplatelets prevent platelet activation while fibrinolytic agents break up clots
List 4 proteins that are naturally antithrombotic
AT3-
What three small molecules can inhibit platelet activation
NO- PGi2- CD39
why might serine proteases be good candidates for anticoagulants
There are several serine proteases which try to cleave AT3 but get STUCK and suicide- turning off coagulation
what factors are inhibited by heparin and how?
Because thet are 2-9-10-11 so it has many targets in coag cascase. It has a LONG GAG side chain to allow it to bind both of them
with what 2 protein does heparin associate to have its anticoag effect?
heparin inhibits 2 by binding to AT3 and thrombin (2) and stabilizing their interaction
how is heparin administed and how long does it last
It can be IV or subQ and short half life- but can be given at home. variable half life
what are risks of heparin and why might you consider it for CABG?
Could get bleeding and oseteoporosis over long term use- but it prevents further clot formation so might use it post CABG or people who have a blood clot. Can also cause low platelets!
How do excess antibodies produced in HATT result from heparin administration
heparin associated thrombocytopenia- because ppl with clot have circulating activated platelets. Heparin binds to PF4 which is secreted by activated platelets. This complex binds platelets- causing immune response to platelets. In some cases these Abs activate Fc receptors on platelets to crosslink- erroneously activating platelets to clot- embolism- TISSUE DAMAGE.
What are some symptoms of HATT and what does HATT do to platelet count
heparin induced skin necrosis due to fall in platelet count. do not screen for Abs unless person has had problem before- just monitor platelets.
What is LMWH
Heparin but ONLY with small side chain. Eg- fondaparinux. This inhibits Xa preferentially to thrombin. Given SQ. dosed by weight.
For which factor is LMWH most sensitive
10 NOT thrombin because it's shorter
Why can't you follow LMWH patients with a PTT?
Because LMWH prefers to inactivate 10a over thrombin. If 10a is inactivated- the PTT will be long but not as long as if both thrombin and 10a were inactivated. So in the tt it's not a big enough difference but in the pt it's therapeutic
How do you monitor heparin therapy
aPTT. It measures contact- 9- 10- prothrombin- PT isn't as sensitive to heparin because TF drives so fast. Both aPTT and PT should increase- however. You should prolong the PTT but 1.5-2x baseline.
List three indications for LMWH
DVT PE-
What are some preexisting conditions which might require prophylaxis for VTE?
afib- previous vte
What are some DTIs and why might you choose to use them over heparin?
only IV - lepirudin- and argatroban. Use these types of molecules ac
What are the sites of excretion and mechanisms of lepirudin and argatraban
lepirudin is renal- leech protein like- and binds to thrombin to inhibit it. and argatroben is liver- inhibits active site.
How do factor Xa inhibitors compare to heparins? (list their names too)
ORAL - rivaroxaban- apixaban- fondaparinux (SQ) which is short but can still inhibit Xa
What's thrombin inhibitor
dabigatran inhibits what??- oral- LONG half life- fixed dose and no monitoring.
Which proteins are affected by warfarin?
warfarin inhibits K..thus inhibiting 2-7-9-10 strongly- and decreases post-trans modification of C and S
which process does warfarin inhibit and what vitmain is necessary
vitamin K activation is inhibited by warfarin- causing an inhibition of clotting proteins
what can happen when you take broad spectrum ABs and don't eat
you have to eat it and it is synthesized by gut flora. If you have vitamin K deficiency.
What two drug interactions are potentially harmful for warfarin users?
Other drugs can displace warfarin from albumin- increasing effective dose. OR other drugs can rev up P450 and excrete warfarin quicker. Diffiuclt to control therapeutic window
How is warfarin metabolized
it is oral- into the bloodstream- some is free and some bound to albumin. Free warfarin in the liver is the active site for Vit K antagonist. P450 cytochrome system excretes warfarin
Do steroids potentiate or attenuate warfarin levels?
Attenuate warfarin levels.
Which coagulation factors are broken down most quickly? Slowly?
Short halflife: 7 long halflife: platelets
How is coumadin administered?
oral. monitor frequently at first and then monthyl
What does coumadin do to PT? PTT?
PT increases greatly due to extrinsic pathway inhibition/factor 7 inhibition by warfarin. PTT can also increase.
What is an INR and if it is high what does it mean?
The INR is a measure of how a patient's PT compares to control PT. Therapeutic if usually 2-3
what is a target INR for PE?
between 2 and 3
What three side effects are possible?
Bleeding (stop with FFP- vit K)
how mgiht skin necrosis arise?
potential for transient procoagulative state if protein c levels fall first (so usu start heparin first)
what is a sign of fibrin degradation in the blood? (and what condition does this diagnose if high)
D-dimers (DIC)
what two things does plasmin cleave?
x-linked fibrin OR fibringogen. these are stimulated by streptokinase to urokinase to tPA.
List a few indications for plasminogen activators
active MI- PE- proximal DVT- catheter occulusion
What does tpa do to fibrinogen levels
Fibrinogen levels decrease with thsi drug
Which plasminogen activator is assoc with alelrgic reactions?
streptokinase (it activates tPA)
Should you give a plasminogen activator to someone with uncontrolled severe hypertension or cranial neoplasm? why or why not?
High bleed risk- allergic reactions- high cost. Risks of massive hemhorrage in the brain
what does PAI-1 do?
It decrases tPA
what is done immediately- and long term for venous thrombus management
Immediate VT management: can give TPA. Then put on heparin LMWH- and put them on coumadin for 3-6 mos
what three sites of action are there for antiplatelet agents?
Receptor antagonists (prevent turn on)- signaling blockers (prevent turn on )- and Integrin a2B3 blockers (prevents platelets form sticking to each other)
Name two antiplatelet RECEPTOR blockers
clopidogrel (plavix)- ticoldipine. Bind to GPCR P2Y12 and prevent ADP from binding and activating platelets
what are two antiplatelet signaling vblockers and how do they work
aspirin and dipyramidole. aspirin prevents formation of TxA2 inside one platelet- preventing recruitment of other platelets/activation of other platelets. Aspirin inhibits COX1 in all platelets- causing decreased recruitment of platelets
why do integrin blockers work
They prevent activated platelet from binding to fibrinogen and sticking to each other. Glanzmann's is an example of this disease. Examples: ReoPro- Integrilin- Tirofiban.All IV.
what does dipyramidole do
it increases cAMP by preventing its degradation in platelets- making them less responsive to activation
what are two system indications for platelet inactivators use?
Heart disease- stroke- cancer
How do antiplatelet agents and anticoagulant agents DIFFER??
Antiplatelets prevent platelet activation or binding of platelets- while anticoagulants stop coagulant proteins
1V pathology of leukocyte trafficking
1V pathology of leukocyte trafficking
Name the four leukocyte subpopulations
Neutrtophils- monocytes- eosinophils (parasite)- and lymphocytes (eg ARDS)
Why might dyregulated integrin expression lead to inflammatory disease
Excessive white cell recruitment may result ininflammation (integrin overexpression or something)
Cadherins and selectins are 2/4 of these-.what are the otehr 2
cell adhesion molecules or CAMS- immunoglobulins and integrins also
what two functions are cadherins normally responsible for
NOT used in WBC recruitment - but mediate homophilic adhesion hold cells of one tissue together. They link epithelial cells all together.
what family's members are expressed on the endothelium and include ICAM- PECAM? What do they do?
Immunoglobulin superfamily includes these - expressed ON endothelium and involved in WBC traficking
where do you find selectins and what do they bind?
these are on cells associated with vascular endothelium only and they bind carbohydrate motifs on leukocytes- platelets- and vascular endothelium
which adhesion molecule is a dimer?
the integrins!
which adhesion molecule is NOT involved in leukocyte/endothelium recruitment
the cadherins
what molecule is important in leukocyte rolling
L-selectin!! it is important in capture
what do integrins participate in
diapedesis
Where is P selectin stored
in weibel palade bodies of platelets
does igSF have a strong orweak hold and when would it because active in the recruitment process
it has a strong hold so it bind durign the stopping process
P selectin is expressed where
in the endothelium- important in capture of fast roll
which selectin mediates slow rolling and why?
E selectin mediates slow rolling because it's synthesized SLOWLY and comes up slowly
what ligand is upregulated in the leukocyte after it is slow rolling and what is shed?
B integrin is upregulated in response to chemokines while concurrently L selectin is shed- causing a stop in leukocyte rolling
What is expressed on the endothelium and what on the WBC to cause firm binding of leukocytes
The integrins on the WBC bind to Ig superfamilar on the endothelium
what are the two routes for diapedesis to occur?
paracellular transendothelial migration OR transcellular transendothelial migration
What are four factors involved in leukocytes traversing the endothelial layer
PECAM1 --> CD99 JAMA--> neutrophil elastase (makes sense because PECAM is an immunoglobulin- there's also a and B integrins from the WBC involved)
What process requires a podosome?
transcellular transendothelial migration while preserving vessel integrity
If patient deficient in B integrin what process defective? What clinical signs?
The slow rolling and transition to stop will not be involved- pt will be immunodeficient
How do type I and type II leukocyte adhesion deficinecy differ? Proteins- explain the chemical phenotype?
Type 1 is absence of B integrins. High blood neutrophil low pus- recurrent infection. Type II is NO E and P selectin on the WBC- compromising WBC trafficking. Same phenotype as blood neutrophil
Why is the phenotype the most severe if you delete E and P selectin?
They are redundant similar function. HOWEVER it is tissue dependent
Why might cell adhesion molecules represent attractive targets for drugs? What types of diseases?
They could be suppressed to decrease recruitment- decreasing inflammatory response in disease Ex: MS- crohn's arthritis
Why might Tysabri work in MS? What are its risks (bc what molecule does it inhibit?)
Risk of immunosuppression - getting PML but on other immunosuppression so drug reintroduced. It tartgets a4 integrin
What does Factor V leiden cause?
Inability of activated protein C to shut off factor V=hypercoagulability