Hemostatis and thrombosis Flashcards
(77 cards)
1
Q
Hemostasis
(2)
A
- “the arrest of blood loss from damaged blood vessels”
- Essential to life
2
Q
Hemostasis
Caused by:
(2)
A
- Platelet adhesion and activation
- Fibrin formation
3
Q
Thrombosis
(3)
A
- “pathological formation of a ‘hemostatic plug’ within the
vasculature in the absence of bleeding” - Hemostasis in the wrong place
- Virchow’s triad
4
Q
Virchow’s triad
A
stasis
vessel wall injury
hypercoagulability
5
Q
White Thrombus
(3)
A
- Arterial clot
- Primarily platelets and some
fibrin mesh - Associated with atherosclerosis
6
Q
Red Thrombus
(3)
A
- Venous clot
- Mostly fibrin and small amount
of platelets - Higher risk of embolus
7
Q
Antithrombin III
A
Prevents coagulation
by lysing
Factor Xa and Thrombin
8
Q
Thrombin (Factor IIa) also
causes
A
platelet activation
9
Q
Intrinsic Pathway
(3)
A
- All components present in the
blood - Starts when blood comes in
contact with foreign object or
damaged endothelium - Monitored by Activated Partial
Thromboplastin time (aPTT)
10
Q
Extrinsic Pathway
(3)
A
- Some components come from
outside blood - Tissue factor
- Starts when tissue damage
releases tissue factor - Monitored by Prothrombin time
(PT) and INR
11
Q
Vitamin K dependent Clotting factors
(3)
A
- Fat soluble vitamin with little stored in the body
- Most vitamin K obtained from diet or produced by bacteria in the gut
- Vitamin K is a cofactor in the formation of several clotting factors
12
Q
Platelet
Adhesion
A
Following
vascular
damage
von
Willebrand
factor
13
Q
Platelet
Activation
A
Mediators:
ADP
TXA2
Collagen
Thrombin
shape change
14
Q
Platelet
Aggregation
A
Final
Common
Pathway
GP IIb/IIIa
receptor
15
Q
Warfarin (Vitamin K Antagonist)
Mechanism of Action
(4)
A
- Acts only in vivo
- Inhibits vitamin K epoxide
reductase component 1
(VKORC1) - The VKORC1 gene is
polymorphic resulting in
different affinities for warfarin - Genetic testing is available for this
polymorphism
16
Q
Warfarin (Vitamin K Antagonist)
Pharmacokinetics
* Rapidly absorbed after — administration
* Highly bound to —
* — metabolized (CYP 450 2C9 and 3A4)
* Onset of action — days
A
oral
plasma proteins (i.e. albumin)
Hepatically
5-7
17
Q
- Hepatically metabolized (CYP 450 2C9 and 3A4)
- Polymorphism of
A
CYP 450 2C9
18
Q
- Onset of action 5-7 days
(4)
A
- Half-life is ~ 40 hours
- Requires new steady-state of clotting factors to be achieved
- Vitamin K dependent clotting factors: II, VII, IX, X, protein C, protein S
- Effects of dose change require 2-3 days to present
19
Q
Warfarin (Vitamin K Antagonist)
Effect of coagulation parameters
Parameter Effect
aPTT:
PT:
INR:
A
?
increase
increase
20
Q
Warfarin exerts an — effect on aPTT
Warfarin is monitored using..
A
inconsistent
INR (usual goal INR 2-3)
21
Q
Warfarin (Vitamin K Antagonist)
Adverse Drug Reactions
(5)
A
- Bleeding (can be life threatening)
- Gastrointestinal bleeding most common
- Rash
- Skin necrosis
- Taste disturbance
- “Purple toe” syndrome
22
Q
Warfarin (Vitamin K Antagonist)
Drug-Drug Interactions
(4)
A
- Drugs that change hepatic metabolism of warfarin
- Drugs that displace warfarin from protein binding sites
- Drugs that change vitamin K levels
- Drugs that increase risk of bleeding
23
Q
- Drugs that change hepatic metabolism of warfarin
- Inhibition: more effect of warfarin=
- Induction: less effect of warfarin=
A
elevated INR
decreased INR
24
Q
- Drugs that displace warfarin from protein binding sites
- More free drug=
A
more effect of warfarin elevated INR
25
* Drugs that change vitamin K levels
* Broad spectrum antibiotics reduce GI flora= less vitamin K and more effect
of warfarin=
* Intake of vitamin K decreases effect of warfarin=
elevated INR
decreased INR
26
* Drugs that increase risk of bleeding
* ASA and NSAIDS inhibit platelet function=
increased risk of bleeding
27
Warfarin (Vitamin K Antagonist)
* Brand name: Coumadin®, Jantoven®
* MOA:
* Use:
* ADRs: (3)
* --- therapeutic index medication
* Drug-Drug interactions:
(2)
Inhibit vitamin K epoxide reductase
component 1 (VKORC1)
Many including Atrial fibrillation, DVT/PE treatment and prevention
bleeding, taste disturbances, skin necrosis
Narrow
* Increased effect with NSAIDs, antibiotics, acetaminophen?
* Decreased effects with barbiturates
28
Warfarin (Vitamin K Antagonist)
Dental Implications
(5)
* Most procedures can be done without holding
* For dental procedure that may result in
excessive bleeding consult prescribing physician
to adjust dose or hold if possible
* Consider local hemostasis measures to prevent
excessive bleeding
* Check INR level prior to performing a dental surgical
procedure
* Antibiotic use after dental procedure may increase risk of
bleeding
29
Heparin
Mechanism of Action
(2)
* Inhibits coagulation in vivo and
in vitro
* Activation of antithrombin III
- Increases antithrombin III affinity
for Factor Xa and Thrombin
30
Heparin
Pharmacokinetics
* Not absorbed from the
* Fast onset:
* Half-life is ~
gastrointestinal (GI) tract
* Administered intravenously (IV) or subcutaneously (SQ)
immediate after IV, 60 minutes after SQ
40-90 minutes
31
Heparin
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT:
PT --
INR --
Heparin is monitored using
increase
aPTT (usual goal 1.5-2.5 times control)
32
Heparin
Adverse Drug Reactions
(5)
* Bleeding (can be life threatening)
* Thrombosis
* Osteoporosis- with long-term treatment, mechanism unclear
* Aldosterone inhibition hyperkalemia
* Hypersensitivity reaction
33
* Bleeding (can be life threatening)
* Protamine can reverse effects (binds heparin)
34
* Thrombosis
(2)
* Heparin associated thrombocytopenia (HAT)
* Heparin induced thrombocytopenia (HIT)
35
Heparin
* Brand name: none
* MOA:
* Use: (3)
* ADRs: (5)
* Drug-Drug interactions:
* Dental implications:
Activation of antithrombin III leading to
inhibition of thrombin and factor Xa
Many including ACS, DVT/PE, Atrial fibrillation, etc..
bleeding, thrombosis, osteoporosis, hyperkalemia,
hypersensitivity
none of significance to dentistry
none beyond bleeding
36
Low Molecular Weight Heparin (LMWH)
Mechanism of Action
(3)
* Inhibits coagulation in vivo and
in vitro
* Smaller portion of the heparin
molecule
* Activation of antithrombin III
37
* Smaller portion of the heparin
molecule
* Not large enough to interact with
thrombin
38
* Activation of antithrombin III
* Increases antithrombin III affinity
for
Factor Xa but NOT thrombin
39
Low Molecular Weight Heparin (LMWH)
Pharmacokinetics
* Not absorbed from the
* Fast onset and predictable response
* Cleared by the kidneys
* Half-life is
GI tract
* Administered subcutaneously (SQ)
4.5-7 hours
40
Low Molecular Weight Heparin (LMWH)
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT --
PT --
INR --
LMWH do NOT require monitoring
of...
coagulation parameters
41
Low Molecular Weight Heparin (LMWH)
Example: enoxaparin
* Brand name: Lovenox®
* MOA:
* Use: Many including (3)
* ADRs: (5)
* Drug-Drug interactions
(1)
Activation of antithrombin III leading to
inhibition factor Xa but NOT thrombin
ACS, DVT/PE, Atrial fibrillation, etc..
bleeding, thrombosis, osteoporosis, hyperkalemia,
hypersensitivity
* Lower incidence of HIT than unfractionated heparin
* Increased risk of bleeding with NSAIDs and Aspirin
42
Low Molecular Weight Heparin (LMWH)
Example: enoxaparin- Dental Implications
(4)
* Determine why patient is taking medication
* Delay procedure until treatment complete
* Do not discontinue therapy
* Consider local hemostasis measures to prevent
excessive bleeding
43
Direct Thrombin Inhibitors
Mechanism of Action
* Derived for the saliva of...
* Binds to the fibrin-binding sites
of thrombin preventing the...
medicinal leeches
conversion of fibrinogen to fibrin
44
Direct Thrombin Inhibitors
Pharmacokinetics
* Intravenous agents:
* Oral agent:
Argatroban and Bivalirudin
Dabigatran (pro-drug)
45
Direct Thrombin Inhibitors
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT:
PT:
INR:
increase
--
--
46
* --- does not require monitoring of coagulation tests
* (2) may be monitored by aPTT depending in indication
Dabigatran
Argatroban and bivalirudin
47
Argatroban has a
drug-lab interaction
resulting in a
falsely
elevated INR
48
Direct Thrombin Inhibitors
Example: Dabigatran
* Brand name: Pradaxa®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions
(1)
* Dental Implications:
(2)
Binds to thrombin preventing conversion of fibrinogen to fibrin
Atrial fibrillation and DVT/PE treatment and prevention
bleeding (reversal agent available- idarucizumab),
dyspepsia/gastritis (25%-35%)- due to formulation
* Increased risk of bleeding with NSAIDs and Aspirin
* High risk of bleeding
* High risk of thrombosis if stopped (short half-life)
49
Factor Xa inhibitors
Mechanism of Action
* Binds to factor Xa and prevent
the conversion of prothrombin
to thrombin
50
Factor Xa Inhibitors
Pharmacokinetics
* Parenteral agent:
* Oral agents: (3)
* --- inhibitors have an inconsistent effect on coagulation tests
* Factor Xa inhibitors do NOT require routine monitoring- do require
Fondaparinux (SQ)
Apixaban, Edoxaban, Rivaroxaban
Factor Xa
renal dosing
51
Factor Xa Inhibitors
Pharmacokinetics
* Effect on coagulation parameters:
Parameter Effect
aPTT:
PT:
INR:
--/increase
--/increase
--/increase
52
Factor Xa Inhibitors
Example: Apixaban
* Brand name: Eliquis®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions
(1)
* Dental Implications:
(2)
Binds to factor Xa and prevents conversion of prothrombin to
thrombin
Atrial fibrillation and DVT/PE treatment and prevention
bleeding (reversal agent available- andexanet alfa)
* Increased risk of bleeding with NSAIDs and Aspirin
* High risk of bleeding
* High risk of thrombosis if stopped (short half-life)
53
Dabigatran
Reversal costs ~
$5,000
54
Apixaban
Reversal costs
between
$25,000-$30,000
55
NOACs
Non-Vitamin K Oral Anticoagulants
* Overarching term referring to:
(4)
* Apixaban
* Dabigatran
* Edoxaban
* Rivaroxaban
56
NOACs
Non-Vitamin K Oral Anticoagulants
* Generally NOACs are recommended in guidelines over warfarin for prevention of
* Also called
stroke and systemic embolism AF
and DVT/PE treatment due to ease of use
DOACs
* Direct-acting Oral Anticoagulants
57
Aspirin
Mechanism of Action
(4)
* Inhibits cyclo-oxygenase 1 (COX 1)
* Prevents formation of
prostaglandin which is
subsequently converted to
thromboxane A2
* Low dose ASA (81mg) inhibits > 95%
of platelet TXA2 formation
* Platelets can not make new COX-1,
ASA effects last for life of platelet 7-
10 days
58
Aspirin
Adverse Reactions
More Common:
(3)
Less common
(3)
* Bleeding- gastrointestinal
* Gastrointestinal distress
* Rash
* Angioedema
* Tinnitus
* Respiratory distress
59
Aspirin
* Brand name: Bayer® and many others
* MOA:
* Use: Many including secondary prevention of (3)
* ADRs: (6)
* Drug-Drug interactions
(2)
Inhibition of COX-1 preventing the formation of TXA2
coronary disease, arthritis, anti-inflammatory
bleeding, rash, GI distress, angioedema, tinnitus,
respiratory distress
* Increased risk of bleeding with NSAIDs and other anticoagulants
* May lower the effectiveness of anti-hypertensive agents
60
Aspirin
Dental Implications
(3)
* Determine why ASA is being taken- most
procedures can be done without holding ASA
* Increased risk of bleeding
* Consider local hemostasis measures to prevent excessive bleeding
61
P2Y12 inhibitors
Adverse Drug Reactions
(3)
* Bleeding
* Skin rash (~ 10%)
* Thrombocytopenia (rare)
62
P2Y12 inhibitors
Adverse Drug Reactions
* Bleeding
(2)
* Less occurrence than aspirin when used as monotherapy
* Increased occurrence when combined with aspirin (DAPT)
63
P2Y12 inhibitors
Adverse Drug Reactions
ADRs unique to ticagrelor:
(2)
* Dyspnea- due to off-target adenosine effects
* Elevated serum creatinine- unknown mechanism usually clinically insignificant
64
P2Y12 inhibitors
Drug-Drug interactions
(4)
* Mainly due to CYP 450 inhibition
* Prodrugs (Clopidogrel & Prasugrel) require activation by CYP 450 therefore have
less activity resulting in increased risk of thrombotic event
* Ticagrelor active upon administered therefore inhibition results in
increased levels and activity leading to increased risk of bleeding
* All P2Y12 inhibitors interact with other medications that increase risk of
bleeding (i.e. anticoagulants, NSAIDs, etc..)
65
* Mainly due to CYP 450 inhibition
* Ticagrelor 3A4, Clopidogrel & Prasugrel 2C19
66
* Prodrugs (Clopidogrel & Prasugrel) require activation by CYP 450 therefore have
less activity resulting in increased risk of thrombotic event
* Proton Pump Inhibitor resulting in a significant drug-drug interaction
67
P2Y12 inhibitors
Example: ticagrelor
* Brand name: Brilinta®
* MOA:
* Use:
* ADRs: (4)
* Drug-Drug interactions
(2)
Inhibition of ADP binding to the P2Y12 receptor
Treatment of Acute Coronary Syndrome
bleeding, rash, dyspnea, elevated serum creatinine
* Increased risk of bleeding with NSAIDs, aspirin, and other
anticoagulants
* CYP 3A4 inhibitors (i.e. macrolide antibiotics and azoles) may
increase effect
68
P2Y12 inhibitors
Example: ticagrelor- Dental Implications
(4)
* Plan for increased bleeding
- Consider local hemostasis measures to prevent
excessive bleeding
* Do not stop/hold without consulting prescribing
physician
* Do not alter aspirin dose prescribed
* Ticagrelor specific- potential shortness of breath
69
Glycoprotein IIb/IIIa inhibitors
Mechanism of Action
(4)
* Bind to GP IIa/IIIb receptor
preventing platelet
aggregation
* Only available intravenously
* Abciximab (no longer available)
- monoclonal antibody
* Eptifibatide and tirofiban
- small molecules
70
Glycoprotein IIb/IIIa inhibitors
Example: Eptifibatide
* Brand name: Integrilin®
* MOA:
* Use:
* ADRs: (2)
* Drug-Drug interactions:
(3)
Bind to GP IIa/IIIb receptor preventing platelet aggregation
Treatment of Acute Coronary Syndrome
bleeding (highest of all antiplatelet agents), thrombocytopenia
* none of significance to dentistry
* other drugs that increase bleeding
* Dental Implications: none
71
PAR-1 antagonist (Vorapaxar)
Mechanism of Action
(2)
* Antagonist of the protease
activated receptor-1 inhibiting
thrombin receptor agonist
peptide (TRAP)- induced
platelet aggregation
* Does NOT effect the
conversion of fibrinogen to
fibrin by thrombin
72
PAR-1 antagonist
Vorapaxar
* Brand name: Zontivity®- approved late 2014
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions:
(1)
* Dental Implications:
(1)
Antagonist of the protease activated receptor-1 inhibiting thrombin
receptor agonist peptide (TRAP)- induced platelet aggregation
secondary prevention of coronary artery disease
bleeding (~25%)
* Other drugs that increase bleeding (i.e. aspirin, NSAIDs, anticoagulants)
* High bleeding risk medication
73
Plasminogen activators
Mechanism of Action
Binds to tissue bound
fibrin and plasminogen
converting plasminogen
to plasmin
(fibrin specific)
Recombinant form of
tissue plasminogen
activator (TPA)
74
Plasminogen activators
Example: Tenecteplase
* Brand name: TNKase®
* MOA:
* Use: (2)
* ADRs:
* Drug-Drug interactions:
(2)
* Dental Implications:
Binds to tissue bound fibrin and plasminogen converting plasminogen
to plasmin
STEMI, Stroke (alteplase only)
bleeding from virtually any site
* None of significance to dentistry
* Other drugs that increase bleeding (i.e. heparin, aspirin, and
clopidogrel)
none
75
Hemostatic Agents
Mechanism of Action
(2)
Competitive inhibition of
plasminogen activation
by binding to
plasminogen
At higher concentrations
non-competitive
inhibition of plasmin
76
Hemostatic Agents
Example: Tranexamic acid
* Brand name: Lysteda®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions:
(2)
Competitive inhibition of plasminogen activation by binding to
plasminogen; at higher concentrations non-competitive inhibition of plasmin
Prophylaxis of bleeding in patients at high risk of bleeding during
dental procedures or surgery
IV- hypotension and giddiness; PO- headache, abdominal pain, and
nasal/sinus symptoms
* Reduces the effectiveness of anticoagulants
* Increased risk of thrombosis
77
Hemostatic Agents
Example: Tranexamic acid- Dental Implications
(2)
* Used as an antifibrinolytic mouthwash following
dental surgery to prevent hemorrhage in
patients taking oral anticoagulants.
* Topical administration should have limited
systemic effects. If systemic administration
considered consult with physician prescribing
anticoagulant.
