Anticoag, antiplatelet, thrombolytics

Question 1

What is the physiology behind hemostasis?

Answer 1

• 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

Pathophys behind bleeding?

Answer 2

• 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

What causes platelet aggregation?

Answer 3

• 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

Where do intrinsic and extrinsic pathway converge?

Answer 4

Xa to becoem common pathway

Question 5

What is the goal of the coagulation cascade?

Answer 5

produce fibrin which staiblizes platelet plug

Question 6

What is vitamin K used for?

Answer 6

factors II, VII, IX, X

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

Question 7

Anti-thrombin’s roll in anticoagulant pharmacology?

Answer 7

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

(a= activated clotting factor)

major endogenous anticoagulant

Question 8

What is plasmin’s role in anticoagulant pathway?

Answer 8

inactive form= plasminogen

enzyme that breaks down a fibrin enriched clot

Question 9

Why do we care about anticoagulants as anesthesia providers?

Answer 9

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

1. anticoagulants (decrease production of fibrin)
2. antiplatelet drugs (reduce paltelet aggregation/function)
   
   • used for arterial thrombosis (ex atherosclerotic plaque rupture)
3. 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

What are some LMWH?

Answer 10

Enoxaparin (lovenox)

daltaparin (fragmin)

fondaparinux (arixtra)

tinzaparin (innohep)

Question 11

Example of Direct Xa inhibitos?

Answer 11

Rivaroxaban (xarelto)

apixaban (eliquis)

Question 12

Examples of direct thrombin inhibitors

Answer 12

Lepirudin (refludan)

bilvarudin (angiomax)

argatroban

dabigatran (pradaxa)

Question 13

What was warfarin originally? Currently used for?

Answer 13

• 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

MOA for warfarin?

Answer 14

• 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

PK/PD warfarin?

Answer 15

• 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

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

Answer 16

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

What is pregnancy category for warfarin?

Answer 17

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

• defastating malformations not compatible with life

Question 18

S/E from warfarin?

Answer 18

• 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

Interactions with warfarin?

Answer 19

• 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

Preop managmeent of patients on warfarin?

Answer 20

• 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

Postop managmenet of patients on warfarin?

Answer 21

• 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

Reversal of warfarin?

Answer 22

• 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

What are the 3 anticoagulants that work on antithrombin III?

Similarities/Differences between the 3?

Answer 23

1. heparin
2. LMWH
3. 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

What is unfractionated heparin?

Answer 24

• 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

Heparin PK/PD? indications for use?

Answer 25

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

What do we test to monitor heparin?

Answer 26

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

Adverse effects of heparin?

Answer 27

• 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

WHat is HIT?

Answer 28

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

What is used to reverse heparin?

Answer 29

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

Caution and contraindication for heparin?

Answer 30

• 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

Takeaway from heparin and neuraxial anesthesia?

Answer 31

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

What are LMWH?

Answer 32

• 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

Adverse effects and contraindications for lmwh?

Answer 33

• 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

What is fondaparinux (arixtra)

Answer 34

• 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

Any reversal agents for fondaparinux? cautions/contraindications?

Answer 35

• 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

What are some direct thrombin inhibitors?

Answer 36

• 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

What is dabigatran?

recommendations to stop before surgery?

Answer 37

• 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

Adverse effects and drug interactions with dabigatran?

Answer 38

• 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

Does dabigatran have a reversal agent?

Answer 39

• 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

What is Rivaroxaban (xarelto)?

Answer 40

• 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

Adverse effects of rivaroxaban (xarelto)?

Answer 41

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

Question 42

Is there a reversal agent for reivaroxaban (xarelto)

Answer 42

• 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

Blood test for xarelto? Recommnedations for xarelto holding preop?

Answer 43

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

Question 44

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

When do we resume?

Answer 44

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

What are the 3 major classes of antiplatelets?

Answer 45

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

Question 46

How do antiplatelets work?

Answer 46

• 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)
    • 2. 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

What is cox1? cox 2?

Answer 47

• 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

What happens with low, med, high dose asa?

Answer 48

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

ASA MOA?

Answer 49

• 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

Indication/ adverse effects ASA?

Answer 50

• 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

What are thienopyridines?

Answer 51

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

Examples of ADP Antagnoists?

Answer 52

• 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

Indications of clopidogrel?

Answer 53

• 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

Pharmacokinetics of Clopidogrel?

Answer 54

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

DRUG/DRUG interactions for Clopidogrel?

Answer 55

• 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

Adverse reaction for clopidogrel?

Answer 56

• 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

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

Answer 57

• 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

What is dipyridamole? 1/2 life? indications?

Answer 58

• 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

Adverse effects of dipyridamole?

Answer 59

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

Question 60

What are glycoprotein IIB/IIIA receptor antagonists? moa?

examples?

Answer 60

• 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

Indications for glycoprotein IIB/IIIA? adverse effects?

Answer 61

• 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

Perioperative management of patients on antiplatelet therapy?

Answer 62

Question 63

Examples of fibrinolytic therapy?

Answer 63

• Streptokinase
• Urokinase
• Tissue plasminogen activator tPA (alteplase)

Question 64

Goal of fibrinolysis?

Answer 64

• 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

Question 65

What is alteplase? indications?

Answer 65

• 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

Question 66

Adverse effects tPA?

Answer 66

• 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)

Question 67

When do we admin TPA?

Answer 67

• 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%

Question 68

Absolute/ relative contraindications for TPA therpay?

Answer 68

• 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

Question 69

What are some examples of procoagulants?

Answer 69

• 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

Question 70

What are lysine analogs?

Answer 70

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

Question 71

What have clinical trials with TXA shown?

Answer 71

**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

Question 72

Administration of TXA?

Answer 72

• 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

Question 73

Pharmacokinetics of TXA?

Answer 73

• 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

Question 74

s/e of TXA?

Answer 74

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