Anticoagulants Flashcards
1
Q
Anticoagulants alters?
A
Alters coagulations cascade
2
Q
Antiplatelets prevent ________by _______
A
Prevent formation of clot by blocking platelets
3
Q
Fibrinolytics
A
Work in fibrinolytics pathway, BREAK DOWN CLOTS
4
Q
**Prothrombin: In particular, this test measures the activity of 3 specific vitamin K dependent clotting factors
A
Factors II, VII, X
5
Q
*****Prothrombin (PT)
Which pathway?
A
Determines the function of the extrinsic system and the
common pathway of the coagulation system
6
Q
activated PTT is
Which pathway?
A
Measures the activity of the intrinsic and common pathway of the coagulation system
7
Q
INR
A
Mathematical correction of prothrombin time
8
Q
aPTT used for what 2 main medications class
A
The aPTT is widely used for monitoring unfractionated heparin and INJECTABLE direct thrombin inhibitors
9
Q
aPTT Measures factors:
A
IXa, Xa, and XIIa
10
Q
aPTT not used for those patients ? used ?
A
Lupus Anticoagulant (LAC); ACT
11
Q
What does ACT measure?
A
• Measures the activity of the intrinsic and common pathway of the coagulation system
12
Q
What is the normal ACT range?
A
100-150
13
Q
Used to manage (ACT Test)
A
Cardiothoracic surgery
PCI
14
Q
What is the goal of ACT for most procedures
A
300-450 seconds
15
Q
Thrombin Time monitors _____and normal is ____
A
Factor IIa; <30seconds
16
Q
If Thrombin time is prolonged, 2 reasons:
A
- deficiency of fibrinogen
- inhibition of thrombin
17
Q
Any drugs that decreases thrombin activity would elevated:–>
A
Thrombin Time
18
Q
Anticoagulants and Spinal/Epidural HEMATOMA WARNING
A
DO a risk assessment before for patients on unfractionated heparin, fonduparix
Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, NSAID’s, platelet inhibitors or other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
19
Q
Unfractionated heparin derived from?
A
Derived from PIG INTESTINE mucosa
20
Q
Unfractionated heparin MOA
A
Heparin acts by FIRST binding to and forming a complex with antithrombin (formally called antithrombin III, AT-III) causing a conformational change in AT which accelerates the action of antithrombin (endogenous coagulants) by 1,000 fold or more.
**The AT/Heparin complex then irreversibly inhibits the activated coagulation factors IIa, IXa, Xa, XIa and XIIa
21
Q
The AT/Heparin complex
A
inhibits the activated coagulation factors IIa, IXa, Xa, XIa and XIIa
22
Q
_______is a required cofactor for UFH anticoagulant effects
A
Antithrombin
23
Q
• By inactivating thrombin (factor IIa), heparin not only prevents fibrin formation but also
A
inhibits thrombin-induced activation of factor V and factor VIII
24
Q
2 main ones carrying the action of heparin
Most sensitive by the AT/Heparin complex
A
Thrombin (IIa)
Factor Xa
25
Heparin must bind to BOTH________And ________ to form a Ternary Heparin/AT/Thrombin Complex in order for thrombin to be
AT and thrombin; inactivated
26
Heparin need __________ via its high-affinity pentasaccharide sequence in order to ______
only bind to AT
| to inactivate factor Xa
27
Heparin blocks the
intrinsic and common pathways of the coagulation cascade
28
Heparin display what kind of pharmacokinetics
nonlinear pharmacokinetics, half life useless
29
Heparin cross lipid barriers?
| Lipid soluble?
Heparin is a poorly lipid-soluble, high-molecular weight substance that cannot cross lipid barriers in significant amounts
30
2 routes for heparin
SC and IV
31
• NEVER give UFH via_______ due to potential for large
| hematoma formation
IM route
32
____ and_______can prolong the biologic t1/2 of heparin
Hepatic disease and renal dysfunction
33
Heparin effects will
vary amont patient to patient
34
Clearance mechanism of Heparin
| 2 mechanisms:
* First, heparin is cleared and degraded primarily by th RETICULOENDOTHELIAL system, this is a rapid and saturable process (that's why its NONLINEAR)
* At therapeutic doses, a large proportion of heparin is cleared through this mechanism
• A second slow and non-saturable process involves renal clearance of undergraded heparin and this predominates at very higher doses
35
Does heparin cross placenta?
| drug of choice for pregnant patient
NO; heparin
36
The anticoagulant activity of heparin can be monitored using any of the following tests:
1. aPTT (activated Partial Thromboplastin Time)
2. ACT (Activated Clotting Time)
3. Heparin anti-factor Xa assay
37
Heparin Anticoagulants monitoring:
monitors?
sensitive to which factors?
APTT ration of ____to _____the control reagent/normal value is the goal for coagulation
aPTT (activated Partial Thromboplastin Time)
• Sensitive to levels of thrombin (IIa), factor IXa, Xa and XIIa
aPTT ratio of 1.5 to 2.5 times the control reagent/normal values is the goal for anticoagulation
38
aPTT assess 2 pathways
Intrinsic and final common pathways
39
Used to monitor higher heparin doses and concentrations given to patients undergoing _____or ______ procedures
PCI and CABG
| ACT (300-450 seconds maintained throughout entire procedures)
40
This is the most accurate assay for monitoring UFH therapy (outside of OR)
Expected therapeutic range is
Heparin anti-factor Xa assay
| 0.3-0.7 anti-Xa units/mL
41
VTE Prophylaxis
• Heparin 5000 units SQ q 8 - 12 hours
42
Coagulation of heparin is based on (dosing)
WEIGHT
43
• Heparin requirements are increased during
pulmonary embolic disease
44
• Heparin requirements are reduced and elimination t1/2 is prolonged in
hypothermia
45
Nitroglycerin has been reported to ________heparin’s
| anticoagulant effects which may the required dose of heparin
decrease; increase
46
Most common site of bleeding for Heparin is the
GI tract
47
Anaphylactoid and hypersensitivity reactions
Fever, chills, urticaria, tachycardia, hypertension, dyspnea, cardiopulmonary arrest
48
Heparin is protein bound
YEs highly,
49
Heparin can displace those drugs
Diazepam and propranolol
50
• Thrombocytopenia resulting from the use of heparin products can be classified into two distinct categories/syndromes
* Heparin-associated thrombocytopenia (HAT)- harmless
| * Heparin-induced thrombocytopenia (HIT)
51
Thrombocytopenia defined as
| platelet range for thrombocytopenia
Early, mild, transient fall in platelet count
| Defined as a platelet count of 100 – 130 × 103/mm3
52
Thrombocytopenia occurs when?
| What percentage of patients
Occurs 1 – 4 days after the start of heparin therapy
| 25%
53
Body from antibodies
IgG
54
Pathophysiology of Thrombocytopenia
- PF4 found on endothelial cells and platelets
- Heparin binds to PF4 forming a heparin-PF4 complex. IgG antibodies in circulation bind to this complex & activate platelets & cause the release of prothrombotic
microparticles, platelet consumption, thrombocytopenia & thrombosis
55
Diagnosis of HIT is based on both clinical and serological findings:
Platelet count
onset within ________days
* Platelet count drop < 150,000 mm3 OR 50% drop in baseline platelet count (even if the platelet count is > 150,000 mm3)
* Onset within 5-14 days after starting ANY UFH product
* Thrombosis associated with thrombocytopenia
* Other causes of thrombocytopenia ruled out
56
****To have a diagnosis of HIT you must have the presence of_____________
Anti-PF4-Antibodies
57
Treatment of HIT
- remove intra-___catheter
| - Used an INJECTABLE Direct thrombin inhibitors.
58
Reversal Agent of heparin
• Protamine sulfate is the antidote to the anticoagulation effect from unfractionated heparin therapy
59
Action of protamine (acid base reaction)
Protamine is a POSITVELY charged strong base polypeptide that interacts with NEGATIVELY charged acidic heparin molecules via a neutralization reaction (acid-base interaction) to form a STABLE SALT COMPLEX that has no anticoagulant properties.
These heparin-protamine complexes are then removed by the RETICULOENDOTHELIAL system
60
Protamine Reversal Dosing
| Dose is _______protamine to inactive ______Units of heparin
• Dose is approximately 1 mg of protamine to inactivate 100 USP units of heparin predicted to still be in circulation
61
• Another calculation used is administration of ______of protamine for each 100 USP units of heparin present as calculated from the ACT
1.3 mg/kg
62
• Clearance of protamine by the reticuloendothelial system (within_______) is more rapid than heparin clearance and this may explain, in part, the phenomenon of heparin rebound
20 minutes)
63
*****• Dose is approximately 1 mg of protamine to inactivate
100 USP units of heparin PREDICTED TO STILL BE IN CIRCULATION
64
To predict how much heparin useful to know
last infusion rate, last 2 hours
65
Protamine sulfate’s t1/2 =
7 minutes (short)
66
Protamine Adverse effects
***Hypotension
***Bradycardia
****Dyspnea
*****Flushing feeling of warmth
Acute pulmonary hypertension
Edema
Bronchoconstriction
RVF
67
Rapid IV injection of protamine may be associated with
```
Histamine release causing :
severe hypotension
bradycardia
facial flushing
dyspnea.
```
68
Rapid IV also can lead to
increase the risk of anaphylactoid reactions
69
Max infusion rate of Protamine
5mg/min
70
Allergic reactions to protamine have been described most often in_________ preparations containing protamine
diabetics receiving insulin
71
• Patients that are _____ _______may have a higher incidence of allergic reactions to protamine since protamine sulfate is derived from fish sperm
allergic to fish
72
• LMWHs are NEVER
clinically interchangeable with one another on a unit-for-unit basis! because of the molecular size and action
73
3 low molecular weights heparin are (-parin)
* Lovenox® (Enoxaparin)
* Fragmin® (Dalteparin)
* Innohep® (Tinzaparin)
74
Low Molecular Weight Heparins:
| Mechanism of Action
• LMWH’s first bind to antithrombin by a unique pentasaccharide sequence ---->a conformational change in antithrombin and this LMWH/AT complex then inactivates factor Xa and inactivates to a lesser degree thrombin (factor IIa), BUT both factors are inactivated
75
LMWH inactivates those two factors
Xa (more) and IIa (less)
76
why LMWH inactivates Xa more because
more selective because they are two short to form the complex
77
Heparin vs. LMWH
Produces a more______and______duration of
anticoagulant response compared to UFH since LMWH’s have less_________ to circulating and cellular proteins compared to UFH
PREDICTABLE & longer ;binding
78
LMWH • t1/2 is dose_______and prolonged in _________
-INDEPENDENT and prolonged in renal dysfunction
79
LMWH Excretion
| • Cleared primarily via the
kidneys
80
Pharmacokinetics of low molecular weight heparin, they do follow linear pharmacokinetics so wait at least ________steady state
4-5
81
• Routine anticoagulant laboratory monitoring for LMWH (necessary/not necessary) due to their predictable anticoagulant response and pharmacokinetic profile
IS NOT necessary
82
***_________level for LMWH is the recommended test if
| anticoagulant monitoring is required
• Antifactor-Xa
83
For LMWH, you must monitor which organ?
renal function
84
Adverse effects of LMWH
Bleeding
85
NO antidote for LMWH but on a test_____________ is the antidote, % of neutralization
Protamine, neutralization up to 60%
86
******Low Molecular Weight Heparins:
| Neuraxial Anesthesia Implications
Spinal anesthesia/epidural anesthesia/LP
• Prior to procedure, wait at least 12 hours (once daily prophylaxis doses) or 24 hours (BID prophylaxis or treatment doses) after the last dose of LMWH BEFORE CONsidERING catheter placement
87
****Administer first dose of LMWH a MINIMUM of
2 hours AFTER the catheter has been removed
88
AriXtra® (fondaparinux)
synthetic pentasaccharide class agent
89
Is AriXtra heparin?
Is a Non-Heparin Product!
90
How does ariXtra acts? selective, (direct/indirect)
• Is a selective, in-direct inhibitor of Factor Xa only!
91
Which factor does ARIXTRA inhibit?
Factor Xa
92
What does ARIXTRA does NOT DO?
DOES NOT increase the rate of thrombin inhibition
| by antithrombin
93
AriXtra indirectly inhibits ONLY factor Xa by
reversibly binding to antithrombin
94
AriXtra half life is
long
95
Main route of elimination for AriXtra
Kidneys
96
Does Arixtra cause HIT?
No
97
There is______reversal agent for fondaparinux (ariXtra)
NO
98
Most serious complication of AriXtra
Bleeding
99
Direct Thrombin Inhibitors
| Mechanism of action
• Direct thrombin inhibitors bind DIRECTLY to thrombin (factor IIa) and inhibit thrombin’s functions/actions
100
****Direct Thrombin inhibitors Inhibits both ____and ________
BOTH free and clot-bound thrombin (factor IIa)
101
Direct thrombin inhibitors do not bind to plasma protein and are
• Are AT-Independent (These agents do not require
| antithrombin as a cofactor for their anticoagulant response)
102
Is there an antidote for PARENTERAL direct thrombin inhibitors?
There is currently no antidote available for any
| PARENTERAL direct thrombin inhibitor agent!
103
* Direct thrombin inhibitors increase/prolong all of the following anticoagulation laboratory tests: most used ?
* aPTT, thrombin time, PT/INR, chromogenic anti-IIa assays, and the ecarin clotting time
ACT,
104
4 direct PARENTERAL Direct thrombin inhibitors
1. Angiomax (bivalirudin)
2. Argatroban
IPRIVASK (desirudin)
REFLUDAN
105
Iprivask® (Desirudin)
Binds irreversibly, selectively & directly to inhibit both clot-bound and free thrombin (Factor IIa)
106
Only monitoring for Desirudin
aPTT
107
• Desirudin is an _______inhibitor!
irreversible
108
Stop time of desirudin prior to surgery
24 hours
109
Lepirudin
| Removed from market for FINANCIAL issue
a 1:1 stoichiometric complex with thrombin and causes irreversible inhibition of thrombin
110
Lepirudin is a derivative of
derivative of hirudin
111
Lepirudin used for patients with ______
USed for HIT patients
112
Direct Thrombin Inhibitors:
| Angiomax® (Bivalirudin) Mechanism of action
Mechanism of action
• Reversibly binds directly to clot-bound and free thrombin and inhibits thrombin and thus inhibits fibrin formation
- Reversibility means thrombin itself can cleave bivalirudin from the active site after bivalirudin has bound to it and thrombin can resume its hemostatic function
113
Elimination of angiomax 2 ways?
Elimination
| • Kidneys (20%) & Enzymatic metabolism (80%)
114
Laboratory monitoring of anticoagulant effects (depends on indication) for angiomax
• HIT________
• PCI or CABG use __________
use aPTT: Goal 1.5–2.5x control
| ACT: Goal 300–450 seconds
115
Angiomax SToP time prior to surgery
4-6 hours
116
To know if effect of Bivalirudin are gone, because those labs correlate very well with those drugs.
ACT or aPTT
117
****Angiomax® (Bivalirudin)
| • Clinical uses
Used as an alternative to heparin in patients undergoing
| cardiopulmonary bypass surgery
118
Argatroban is a _________inhibitor derived from the amino acid _________
inhibitor derived from L-arginine
119
Argatroban Mechanism of action
Competitive inhibitor of thrombin that binds reversibly to the active site of both clot-bound and free thrombin and inhibits thrombins function and thus inhibits fibrin formation
• Reversibility means thrombin can cleave argatroban from the active site after argatroban has bound to it and thrombin can resume its hemostatic function
120
Clinical uses ARGATROBAN
Is an alternative to heparin for anticoagulation in patients requiring CABG, especially in the presence of HIT
121
Direct Thrombin Inhibitors:
| Argatroban Metabolism
Hepatic
122
Dialysis /RENAL Dysfunction patients may use
Argatroban
123
Laboratory monitoring of anticoagulant effects (depends on indication) for ARGATROBAN
• HIT________
• PCI or CABG use __________
use aPTT: Goal 1.5–2.5x control
| ACT: Goal 300–450 seconds
124
Oral Direct Thrombin Inhibitor
Pradaxa (dabigatran)
125
Pradaxa (selective, reversible, competitive)
Is a synthetic, selective, reversible, competitive direct thrombin inhibitor that is only given ORALLY
126
Pradaxa® (dabigatran) is _______and requires conversion into its pharmacologically active form
prodrug
127
After oral administration, dabigatran etexilate is metabolized by
esterase enzymes into the active form dabigatran
128
• Dabigatran (the active form) is then further metabolized in the liver by
non-CYP 450 pathways forming several glucuronide active metabolites that have similar pharmacological activity to dabigatran
129
Pharmacokinetics of dabigatran
| hafl life/Clearance via?
long half life
| Clearance kidneys
130
__________monitoring is required to assess the anticoagulant effect since dabigatran exhibits a predictable pharmacokinetic and pharmacodynamic profile
No routine coagulation
131
if patient is on pradaxa, check those 2 labs before spinal anesthesia, if elevated do not administer spinal anesthesia
Thrombin time
| Ecarin clotting time
132
Adverse effects of PRADAXA
Dyspepsia
| Bleeding
133
Pradaxa® (Dabigatran etexilate):
Neuraxial Anesthesia Implications
• Spinal anesthesia/epidural anesthesia/LP
Prior to procedure wait a minumum of _______
Pradaxa® is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters in place
• Prior to procedure, wait a minimum of 72 hours or longer in renal failure BEFORE catheter placement
• Administer first dose of Pradaxa® a MINIMUM of 2 hours after the catheter has been removed
134
Idarucizumab (Praxbind)
monoclonal antibody fragment
135
Antidote of PRADAXA
Idarucizumab (Praxbind)
136
Mechanism of action of Idarucizumab?
• Idarucizumab binds directly to dabigatran and its metabolites with higher affinity than the binding of dabigatran to thrombin and neutralizes their anticoagulant effect immediately after administration
137
3 Oral Direct Factor Xa Inhibitors: (-xaban)
Rivaroxaban (Xarelto®)
• Apixaban (Eliquis®)
• Edoxaban (Savaysa®)
138
Oral Direct Factor Xa Inhibitors: (-xaban) Mechanism of action
These agents bind to and inhibit both free factor Xa, clot-bound factor Xa, and factor Xa within the prothrombinase complex and thus inhibit thrombin (factor IIa) generation indirectly via inhibition of factor Xa
139
For oral direct factor Xa inhibitors, anticoagulation effects usually take how long ?
anticoagulant effects usually within 1-3 hours depending on the agent
140
Rivaroxaban , Apixaban and Edoxaban MOA and excretion
Direct Factor Xa Inhibitors
| Kidney and feces
141
_____________is the most useful test to check the anticoagulant effect of rivaroxaban or apixaban
A chromogenic anti-Xa assay
142
Monitor for Oral direct factor Xa
bleeding
143
Rivaraxaban and Apixaban antidotes
ANDEXXA
144
ANDEXXA adverse reaction
UTI, Pneumonia
145
Rivaroxaban, Apixaban, Edoxaban:
Neuraxial Anesthesia Implications
• CONTRAINDICATED to use_____________
• Concomitant use of antiplatelet agents (ASA, clopidogrel, etc.), NSAIDs or any other medication that also causes bleeding withrivaroxaban, apixaban, or edoxaban further increases the patients risk of bleeding
FULL anticoagulant doses of these agents while spinal catheter is in place
146
Coumadin® (Warfarin):
| Mechanism of Action
Warfarin acts by inhibiting the enzyme vitamin K epoxide
reductase (VKOR). Inhibiting this enzyme prevents the
conversion of oxidized vitamin K epoxide into its reduced form and this prevents the SYNTHESIS of the vitamin K-dependent clotting factors II (prothrombin), VII, IX, X
147
is the only vitamin K antagonist agent available for
| clinical use
• Warfarin
148
Warfarin does not attach to
| What does it inhibit?
Any factors
| inhibit enzymes responsible to make those factors
149
Affects liver's abiltiy to synthesize
protein C and protein S
150
Warfarin is available as a racemic mixture of R and S isomers both
• Warfarin interferes with the
active
| extrinsic pathway
151
Warfarin pharmacokinetics absorption
Rapid and completely absorbed
152
Warfarin Protein binding:
97% protein bound to albumin
153
Metabolism of warfarin:
Metabolized in the liver via multiple CYP 450 enzymes into inactive metabolites, which are excreted in both the bile and urine
154
Enhanced anticoagulant effect of warfarin in the presence of _____disease
liver
155
The elimination of warfarin is almost entirely by _______
Metabolism
156
Warfarin half life ranges between
20 – 60 hours
157
Warfarin acts by inhibiting the enzyme
vitamin K epoxide reductase (VKOR).
158
Pharmacodynamics of warfarin
| The time to onset and offset of the anticoagulant effect of warfarin is delayed by 2 main factors:
1. The long elimination half-life of warfarin (20 – 60 hours)
2. The elimination half-life of the already made 4 vitamin Kdependent clotting factors
159
* ***Onset of effect of warfarin: within_____ hours (due to___ depletion)
* ***Full effect:______ (due to Factor____ depletion)
24; Factor VII
| 5-7 days; Factor II
160
Coumadin® (Warfarin):
Reversal Agents
Anticoagulant effects are reversed by administering: (5)
1. Vitamin K (IV or PO)
2. FFP
3. Prothrombin Complex Concentrates(PCC)
4. Activate prothrombin Complex concentrates
5. Recombinanct factor VIIa (last resort)
161
• Do not administer vitamin K
SQ or IM
162
• Vitamin K IV can cause ________ reactions – mix in a minimum of __________and infuse over a minimum of to minimize this from occurring
anaphylactic reactions ; 50 ml of IV fluid; 20 minutes
163
______ Is the first FDA-Approved 4-Factor Prothrombin Complex Concentrate (PCC) for warfarin reversal in the United States
Prothrombin Complex Concentrate (Human),
| Kcentra
164
Warfarin tells body to stop ______(making those factors)
Factor II, VII, IX and X
165
• Mechanism of action of Kcentra
Contains factors ___ ___ ____ ___ and _______ and ____
This product rapidly ________________ as well as ____________ (these factors are_____by warfarin)
"Just giving what warfarin prevented the body from making"
• Kcentra® contains factors II (prothrombin), VII, IX and X, and antithrombotic proteins C and S
• This product rapidly increases plasma levels of the vitamin K- dependent coagulation factors II, VII, IX, and X as well as the antithrombotic proteins C and S (these are all factors that are reduced by warfarin)
166
KCentra is only given via which route?
IV
167
• Warfarin + CYP 450 inhibitor
* Increases warfarin plasma levels & increase risk of bleeding
* i.e.: Amiodarone, quinidine
168
INR >2
cannot do spinal anesthesia
169
• Warfarin + CYP 450 inducer
* Decreases warfarin plasma levels & decreases risk of bleeding & increases risk of possible thrombotic complications
* i.e.: Rifampin, phenytoin, barbiturates, carbamazepine
170
Goal INR therapy is
2-3
171
Warfarin Anticoagulant effects are monitored using the
prothrombin time/international normalized ratio (INR) test
172
• The higher the INR,
the greater the risk of bleeding
173
Can warfarin cross placenta
yes
174
Surgical and Spinal Anesthesia Implications
• Spinal anesthesia/epidural anesthesia/LP
**** Hold Time Before Epidural Placement:_______
*****4-5 days & INR < 1.5
175
Contraindicated while catheter is in place
| • Hold Time After Epidural Removal:_______
2 hours
176
• Urgent reversal of warfarin prior to surgery – administer
Vitamin K IV via slow infusion or can give FFP or Kcentra®
177
Assess for bleeding risks:
thrombotic risks and the type of surgical procedure.
178
Pradaxa, to know is not present, what test?
Ecarin Clotting time (ECT) and thrombin time (TT)
