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anticoags, antiplatelets, fibrinolytics Flashcards

1
Q

anticoagulant basic definition

A

prevent clot formation or extension of existing clot

have no effect after clot is formed

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2
Q

antiplatelet/antithrombotic basic definition

A

reduce PLT aggregation on the surface of the PLT

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3
Q

thrombolytics/fibrinolytics

A

converts endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed blood clots

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4
Q

what are the four major intrinsic anticoagulant mechanisms/pathways

A

fibrinolysis
tissue factor plasminogen inhibitor
protein C system
serine protease inhibitors

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5
Q

what is the main source of anticoagulation factors

A

the capillary endothelium

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6
Q

in what ways do we prevent blood coagulation outside the bodyo

A

siliconized containers
citrate ion (eats calcium)
heparin or CPB in artificial kidney disease

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7
Q

Tissue factor plasminogen inhibitor

A

a polypeptide produced by endothelial cells that acts as a natural inhibitor of the the extrinsic pathway by inhibiting the TF-VIIa complex

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8
Q

what are the 4 key elements of the Protein C pathway

A

Protein C
thrombomodulin
endothelial protein C receptor
protein S

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9
Q

what is protein C

A

an enzyme with potent anticoagulant, fibrinolytic, and anti-inflammatory properties that is activated by thrombin to form activated protein C (APC) and acts by inhibiting activated factors V and VIII (with protein S and phospholipids acting as cofactors)

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10
Q

what is thrombomodulin

A

a transmembrane receptor on the endothelial cells that prevents the formation of the clot in the undamaged endothelium by binding to the thrombin

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11
Q

what is endothelial protein C receptor

A

a transmembrane receptor that helps in the activation of protein C

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12
Q

what is protein S

A

a vitamin K dependent glycoprotein, synthesized in the endothelial cells and hepatocytes

unbound form acts as a cofactor to APC in the inactivation of factor Va and VIIIa

bound form acts as an inhibitor of the complement system and is up-regulated in the inflammatory states which reduce the protein S levels, resulting in a pro-coagulant state

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13
Q

SERPIN

A

formerly known as antithrombin III and is the MAIN INHIBITOR OF THROMBIN

binds and inactivates thrombin, IIa, IXa, Xa, XIa, and XIIa

enzymatic activity is enhanced in the presence of heparin

synthesized in the liver and the plasma half life is 2.5-3.8 days

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14
Q

SERPIN/AT3 deficiency

A

hereditary is 1 in 2,000-5,000

acquired (d/t prolonged heparin infusions >4-5days) shows decreased plasma AT activity by 50-60% of normal

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15
Q

citrate ion and anticoagulation

A

citrate deionizes calcium because it is negatively charged and it binds to the positively charged calcium to cause an un-ionized calcium compound

citrate ion is removed by the lier and polymerized into glucose or metabolized
**if there is liver damage or massive transfusion, the citrate ion might not be removed quickly enough and this can greatly depress the level of calcium ion in the blood

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16
Q

what are the 5 types of anticoagulants listed on her slide

A 
vitamin K antagonist
 unfractionated heparin
low molecular weight heparin and fondaprinux
direct thrombin inhibitors
direct oral anticoagulants
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17
Q

coumadin/warfarin is what type of anticoagulant

A

vitamin K antagonist

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18
Q

mechanism of action of coumadin

A

inhibits vitamin K which results in hemostatically defective vitamin K dependent coagulation proteins (II, VII, IX, and X)

this is caused by competing with vitamin K for reactive sites in the enzymatic processes for formation of prothrombin and the other clotting factors, thereby blocking the action of vitamin k

platelet activity is not altered

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19
Q

which are the vitamin K dependent clotting factors

A

II, VII, IX, X

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20
Q

coumadin PK

A

rapidly and completely absorbed
97% protein bound
long elimination half time (24-36h) after PO
crosses placenta and is teratogenic so NO TO PREGNANT MOMS
metabolized into inactive metabolites that are conjugated and excreted in bile and urine

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21
Q

dosing of coumadin

A

2.5-10mg orally, dose varies

onset 3-4 days

single dose duration 2-4 days

effects seen on INR for 8-12 hours d/t depletion of factor VII, but full clinical effects are not appreciated for several days

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22
Q

how do you measure coumadin anticoagulation?

A

PT/INR

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23
Q

what is your INR goal for a patient taking coumadin with A-fib, VTE, PE, tissue heart valve, or VTE prophylaxis?

A

2-3

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24
Q

what is your INR goal in a patient with a mechanical heart valve, prevention of recurrent MI, history of VTE with INR 2-3

A

2.5-3.5

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25
Q

coumadin management before surgery

A

CHECK PT/INR

minor surgery: d/c 1-5 days preop for PT 20% within baseline and restart 1-7 days post op

immediate surgery (24-48h) or active bleeding: give vitamin K

emergency: give FFP or 4-factor concentrate (Kcentra)

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26
Q

what is the dose of vit K for coumadin reversal

A

2.5-20mg orally or 1-5mg IV at a rate of 1mg/min

PT to normal range within 4-24 hours

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27
Q

what is heparin and where does it come from

A

a naturally occurring polypeptide that inhibits coagulation

it is released endogenously by mast cells and basophils and used widely as an anticoagulation drug

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28
Q

where does unfractionated heparin come from

A

derived from porcine intestine or bovine lung and is a mix of sulfated glycosaminioglycans that produce an anticoagulant effect by binding to and enhancing the naturally occurring effects of antithrombin

**more predictable than LMWH

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29
Q

how does unfractionated heparin work

A

it binds to antithrombin and enhances the ability of antithrombin to inactive thrombin, Xa, XII, XI, and IX by 1000X

accelerates the normally occurring antithrombin-induced neutralization of activated clotting factors

long story short, decreased thrombin = decreased fibrin = decreased clotting

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30
Q

unfractionated heparin prepartions

A

large molecular weight

only1/3 of what is administered binds to antithrombin to cause effect

1 unit of activity is the amount of heparin that maintains fluidity of 1 ml of citrated plasma for 1 hour after recalcification

must contain at least 120 UPS units/ml

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31
Q

unfractionated heparin PK

A

poorly lipid soluble because it is large
cannot cross lipid barriers or placenta - safe for OB
circulates bound to plasma proteins which occurs instantly
action is 1.5-4 hours
decrease in body temp prolongs half time

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32
Q

what are the dose-response relationships for heparin?

A

100u/kg IV elimination half time = 56 minutes

400u/kg IV elimination half time = 152 minutes

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33
Q

aPTT on heparin

A

should be 1.5 to 2.5 time longer than pre-drug(25-35s normal)

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34
Q

when to draw ACT on heparin

A

baseline
3-5 minutes post admin
30min-1hr intervals post admin

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35
Q

what are the three labs for monitoring unfractionated heparin

A

aPTT
ACT
HEPTEM

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36
Q

what are the clinical uses of heparin

A

SQ VTE and PE prophylaxis
warfarin bridge
vascular or non-CPB cases with goal ACT >200-300sec
interventional aneurysm clipping/coiling with goal ACT>250sec
CPB/ECMO with goal ACT>400-480sec (inadequate <180)

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37
Q

how would you dose unfractionated heparin for thromboembolism prophylaxis

A

5,000u SQ every 8-12 hours

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38
Q

unfractionated heparin dosing for treatment of thromboembolism

A

5,000u SQ followed by continuous gtt for goal PTT 1.5-2.5X control

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39
Q

unfractionated heparin dosing for CPB/ECMO

A

400u/kg IV

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40
Q

unfractionated heparin dosing for vascular interventions

A

100-150u/kg

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41
Q

heparin side effects

A 
hemorrhage/hematomas
HIT
allergic reaction
hypotension with large doses
altered protein binding
chronic exposure can progress to reduction of antithrombin activity
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42
Q

incidence of intraspinal hematoma

A

0.1 per 100,000 patients per year

more likely to occur in anticoagulated or thrombocytopenic patients, those with neoplastic disease, liver disease, or alcoholism

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43
Q

IV heparin and neuraxial anesthesia

A

1 hour delay between needle placement and heparin administration

catheter should be removed for 1 hour before heparin administration and 2-4 hours after last dose

monitor PTT or ACT

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44
Q

heparin induced thrombocytopenia

A

heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia

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45
Q

mild/type I HIT

A

30-40% of heparin treated patients

non immune mediated
plt count <100,000 cells/mm3
typically presents in 3-15 days after initiation of therapy

46
Q

severe/type II HIT

A

0.5-6% of heparin treated patients
immune mediated
plt count <50,000 cell/mm3
present 6-10 days after initiation of therapy

47
Q

how do you confirm HIT in patients with low platelet counts that you suspect this disease

A

lab tests for presence of antibodies

48
Q

antithrombin deficiency and heparin

A

patients with this will have resistance to heparin because heparin binds to AT

this occurs in up to 22% of patients undergoing cardiac surgery
common in patients who receive intermittent or continuous heparin therapy

estrogen also decreases heparin’s ability to bind to AT

you can treat this by restoring normal values with 2-4u FFP in adults or antithrombin concentrate

49
Q

what is the reversal for heparin

A

protamine or FFP

50
Q

what is the dose of protamine?

A

1-1.5mg for each 100u of heparin administered

51
Q

low molecular weight heparins

A

derived from standard commercial grade unfractionated heparins by chemical depolymerization to yield fragments approximately 1/3 the size of heparin

the depolymerization results in changes to the anticoagulant profile, PK, and effects on platelet function

52
Q

differences in LMWH to unfractionated heparin (there are 4)

A

anti-activated factor X to anti-activated factor II activity:

  • LMWH: 4:1-2:1
  • unfract: 1:1

molecular weight:

  • LMWH: 4,000-5,000 Daltons
  • unfract: 30,000 Daltons

protein binding:

  • LMWH: less strong
  • unfract: strongly

elimination half life/dosing:

  • LMWH: 24h/once daily
  • unfract: 2-3h/8-12h(BID-TID)
53
Q

lovenox

A

binds to and accelerates antithrombin and inhibits factor Xa and factor IIa
= decreased thrombin activity and prevention of fibrin clot formation
used for DVT prophylaxis

54
Q

dose of lovenox dvt prophylaxis

A

30mg SQ every 12h

55
Q

advantages of using a LMWH like lovenox

A 
reduced dosing frequency
lack of need for monitoring
more predictable PK
fewer effects on platelet function
reduced risk for HIT
56
Q

disadvantages of using a LMWH like lovenox

A

more expensive
surgery must be delayed for 12h after last dose
protamine only neutralizes about 65% of anti-factor X activity, so a more complete reversal requires FFP

57
Q

direct oral anticoagulants are used for

A

alternatives to warfarin
treatment of VTE
prevention of embolic stroke
prophylaxis in patients undergoing surgery

58
Q

what are the DOACs approved in most countries

A

direct thrombin inhibitor (IIa) - dabigatran

direct factor Xa inhibitor - rivaroxaban, apixaban, edoxaban

59
Q

advantages of DOACs

A

rapid onset with peak effect in 2-4h
predictable PK/PD
minimal drug interactions
no required routine lab monitoring

60
Q

dabigatran (pradaxa)

A

direct thrombin (IIa) inhibitor

metabolized via renal elimination

half life is 12 hours unless reduced renal function

monitor via coagulation assay

reverse with idarucizumab (praxbind)

61
Q

what is included in a coagulation assay

A

dilute thrombin time (more reliable and precise)
aPTT (normal does not mean no residual anticoag effects)
ROTEM (might correlate but less specific than dilute thrombin time)

62
Q

idarucizumab - praxbind

A

this is an antidote for pradaxa aka dabigatran

binds to dabigatran with 350X more affinity than thrombin

half life is 45 minutes

63
Q

factor Xa inhibitors name them

A

rivaroxaban (xarelto)
apixaban (eliquis)
edoxaban (savaysa)

64
Q

metabolism of direct factor xa inhibitors

A

hepatic

65
Q

monitoring for direct factor Xa inhibitors

A

coagulation assay - anti-xa (not widely available)
ROTEM is not sensitive
PT can be a helpful indicator of rivaroxaban only

66
Q

general management of DOAC-treated patients undergoing surgery

A

minimal bleeding risk procedures are likely to undergo with no DOAC interruptions

low bleeding risk procedures - stop DOAC for 24h prior to elective surgery

high bleeding risk procedures - stop DOAC for 48h prior to elective surgery

67
Q

what is the reversal for dabigatran

A

idarucizumab

68
Q

what is the reversal for apixaban and rivaroxaban?

A

andexanet alfa

69
Q

what is the reversal for vitamin K antagonists

A

PCC - prothrombin compex concentrates

70
Q

what are the antiplatelet agents

A

cox inhibitors
P2Y12 receptor antagonists
GP IIb/IIIa inhibitors

71
Q

antiplatelets

A

suppress platelet function (aka inhibit platelet aggregation) for the prevention of thrombosis

72
Q

when is antiplatelet therapy indicated

A

for patients at risk for CVA, MI, or other vascular thrombosis complications

73
Q

asprin

A

inhibits platelet aggregation by inhibiting thromboxane A2 synthesis by interfering with cox and the subsequent release of ADP by platelets and their aggregation

effects are irreversible and last the life of the platelet (8-12 days)

74
Q

what is the dose of aspirin

A

81-325mg

75
Q

how does aspirin work

A

cox is rendered non-functional because the acetyl group of ASA causes acetylation of cox which is the enzyme that converts arachidonic acid to thromboxane

76
Q

NSAIDs

A

ketorolac, naprosyn, ibuprofen

same MOA as aspirin but they reversibly depress thromboxane A2

so effects are only 24-48h and are often held prior to surgery

77
Q

how to manage ASA in periop period

A

primary prophylaxis: ASA should be continued in periop period for up to and including day of procedure, but could be held for a few days at discretion of surgeon
- think patients with hyperlipidemia but no established CV disease

secondary prophylaxis: ASA should be continued in periop period for up to and including day of procedure, and should not be stopped unless there has been an explicit discussion with their cardiac/vascular physician to establish cardiac risk vs bleeding risk
- think patients with a-fib, previous MI, stent

HOLD ASA for intracranial, middle ear, posterior eye, or intramedullary spine surgery, possibly in prostate surgery and DOCUMENT decision

78
Q

P2Y12 receptor antagonist MOA

A

inhibitors of platelet activation and aggregation through the irreversible binding of its active metabolite to the to the P2Y12 class of ADP receptors on platelets

79
Q

clopidrogel

A

aka plavix

P2Y12 receptor antagonist

this is a pro-drug and must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation for the life of the platelet

80
Q

ticagrelor

A

aka brillinta

P2Y12 receptor antagonist

does not need hepatic activation and might work better for pateints with genetic variants

better mortality rates in treating patients with ACS

81
Q

how long must you hold P2Y12 inhibitors?

A

7 days prior to elective surgery

82
Q

if your patient is having emergency surgery and they are on a P2Y12 inhibitor, what could you do?

A

platelet transfusion

83
Q

indications for P2Y12 antagonists

A 
secondary prevention of MI, CVA
coronary artery stenting
ACS
PAD
PCI
84
Q

PCI and stent placement

A

PCI causes endothelial and medial damage that heals by neointimal formation usually within 2-6 weeks with BMS

DES - this healing is delayed which can cause risk for platelet aggregation and thrombus formation, so they are usually anticoagulated for up to a year

elective surgery should be delayed by at least 6-12 months following DES placement

85
Q

if you see a patient taking aspirin and plavix what should you think

A

ASA and P2Y12 antagonists act synergistically so they are going to be a high bleed risk

86
Q

over 10% or ACS in periop period is associated with what

A

preop cessation of ASA

87
Q

how long are patients with stents at a high risk of thrombotic events?

A

the first 3 months after insertion

88
Q

platelet GP IIa/IIIb antagonists MOA

A

act at the corresponding fibrinogen receptor that is important for platelet aggregation to block fibrinogen which is the final common pathway of platelet aggregation

89
Q

when are GP IIa/IIIb antagonists used

A

ACS, angioplasty failures, stent thrombosis

90
Q

what are the GP IIa/IIIb antagonists

A

abciximab (reopro)
tirofiban (aggrastat)
eptifibatide (integrilin)

91
Q

how to monitor GP IIa/IIIb antagonists

A

ACTs (maintained between 200-400sec)

platelet counts - d/c if thrombocytopenia (<100,000 cells/mm3) develops

92
Q

how do you reverse the effects of GP IIa/IIIa antagonists?

A

platelet transfusions

93
Q

what are the herbal anticoagulants

A 
garlic
gingko
ginseng
black cohosh
fish oil
feverfew
94
Q

garlic

A

inhibits platelet aggregation - d/c for seven days

95
Q

gingko

A

inhibits platelet activating factor - d/c for 36h

96
Q

ginseng

A

inhibits platelet aggrevation and lowers blood glucose

check PT/PTT/glucose

d/c for 24h but preferably 7 days

97
Q

black cohosh

A

claims to be useful for menopausal symptoms

contains small amounts of anti-inflammatory compounds including salicylic acid

98
Q

fish oil

A

claims to prevent/treat atherosclerotic CV disease (800-1500mg/day)
also used to treat triglycerides (>4g/day)

dose-dependent bleeding risk with >3g/day

99
Q

feverfew

A

claims to prevent migraines

increases the risk of bleeding because it individually inhibits platelet aggregation

has additive effects with other antiplatelet drugs and additive effects with warfarin

100
Q

plasminogen

A

a serum protein that is absorbed into the clot as it forms

it is cleaved into plasmin which breaks down the fibrin and fibrinogen of a clot

activated by t-PA and urokinase-type-PA

101
Q

which thrombolytics are fibrin specific and which are non-fibrin specific

A

fibrin specific: alteplase, reteplase, tenecteplase

non-fibrin specific: streptokinase

102
Q

thrombolytics

A

possess inherent fibrinolytic effects or enhances the body’s fibrinolytic system by converting the endogenous pro-enzyme plasminogen to the fibrinolytic enzyme plasmin

they are more capable of dissolving newly formed clots which are platelet rich and have weaker fibrinogen bonds

103
Q

why do we use thrombolytics

A

to restore circulation through a previously occluded vessel

  • STEMI
  • acute ischemic stroke
  • acute massive PE
104
Q

when are thrombolytics contraindicated

A

trauma, severe HTN, active bleeding, pregnancy

105
Q

what is the most common risk of thrombolytics

A

hemorrhage or bleeding

106
Q

what is the window from event time to giving a thrombolytic

A

6 hours

107
Q

alteplase (recombinant tissue plasminogen activator)

A

a fibrin-specific thrombolytic drug synthesized by endothelial cells

limited to use int he first 3-6h of ischemic stroke

can be administered systemically or directly into embolism

t1/2 5 minutes - usually administered as a bolus and then infusion

108
Q

streptokinase

A

protein produced by beta-hemolytic streptococci

it is not an enzyme

it non-covalently bonds to plasminogen and converts it to a plasminogen activator complex that acts on other plasminogen molecules to generate plasmin

it is the lease expensive of the thrombolytics

but since it is made from bacteria, antibodies may form and you could have allergic reaction

109
Q

what are the thrombolytic therapy adverse effects

A

bleeding

re-thrombosis so administer with other anticoagulants that are longer acting

110
Q

what does the efficacy of thrombolytic therapy depend upon

A

age of clot

older clots have more crosslinking and are more compacted so they are more difficult to dissolve

Advanced Pharm (11 decks)

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