Anticoagulants, Antiplatelets and thrombolytics Flashcards
1
Q
What do Anticoagulants do?
A
prevent clot formation or extension of existing clot
2
Q
What do Antiplatelet agents do?
A
reduce platelet aggregation on the surface of the plateelt
3
Q
What do thrombolytics do?
A
convert endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed clots
4
Q
What are the four major counter-regulatory pathways of the intrinsic anticoagulant system?
A
fibrinolysis
tissue factor plasminogen inhibitor (TFPI)
protein C system
serine protease inhibitors (SERPINs)
5
Q
What is the main source of anticoagulation factors?
A
capillary endothelium
6
Q
How is prevention of blood coagulation outside the body maintained?
A
silionized containers
heparin in CPB or artifical kidney machines
citrate ion
7
Q
Tissue Factor Plasminogen Inhibitor
A
polypeptide produced by endothelial cells
acts as a natural inhibitor of the extrinsic pathway by inhibiting TF-VIIa complex
8
Q
What are the four key elements of the Protein C pathway?
A
protein C
thrombomodulin
endothelial protein C receptor
protein S
9
Q
How does protein C contribute to the APC?
A
enzyme with potent anticoagulant, profibrinolytic and anti-inflammatory properties. It 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
10
Q
How does thrombomodulin contribute to the APC?
A
a transmembrane receptor on the endothelial cells, it prevents the formation of the clot in the undamaged endothelium by binding to the thrombin
11
Q
How does endothelial protein receptor C contribute to the APC?
A
another transmembrane receptor that helps in the activation of Protein C
12
Q
How does Protein C contribute to the APC?
A
vitamin K dependent glycoprotein, synthesized by endothelial cells and hepatocytes. Activity can be free or bound. When bound it acts as an inhibitor to the complement system and is up regulated in the inflammatory states, which reduce the Protein S level thus resulting in a procoagulant state
It functions as a cofactor to APC in the inactivation of FVa and FVIIIa
13
Q
Antithrombin
A
previously known as AT III
it is the main inhibitor of thrombin
Binds and inactivates thrombin, factor 2a, IXa, Xa, XIa and XIIa
14
Q
When is the enzymatic activity of antithrombin (AT) enhanced?
A
In the presence of heparin
15
Q
Deficiency in Antithrombin
A
hereditary AT deficiency is estimated to be 1 in 2000-5000 acquired deficiency (prolonged heparin infusions >4-5 days decreased plasma AT activity by 50-60% of normal
16
Q
Antithrombin inhibits
A
Xa and IIa but also inhibits VIIa, IXa and XIIa
17
Q
Citrate Ion
A
any substance that deionizes the blood calcium will prevent coagulation
18
Q
How is an un-ionized calcium compound formed?
A
negatively charged citrate ion combines with positively charged calcium in the blood to cause un-ionized calcium compound
19
Q
What occurs with liver dysfunction or massive transfusion and citrate ion,
A
the citrate ion may not be removed quickly enough, and this can greatly depress the level of calcium in the blood
20
Q
Anticoagulants
A
vitamin K antagonist unfractionated heparin low molecular weight heparin and Fondaprinux direct thrombin inhibitors direct oral anticoagulants
21
Q
Coumadins are
A
vitamin K antagonist
22
Q
Coumarin
A
precursor reagent in the synthesis of a number of synthetic anticoagulants, warfarin
23
Q
Mechanism of action of Warfarin (Coumadins)
A
inhibit vitamin K which results in the hemostatically defective vitamin K dependent coagulation proteins (II,VII, IX, and X)
24
Q
MOA of Warfarin
A
competition of vitamin K for reactive sites (antagonism) in the enzymatic processes for formation of prothrombin and other clotting factors, producing the blocking action of vitamin K
25
Is platelet activity altered with warfarin adiministration?
no
| Its effects the coagulation cascade
26
Pharmacokinetics of Coumadin
rapidly and completely absorbed
97% protein bound
long elimination half time of 24-36 hours after oral administration
not suitable for pregnancy
metabolized to inactive metabolites that are conjugated and excreted in bile and urine
27
Why is coumadin unsafe for pregnancy?
it crosses the placenta and severely teratogenic
28
What is coumadin effective for?
prevention of thromboembolisms
29
What is the dose of coumadin?
2.5mg-10mg, dose varies
30
Onset of coumadin
3-4 days
31
Duration of single dose of coumadin
2-4 days
32
How are the effects of coumadin best tested?
PT/INR
33
INR Goals and Coumadin 2-3
Afib
Treatment of VTE, PE
prevention of VTE in high risk surgery
tissue heart valves
34
INR Goals of Coumadin (2.5-3.5)
Mechanical heart valve
prevention of recurrent MI
History of VTE with INR 2-3
35
Coumadin Management before surgery (minor surgery)
check PT/INR
d/c 1-5 days preoperative for PT 20% within baseline
restart 1-7 days postop
36
Coumadin Management before surgery (Immediate surgery)
24-48 hours prior or active bleeding
Vitamin K
2.5mg-20mg PO or 1-5 mg IV @ 1mg/min
PT to normal range within 4-24 hours
37
Coumadin Management before surgery (emergency)
FFP or 4 factor concentrate (Kcentra)
38
What is heparin
a naturally occurring polysaccharide that inhibits coagulation
released endogenously by mast cells and basophils and used widely as an anticoagulation drug
39
Which heparin is more unpredictable?
Unfractionated Heparin
40
Unfractionated Heparin
binds to anti-thrombin (antithrombin III)
which enhances the ability of antithrombin to further inactivate thrombin IIa, Factors Xa,XII,XI and IX
Functions as an anticoagulant by accelerating the normally occuring anti-thrombin induced neutralization of activated protein factors
neutralized thrombin prevents the conversion of fibrinogen to fibrin
41
Preparation of Unfractionated Heparin Preparation
large molecular weight
only about 1/3 of the administered heparin binds to antithrombin and this fraction is responsible for its anticoagulant effect
Must contain atleast 120 UPS Units/ml
Prescribed in units
42
Pharmacokinetics of Unfractionated Heparin
poor lipid solubility (large molecule)
cannot cross lipid barriers in significant amounts
does not cross placenta (safe in obstetrics)
once injected it circulates bound to plasma proteins
most commonly monitored by biologic activity
dose-response relationship
Decreaes in body temp prolongs elimination
43
Clinical Monitoring of Unfractionated Heparin
aPTT
ACT
HEPTEM
44
aPTT for monitoring Unfractionated heparin
1.5-2.5 times pre-drug value (30-35 seconds)
45
ACT for Unfractionated Heparin
baseline
3-5 min post administration
30 mins to 1 hour intervals post administration
46
Clinical Uses of Heparin
SQ VTE and PE prophylaxis
Warfarin bridge
vascular or non CPB cases vary ACT >200-300 seconds
interventional aneurysm clipping/coiling >250seconds
CPB: ACT >400-480 seconds (inadequate <180seconds)
47
Prophylaxis again Thromboembolism Dose of Unfractionated Heparin
5000units SC Q8-12 hours
48
Treatment of thromboemobolism Dose of Unfractionated Heparin
5000units IV following by continuous infusion for goal Ptt 1.5-2.5 times control value
49
Cardiopulmonary Bypass Dose of Unfractionated Heparin
400units/kg IV
50
Vascular Interventions Dose of Unfractionated Heparin
100-150units/kg IV
51
Side effects of Heparin
```
hemorrhage/hematomas
thrombocytopenia (HIT)
allergic reaction
hypotension with large doses
altered protein binding
chronic exposure cna progress to reduction of antithrombin activity
```
52
Heparin Induced Thrombocytopenia
heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia
53
Mild or Type 1 HIT
30-40% of heparin treated patients
nonimmune mediated
PLT count < 100,000 cells/mm3
typically presents 3-15 days after initiation of therapy starts
54
Severe or Type 2 HIT
immune mediated
plt count < 50,000
typically presents after 6-10 days after initation therapy
0.5-6% of treated pts
55
How do you confirm HIT?
laboratory tests for antibodies
56
Allergic reactions to Heparin
fever, urticaria and hemodynamic changes
57
Heparin Reversal
Protamine for heparin neutralizaion (100%)
| FFP
58
What is the dose of protamine for heparin reversal?
1-1.5mg for each 100 units of heparin administered
59
Low Molecular Weight Heparins
are derived from standard commerical grade unfractionated heparin by chemical depolymerization to yield fragments approximately 1/3 the size of heparin
60
What is the difference in the anti-activated factor ten to anti-activated factor 2 in LMWH vs unfractionated heparin?
LMWH - antiactivated factor X to antiactivated factor 2 activity is 4:1 to 2:1
UH- antiactivated factor X to anti-activated factor 2 activity is 1:1
61
Compare the protein binding of LMWH vs UH
LMWH less protein bound
| UH strongly protein bound
62
Compare dosing between LMWH and UH
LMWH- elimination 1/2 life 24 hours, once daily dosing
| UH- elimination 1/2 life 2-3 hours, repeat dosing every 8-12 hours
63
Advantages of LMWH
reduced dosing frequency and the lack of need for monitoring
more predictable pharmacokinetic response
fewer effects on platelet function
reduced risk for heparin induced thrombocytopenia
64
Disadvantages of LMWH
more expensive
surgery must be delayed 12 hours after last dose
protamine only neutralizes 65% of anti-factor X activity of LMWH a more complete reversal of LMWH must be wuth FFP
65
Enoxaparin
binds to and accelerates anti-thrombin
| inhibits factors Xa nad IIa
66
What does factor Xa in enoxaparin do?
catalyzes the conversion of prothrombin to thrombin, so enoxaparin's inhibition of this process results in decreased thrombin activity and prevention of fibrin clot formation
67
Direct Oral Anticoagulants are
alternatives to warfarin
68
Direct oral anticoagulants indications
treatment of VTE
prevention of embolic stroke
prophylaxis in patients undergoing surgery
69
Advantages of Direct Oral Anticoagulants
rapid onset with peak effect in 2-4 hours
predictable pharmacodynamics
minimal drug interactions
no required routine laboratory monitoring
70
Direct thrombin IIa inhibitor
dabigatran (pradaxa)
71
Dabigatran
renally eliminated (reduce dose)
1/2 life 12 hours
Reversal- idarucizumab (praxbind)
72
Monitoring of Dabigatran (Pradaxa)
coagulation assay
dilute thrombin time (more reliable and precise measurement)
aPTT (however, a normal aPTT does not exclude residual anticoagulant effect)
73
Idarucizumab
specific antidote for dabigatran
binds to dabigatran with 350 fold higher than thrombin
1/2 life is 45 mins
74
Direct Factor Xa inhibitors
rivaroxaban (xarelto)
apixaban (Eliquis)
Edoxaban (Savaysa)
75
Edoxaban (Savaysa)
Direct Factor Xa inhibitor
| MOA hepatic metabolism
76
Monitoring of Edoxaban (Savaysa)
coagulation assay - anti Xa
ROTEM is not sensitive
PT can be helpful indicator for rivaroxaban only
77
DOAC treated Patients undergoing Surgery (minimal bleeding)
likely safe to undergo with no DOAC interruptions (minor dental procedures, cataracts, skin biopsies)
78
DOAC treated Patients undergoing Surgery (low bleeding risk)
hernia repair
| generally recommended stopping DOCAs for 24 hours prior to elective surgery
79
DOAC treated Patients undergoing Surgery (high risk)
cardiac, intracranial
generally recommend interruption of DOAC therapy prior to 48 hours to surgery
* longer needed for renal patients taking dabigatran
80
Categories of Antiplatelet Agents
cyclooxygenase inhibitors
P2Y12 Receptor antagonist
Glycoprotein IIB/IIIA inhibitors
81
Antiplatelets
suppress platelet function (inhibit platelet aggregation) for prevention of thrombosis
82
Aspirin
exerts antithrombic effects by inhibiiting platelet aggregation
inhibits thromboxane A2 synthesis by interfering wiht the activity of cyclogenase 1 and 2 enzymes and the subsequent release of ADP by platelets and their aggregation
effects are irreversible and last the life of the platelet
83
Dose of aspirin
81-325mg
84
NSAIDs
ketorolac, naprosyn, ibuprofen
85
MOA of NSAIDs
```
same mechanism of action as aspirin (nonselective cox inhibitors) but they are reversibly depress thromboxane A2 production by platelets
more temporary (24-48 hours) and are often held prior to surgery
```
86
Primary prophylaxis in the management of ASA in the perioperative period
hyperlipidemia in the absence of established CV disease
ASA should be continued in the perioperative period up to and including the day of the procedure
ASA may be held for a few days at the discretion of the surgeon or procedural physician due to possible heightened risk for perioperative bleeding
87
Secondary prophylaxis in the management of ASA in the perioperative period
A fib, previous MI, stent
| ASA should be continued in the perioperative period up to and including the day of the procedure
88
What specific circumstances do you hold ASA?
intracranial, middle ear, posterior eye or intramedullary spine surgery; possibly in prostate surgery
89
P2Y12 receptor antagonist
clopidogrel (plavix) and ticagrelor (brillinta)
| must be discontinued 7 days prior to elective surgery
90
Clopidogrel and ticagrelor are
inhibitors of platelet activation and aggregation through irreversible binding of its active metabolite to the P2Y12 class of ADP receptors in platelets
91
What is Clopidogrel metabolized by and what is its effect?
prodrug
metabolized by CYP450 enzymes to produce the active metabolites that inhibits platelet aggregation for the the life of the platelet
92
What is best to restore hemostasis for emergent surgery with a patient taking P2Y21 receptor antagonist or Platelet Glycoprotein IIB/IIIa antagonist ?
platelet transfusion
93
Indications for P2Y12 receptor antagonist
```
secondary prevention of MI, CVA
coronary artery stenting
acute coronary syndrome
peripheral artery disease
as a general approach, elective surgical procedures should be delayed by at least 6 weeks after BMS and ideally 6 months after DESd
```
94
ASA and P2Y12 receptor antagonists work
synergistically
95
Withdrawl of ASA in patients with CAD is associated with a
2-4 fold increase in death/MI
96
Platelet Glycoprotein IIB/IIIa antagonist act at teh
corresponding fibrinogen receptor that is important for platelet aggregation
blocks fibrinogen which is the final common pathway of platelet aggregation
97
What are Platelet Glycoprotein IIB/IIIa antagonist used for?
ACS, angioplasty failure, stent thrombosis
98
Platelet Glycoprotein IIB/IIIa antagonist are
abciximab (reopro)
tirofiban (aggrastat)
epitifibatide (integrilin)
99
Platelet Glycoprotein IIB/IIIa antagonist Monitoring
their effects can be monitoring with ACTs and reversible with the clearance of the drug
most of these agents are renally excreted and have half-lives around 2.5 hours except abciximab
100
Garlic
inhibits platelet aggregation d/c for 7 days
101
Gingko
inhibits platelet aggregation factor discontinue for 36 hours
102
Ginseng
inhibits platelet aggregation and lowers BG
| check pt/ptt and glucose d/c for 24 hours (preferably 7 days)
103
Black Cohosh
includes small amounts of anti-inflammatory compounds, including salicylic acid
104
Feverfew
prevents migraines
increases risk of bleeding because it individually inhibits platelet aggregation, has additive effects with other antiplatelet drugs
105
Feverfew has additive effects with
warfarin
106
Plasminogen
is a serum protein that is absorbed into the clot at its formation
107
Plasmin
breaks down fibrin and fibrinogen
| is cleaved from plasminogen
108
Where is tissue pasminogen activator and urokinase-type plasminogen activators released from
capillary endothelium
109
Fibrin specific agents (thrombolytics)
alteplase
reteplase
tenecteplase
110
Non-fibrin specific agents
streptokinase
111
Thrombolytics
possess inherent fibrinolytic effects or enhances the body's fibrinolytic system by converting endogenous pre-enzyme plasminogen to the fibrinolytic enzyme plasmin
112
Thrombolytics (contd)
convert plasminogen to the active form, plasmin
| plasmin breaks down fibrin
113
Alteplase
recombinant tissue plasminogen activator
fibrin specific thrombolytic drug synthesized by endothelial cells
limited to use to the first 3-6 hours of ischemic stroke
can be administered systemically or directly into embolism (place of invasive lines before administration)
short 1/2 life (about 5 mins) usually administered as bolus then infusion
114
Streptokinase
protein produced by beta hemolytic streptococci
not an enzyme, noncovalently binds to plasminogen and converts it to a plasminogen-activator complex that acts on other plasminogen molecules to generate plasmin
elimination half time is 20 minutes
bacterial product is may stimulate antibody production and subsequent allergic reactions (even if years later)
it is least expensive of thrombolytic drugs
115
Adverse effects of Thrombolytics
bleeding
re-thrombosis
efficiacy depends on clot
116
Thrombolytics possess
inherent fibrinolytic effects
117
Antithrombotic drugs influence
the formation of clot by inhibiting platelet activity
