Hemostasis and thrombosis Flashcards by Michael McMahan

“the arrest of blood loss from damaged blood vessels”
Essential to life
Caused by:
Platelet adhesion and activation
Fibrin formation

Hemostasis

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• “pathological formation of a ‘hemostatic plug’ within the
vasculature in the absence of bleeding”
• Hemostasis in the wrong place
• Virchow’s triad

Thrombosis

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What are the 3 components of Virchow’s triad?

Stasis
Endothelial injury
Hypercoaguability

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\_\_\_\_ Thrombus
• Arterial clot
• Primarily platelets and some 
fibrin mesh
• Associated with atherosclerosis

White thrombus

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\_\_\_ Thrombus
• Venous clot
• Mostly fibrin and small amount 
of platelets
• Higher risk of embolus

Red thrombus

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Prevents coagulation
by lysing
Factor Xa and Thrombin

Antithrombin III

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______ also

causes platelet activation

Thrombin (Factor IIa)

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What are the 4 vitamin K dependent clotting factors?

2, 7, 9, 10

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\_\_\_\_\_\_ 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

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______ 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

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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

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What factor is involved in platelet adhesion?

von Willebrand factor

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What are the 4 mediators of platelet activation?

ADP
TXA2
Collagen
Thrombin

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Which factor of platelet activation does not have a pharmacological inhibitor at this time?

Collagen

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What is the receptor involved in platelet aggregation?

GP IIb/IIIa

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What is the key mediator of fibrinolysis?

Plasmin

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• 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

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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

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How does Warfarin affect coagulation parameters?

Increases INR

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Adverse Drug Reactions
• Bleeding (can be life threatening)
• Gastrointestinal bleeding most common
• Rash
• Skin necrosis 
• Taste disturbance
• “Purple toe” syndrome

Warfarin

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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

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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®

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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®