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Pharmacology > Hemostatis and thrombosis > Flashcards

Hemostatis and thrombosis Flashcards

1
Q

Hemostasis
(2)

A
  • “the arrest of blood loss from damaged blood vessels”
  • Essential to life
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2
Q

Hemostasis
Caused by:
(2)

A
  • Platelet adhesion and activation
  • Fibrin formation
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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
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4
Q

Virchow’s triad

A

stasis
vessel wall injury
hypercoagulability

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5
Q

White Thrombus
(3)

A
  • Arterial clot
  • Primarily platelets and some
    fibrin mesh
  • Associated with atherosclerosis
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6
Q

Red Thrombus
(3)

A
  • Venous clot
  • Mostly fibrin and small amount
    of platelets
  • Higher risk of embolus
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7
Q

Antithrombin III

A

Prevents coagulation
by lysing
Factor Xa and Thrombin

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8
Q

Thrombin (Factor IIa) also
causes

A

platelet activation

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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)
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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
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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
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12
Q

Platelet
Adhesion

A

Following
vascular
damage
von
Willebrand
factor

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13
Q

Platelet
Activation

A

Mediators:
ADP
TXA2
Collagen
Thrombin

shape change

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14
Q

Platelet
Aggregation

A

Final
Common
Pathway
GP IIb/IIIa
receptor

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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
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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

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17
Q
  • Hepatically metabolized (CYP 450 2C9 and 3A4)
  • Polymorphism of
A

CYP 450 2C9

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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
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19
Q

Warfarin (Vitamin K Antagonist)
Effect of coagulation parameters
Parameter Effect
aPTT:
PT:
INR:

A

?
increase
increase

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20
Q

Warfarin exerts an — effect on aPTT
Warfarin is monitored using..

A

inconsistent
INR (usual goal INR 2-3)

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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
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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
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23
Q
  • Drugs that change hepatic metabolism of warfarin
  • Inhibition: more effect of warfarin=
  • Induction: less effect of warfarin=
A

elevated INR
decreased INR

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24
Q
  • Drugs that displace warfarin from protein binding sites
  • More free drug=
A

more effect of warfarin  elevated INR

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25
Q
  • 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=
A

elevated INR
decreased INR

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26
Q
  • Drugs that increase risk of bleeding
  • ASA and NSAIDS inhibit platelet function=
A

increased risk of bleeding

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27
Q

Warfarin (Vitamin K Antagonist)
* Brand name: Coumadin®, Jantoven®
* MOA:
* Use:
* ADRs: (3)
* — therapeutic index medication
* Drug-Drug interactions:
(2)

A

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
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28
Q

Warfarin (Vitamin K Antagonist)
Dental Implications
(5)

A
  • 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
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29
Q

Heparin
Mechanism of Action
(2)

A
  • Inhibits coagulation in vivo and
    in vitro
  • Activation of antithrombin III
  • Increases antithrombin III affinity
    for Factor Xa and Thrombin
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30
Q

Heparin
Pharmacokinetics
* Not absorbed from the
* Fast onset:
* Half-life is ~

A

gastrointestinal (GI) tract
* Administered intravenously (IV) or subcutaneously (SQ)

immediate after IV, 60 minutes after SQ
40-90 minutes

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31
Q

Heparin
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT:
PT –
INR –
Heparin is monitored using

A

increase

aPTT (usual goal 1.5-2.5 times control)

32
Q

Heparin
Adverse Drug Reactions
(5)

A
  • Bleeding (can be life threatening)
  • Thrombosis
  • Osteoporosis- with long-term treatment, mechanism unclear
  • Aldosterone inhibition hyperkalemia
  • Hypersensitivity reaction
33
Q
  • Bleeding (can be life threatening)
A
  • Protamine can reverse effects (binds heparin)
34
Q
  • Thrombosis
    (2)
A
  • Heparin associated thrombocytopenia (HAT)
  • Heparin induced thrombocytopenia (HIT)
35
Q

Heparin
* Brand name: none
* MOA:
* Use: (3)
* ADRs: (5)
* Drug-Drug interactions:
* Dental implications:

A

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
Q

Low Molecular Weight Heparin (LMWH)
Mechanism of Action
(3)

A
  • Inhibits coagulation in vivo and
    in vitro
  • Smaller portion of the heparin
    molecule
  • Activation of antithrombin III
37
Q
  • Smaller portion of the heparin
    molecule
  • Not large enough to interact with
A

thrombin

38
Q
  • Activation of antithrombin III
  • Increases antithrombin III affinity
    for
A

Factor Xa but NOT thrombin

39
Q

Low Molecular Weight Heparin (LMWH)
Pharmacokinetics
* Not absorbed from the
* Fast onset and predictable response
* Cleared by the kidneys
* Half-life is

A

GI tract
* Administered subcutaneously (SQ)

4.5-7 hours

40
Q

Low Molecular Weight Heparin (LMWH)
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT –
PT –
INR –
LMWH do NOT require monitoring
of…

A

coagulation parameters

41
Q

Low Molecular Weight Heparin (LMWH)
Example: enoxaparin
* Brand name: Lovenox®
* MOA:
* Use: Many including (3)
* ADRs: (5)
* Drug-Drug interactions
(1)

A

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
Q

Low Molecular Weight Heparin (LMWH)
Example: enoxaparin- Dental Implications
(4)

A
  • Determine why patient is taking medication
  • Delay procedure until treatment complete
  • Do not discontinue therapy
  • Consider local hemostasis measures to prevent
    excessive bleeding
43
Q

Direct Thrombin Inhibitors
Mechanism of Action
* Derived for the saliva of…
* Binds to the fibrin-binding sites
of thrombin preventing the…

A

medicinal leeches
conversion of fibrinogen to fibrin

44
Q

Direct Thrombin Inhibitors
Pharmacokinetics
* Intravenous agents:
* Oral agent:

A

Argatroban and Bivalirudin
Dabigatran (pro-drug)

45
Q

Direct Thrombin Inhibitors
Pharmacokinetics
Effect on coagulation parameters:
Parameter Effect
aPTT:
PT:
INR:

A

–

46
Q
  • — does not require monitoring of coagulation tests
  • (2) may be monitored by aPTT depending in indication
A

Dabigatran
Argatroban and bivalirudin

47
Q

Argatroban has a
drug-lab interaction
resulting in a

A

falsely
elevated INR

48
Q

Direct Thrombin Inhibitors
Example: Dabigatran
* Brand name: Pradaxa®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions
(1)
* Dental Implications:
(2)

A

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
Q

Factor Xa inhibitors
Mechanism of Action

A
  • Binds to factor Xa and prevent
    the conversion of prothrombin
    to thrombin
50
Q

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

A

Fondaparinux (SQ)
Apixaban, Edoxaban, Rivaroxaban

Factor Xa
renal dosing

51
Q

Factor Xa Inhibitors
Pharmacokinetics
* Effect on coagulation parameters:
Parameter Effect
aPTT:
PT:
INR:

A

–/increase
–/increase
–/increase

52
Q

Factor Xa Inhibitors
Example: Apixaban
* Brand name: Eliquis®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions
(1)
* Dental Implications:
(2)

A

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
Q

Dabigatran
Reversal costs ~

A

$5,000

54
Q

Apixaban
Reversal costs
between

A

$25,000-$30,000

55
Q

NOACs
Non-Vitamin K Oral Anticoagulants
* Overarching term referring to:
(4)

A
  • Apixaban
  • Dabigatran
  • Edoxaban
  • Rivaroxaban
56
Q

NOACs
Non-Vitamin K Oral Anticoagulants
* Generally NOACs are recommended in guidelines over warfarin for prevention of
* Also called

A

stroke and systemic embolism AF
and DVT/PE treatment due to ease of use

DOACs
* Direct-acting Oral Anticoagulants

57
Q

Aspirin
Mechanism of Action
(4)

A
  • 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
Q

Aspirin
Adverse Reactions
More Common:
(3)
Less common
(3)

A
  • Bleeding- gastrointestinal
  • Gastrointestinal distress
  • Rash
  • Angioedema
  • Tinnitus
  • Respiratory distress
59
Q

Aspirin
* Brand name: Bayer® and many others
* MOA:
* Use: Many including secondary prevention of (3)
* ADRs: (6)
* Drug-Drug interactions
(2)

A

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
Q

Aspirin
Dental Implications
(3)

A
  • 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
Q

P2Y12 inhibitors
Adverse Drug Reactions
(3)

A
  • Bleeding
  • Skin rash (~ 10%)
  • Thrombocytopenia (rare)
62
Q

P2Y12 inhibitors
Adverse Drug Reactions
* Bleeding
(2)

A
  • Less occurrence than aspirin when used as monotherapy
  • Increased occurrence when combined with aspirin (DAPT)
63
Q

P2Y12 inhibitors
Adverse Drug Reactions
ADRs unique to ticagrelor:
(2)

A
  • Dyspnea- due to off-target adenosine effects
  • Elevated serum creatinine- unknown mechanism usually clinically insignificant
64
Q

P2Y12 inhibitors
Drug-Drug interactions
(4)

A
  • 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
Q
  • Mainly due to CYP 450 inhibition
A
  • Ticagrelor 3A4, Clopidogrel & Prasugrel 2C19
66
Q
  • Prodrugs (Clopidogrel & Prasugrel) require activation by CYP 450 therefore have
    less activity resulting in increased risk of thrombotic event
A
  • Proton Pump Inhibitor resulting in a significant drug-drug interaction
67
Q

P2Y12 inhibitors
Example: ticagrelor
* Brand name: Brilinta®
* MOA:
* Use:
* ADRs: (4)
* Drug-Drug interactions
(2)

A

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
Q

P2Y12 inhibitors
Example: ticagrelor- Dental Implications
(4)

A
  • 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
Q

Glycoprotein IIb/IIIa inhibitors
Mechanism of Action
(4)

A
  • Bind to GP IIa/IIIb receptor
    preventing platelet
    aggregation
  • Only available intravenously
  • Abciximab (no longer available)
  • monoclonal antibody
  • Eptifibatide and tirofiban
  • small molecules
70
Q

Glycoprotein IIb/IIIa inhibitors
Example: Eptifibatide
* Brand name: Integrilin®
* MOA:
* Use:
* ADRs: (2)
* Drug-Drug interactions:
(3)

A

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
Q

PAR-1 antagonist (Vorapaxar)
Mechanism of Action
(2)

A
  • 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
Q

PAR-1 antagonist
Vorapaxar
* Brand name: Zontivity®- approved late 2014
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions:
(1)
* Dental Implications:
(1)

A

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
Q

Plasminogen activators
Mechanism of Action

A

Binds to tissue bound
fibrin and plasminogen
converting plasminogen
to plasmin
(fibrin specific)
Recombinant form of
tissue plasminogen
activator (TPA)

74
Q

Plasminogen activators
Example: Tenecteplase
* Brand name: TNKase®
* MOA:
* Use: (2)
* ADRs:
* Drug-Drug interactions:
(2)
* Dental Implications:

A

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
Q

Hemostatic Agents
Mechanism of Action
(2)

A

Competitive inhibition of
plasminogen activation
by binding to
plasminogen
At higher concentrations
non-competitive
inhibition of plasmin

76
Q

Hemostatic Agents
Example: Tranexamic acid
* Brand name: Lysteda®
* MOA:
* Use:
* ADRs:
* Drug-Drug interactions:
(2)

A

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
Q

Hemostatic Agents
Example: Tranexamic acid- Dental Implications
(2)

A
  • 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.

Pharmacology (13 decks)

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