Hemostasis and thrombosis Flashcards
- “the arrest of blood loss from damaged blood vessels”
- Essential to life
- Caused by:
- Platelet adhesion and activation
- Fibrin formation
Hemostasis
• “pathological formation of a ‘hemostatic plug’ within the
vasculature in the absence of bleeding”
• Hemostasis in the wrong place
• Virchow’s triad
Thrombosis
What are the 3 components of Virchow’s triad?
Stasis
Endothelial injury
Hypercoaguability
\_\_\_\_ Thrombus • Arterial clot • Primarily platelets and some fibrin mesh • Associated with atherosclerosis
White thrombus
\_\_\_ Thrombus • Venous clot • Mostly fibrin and small amount of platelets • Higher risk of embolus
Red thrombus
Prevents coagulation
by lysing
Factor Xa and Thrombin
Antithrombin III
______ also
causes platelet activation
Thrombin (Factor IIa)
What are the 4 vitamin K dependent clotting factors?
2, 7, 9, 10
\_\_\_\_\_\_ Pathway of coagulation cascade • 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)
Intrinsic
______ Pathway of coagulation cascade
• Some components come from outside blood • Tissue factor • Starts when tissue damage releases tissue factor • Monitored by Prothrombin time (PT) and INR
Extrinsic Pathway
- Fat soluble vitamin with little stored in the body
- Mostly obtained from diet or produced by bacteria in the gut
- iT is a cofactor in the formation of several clotting factors
Vitamin K
What factor is involved in platelet adhesion?
von Willebrand factor
What are the 4 mediators of platelet activation?
ADP
TXA2
Collagen
Thrombin
Which factor of platelet activation does not have a pharmacological inhibitor at this time?
Collagen
What is the receptor involved in platelet aggregation?
GP IIb/IIIa
What is the key mediator of fibrinolysis?
Plasmin
• Acts only in vivo • Inhibits vitamin K epoxide reductase component 1 (VKORC1) • The VKORC1 gene is polymorphic resulting in different affinities for it • Genetic testing is available for this polymorphism
Warfarin
- Rapidly absorbed after oral administration
- Highly bound to plasma proteins (i.e. albumin)
- Hepatically metabolized (CYP 450 2C9 and 3A4)
- Polymorphism of CYP 450 2C9
- Onset of action 5-7 days
- 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
Warfarin
How does Warfarin affect coagulation parameters?
Increases INR
Adverse Drug Reactions • Bleeding (can be life threatening) • Gastrointestinal bleeding most common • Rash • Skin necrosis • Taste disturbance • “Purple toe” syndrome
Warfarin
DDI for what drug?
• Drugs that change hepatic metabolism of warfarin
• Inhibition more effect of warfarin elevated INR
• Induction less effect of warfarin decreased INR
• Drugs that displace warfarin from protein binding sites
• More free drug more effect of warfarin elevated INR
• Drugs that change vitamin K levels
• Broad spectrum antibiotics reduce GI flora less vitamin K and more effect
of warfarin elevated INR
• Intake of vitamin K decreases effect of warfarin decreased INR
• Drugs that increase risk of bleeding
• ASA and NSAIDS inhibit platelet function increased risk of bleeding
Warfarin
- MOA: Inhibit vitamin K epoxide reductase component 1 (VKORC1)
- Use: Many including Atrial fibrillation, DVT/PE treatment and prevention
- ADRs: bleeding, taste disturbances, skin necrosis
- Narrow therapeutic index medication
- Drug-Drug interactions:• Increased effect with NSAIDs, antibiotics, acetaminophen?
- Decreased effects with barbiturates
Warfarin (Vitamin K Antagonist)
• Brand name: Coumadin®, Jantoven®
Dental Implications
• 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
Warfarin
Mechanism of Action • Inhibits coagulation in vivo and in vitro • Activation of antithrombin III • Increases antithrombin III affinity for Factor Xa and Thrombin
Heparin
- Not absorbed from the gastrointestinal (GI) tract
- Administered intravenously (IV) or subcutaneously (SQ)
- Fast onset: immediate after IV, 60 minutes after SQ
- Half-life is ~ 40-90 minutes
Heparin
What is the Effect on coagulation parameters of heparin?
Increased aPTT
Adverse Drug Reactions
• Bleeding (can be life threatening)
• Protamine can reverse effects (binds heparin)
• Thrombosis
• Heparin associated thrombocytopenia (HAT)
• Heparin induced thrombocytopenia (HIT)
• Osteoporosis- with long-term treatment, mechanism unclear
• Aldosterone inhibition hyperkalemia
• Hypersensitivity reaction
Heparin
- MOA: Activation of antithrombin III leading to inhibition of thrombin and factor Xa
- Use: Many including ACS, DVT/PE, Atrial fibrillation, etc..
- ADRs: bleeding, thrombosis, osteoporosis, hyperkalemia, hypersensitivity
- Drug-Drug interactions: none of significance to dentistry
- Dental implications: none beyond bleeding
Heparin
Mechanism of Action • Inhibits coagulation in vivo and in vitro • Smaller portion of the heparin molecule • Not large enough to interact with thrombin • Activation of antithrombin III • Increases antithrombin III affinity for Factor Xa but NOT thrombin
Low Molecular Weight Heparin (LMWH)
- Not absorbed from the GI tract
- Administered subcutaneously (SQ)
- Fast onset and predictable response
- Cleared by the kidneys
- Half-life is 4.5-7 hours
Low Molecular Weight Heparin (LMWH)
• MOA: Activation of antithrombin III leading to
inhibition factor Xa but NOT thrombin
• Use: Many including ACS, DVT/PE, Atrial fibrillation, etc..
• ADRs: bleeding, thrombosis, osteoporosis, hyperkalemia,
hypersensitivity
• Lower incidence of HIT than unfractionated heparin
• Drug-Drug interactions
• Increased risk of bleeding with NSAIDs and Aspirin
Dental Implications
• Determine why patient is taking medication
• Delay procedure until treatment complete
• Do not discontinue therapy
• Consider local hemostasis measures to prevent
excessive bleeding
enoxaparin
• Brand name: Lovenox®
Mechanism of Action • Derived for the saliva of medicinal leeches • Binds to the fibrin-binding sites of thrombin preventing the conversion of fibrinogen to fibrin
Direct Thrombin Inhibitors
- Intravenous agents: Argatroban and Bivalirudin
- Oral agent: Dabigatran (pro-drug)
- Effect on coagulation parameters:
- Dabigatran does not require monitoring of coagulation tests
- Argatroban and bivalirudin may be monitored by aPTT depending in indication
Direct thrombin inhibitors
• MOA: Binds to thrombin preventing conversion of fibrinogen to fibrin
• Use: Atrial fibrillation and DVT/PE treatment and prevention
• ADRs: bleeding (reversal agent available- idarucizumab),
dyspepsia/gastritis (25%-35%)- due to formulation • Drug-Drug interactions
• Increased risk of bleeding with NSAIDs and Aspirin
• Dental Implications:
• High risk of bleeding
• High risk of thrombosis if stopped (short half-life)
Dabigatran
• Brand name: Pradaxa®
Mechanism of Action
• Binds to factor Xa and prevent
the conversion of prothrombin
to thrombin
Factor Xa inhibitors
Pharmacokinetics
• Parenteral agent: Fondaparinux (SQ)
• Oral agents: Apixaban, Edoxaban, Rivaroxaban
• Effect on coagulation parameters:
• Factor Xa inhibitors have an inconsistent effect on coagulation tests
• Factor Xa inhibitors do NOT require routine monitoring- do require renal dosing
Factor Xa Inhibitors
• MOA: Binds to factor Xa and prevents conversion of prothrombin to
thrombin
• Use: Atrial fibrillation and DVT/PE treatment and prevention
• ADRs: bleeding (reversal agent available- andexanet alfa)
• Drug-Drug interactions
• Increased risk of bleeding with NSAIDs and Aspirin
• Dental Implications:
• High risk of bleeding
• High risk of thrombosis if stopped (short half-life)
Apixaban
• Brand name: Eliquis®
• Overarching term referring to: • Apixaban • Dabigatran • Edoxaban • Rivaroxaban • Generally NOACs are recommended in guidelines over warfarin for prevention of stroke and systemic embolism AF and DVT/PE treatment due to ease of use • Also called DOACs • Direct-acting Oral Anticoagulants
NOACsNon-Vitamin K Oral Anticoagulants
Mechanism of Action • 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
Aspirin
Adverse Reactions More Common: • Bleeding- gastrointestinal • Gastrointestinal distress • Rash Less common • Angioedema • Tinnitus • Respiratory distress
Aspirin
• MOA: Inhibition of COX-1 preventing the formation of TXA2
• Use: Many including secondary prevention of coronary
disease, arthritis, anti-inflammatory
• ADRs: bleeding, rash, GI distress, angioedema, tinnitus,
respiratory distress
• Drug-Drug interactions
• Increased risk of bleeding with NSAIDs and other anticoagulants
• May lower the effectiveness of anti-hypertensive agents
Dental Implications
• 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
Aspirin
• Brand name: Bayer® and many others
Mechanism of Action
Inhibition of ADP binding to the P2Y12 receptor
P2Y12 inhibitors
The following drugs are what type of drug? Cangrelor Clopidogrel Prasugrel Ticagrelor
P2Y12 inhibitors
Adverse Drug Reactions
• Bleeding
• Less occurrence than aspirin when used as monotherapy
• Increased occurrence when combined with aspirin (DAPT)
• Skin rash (~ 10%)
• Thrombocytopenia (rare)
• ADRs unique to ticagrelor:
• Dyspnea- due to off-target adenosine effects
• Elevated serum creatinine- unknown mechanism usually clinically insignificant
P2Y12 inhibitors
Drug-Drug interactions
• Mainly due to CYP 450 inhibition
• Ticagrelor 3A4, Clopidogrel & Prasugrel 2C19
• 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
• 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..)
P2Y12 inhibitors
• MOA: Inhibition of ADP binding to the P2Y12 receptor
• Use: Treatment of Acute Coronary Syndrome
• ADRs: bleeding, rash, dyspnea, elevated serum creatinine
• Drug-Drug interactions
• Increased risk of bleeding with NSAIDs, aspirin, and other
anticoagulants
• CYP 3A4 inhibitors (i.e. macrolide antibiotics and azoles) may
increase effect
Dental Implications
• 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
ticagrelor
• Brand name: Brilinta®
Mechanism of Action • Bind to GP IIb/IIIa receptor preventing platelet aggregation • Only available intravenously • Abciximab (no longer available) • monoclonal antibody • Eptifibatide and tirofiban • small molecules
Glycoprotein IIb/IIIa inhibitors
- MOA: Bind to GP IIb/IIIa receptor preventing platelet aggregation
- Use: Treatment of Acute Coronary Syndrome
- ADRs: bleeding (highest of all antiplatelet agents), thrombocytopenia
- Drug-Drug interactions:
- none of significance to dentistry
- other drugs that increase bleeding
- Dental Implications: none
Eptifibatide
• Brand name: Integrilin®
Mechanism of Action • 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
PAR-1 antagonist (Vorapaxar)
• MOA: Antagonist of the protease activated receptor-1 inhibiting thrombin
receptor agonist peptide (TRAP)- induced platelet aggregation
• Use: secondary prevention of coronary artery disease
• ADRs: bleeding (~25%)
• Drug-Drug interactions:
• Other drugs that increase bleeding (i.e. aspirin, NSAIDs, anticoagulants)
• Dental Implications:
• High bleeding risk medication
Vorapaxar
• Brand name: Zontivity®- approved late 2014
Does the ADA recommend routinely stopping anticoag and antiplatelet meds for dental tx?
No; will under certain circumstances following a med consult
Mechanism of Action Binds to tissue bound fibrin and plasminogen converting plasminogen to plasmin (fibrin specific) Recombinant form of tissue plasminogen activator (TPA)
Plasminogen activators
• MOA: Binds to tissue bound fibrin and plasminogen converting plasminogen to plasmin • Use: STEMI, Stroke (alteplase only) • ADRs: bleeding from virtually any site • Drug-Drug interactions: • None of significance to dentistry • Other drugs that increase bleeding (i.e. heparin, aspirin, and clopidogrel) • Dental Implications: none
Tenecteplase
• Brand name: TNKase®
Mechanism of Action Competitive inhibition of plasminogen activation by binding to plasminogen At higher concentrations non-competitive inhibition of plasmin
Hemostatic Agents
• MOA: Competitive inhibition of plasminogen activation by binding to
plasminogen; at higher concentrations non-competitive inhibition of plasmin
• Use: Prophylaxis of bleeding in patients at high risk of bleeding during
dental procedures or surgery
• ADRs: IV- hypotension and giddiness; PO- headache, abdominal pain, and
nasal/sinus symptoms
• Drug-Drug interactions:
• Reduces the effectiveness of anticoagulants
• Increased risk of thrombosis
Dental Implications
• 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.
Tranexamic acid
• Brand name: Lysteda®
