Anticoag, antiplatelet, thrombolytics Flashcards

Question 1

Q

What is the physiology behind hemostasis?

Answer

A

Important to stop blood loss from damaged vessel; life preserving!
1. Plt activation and adhesion (hemostatic plug) and localized vasoconstriciton
2. fibrin stabilization of plt plug via 2 coag pathways
  - intrinsic pathway contact between the damaged surface with coag factors in the blood results in activation
  - extrinsic pathway is activated when damaged tissue reveals tissue factor

Question 2

Q

Pathophys behind bleeding?

Answer

A

Thrombi devleop when clotting cascade is activated within a vein or artery in the absence of bleeding
- vessel wall injury, altered blood flow, abnormal coagulability
- abnormal coagulation- pregnancy, genetics, oral contraceptives

Question 3

Q

What causes platelet aggregation?

Answer

A

Blood vessel damage= exposed collagen
platelets are attracted to exposed collagen and being to aggregate
- glycoprotein IIB/IIIa receptors form unstable fibrinogen bridges between platelets. these receptors are activated by
  - thromboxane A2
  - thrombin
  - collagne
  - platelet activating factor
  - adp
Each PLT has 50-80,000 GPIIB/IIIA receptors. activation of these receptors permits the binding of fibrinogen, which causes activation by promoting crosslinking by plts

Question 4

Q

Where do intrinsic and extrinsic pathway converge?

Answer

A

Xa to becoem common pathway

Question 5

Q

What is the goal of the coagulation cascade?

Answer

A

produce fibrin which staiblizes platelet plug

Question 6

Q

What is vitamin K used for?

Answer

A

factors II, VII, IX, X

Fat soluble vitamin occuring naturally in plants and in a series of bacterial formed in the gut

Question 7

Q

Anti-thrombin’s roll in anticoagulant pharmacology?

Answer

A

prevents wide spread coagulation by inhibiting IIa(thrombin), IX a, Xa, XIa, XIIa

(a= activated clotting factor)

major endogenous anticoagulant

Question 8

Q

What is plasmin’s role in anticoagulant pathway?

Answer

A

inactive form= plasminogen

enzyme that breaks down a fibrin enriched clot

Question 9

Q

Why do we care about anticoagulants as anesthesia providers?

Answer

A

given most commonly in perioperative setting durign CV procedures, to prevent DVT (10-40% sx patients) and to patients with chronic atrial fibriallation

anticoagulants (decrease production of fibrin)
antiplatelet drugs (reduce paltelet aggregation/function)
- used for arterial thrombosis (ex atherosclerotic plaque rupture)
thrombolytic drugs (promote clot lysis/fibrinolysis)
- systemic thrombolytics will break down clots everywhere
- used more for venous issues (vesous thrombosis, venous stasis, dvt)

Question 10

Q

What are some LMWH?

Answer

A

Enoxaparin (lovenox)

daltaparin (fragmin)

fondaparinux (arixtra)

tinzaparin (innohep)

Question 11

Q

Example of Direct Xa inhibitos?

Answer

A

Rivaroxaban (xarelto)

apixaban (eliquis)

Question 12

Q

Examples of direct thrombin inhibitors

Answer

A

Lepirudin (refludan)

bilvarudin (angiomax)

argatroban

dabigatran (pradaxa)

Question 13

Q

What was warfarin originally? Currently used for?

Answer

A

originally marketed as a rate poinsin, in much higher doses
currently used for long term thrombosis prophylaxis
- dvt
- atrial fibrillation
- prosthetic heart valves
- recurrent TIA/MI

Question 14

Q

MOA for warfarin?

Answer

A

Inhibitors vitamin K epoxide reductase complex I (VKORC1) preventing synthesis of active vitamin K
- normal physio- VKORC1 takes oxidized vitamin K and reduces it and it’s an improtant component in prothrombin.
- warfarin- reduces vkorc1 and reduces clotting factors dependent on vitamin K
decreases production (30-50%) of vitamin k dependent clotting factors:
- II, VII, IX, X
Lots of genetic variability in VKORC1 or CYP 2C9 and are increased risk of warfarin bleeding/require a lower dose. FDA now recommends testing for genetic variation before starting coumadin therapy
does nothing to clotting factors that are already present, so have to wait for turnover of all existing clotting factors
half life 6 hours-2.5 days depending on coag factor
see effect 8-12 hours with peak effect after several days
d/c of drug, coag remains inhibited 2-5 days b/c long half life 1.5-2 days

Question 15

Q

PK/PD warfarin?

Answer

A

Absorption 1-2 hours but effect is dependent on depletion of clotting factors (II, VII, IX, X)
- need over week to see full effect
Stoelting peak effect 36-72 hours
e1/2 t 24-36 hours
97% protein bound
veyr narrow therapeutic index
- highly protein bound with narrow therapeutic index can cause lots of issues!

Question 16

Q

What test is used to monitor warfarin? Normal values? Therapeutic?

Answer

A

INR

(pt test/ptnormal)

Normal value for a patient not on warfarin is 0.8-1.2
patients with DVT, AF, PE and other clotting issues range is 2-3

Question 17

Q

What is pregnancy category for warfarin?

Answer

A

pregnancy category X and do not use while breast feeding!!

defastating malformations not compatible with life

Question 18

Q

S/E from warfarin?

Answer

A

Normally well tolerated
bleeding is major side effect
- bruising, bloody nose, and bleeding when brushing teeth
- blood in urine/stool, pelvic pain, HA, dizziness, low BP, and or tachycardia require medical attention!
- patient should wear a medic alert bracelet

Question 19

Q

Interactions with warfarin?

Answer

A

Food that contain vitamin K antagonize the effect of coumadin; key is consistent diet
- foods high in vit K include mayo, canola oil, soybean oil, green leafy vegetables
- dont’ avoid, just eat in consistent amounts
many med interfere
- increase or decrease anticoag effects bleeding/thrombosis risk
  - alter protein binding (Free fraction)
  - alter function cyp enzymes
    - acetaminopehn increased risk of bleeding
    - several anti seizure meds
  - alter the synthesis or function of clotting factors and or plt
    - heparin, nsaids, asa, clopidogrel, dipyridamole
  - alter absorption of warfarin
    - antibiotics- effect varies, effect gut flora (bactrim, avelox, falgyl have interactions)

Question 20

Q

Preop managmeent of patients on warfarin?

Answer

A

D/C warfarin at lest 5 days before elctive procedure
asess INR 1-2 days prior to sx, if >1.5, consider 1-2 mg oral vitamin k
reversal for urgen sx/procedure, consider 2.5-5 mg oral of IV vitamin K for immediate reversal
- consider PCC, FFP
Patients at high risk of thromboembolism
- bridge with therapeutic sc lmwh (preferred) or IV UFH
- Last dose preop LMWH administered 24 h before sx, administer half of the daily dose
- IV heparin d/c 4-6 horus before sx
no bridging necessary for pt at low risk of thromboemvolism

Question 21

Q

Postop managmenet of patients on warfarin?

Answer

A

Patients at low risk of thromboembolism
- resume on warafarin on POD ____(?? need clarification from bowman)
Patient at high risk of thromboembolism (who recieved preop bridging therapy)
- minor sx procedure- resume therpeutic LMWH 24 h postop
- major sx proceudre- resume therapeutic LMWH 48-72 H postop or adminster low dose LMWH
Assess bleeding risk and adequacy of hemostasis when considering timing of the resumption of LMWH, or UFH therapy

Question 22

Q

Reversal of warfarin?

Answer

A

INRs that are elvated may require varying responses
INRs that are slightly above range (less than 6), we recommend to hold 1-2 doses of warfarin
if patients have higher INRs or are showing signs of bleeding, it may be appropriate to reverse effect with vitamin K
- low doses; oral route
- SQ and IM is not recommnede
- IV may be used in pt with absorption issues

Question 23

Q

What are the 3 anticoagulants that work on antithrombin III?

Similarities/Differences between the 3?

Answer

A

heparin
LMWH
Fondaparinux

all three have same pentasaccharide sequence
- the sequence binds to antithrombin III (major endogenous anticoagulant)
  - increases affinity to factor Xa and thrombin (for uFH) only!- inhibits Xa and thrombin through enhancement of antithrombin III activity (thrombin inhibiriton is only heparin!)
unfractionated heparin has long, random polysaccharide chain on either end and bind to many things. it causes it to be unreliable and unpredictable
- need constant lab testing because hard ot predict therapeutic effect d/t nonspecific binding
- added benift is that it wraps around thrombin and inhbits thrombin well
LMWH- shorter chain, antithrombin III–> increases affinity to inhibit Xa (only Xa)
fondaparinux- binds to antibthrombin iii only inhibits factor Xa (but less so than LMWH)

Question 24

Q

What is unfractionated heparin?

Answer

A

highly sulfated glycosaminoglycan
- negatively charged, huge molecule that does not cross placenta or BBB
potency varies always prescribed in unite
- 1 unit heparin: volumte of heparin solution that will prevent 1 mL of citrated sheep blood from clotting for 1 hour after the addition of0.2 mL of 1:100 calcium chloride

Question 25

Q

Heparin PK/PD? indications for use?

Answer

A

VARIABLE

baseline antithrombin activity can influence patient response
- if have a lot of baseline antirhombin III activity, then need less heparin
- if lower, need more heparin!
temp dependent (more active at higher body temp)
highly polar and large MW (3000-300000 dlatons, does nto cross biological membrane)
- iv/sq only
- good choice in pregnancy and breast feeding!!
protein binding
- lots of non speicifc binding- variable free drug/unpredictable resposne
metabolism
- onset : minutes IV, SQ 1-2 hours
- 1/2 life- 1 hours- precise mechanism of clearnace/metabolism is unclrea, hepatic metabolism, renal excretion
indications:
- PE, DVT, DVT prevent, acute MI, stroke, dialysis, CPB, DIC

Question 26

Q

What do we test to monitor heparin?

Answer

A

aptt (activated partial thromboplastin time)

typical goal 1.5-2 x normal (30-25 seconds)
activated clotting time (act) used with high dose (CPB)
- baseline, 3-5 min after heparin and every 30 min

Question 27

Q

Adverse effects of heparin?

Answer

A

hemorrhage
HIT (heparin induced thrombocytopenia) sometimes occurs after 5-7 days on heparin
- 50% decrease in plt count <100,000 cells/mm3 with thomrobsis
osteoporosis
hypersensitivity
- animal tissue extraction source

Question 28

Q

WHat is HIT?

Answer

A

Heparin induced thrombocytopenia

potentially fatal immune mediated d/o characterized by reduced plt counts and a paradoxical increase in thrombotic events
underlying cuase is antibodies agonist heparin-plt protein complexes
antibodies activate PLT and promote thombosis and loss of circulating plts
- DVT, PE, Coronary thombus, loss of ciruclation to an extremity requiring amputation
- 1-3% develop HIT when they receive heparin for >4 days
monitor plt count q 2-3 days for first 3 weeks of heparin use and then every month
Txmt- d/c heparin and change ot non-heparin anticoag

from later slide—>

Heparin binds to PF4 (platelet factor 4)
This exposes new surface of PF4 –> antibodies
The antibody binds the PF4/Heparin complex
The Ab binds the Fc receptor on platelets
This activates the platelet → releasing more PF4
And activating thrombin –> blood clots!
- Tx: antithrombin drugs (but not heparin)

Question 29

Q

What is used to reverse heparin?

Answer

A

protamine

Alkaline and positively charged (heparin acidic and – charged) → neutralize heparin
DOA: 2 hours (may need a redose)
1 mg protamine /per 100 units heparin
- Give slowly! (fast = hypotension)
- And consider how much heparin has been metabolized at the time of reversal

Question 30

Q

Caution and contraindication for heparin?

Answer

A

Liver or kidney disease
Indwelling epidural catheter- leave in until hep metabolized
Traumatic placement of epidural or spinal anesthetic
Other anti-platelet or anti-coagulation medications (and herbals)
Peri-surgical: eye, brain or spinal cord (comp bleeding bad)
Patients at high risk for bleeding
- Ex: Hemophilia, aneurysm, severe HTN, GI bleed risk (i.e. PUD), thrombocytopenia

Question 31

Q

Takeaway from heparin and neuraxial anesthesia?

Answer

A

Spinal Hematomas:

No heparin
- Atraumatic – 1.00 (set as control)
- Traumatic placement w/o heparin- 11.2
- Aspirin- 2.5 risk than with an atraumatic pt
Heparin following neuraxial procedure
- Atraumatic- 3.16
- Traumatic- 112 (HUGE RISK OF SPINAL HEMATOMA)
  - If had a traumatic placement → don’t want to give heparin/anticoag after…
- Heparin >1 hr after puncture- 2.18 (WAIT AN HOUR for heparin bolus → LOWERS RISK)
- Heparin < 1 hr after puncture- 25.2
- With Aspirin- 26 (d/c w/in 7 days to decrease risk)

Takeaway:

DON’T GIVE HEPARIN AFTER TRAUMATIC PLACEMENT
WAIT 1 HR AFTER PUNCTURE TO GIVE HEPARIN

Question 32

Q

What are LMWH?

Answer

A

Enoxaparin (Lovenox)
- Dalteparin (Fragmin)
- Tinzaparin (Innohep)
1^st line therapy for DVT prophylaxis and tx
Also used in unstable angina/MI/coronary ischemia
Equal efficacy compared with heparin (even though just blocking Xa)
- Same 5 sugar sequence inactivates Xa
- Not as effective in inactivating thrombin
More predictable pharmacokinetics
- Higher bioavailability
- Longer half life (up to 6X that of heparin)
- No aPTT monitoring required
- No hospitalization required

Question 33

Q

Adverse effects and contraindications for lmwh?

Answer

A

Adverse Effects
- Bleeding (lower risk compared with unfractionated heparin)
- HIT – if hx (no heparin for rest of life)
Contraindications/Precautions
- Effect greatly prolonged in renal failure → use unfractionated heparin instead
- Spinal or epidural anesthesia
- Anti-plt or anti-coagulant drugs
- Delay surgery 12 hours after last dose

Question 34

Q

What is fondaparinux (arixtra)

Answer

A

Exclusively inactivates Xa by enhancing antithrombin III activity (no direct effect on thrombin activity)
Chemically identical to the 5 sugar active site of heparin and LMWH
- Much smaller than heparin and LMWH
Half-life LONG (over 3x as long as LMWH)
- E1/2t = 15 hours
- Effect onset 2 hours/effect lasts 2-4 days after last dose
  - ~ Stop med earlier than unfractionated heparin/LMWH

Question 35

Q

Any reversal agents for fondaparinux? cautions/contraindications?

Answer

A

No reversal agent
HIT does not occur
thrombocytopenia occurs (3%) → not r/t HIT
Contraindications (excessive risk of bleeding):
- Severe Renal Impairment (CrCl < 30ml/min)
- Weight < 50kg undergoing hip fracture/replacement surgery, or knee replacement surgery (too dramatic of effect)
Caution:
- Elderly patients
- CrCl (30-50ml/min) – borderline
Epidural or spinal anesthesia – long half life → d/c long enough?

Question 36

Q

What are some direct thrombin inhibitors?

Answer

A

Directly bind thrombin at both the catalytic and fibrinogen binding site.
- Bind to circulating thrombin and thrombin already associated in clot
Useful in history of HIT
all approved fairly recently (2010/2011)

examples:

Dabigatran (Pradaxa) – most common recognize this one
- PO
Desirudin
- SQ
- Approved for DVT prevention in patients undergoing elective hip replacement
Lepirudin (Refludan)
- IV infusion only
- Approved for thrombus prevention in patients with HIT
Bilvarudin (Angiomax)
- IV infusion only
- Used with ASA in coronary angioplasty for thrombus prevention
- E 1/2 time is 25 minutes
Argatroban
- IV infusion only
- Approved for thrombus prevention in patients with HIT

Question 37

Q

What is dabigatran?

recommendations to stop before surgery?

Answer

A

Pro-drug: binds and reversibly inhibits circulating thrombin and clot integrated thrombin
FDA approval: Indicated for Atrial Fibrillation only
- Rapid onset; E1/2t = 13 hours
- Effect measured by thrombin times TT (best) or aPTT
- Not significantly metabolized by hepatic enzymes
- Primarily cleared by the kidneys (renal fx important!)
  - Encourage fluid intake
Recommendations to D/C:
- Normal renal fx: d/c 48 hours before sx
- Abnormal renal fx: d/c 72-96 hours before sx
- High risk for bleed during sx: d/c 5 days before

Question 38

Q

Adverse effects and drug interactions with dabigatran?

Answer

A

Adverse Effects
- Bleeding (17% all types with 3% major bleed)
  - Risk of life-threatening bleed: Warfarin > Dabigatran
- GI (35%)
  - Dyspepsia
  - Gastritis
Drug interactions
- P-glycoprotein inhibitors will increase drug levels of dabigatran
  - Ex: Ketoconazole, amiodarone, verapamil, quinidine → can push super therapeutic risk

Question 39

Q

Does dabigatran have a reversal agent?

Answer

A

Praxbind^® (idarucizumab)
- humanized monoclonal antibody fragment (Fab)
  - binds to dabigatran and metabolites with higher affinity than the binding affinity of dabigatran to thrombin → neutralizing their anticoagulant effect immediately after administration
- FDA has granted full approval in 2018

Question 40

Q

What is Rivaroxaban (xarelto)?

Answer

A

Highly selective direct factor Xa inhibitor
- Can inhibit free Factor Xa or bound Xa (heparins only bind free)
Marketed for use in hip and knee replacement surgery as DVT/PE prophylaxis & approved in Afib
Metabolized by CYP3A4 & Substrate for P-glycoprotein (interactions)
~35% eliminated unchanged by kidneys

Question 41

Q

Adverse effects of rivaroxaban (xarelto)?

Answer

A

Adverse effect
- Bleeding (potentially fatal)
  - but lower risk compared with warfarin
Contraindicated
- Renal, hepatic disease, major bleeding risk, etc.

Question 42

Q

Is there a reversal agent for reivaroxaban (xarelto)

Answer

A

Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) for reversal (bind and neutralize drug)
- Fast-track status → be aware of unanticipated SE
- FDA just approved (2018)

Question 43

Q

Blood test for xarelto? Recommnedations for xarelto holding preop?

Answer

A

No blood test reliably estimates effect
- Recommendations preop:
  - Preop: Hold 48 hours
  - High risk for bleed during sx: 5 days

Question 44

Q

How long do we need to wait to perform neuraxial/PNB in patient on new direct oral anticoagulants?

When do we resume?

Answer

A

For the new direct oral anticoagulants (direct thrombin/Xa inhibitors):

ASRA guidelines:
- Interval of 5 half-lives of the drug before a regional/pain intervention. → then eligible
- Resumption of drug after a neuraxial procedure → 6 hours
- Resumption of drug after pain intervention → 24 hours

Question 45

Q

What are the 3 major classes of antiplatelets?

Answer

A

Thromboxane inhibitor
- Aspirin (ASA)
P2Y₁₂ ADP Antagonists
- Ticlopidine (Ticlid)
- Clopidogrel (Plavix)
- Aspirin/dipyridamole (Aggrenox)
GIIb/IIIa Antagonists → intense drugs
- Abciximab (Reopro)
- Tirofiban (Aggrestat)
- Eptifibatide (Integrilin)

Question 46

Q

How do antiplatelets work?

Answer

A

Plts have receptors → GPiib./IIIa
- GPiib./IIIa – tons of these
- Bind fibrinogen (goal of coag cascade is convert fibrinogen → fibrin)
- Want GPiib./IIIa receptors to be in optimal shape/confirmation to bind fibrinogen (bc then will convert to fibrin → plt plug)
- Several things work to stabilize confirmation:
  - 1. Thromboxane A2 (TXA2)
  - 1. ADP (P2Y12 receptor which binds ADP)
      * Drugs we use INHIBIT these signals
Ex: Aspirin INHIBITS TXA2
- → less GPiib./IIIa receptors in optimal shape (no binding fibrinogen → discourages plt aggregation)

Question 47

Q

What is cox1? cox 2?

Answer

A

COX-1: Produced by platelets
- No nuclei
  - So once inhibited → platelets cannot produce more COX-1
- Induces platelet aggregation and vasoconstriction via thromboxane A2
  - PROCOAGULANT factors
COX-2: Produced by vascular endothelial cells
- Have nuclei, can replace inhibited enzyme
- Inhibits platelet aggregation and promotes vasodilation via prostacyclin
  - ANTICOAGULANT factors stimulated

Question 48

Q

What happens with low, med, high dose asa?

Answer

A

Low doses (75 to 81 mg/day): lifetime plt inhibition (7-10 days) <– hold prior sx

Selectively/irreversibly inhibit (COX)-1 → inhibits generation of

thromboxane A2 → GPiib./IIIa receptors not in optimal confirmation shape →

Antithrombotic effect
less vasoconstriction too (Less TXA2)

Intermediate doses (650 mg to 4 g/day):

inhibit COX-1 and COX-2 → blocking prostaglandin (PG)

production → analgesic and antipyretic effects

COX 2: don’t want to block (has endogenous anticoag, dilation effect)
Higher doses → lose anticoag effects…

High doses (4 and 8 g/day):

anti-inflammatory effect - COX-2 dependent PGE2
Limited by toxicity: tinnitus, hearing loss, and gastric intolerance

Question 49

Q

ASA MOA?

Answer

A

Arachidonic pathway uses cyclooxygenase (COX) to produce thromboxane A2 (TXA2) and prostacyclin I2 (PGI2)
ASA irreversibly inhibits the COX pathway
- 7-10 days (hold for this period before surgery unless risk of bleeding< benefit of continuing)
  - Effect of cox 1 inhibition- TXA2 inhibition decreases vasoconstriction and decreases degranulation of platelets
  - Effect of cox 2 inhibition (higher doses of ASA)- PGI2 inhibition reduces vasodilation and promotes platelet degranulation

Question 50

Q

Indication/ adverse effects ASA?

Answer

A

Indications
- Transient ischemic attack/ischemic stroke
- Stable and unstable angina
- Prevention and treatment of MI (research varies)
  - Maintenance of patent coronary stents
Adverse Effects:
- GI bleed
- Hemorrhagic stroke

Question 51

Q

What are thienopyridines?

Answer

A

P2Y12 Adenosine Diphosphate (ADP) receptor antagonist

Structurally related class of compounds reduce plt aggregation
- Inhibition of the P2Y12 ADP receptor (P2Y12 receptor which binds ADP)
  - Blocks stimulated adenylyl-cyclase activity
    - Prevents GPiib./IIIa receptor optimization
- Prodrugs: subject to genetic variability
  - Converted in vivo to thiol-containing active metabolites
  - Metabolism pathways are different for each member of this class.

Question 52

Q

Examples of ADP Antagnoists?

Answer

A

Irreversible blockade for life of plt: 7-10 days
- Ticlopidine – 1^st generation
  - Use less common
- Clopidogrel – 2^nd generation
  - Most commonly used
- Pasugrel – 3^rd generation
  - Black Box Warning for bleed risk in >75 year

< 60 kg /TIA/Stroke patients

Reversible blockade:
- Ticagrelor

Question 53

Q

Indications of clopidogrel?

Answer

A

Indications:
- Inhibits plt aggregation ~50%
  - Maintenance of coronary stent patency
  - Prevention of MI/Stroke/vascular occlusion in high risk patients (usually combined with ASA in acute coronary syndromes)
  - Alternative primary prevention in ASA intolerant patients
    - Ex: Aspirin increases leukotrienes → asthmatics get bronchodilation

Question 54

Q

Pharmacokinetics of Clopidogrel?

Answer

A

class: ADP receptor antaognists

Pharmacokinetics
- Rapid oral absorption
- Onset 2 hours (delayed- Prodrug → needs metabolism to active form)
- Peak 3-7 days
- Once daily dosing regimen considered sufficient
Pro-drug: Must undergo metabolism by CYP2C19 to become active
- “Poor metabolizers” (variant CYP2C19) may fail therapy
- Black Box Warning*
  - Consider prasugrel or ticagrelor in these patients

Question 55

Q

DRUG/DRUG interactions for Clopidogrel?

Answer

A

Other medications that increase bleeding
Drugs that inhibit CYP2C19
- Ex: Proton-pump inhibitors- want to put pts on PPI for increase GI bleed risk but actually prevents clotting
- Still used together but with caution

Question 56

Q

Adverse reaction for clopidogrel?

Answer

A

Severe rash
Diarrhea
Bleeding complications
- really these patients will just be bloodies, even if clopidorgrel stopped before surgeyr
- be smart about ordering blood!
Thrombocytopenia (rate similar to aspirin)
TTP – usually within the first two weeks of therapy
- (Diff mechanism to HIT), r/t genetic condition in ADA enzyme- monitor when first started
No significant rate of neutropenia (contrast with ticlopidine)

Question 57

Q

What med can you add to clopidogrel to incrase anticoagulation effects?

Answer

A

Clopidogrel + aspirin vs aspirin alone: CURE & COMMIT trials - combination better
- Complimentary mechanisms → additive effect
- Effective for patients undergoing PCI and med mgmt.
  - Combo better but increase risk of bleeding

Question 58

Q

What is dipyridamole? 1/2 life? indications?

Answer

A

P2Y12 ADP receptor antagnoist
A pyrimidopyrimidine derivative with vasodilator and antiplatelet properties
Mechanism of action is not clear
- Increases plasma adenosine levels
Half Life: 10 hours
- Requires BID dosing
Indication:
- Used in combination with warfarin
- Indicated for prevention of thrombus following heart valve replacement
- Aggrenox: Combined with aspirin → reduce the risk of ischemic stroke
  - FDA approved as combination medication for stroke prevention
  - No intrinsic antiplatelet activity or increased bleeding risk noted when used alone (w/o aspirin)
    - ~ Good to add to aspirin w/o having increased risk of bleeding

Question 59

Q

Adverse effects of dipyridamole?

Answer

A

Adverse Events:
- Headache (most common) - dilation
- Hypotension (vasodilator properties)
- Bronchospasm/dyspnea
- Myocardial ischemia/infarction
- Arrhythmias
- Nausea/dizziness
- Rash/flushing

Question 60

Q

What are glycoprotein IIB/IIIA receptor antagonists? moa?

examples?

Answer

A

Glycoprotein IIb/IIIa Receptor: Receptor responsible for binding fibrinogen → which ultimately makes fibrin→ plt plug
Antagonists:** **powerful antiplts
Abciximab (IV only)
Tirofiban (IV only)
Eptifibatide (IV only)

ONLY used in Acute situations (IV only!)

Mechanism of action: Reversible blockade of GP-IIb/IIIa receptors -the final step of plt aggregation
- This prevents platelets from attaching to each other despite TXA2, ADP, thrombin or plt activation factor stimulation.
- Most effective form of antiplatelet activity

Question 61

Q

Indications for glycoprotein IIB/IIIA? adverse effects?

Answer

A

Indications
1. Unstable angina, acute MI
2. Percutaneous coronary intervention (angioplasty, etc.)
*Can develop allergy after 1 dose*
Prototype: Abciximab
1. Purified Fab fragment of monoclonal antibody that binds near the GPIIb/III receptor occluding the binding of fibrinogen (blocks fibrinogens ability to binds)
2. Adverse effects:
  - Bleeding risk 2X increase (only use in acute care situations)

Question 62

Q

Perioperative management of patients on antiplatelet therapy?

Question 63

Q

Examples of fibrinolytic therapy?

Answer

A

Streptokinase
Urokinase
Tissue plasminogen activator tPA (alteplase)

Question 64

Q

Goal of fibrinolysis?

Answer

A

Fibrinolytic system dissolves intravascular clots
- Plasminogen → plasmin (active form)
- Plasmin is a nonspecific protease → digests fibrin clots and other proteins in clot
Fibrinolytic drugs are also non-specific (breakdown any clot in path)
- Both protective thrombi and target thromboemboli are broken down
- Potential for hemorrhage is high

Answer 64

A

A version of tissue plasminogen activator (tPA) produced by recombinant DNA technology
- IV infusion
- E1/2T = 5 minutes (very short)
Binds plasminogen catalyzing the reaction: plasminogen→plasmin
- Plasmin digests fibrin (breaks down thrombi)
- Plasmin breaks down fibrinogen and other clotting factors (increasing risk of subsequent hemorrhage
Indicated:
- Acute MI
- Acute ischemic stroke (after CT scan to r/o hemm stroke)
- Symptomatic PE

Answer 65

A

Bleeding!!!! 5-30%
- Intracranial hemorrhage (r/o hemorrhagic stroke) - 1.7-8%
  - Pretherapy CT critical
- Healing area with previous clot formation
  - (wounds, intravenous & arterial lines, invasive procedure)
- May need to administer blood products to restore hemostasis
- Angioedema → (especially if also on ACE inhibitor)

Answer 66

A

Must administer quickly after symptom onset
- GUSTO-I trial (coronary artery occlusion)
  - Administered within 2 hours death rate: ~5%
  - Administered within 2-4 hours death rate ~6.7%
  - Administered within 4-6 hours death rate ~ 9.4%

Answer 67

A

Absolute
- Intracranial hemorrhage/brain tumor/cerebral vascular lesion
- Known source of internal bleeding
- Aortic dissection
Relative → risk of bleed…
- Severe HTN (> 180/110 mmHg)
- Intracerebral issues not noted in absolute contraindications
- Other anti-coagulants/anti-plt drugs (increase bleeding risk)
- Known bleeding pathophysiology/non-compressible vascular puncture
- History of traumatic injury major surgery, internal bleeding ~ 3 wks
- Pregnancy
- Peptic ulcer disease

Answer 68

A

Antifibrinolytic Agents
- Lysine analogs
- Aprotinin (not currently available in US secondary to safety concerns- see BART trial)
Recombinant Proteins - see chapter 29
- Activated Factor VIIa
- Factor XIII
- Prothrombin Concentrates

Answer 69

A

Antifibrinolytics: lysine analogs- help people stop hemorrhaging

ex- transexamic acid and aminocaproic acid

MOA: competitively inhibits plasminogen activation
- (binds to the kringle domain in place of lysine on plasminogen)
- reducing plasmin concentration and fibrinolytic activity.
  - TXA will directly inhibit plasmin at high doses.
    - Opposite of TPA- see inhibition of fibrolytic activity
- Basic science is still examining exact MOA
  - Alternative hypothesis has been suggested: TXA improves survival via reduction of pro-inflammatory plasmin activity
Blood loss and need for transfusion are reduced in surgical patients- elective and traumatic cases
No increase of risk for thromboembolic events based on current evidence
- No MI, stroke risk

Answer 70

A

**Give within 3 hours for reduced risk of death due to bleeding in trauma and obstetrical hemorrhage

CRASH -2:

Randomized, prospective study of trauma patients
247 hospitals, 40 countries, n = >20,000
- All cause mortality decreased by 10% (RR 0.91, 95% CI 0.85-0.97)
- Risk of death from bleeding decreased by 15% (RR 0.85, 95% CI 0.76-0.96)
  - Best outcome if given within 3 hours of injury
- ~ After traumatic activity and in OB → increased activity of plasmin (helps offset paradoxical effect)

WOMAN Trial

Randomized, prospective study of obstetric patients
191 hospitals, 20 countries, n= >20,000
- Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008).
Takeaway: if pt hemorrhaging (elective, trauma, obstetrics) → admin w/in 3 hr → IMPROVES OUTCOMES

Answer 71

A

1 gm in 100cc/NSS given over 10 minutes (loading dose) → Followed by 1gm in 100cc/NSS over 8 hrs
Do not administer in the same line as blood products, rFVIIa or Penicillin
Should be stored between 15-30C or 56-86F

Answer 72

A

3% protein bound (does not bind to albumin)
Vd 9-12 liters
95% excreted unchanged
- Reduce dose in renal disease (see below)
Onset 5-15 min; duration 3 hours
E1/2 t= 2- 11 hours

Answer 73

A

Seizures
- GABA blockade in frontal cortex
Vision changes – particularly color vision
Ureteral obstruction and bleeding
Renal toxicity