Anticoagulation Flashcards
(127 cards)
1
Q
Hemostasis
A
process that prevents blood loss from damaged blood
vessels
2
Q
3 parts of Hemostasis
A
Vasoconstriction
• Adhesion and activation of platelets (platelet plug)
• Formation of fibrin
3
Q
Thrombosis
A
pathological formation of a ‘hemostatic’ plug
within the vasculature in the absence of bleeding
4
Q
3 things that cause thrombosis
A
Injury to blood vessel wall ~ atherosclerosis, plaque rupture
• Altered blood flow ~ veins of leg after sitting for long time
• Abnormal coagulability of blood ~pregnancy, certain drugs, inheritable disease
5
Q
Venous thrombosis
A
associated with red blood cells enmeshed in fibrin, often called red
thrombi
6
Q
Where do most venous thrombi occur
A
in the superficial or deep veins of the leg
7
Q
When is thrombosis the most dangerous
A
Deep vein Thrombosis (DVT) in the larger veins -at or above the knee is more serious because such thrombi more often embolize to the lungs and give rise to pulmonary infarction
-lower extremity DVTs are associated with hypercoaguable states
8
Q
Arterial thrombosis
A
- composed of platelets with little fibrin or red cells, giving the appearance of white thrombi
- **usually occurs after the erosion or rupture of atheroscleoritc plaque
- platelet-mediated thrombi can cause ischemic injuries in tissues with a terminal vascular be
- **cardiac ischemia and stroke are the most severe cilnical manifestations of atherothrombosis
9
Q
Describe the relationship between all of the major anti-coagulation drugs
A
they all have the same aim, anti-coagulation, but NOT THE SAME MECHANISM, to prevent complications of thrombosis
10
Q
List the drugs responsible for inhibition of coagulation
anticoagulants
A
- Heparin
- Enoxaparin (LMWH)
- Bivalirudin
- Fondaparinux
- Warfarin
- Dabigatran
- Rivaroxaban
- Apixaban
11
Q
Fibrinolytic agents/”clot-busters”
lysis of existing thrombus
A
- Tissue plasminogen factor
- Alteplase
- Tenecteplase
12
Q
Antiplatelet drugs
Inhibition of platelet aggregation
A
- Aspirin
- Abciximab/Eptifibatide
- Dipyridamole
- Clopidogrel/Ticlopidine
- Prasugrel/Ticagrelor
13
Q
What is a side effect of ALL of these anticoagulant drugs
A
increased bleeding/ hemorrhage
14
Q
Protamine sulfate
A
antagonist of heparin
15
Q
Idarucizumab:
A
antagonist of dabigatran
16
Q
Aminocaproic acid:
A
antagonist of thrombolytics
17
Q
Coagulation cascade
A
-series of transformations of proenzymes to activated enzymes resulting in the formation of thrombin (IIa) which converts soluble fibrinogen to insoluble fibrin
- activation of Factor X to Xa
- conversion of prothrombin (II) to thrombin (IIa)
- thrombin-mediated transformation of fibrinogen to fibrin (the GLUE)
18
Q
Synthesis of which factors is dependent on Vitamin K
A
II, IX, X, VII
19
Q
heparin (unfractionated)
-physical properties
A
- heterogenous mixture of sulfated polysaccharides
- highly negatively charged
- HIGH molecular weight
- there is heterogeneity in composition in different commercial preps of heparin
20
Q
Mechanism of action of heparin unfractionated
A
- Antithrombin is a suicide substrate for a number of different activated coagulation factors, especially thrombin and Xa (also IXa, XIa, XIIa)
- activated coagulation factor attacks a specific Arg-Ser peptide bond in the reactive site of AT
- When thrombin is bound to antithrombin it becomes trapped and is inactivated
- the way hearin works is it causes a 1000-fold increase in the reaction rate of antithrombin and thrombin inthe pressence of heparin
- heparin serves as a catalytic template to which both AT and activated coagulation factor can bind.
- Heparin induces a conformational change in AT making reactive site more accessible to proteases
21
Q
Compare the ability of Unfractionated heparin vs low molecular weight heparin at catalyzing the inhibition of thrombin by AT
A
low molecular weight heparins poorly catalyze inhibition of thrombin by AT bc low molecular weight heparin isnt able to bind around antithrombin like unfractionated heparin does.
22
Q
Name two common misconceptions about heparin, two things that heparin DOES NOT DO
A
Heparin DOES NOT-
- affect the synthesis of clotting factors
- does not lyse the existing clot
23
Q
Name two things that heparin DOES DO
A
prevent further cloth formation
-prevent further extension of clot
24
Q
How is heparin absorbed
A
it is not abrobed orally bc it is extremely large and negatively charged. it is given via IV infusion or subcutaneous injection
-Immediate onset of action if given IV
25
BRIEFLY explain the complicated kinetics of heparin
-Half-life dependent on dose
26
Is heparin safe to use during preganncy
YES it does not cross the placenta
27
How do you know heparin is working
- by measuring the activated partial thromboplastin time (aPTT)
* intrinsic and common pathway
- Heparin is therapeutic when the aPTT is 1.5 to 2.5 times the normal mean
-this is done by collecting a blood sample with citrate to inactivate calcium and prevent clotting, then negatively charged phospholipids are added, and a particulate substance like aluminum sulfate and calcium
28
adverse reaction heparin
Bleeding/Hemorrhage
MAJOR ADVERSE REACTION
the bleeding is controlled with an antagonist, protamine sulfate
29
How do you treat increased bleeding that occurs as an adverse reaction from heparin
the antagonist protamine sulfate
30
Heparin-induced Thrombocytopenia
- platelet counts decrease by 50% from normal values
- occurs in a small number of patients (greater incidence in women)
- can be life threatening and lead to amputation, limb ischemia, myocardial infarction, stroke
31
Mechanism for Heaparin Induced Thrombocytopenia
-IgG antibodies form against heparin-platelet factor 4
*Chemokine released during platelet activation/forms complex with proteoglycans like heparin
-Complex activates platelets by binding to FcγIIa receptors on the
platelet
-This causes platelet aggregation, release of PF4 and thrombin
generation; results in formation of clots and fall in platelet number
32
What do you do if someone has heparin induced thrombocytopenia
discontinue Heparinimmediately
33
Contraindication to the use of heparin
active bleeding
- severe uncontrolled hypertension (bc of risk of hemorrhagic stroke)
- recent surgery of eye, brain, spinal cord
34
Therapeutic clinical indications for heparin
- Deep Vein Thrombosis or pulmonary embolism
* initial treatment is heparin IV infusion
* also low dose heparin may be used as prevention in surgical patients
- INITIAL management of unstable angina or acute MI
- drug of choice for anticoagulation during pregnancy bc it doesn't cross the placenta so it is safe
35
Why is heparin not used for chronic anticoagulation use
it is difficult to give, it has to be given via IV so it just doesn't really make sense to be used chronically
36
What is low molecular weight heparin called
Enoxaparin
37
properties of low molecular weight Heparin- Enoxaparin
- it is fragments of standard MW heparins
- administered subcutaneously
* *has a longer half-life than heparin
38
Mechanism of action for Enoxaparin
- this is low molecular weight heparin
- Heparin normally binds to antithrombin and wraps around it and binds to thrombin to really increase their binding so AT can inactivate thrombin
- Enoxaparin binds to just antithrombin (bc it is small and can't wrap around) so it primarily works to inhibit the anti-thrombin Xa complex
- Enoxaparin is a poor inactivator of thrombin bc it can't wrap around to bind to thrombin
39
Difference in mechanism of action of unfractionate heparin and Enoxaparin
Enoxaprin binds to only AT and Xa
```
Heparin binds to AT and Xa AND
AT andThrombin (bc it is big and can wrap around to bind to thrombin)
```
40
Pharmacokinetics of Enoxaparin
- longer half-life than heparin: advantage in hospital setting
- renal elimination: risk in patient with renal disease
41
Adverse effects of Enoxaparin
- less risk of bleeding that unfractionated heparin
| - lower risk (theoretically) of thrombocytopenia compared to heparin
42
Contraindications of Enoxaparin
- similar to heparin ALSO renal impairment (bc Enoxaparin is excreted renally)
- active bleeding, uncontrolled hypertension, recent surgery of the eye brain spinal cord
43
Therapeutic uses of Enoxaparin
-similar to unfractionated heparin
- Acute DVT
- Act and unstable angina and MI
44
other parenterally administered anticoagulations other than heparin and Enoxaparin
- fondaparinux: selective Xa inhibitor, requires AT
| - Bivalirudin: Direct Thrombin Inhibitors, does not require AT
45
Fondaparinux
-MOA
-Administration
Adverse effect
- selective Factor Xa inhibitor
- MOA: No effect on the AT-Thrombin complex, it only acts on the AT-Xa complex. BC just like Enoxaparin it isn't big enough to wrap around and bind thrombin
-SQ administration: Important distinction to rivaroxaban –in
addition to different mechanism!
-hemorrhage
46
Bivalirudin
- administration
- MOA
- excretion
- adverse effect
- contraindications
- therapeutic use
DIRECT thrombin inhibitor
- synthetic polypeptide, derived from leeches.
- MOA: inactivate thrombin by blocking the substrate binding site in a 1:1 complex
- doesn't bind to/require antithrombin
- IV administration
- renal excretion
- adverse side effect is hemorrhage
- therapeutic use: alternative to heparin in patients who have had heparin-induced thrombocytoenia
47
Explain the advantages of a direct thrombin inhibitor
SO thrombin bund to fibrin (within a clot) within a thrombus remains enzymatically active (activates clotting factors) and is protected from inactivation b antithrombin (antithrombin cant bind to fibrin bound thrombin)
- fibrin bound thrombin can locally activate platelets and trigger coagulation thereby causing thrombus growth
- so drugs that are thrombin inhibitors are able to inactive thrombin even when it is bound to fibrin, but drugs (like heparin) that work via AT are not able to inhibit thrombin that is fibrin bound, bc AT can't bind to fibrin bound thrombin
48
Protamine sulfate
- Low MW, positively charged
- chemical antagonist 1:1 binding with heparin results in an inactive complex
- adverse effect: anaphylactic reaction
- therapeutic use: heparin overdose with acute bleeding that cant be controlled by stopping heparin
- reverse heaparin following cardiopulmonary bypass
49
What are the three oral anticoagulants
- Warfarin
- Dabigatran
- Rivaroxaban
50
Warfarin physical properties
- structural analog of vitamin K
| - Vitamin K is in the diet in leafy greens, and is synthesized in the gut bacteria
51
How is warfarin administered
- orally
- it is administered in a racemic mixture os S-warfarin and R-Warfarin
- S-warfarin is the more active form
52
-
-prevents the γ-carboxylation of several
glutamate residues
-blockade results in incomplete coagulation
factor molecules that are biologically
inactive
-protein carboxylation reaction is coupled to
the oxidation of vitamin K. The vitamin
must then be reduced to reactivate it.
-S-Warfarin prevents reductive
metabolism of the inactive vitamin K
epoxide back to its active hydroquinone
form
-Competitive inhibition because Vit K
administration will displace warfarin
53
How do you know warfarin is working?
prothrombin time (PT)
Normal INR between 0.8 and 1.2
54
Why is the Therapeutic effect of warfarin not seen for several hours to days
-bc it inhibits the synthesis of clotting factors, and doesn't effect the clotting factors that are already made. So it takes time for the effects to be seen
-Remember circulating factors (those already
synthesized) are not inhibited by warfarin
-End up with some already synthesized factors still around while no longer able to synthesize any more factors that can be
activated by the clotting cascade
-Depends on the half-life of the particular clotting
factor/varies with each
55
absorption/metabolism/pharmacokinetics of warfarin
-oral administration
inactivated by liver microsomes (CYP)
-metabolized by CYP2C9 (S-warfarin)
56
major adverse reaction to warfarin
hemorrhage
57
contraindication to warfarin
- similar to heparin but include:
- CYP2C9 polymorphisms
- genetic variations in VIt K epoxide reductase complex protein 1
- pregnancy/teratogenic
- Liver, kidney disease, vitamin K deficiency
58
Reversal of warfarin
- if INR is greater than 5 vitamin K is administered but there would be a time delay for effectiveness
- Mechanism of delay? It take a while for new clottin g factors to be synthesized
59
WHy is it important to monitor INR in patients taking Warfarin
- Increased INR means increased risk for bleeding
| - Decreased INR means increased risk of thrombosis
60
How common are drug interactions with warfarin
very common CYP2C9
61
Food interactions with warfarin
green vegetables has a lot of vitamin K and this decreases INR and causes the drug to not work as well leading to more risk of thrombosis (bc it is sort of competitive inhibition of VKORC1 with vit K so if you increase VIt K then the drug is less effective)
some food also increase INR and increase risk of bleeding
62
Therapeutic clinical indications for warfarin
-Long-term treatment of venous thromboembolic disease.
-Prophylaxis against thromboembolism in atrial fibrillation.
-Prophylaxis against thromboembolism in patients with prosthetic
heart valves.
-Remember it takes time for warfarin to work so if you need immediate anticoagulation, will give heparin (or LMWH) followed by warfarin = bridging effect
63
What is the bridging effect
Remember it takes time for warfarin to work so if you need immediate anticoagulation, will give heparin (or LMWH) followed by warfarin = bridging effect
64
Dabigitran
pro-drug which is metabolized in vivo to an active entity dabigatran
65
Dabigitran mechanism of action
-interacts with the active site of thrombin
-a potent, reversible,
competitive direct thrombin inhibitor
-inhibits both fibrin-bound
and free thrombin (rememeber if something works on the AT-thrombin complex then you can't inactivate the thrombin when it is bound to a clot)
66
Monitoring for Dabigitran
NONE (unlike warfarin)
67
Dabigatran pharmacokinetics
- oral administration, rapid onset (peak plasma levels by 2 hours)
- short half-life
* *it works immediately unlike warfarin
- Not a substrate for a CYP450
- excreted by the kidney and used therefore is carefully at doses appropriate for a patients renal function
68
Dabigatran adverse effects
- risk of bleeding
- w/o antidote: reversal of dabigatran's effects depends on excretion, with a plasma half-life of 14 hours
- w antidote: Idarucizumab binds to dabigatran and neutralizes the anticoagulant effect within minutes
69
Idarucizumab:
humanized monoclonal antibody fragment (Fab) that binds to dabigatran and neutralizes the anticoagulant effect within minutes
70
Disease related concerns for dabigatran
renal impairment: concentrations may increase in any degree of renal impairment and increase the risk of bleeding
-Valvular heart disease: not recommended in patients with bioprosthetic heart valves
• contraindicated in patients with mechanical prosthetic heart valves
71
What is the only drug interaction with Dabigatran
P-glycoprotein limits oral absorption of drugs by transporting them back into the GI
-so P-glycoprotein could limit oral absorption
72
Therapeutic use Dabigatran
-patients with nonvalvular atrial fibrillation at risk for
stroke or systemic embolism
-Not recommended for patients with coexisting prosthetic heart valve
73
Rivaroxaban
direct factor Xa inhibitor
74
Factor Xa
primary site of amplification of thrombin generation bc it is activated by both the intrinsic and extrinsic pathway
75
Factor Xa inhibition
- rivaroxaban
- apixaban
- inhibition decreases the amplified generation of thrombin without affecting existing thrombin levels
- this remaining thrombin should be sufficient to ensure primary hemostasis, resulting in a favorable safety margin
- so basically it decreases thrombin levels but keeps it at a safe enough level bc it just decreases amplification of thrombin not production
76
Rivaroxaban- Mechanism of action
- inhibits both free Factor Xa and Factor Xa in the prothrombinase complex
- capable of gaining access to clotbound Factor Xa
- the resulting inhibition of clot-bound Factor Xa prevents extension of the thrombus by blocking further generation of thrombin from within the clot
77
Rivaroxaban Pharmacokinetics
- administration
- metabolism
- elimination
-oral administration with rapid onset of action (peak by four hours)
- metabolism 2 ways
1. hepatic by CYP3A4/5 and CYP2J2
2. CYP-independent mechanism
- a dual mode of elimination
* 2/3 of drug undergoes metabolic degradation in the liver
* 1/3 of dose is eliminated as unchanges drug in the urine
- It is a substrate for P-glycoprotein
78
Major adverse effect of Rivaroxaban
bleeding
79
Drug interactions for Rivaroxaban
- CYP3A4 inhibitor/inducers
| - P-glycoprotein inhibitors/inducers
80
monitoring of Rivaroxaban
-In major clinical trials, monitoring of aPTT, PT/INR, or
anti-factor Xa levels did not occur.
-However, certain patient populations (eg, renal
insufficiency, hepatic impairment, low body weight,
extreme obesity) may require monitoring of the PT time
81
Therapeutic use of Rivaroxaban
patients with nonvalvular atrial fibrilation at risk for stroke or systemic embolism, similar to dabigatran
82
Apixaban
inhibits Xa
- oral drug with reduced bioavailability
- CYP P450 metabolism
- Cleared by kidney (unmetabolized)
- same concerns in patients as rivaroxaban
- same clinical use as rivaroxaban
83
NOAC
New Oral Anticoagulants
84
What are the advantages to NOAC compared to warfarin
- NOAC has faster onset and offset : reduces the need for "bridgin" in patients at high risk for thrombosis
- absence of food interactions
- few strong drug interactions
- greater convenience for patients and physicians (less monitoring)
- wide therapeutic window
- fewer adverse side effects
- lower risk of bleeding complications
85
Disadvantages of NOAC compared to warfarin
- Severe chronic kidney disease (don't use or use lower dose)
- More expensive
- No specific antidote
* *exception is new antidote for dabigitran
86
List the thrombolytic agents
* Aminocaproic Acid
* Tissue Plasminogen Activator (t-PA)
* Alteplase
* Tenecteplase
87
What is the triggering event in an MI
obstruction of coronary artery by thrombus (platelet origin)
88
Reperfusion therapy
-thrombolytics (pharmacological reperfusion)
89
T o dissolve clots plasminogen is converted to
plasmin (active version)
90
Describe the cleavage of plasminogen (inactive precursor) to plasmin (active)
- cleavage of single peptide bond
- generation of a two chain disulfide linked molecule
- Exposes the kringles
91
Endogenous activator of plasminogen to plasmin
t-PA
92
t-PA
Tissue Type plasminogen activator cleaves plasminogen to plasmin.
It is inhibited (a lot at the beginning of clot formation so that the brand new clot isn't broken up)
inhibited by t-PA-I
93
What happens to the free plasmin
FREE Plasmin inactivated by α2-antiplasmin
94
Explain theconversion of plasminogen to plasmin
- cleavage of Arg560 resulting in two-chained disulfide linked molecule
- Exposes lysine-binding sites (kringles): bind fibrin
- Cleavage initiated by plasminogen activators
- Activity of t-PA controlled by endogenous inhibitors (PAI-1, PAI-2)
- FREE Plasmin inactivated by α2-antiplasmin
95
Alteplase
- tissue Plasminogen activator (t-PA)
- produced by recombinant DNA technology
- activates bound plasminogen several hundred- fold more rapidly than free plasminogen
- very short half-life/requires I infusion
96
Tenecteplase
- tissue-Plasminogen Activator (t-PA)
- produced by recombinant DNA technology
- longer half-life bc is resistant to the inhibitor
- single bolus administration
- resistant to inhibition of PAI-1
97
What is the advantage of fibrin specificity
to limit systemic lysis/ increase bleeding risk
98
Complications of thrombolytic therapy
Hemorrhage-systemic lytic state results from systemic formation of plasmin
but hemorrhage is just as common as with t-PA
-more bleeding combinations if combined with heparin and or aspirin
99
therapeutic Indications for thrombolytic therapy
- acute MI (STEMI)
| - stroke ( only alteplase): within first 3 hours
100
describe the contraindications of thrombolytic therapy
bleeding
| some effects are absolute and some are relative
101
Aminocaproic acid
a potent inhibitor of fibrinolysis
-lysine analog that binds to lysine binding sites on
plasminogen and plasmin thus blocking the binding
of plasmin to fibrin
102
Low dose aspirin-Platelets
```
-Irreversibly acetylates
cyclooxygenase-1 in
platelet
• No COX-2 in platelet
-Blocks production of
thromboxane
-Platelets lack nuclei so
permanant effect of aspirin
```
103
Low dose aspiring other cell types than platelets
Endothelial cells produce
prostacyclin (do have COX-1 and COX-2) but endothelial cells have a nucleus and can just synthesize more COX, so the effects don't last as long, whereas platelets do not have a nucleus
104
Adverse effects of aspirin
- Bleeding
| - GI-dose related
105
Therapeutic uses of low dose aspirin
MI prophylaxis
| stroke prophylaxis
106
Dipyridamole
-Both a vasodilator and inhibitor of platelet aggregation
MOA:
*inhibition of phosphodiesterase
(probably both PDE3 and PDE5)
* this increases cAMP in platelet
*Inhibits platelet aggregation
-Therapeutic use: in combination with aspirin for prevention of MI or TIA
107
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
| -MOA
-act through P2Y1
/P2Y12 receptors to inhibit ADP- induced platelet aggregation
-All are irreversible
EXCEPT ticagrelor
108
Disadvantage of irreversible platelet inhibitor ?
If patient requires surgery (like coronary bypass
surgery) and is taking drug like clopidogrel (or
aspirin), waiting period is necessary to prevent
platelet function to return to normal.
109
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor Pharmacokinetics
Prasugrel is a prodrug
Clopidogreal and Ticlopidine are prodrugs that are metabolized to active compound by CYP2C9
110
Prasugrel
- prodrug
- increased potency because more efficient generation of active metabolite
- More predictable effects on platelets than other P2Y antagonist drugs
111
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
| adverse effects
- Bleeding all drugs
- Ticagrelor specific dyspnea
- Ticlopidine neutropenia
112
Clopidorgrel adverse reactions
- 3-20% of poopulation have CYP2C19 polymorphism
- poor metabolizers
- Means that individuals don't get as much active drug bc clopidrogrel is a prodrug and requires CYP2C19 to activate it
113
What is another drug that is metabolized by 2C19
Omeprazole
114
therapeutic Indications for antiplatelets drugs
-used in cases where there is increase risk of platelet aggregation that contributed to thrombus
115
Clopidogrel therapeutic indications
STEMI (occlusive thrombus)
recent myocardial infarction
116
Abciximab
-Fab fragmen
-Prevents binding of fibrinogen,
vW factor, and other adhesive molecules
-Steric hindrance a/o
conformational change
*blocks access of the molecules to
the receptor
-non-competitive
117
Eptifibatide
```
Contains a KGD (Lys-Gly-Asp)
sequence motif that binds
specifically to GP IIb-IIIa
receptors on the platelet surface,
thereby blocking the binding of
fibrinogen activated platelets
-competitive reversible inhibitor
```
118
Pharmacokinetics of Abciximab
- IV administration
- quick onset of action but delayed clearance
- effective up to t7 days
119
Pharmacokinetics of Eptifibatide
- IV Administration
- quick onset
- quick offset 9platelet aggregation normal within 18 hours of stopping the drug
- renal clearance
120
Adverse effects of Eptifibatide and Abciximab
bleeding
121
Clinical use Eptifibatide
```
Patients undergoing
percutaneous coronary
intervention (PCI),
including angioplasty or
stent placement
```
122
Clinical use Abciximab
Patients undergoing percutaneous coronary intervention (PCI) including angioplasty or stent placement
123
Acute deep vein thrombosis (DVT) or pulmonary embolism (PE)
think heparin
124
Chronic prevention of DVT or PE
think warfarin or NOAC
125
Acute coronary syndrome
think thrombolytic
| prevention: think aspriin
126
stroke
- think thrombolytic if within 3 hours
| - prevention: think aspirin
127
Atrial Fibrillation
-think warfarin or NOAC unless there is artificial value then think warfarin
