Part 27: Hemostasis & Anticoagulants Flashcards
1
Q
what is hemostasis in a general sense?
A
the process by which our body keeps our blood through our body and contained in the vascular system
2
Q
thombrosis is related to ____ (excessive or impaired) clotting
A
excessive
3
Q
the immediate reaction of BV that have been damaged is to ____ (dilate/constrict). Why?
A
constrict to prevent excess blood loss
4
Q
when a breach in the endothelial lining of blood vessel is detected by circulating ____ and they become activated and they clump together to “plug the hole” in the bleeding vessel
A
platelets
5
Q
when a bv is cut, in parallel to the activation of platelets, the _____ cascade is started to form a strong ____ clot to seal the hole until repair can be made
A
coagulation; fibrin polymer
6
Q
the healing process for a minor cut may take ____ (time) and more major cuts may take ____ (time)
A
a few days; several weeks
7
Q
when the injury is repaired and the fibrin clot is no longer needed, it will be broken down by ___ and the clot will be removed
A
plasmin
8
Q
___ makes ___ which makes ____ which makes fibrin
A
prothrombrin, thrombin, fibrinogen
9
Q
when a BV is injured, ___ and ___ become exposed, allowing platelets to bind to them and become activated
A
collagen; von Willebrand factor
10
Q
activated platelets secrete ___, ___, & ___ to cause the initial vasoconstriction and to recruit and activate other platelets to the injury site
A
ADP; thromboxane and serotonin
11
Q
activated platelets cross-link to form the ____, while the fibrin clot begins to form
A
platelet plug
12
Q
____ and ____ are key mediators of fibrin formation within the coagulation cascade, making them important pharm targets when modulating hemostasis
A
factor X and thrombin (factor 2A)
13
Q
another important mediator is ___, which regulates clot size and extent of spread within the vessel
A
prostacyclin (PGI2)
14
Q
prostacyclin is secreted by ____ cells and acts like a traffic controller to keep the clot containe dto the injury site so it doesnt overgrow and occlude bloodflow completely
A
neighbouring
15
Q
as the injured vessel is repaired, ____ breaks down the clot upon activation of plasmin
A
fibrinolysis
16
Q
thrombosis can be pathologic when ___
A
a clot is made unnecessarily or when the clot becomes mobile
17
Q
when a blood clot becomes mobile it is called a ____
A
embolus
18
Q
an embolus can cause what kinds of bad things?
A
stroke, MI, pulmonary embolism
19
Q
what patient populations are likely to be on antiplatelet drug?
A
those at increased risk for blood clots (ex: past MI, certain arrhythmias like A fib) or after a surgery
20
Q
if someone is bedridden, the are ___ (more/less) likely to develop a blood clot. why?
A
more; bc blood tends to pool in the lower extremeties and not circulate well
21
Q
antiplatelets are typically used ___ (chronically/acutely)
A
chronically
22
Q
fibrinolytic drugs are typically used ___ (chronically/acutely)
A
acutely (when a clot as already formed), must be given as quickly as possible to reduce risk of downstream effects of obstructed blood flow (like cardiac ischemia caused by an MI)
23
Q
what is a slang term for fibronolytic agents?
A
clot busters
24
Q
ASA, clopidogrel and tirofiban are all examples of ___ type drugs
A
antiplatelts
25
when platelets are activated, they release ___, ___ and ___ that contrubute to early vasoconstriction of the injured vessel and initiate a cascade of activating and aggregating additional platelets
thromboxane A2, ADP and serotonin
26
____ is one of the many mediators produced in the arachidonic acid pathway where COX is a central enzyme and pharm target
thromboxane A2
27
reducing thromoxane production by inhibiting ____ enzymes will reduce the activation and aggregation signals
COX
28
platelets express ADP P2Y receptors, which are activated by the ____ released from activated platelets
ADP
29
blocking ADP P2Y receptors reduces the intracellular signal to secrete ____ and ____
mediator granules and aggregate
30
the ADP P2Y signalling pathway is involved in the ____ (increased/decreased) expression of glycoprotein receptors which are involved in platelet adhesion and aggregation
increased
31
one glycoprotein activated by the ADP P2Y signalling pathway that acts to increase platelet adhesion and aggregation is the ____ complex
glycoprotein 2b/3a (GP 2b/3a)
32
the GP2b/3a complex acts as a receptor for ____ to link platelets togther, forming the platelet plug
fibrinogen
33
blocking the CP2b/3a receptors leads to decreased platelet ____ (aggregation/dissociation)
aggregation
34
____ is the most commonly recognized antiplatelet agent used clinically
ASA (asprin)
35
ASA's inhibition of COX-1 is ____ (reversible or irreversible)
irreversible (covalent)
36
ASA ____ (increases/decreased) the thromboxane A2 (TXA2) production
decreases
37
prostaglandins are important to inflammatory reponse and pain signalling, but they are also importnat to ____
hemostasis
38
in the arachidonic acid pathway, membrane lipids are used to produce inflammatory mediators along with thromboxane in ___ and prostacyclin in ___
platelets; endothelial cells
39
prostaglandins are pro-____ and cyto____
inflammatory; protective
40
thromboaxane and prostacyclin regulate platelet ___
aggregation
41
platelets express COX-1 to produce ___
thromboxane A2
42
what is the MOA of ASA?
bind covalently to COX 1 to inhibit enzymatic activity and reduce platelet activation & aggregation
43
the dose of ASA needed to have antiplatelet effects is much ____ (higher/lower) than the dose needed for pain/inflammation
lower
44
why is ASA blocking COX1 permanent?
platelets are anuclear so they cant make new proteins like the COX receptors
45
what is the typical dose of ASA used for anti-platelet?
81-325mg
46
what is the typical dose of ASA used for anti-inflammatory?
600mg+
47
what is the MOA of clopidogrel
irreversibly inhibits the ADP P2Y receptor on platelets, which acts to reduce platelet aggregation
48
t/f clopidogrel is a prodrug
t
49
clopidogrel is activated by ____ enzyme in the liver prior to having any anti-platelet effects
CYP2C19
50
what is a downside of clopidogrel being a pro-drug?
may be subject to genetic variation and or drug-drug interactions related to the CYP2C19 enzyme that metabolizes it
51
what is a clinically relevant drug-drug interaction with clopidogrel?
omeprazole will result in sub-therapeutic levels of clopidogrel
52
t/f there are now ADP-P2Y inhibitors that are not pro-drugs, so clopidogrel is not used as much anymore
t
53
clopidogrel can be used as a monotherapy or in combo with ____
ASA
54
what is the moa of tirofiban?
binds to the glycoprotein 2b/3a receptor to prevent fibrinogen from binding and causing the cross-linking of platelets (decreases platelet aggregation by blocking this)
55
Tirofiban is only available as a _____ formulation and is most often used in the ____ setting for ____(long/short) term treatment
IV; hospital; short (usually post-op)
56
can a patient be switched back to their regular clopidogrel/ASA treatment after post-op treatment with tirofiban?
yes
57
antiplatelet agents are typically used in ____(lower/higher) risk and agents that modulate the coagulation cascade are used in ____ (lower/higher) risk pts
lower; higher
58
anticoagulants are classed based on ___ and ____
where they interact within the coagulation cascade and whether they have direct intercation with a target or an action that has indirect reduction in thrombin production
59
t/f the coagulation cascade actually exists as many processes occuring in parallel and can feed back onto each other to potentiate clotting
t
60
in the coagulation cascade, the ___ clotting factors are produced an circulating at all times
inactive
61
when a circulating inactive clotting factor interacts with ___ on the exposed endothelium, factor ___ is activated and the coagulation cascade begins, causing the activation of factor ____, which catalyzes the formation of _____ which then catalyzes the reactions of converting ____ to ___ to form the blood clot
tissue factor (TF); factor 7; factor ten (AKA 10A); thrombin (AKA factor 2A); soluble fibringogen to insoluble fibrin
62
____ is one of the oldest clinically used anticoagulants
warfarin
63
warfarin is classed as a ____ acting anticoagulant. Why?
indirect; bc its MOA does not involve physically interacting with any component of the coagulation cascade itself, but rather by influencing the synthesis of several clotting factors
64
warfarin is a synthetic ____ compound, which were originally isolated from natural products after discovery of their anticoagulation properties
coumarin
65
what was the original use of warfarin and other related compounds?
pest control (causes rats to hemorrhage and die)
66
use of warfarin in small doses for anticoagulation began in the ____ (timeframe)
1950's
67
warfarin is a competitive inhibitor of vitamin ___ epoxide
K
68
the enzyme ___ is required to reactivate vitamin K
vitamin K epoxide
69
vitamin K is a cofactor in the biosynthesis of several ____
clotting factors
70
the vitamin K dependent clotting factors are __, __, __ and ___
7,9,10 & 2
71
clotting factor 2 is also called ___
prothrombin
72
t/f in the presence of warfarin, vitamin K cannot be reactivated and the production of clotting factors
t
73
why does coagulation become impaired in the presence of warfarin?
reduced formation of fibrin at the end of the coagulation cascade
74
warfarin inhihitis vitamin K epoxide ____ (competitively/non-competiticely)
competively
75
t/f if the presence of vitamin K is high, it can out-compete warfarin
t (pts need to be conscious of their K levels/intake)
76
an important consideration with the initiation of warfarin is that there is a delay in the onset of therapeutic effect that is related to the ___ of the circulating clotting factor
half lives
77
why does it take a while for the therapeutic effects of warfarin to kick in?
we have premade clotting factors circulating in our blood, so these must be depleted b4 the full extent of warfarin effects can be seen
78
what is the onset time when targeting factor 7 with warfarin?
4-6 hours
79
what is the onset time when targeting factor 9 with wrfarin?
24 hrs
80
what is the onset time when targeting factor 10 with warfarin?
48-72 hrs
81
what is the onset time when targeting factor 2 with warfarin?
60 hours
82
t/f regular monitoring of warfarin includes measuring how long it takes for a patient's blood to clot
t
83
what is INR and what is it usd for?
international normalized ratio; used as a tool to assess the clotting time in comparision to a normal patient population
84
what is the ratio used for INR?
patient prothrombin time / mean of normal prothrombin time
85
what is the ideal INR range during warafrin treatment?
~2.0 -- 3.0
86
if the INR is less than ___, the patient is at risk of a clot
2.0
87
if the INR is greater than ___ the patient is at risk of hemorrhage
3.0
88
invasive surgeries are not recommended if the INR is greater than ___
4
89
in the case of a very high INR (warfarin overdose), what can be administered?
vitamin K
90
an INR of 2-3 means ___ when on warfarin
it takes 2-3 times longer for the warfarin patient to form a clot
91
warfarin is metabolized by CYP enzymes, primarily ____, but also others including _____
CYP2C9; CYP3A4
92
what are 5 examples of drug classes that can have serious drug-drug interactions with warfarin?
1. some antibiotics
2. some analgesics
3. antidepressants, hypnotics, psychostimulants
4. oral contraceptives
5. natural products, food
93
do heparins interact directly with the coagulation factors themselves?
no
94
heparin interacts with ____ to enhance the inactivation of factor Xa and thrombin, thus reducing the availability of active coagulation factors and causing an anticoag effect
antithrombin
95
heparins are ___ polymers that are produced naturally in the body as regulators of hemostasis
mucopolysaccharide
96
_____ is a naturally sourced product that contains a mixture of heparin polymers with a wide range in sizes upto a very large MW (~30 000 daltons) to very small MW (4-5 kilodaltons)
unfractionated heparin
97
heparin is a ____ acting anticoag
indirect
98
give an example of a low MW heparin (LMWH)
enoxaparin
99
all heparin polymers that contain the necessary ____ sequence to bind to the ____ enzyme have anticoag effects, regardless of their overall
5 sugar; antithrombin
100
heparin binds to the antithrombin enzyme by the ____ sequence within the heparin polymer
pentasaccharide
101
when heparin is bound to the antithrombin, the affinity of binding with active clotting factors is significantly ____ (increased/decreased)
incerased
102
when factor Xa or thrombin binds to antithrombin, they become ____
inactive (can no longer participate in the coag cascade)
103
antithrombin is active w/o heparin, but in the presence of heparin, its activity can be increased as much as ______x
1000
104
what is an additional bonus of larger heparin polymers?
the long polysaccharide tails are able to bind to thrombin and antithrombin, hugging the 2 togther to further accelerate the inactivation of thrombin
105
heparins bind ____ (reversibly / irrreversibly) to antithrombin
reversibly
106
antithrombin activity by heparin causes increased ____ of clotting factors
inactivation
107
why do UfH (large MW) have greater activity in accelerating inactivation of thrombin than LMWH?
the long tails of UfH reach around and hug thrombin into the active site of the antithrombin
108
both UFH and LMWH are able to facilitate the inactivation of factor ____ , and LMWH only poorly inactivate ____
XA; thrombin
109
bleeding risk of heparin can be enhanced when pts are taking other drugs than can increase bleeding, such as ____
NSAIDs
110
t/f INR testing is not needed for heparin, but other tests are performed
t
111
if heparin levels are too high, ___ can be administered to bind to circulating heparin molecules and prevent them from binding to antithrombin
protamine sulfate
112
the interaction between heparin and protamine is a ____ type bond
ionic (positive protamine and negative heparin)
113
the anticoag actions of heparin are achieved through the binding with the enzyme ____, they dont interact directley with Xa or thrombin without this enzyme
antithrombin
114
give 2 examples of direct actiing anticoags classes
1. factor Xa inhibitors
| 2. direct thrombin inhibitors
115
give an example of a direct acting factor Xa inhibitor
rivaroxaban
116
give an example of a direct acting thrombin inhibitor
dabigatran
117
what is the effect of rivoroxaban on thrombin?
no effect; selective for Xa
118
rivoroxaban binds directly to the ____ site of the Xa, preventing its activity in the coa g cascade
catalytic
119
what is the effect of dabigatran of Xa?
no effect; selective for thrombin
120
dabigatran binds to the catalytic site of thrombin to prevent its activation of ____
fibrin
121
factor Xa and thrombin inhibitors are given as fixed ___ dosing regimens
oral
122
what does it mean that Xa and thrombin inhibitors are fixed dose?
there is no real fine-tuning of doses like there is with warfarin, but there also is less monitoring bc the anticoag effects are more predictable
123
what is the therapeutic goal of fibrinolytics?
breakdown clot after its formation in emergency situations like MI, stroke etc.
124
give an example of a synthetic tPA fibrinolytic
altesplase
125
what is tissue plasminogen activator (tPA)?
an endogenous protein that is released from endothelial cells in response to injury
126
what is the normal physiologic role of tPA?
to regulate the extent of clot formation and also remove the clot after tissue repair
127
tPA catalyzes the formation of ___- from ___, which breaks apart the fibrin polymers that make up a blood clot
plasmin plasminogen
128
what is the timeframe of administering fibrinolytic agents like alteplase after onset of blood clot symptoms that has been shown to reduce complications associated with ischemia and loss of blood flow?
within the first few hours
129
when thinking of giving a fibrinolytic for a stroke, it is important to determine if the stroke is a ____ type stroke before administering. why?
hemorrhagic; bc if it is hemorrhagic (bleeding into the brain), a fibrinolytic will make the bleeding worse
130
how soon after symptoms of stroke should a fibrinolytic be given>
within 3 hours
131
how soon after symptoms of mI should a fibrinolytic be given?
within 6-12 hours (sooner the better)
132
why is the bleeding risk not so bad for fibrinolytics?
they have a short half life and used acutely for emergencies
133
what is the primary fibrinolytics?
bleeding
