32 Antithrombotic Therapy

Question 1

The most common adverse effect of antithrombotics

Answer 1

Bleeding

Question 2

Decrease fibrin formation by inhibiting
thrombin or thrombin formation

Answer 2

Anticoagulant

Question 3

Inhibit platelet function

Answer 3

Antiplatelet

Question 4

Activate plasminogen and accelerate clot
lysis

Answer 4

Fibrinolytic agents

Question 5

Competitive inhibitors of vitamin K

Answer 5

Coumarins or VKAs

Question 6

VKAs MOA: inhibit γ-carboxylation reactions in the posttranslational modification of the coagulation factors ______________as well as the natural inhibitors ___________

Answer 6

Coagulation factors II, VII, IX, and X

Proteins C and S

Question 7

VKA: water soluble and rapidly absorbed after oral administration, reaching a peak concentration after _________ minutes

Answer 7

60–90 minutes

Question 8

Warfarin is metabolized through the _____________-system, the activity of which is influenced by environmental factors and genetic polymorphisms.

Answer 8

Cytochrome P450 (CYP) system

Question 9

Hereditary resistance to warfarin has been described and is related to specific mutations in ______________.

Answer 9

Vitamin K epoxide reductase

Question 10

Potentiate effect of VKA

Answer 10

Immediate:
* Acetaminophen

Typically within 1 week:
* Ciprofloxacin
* Metronidazole
* Clarithromycin
* Prednisone
* Erythromycin
* Trimethoprim-sulfamethoxazole

Progressive, prolonged:
* Amiodarone

Results from combined inhibition of platelet function:
* Acetylsalicylic acid (avoid dosing >100 mg)
* Nonsteroid antiinflammatory drugs

Reduced vitamin K intake:
* Weight reduction diet
* Illness
* No food intake

Increased warfarin sensitivity:
* Broad spectrum antibiotics
* Liver disease
* Hyperthyroidism

Question 11

Depress effect of VKA

Answer 11

Drugs: Barbiturates Phenobarbital Carbamazepine Rifampin Phenytoin Vitamin K

Increase Vitamin K intake: Excess of dark green vegetables, Some enteral feeds

Warfarin resistance: Mutation in VKOR

Decreased warfarin absorption: Diarrhea, Avocado

Decreased metabolism of coagulation factors: Hypothyroidism

Question 12

Coagulation half life (shortest to longest)

Answer 12

• Factor VII - 5 hours
• Factors X and IX- 24 hours)
• Factor II (prothrombin) (72 hours)

Question 13

TRUE OR FALSE

Because protein C is a natural inhibitor of coagulation with a short half-life (approximately 8 hours), its level may also fall rapidly, theoretically inducing a procoagulant state during initiation of therapy.

Answer 13

TRUE

Because protein C is a natural inhibitor of coagulation with a short half-life (approximately 8 hours), its level may also fall rapidly, theoretically inducing a procoagulant state during initiation of therapy.

Question 14

Smaller amounts of Warfarin should be used for

Answer 14

• Frail
• Elderly
• Poorly nourished patients
• Those with an increased bleeding risk

Question 15

During initiation of therapy, the INR is checked every_____________ until a stable therapeutic effect is achieved.

Answer 15

Every 2–3 days for 1–2 weeks

Question 16

VKA: The target INR for most indications is _______, with a desirable therapeutic range from ________.

Answer 16

2.5

2 to 3

Question 17

The clearance of warfarin is the result of hepatic metabolism, and _________is the most important enzyme mediating its clearance.

Answer 17

CYP2C9

The most important are CYP2C92 and CYP2C93, which are found in approximately 11% and 7% of patients and result in reductions of enzymatic activity of approximately 30% and 80%, respectively.

Question 18

Converts oxidized vitamin K to the active reduced form as required for posttranslational carboxylation

The target of warfarin, which functions as a competitive inhibitor.

Answer 18

VKORC1

Question 19

Score for Predicting Bleeding Risk on Warfarin

Answer 19

HAS-BLED Score

Question 20

Variable included in HAS-BLED Score

Answer 20

• Hypertension
• Abnormal renal or liver function
• Stroke
• Prior bleeding complications
• Labile INR
• Age older than 65 years
• Drug or alcohol abuse

Question 21

The most important predictor of bleeding risk (HASBLED)

Answer 21

INR

Question 22

Cause of skin necrosis in with warfarin use

Answer 22

Disproportionately rapid reduction in proteins C and S

Question 23

TRUE OR FALSE

Oral anticoagulation should be avoided in pregnancy because warfarin crosses the placenta, and exposure during organogenesis in the second trimester can lead to fetal embryopathy with significant cranial bone malformations.

Answer 23

FALSE

Oral anticoagulation should be avoided in pregnancy because warfarin crosses the placenta, and exposure during organogenesis in the first trimester can lead to fetal embryopathy with significant cranial bone malformations.

Question 24

TRUE OR FALSE

Vitamin K antagonists are safe during lactation

Answer 24

TRUE

Vitamin K antagonists are safe during lactation

Question 25

Reversing Warfarin Therapy INR <6

Answer 25

Lower the dose, consider withholding 1 or more doses Recheck in 3–7 days

Question 26

Reversing Warfarin Therapy INR 6-10

Answer 26

Lower the dose and withhold 1–3 doses Vitamin K, 1–2 mg orally if increased risk for bleeding Recheck INR in 24–48 hours

Question 27

Reversing Warfarin Therapy INR >10

Answer 27

Withhold doses until INR is in desired range and cause of elevation ascertained Give vitamin K, 2–4 mg orally Recheck INR in 24 hours

Question 28

INR >1.5 and serious bleeding

Answer 28

Administer four-factor prothrombin complex concentrate if available for rapid reversal. If four-factor prothrombin complex concentrate not available, administer fresh-frozen plasma. Also give 5–10 mg vitamin K intravenously

Question 29

TRUE OR FALSE Heparin has direct anticoagulant effect and serves to activate plasma antithrombin (AT), a serine protease inhibitor.

Answer 29

FALSE Heparin has no direct anticoagulant effect but serves to activate plasma antithrombin (AT), a serine protease inhibitor.

Question 30

Half life of heparin

Answer 30

1–2.5 hours

Question 31

Monitoring for heparin

Answer 31

Activated partial thromboplastin time (aPTT) The usual aPTT range for heparin therapy is between 1.5 and 2.5 times the mean of the normal range. Anti-Xa levels

Question 32

Considered in patients who does not display an adequately prolonged aPTT after treatment with unfractionated heparin, despite having received apparently adequate or even supratherapeutic doses of the drug Patients who require heparin doses of more than 35,000 U/day to increase the aPTT into the therapeutic range,

Answer 32

Heparin resistance Usually caused by an acute-phase response that results in high levels of procoagulant proteins, including factor VIII.

Question 33

TRUE OR FALSE Monitoring is recommended when low doses of heparin are used for prophylaxis of venous thromboembolic disease

Answer 33

FALSE No monitoring is recommended when low doses of heparin are used for prophylaxis of venous thromboembolic disease

Question 34

Reversal agent for heparin

Answer 34

Protamine sulfate

Question 35

Dosage of protamine sulfate

Answer 35

1 mg to neutralize 100 units of heparin

Question 36

An immune-mediated platelet consumption caused by an antibody directed against a complex of heparin and platelet factor 4

Answer 36

HIT

Question 37

Scoring used for HIT

Answer 37

“4T’ score

Question 38

Vitamin K antagonists should be given only after the platelet count has risen to higher than ______________-

Answer 38

150,000/μL

Question 39

Difference of LMWH from UFH

Answer 39

Greater inhibition of factor Xa than of thrombin Completely absorbed Exhibit less binding to plasma proteins and cells Longer plasma half-life Significant renal clearance Protamine sulfate does not completely reverse the anticoagulant effect of LMWH HIT is much less common Osteoporosis may be less common

Question 40

Plasma half-life of Danaparoid

Answer 40

24 hours

Question 41

Clearance of Danaparoid

Answer 41

Renal

Question 42

Monitoring of Danaparoid

Answer 42

Anti– factor Xa assays

Question 43

A unique heparinlike anticoagulant with highly selective AT-dependent anti–factor Xa activity

Answer 43

Fondaparinux

Question 44

TRUE OR FALSE Fondaparinux is synthesized in a structurally homogenous form containing no animal products. Consequently, fondaparinux does not induce allergic responses.

Answer 44

TRUE Fondaparinux is synthesized in a structurally homogenous form containing no animal products. Consequently, fondaparinux does not induce allergic responses.

Question 45

Fondaparinux: maximum plasma levels are reached approximately ______ hours after subcutaneous administration

Answer 45

Two hours

Question 46

Fondaparinux: half-life

Answer 46

17 hours

Question 47

Clearance of Fondaparinux

Answer 47

Renal

Question 48

Monitoring of Fondaparinux

Answer 48

Anti–factor Xa assay But there is no effect on other coagulation assays including the activated clotting time (ACT), aPTT, or thrombin clotting time

Question 49

A direct thrombin inhibitor, is a recombinant protein based on the structure of hirudin, is composed of a dodecapeptide analogue of the carboxyterminal region of hirudin linked by a four-glycine residue to a structure directed to the active site of thrombin.

Answer 49

Bivalirudin

Question 50

Bivalirudin: half-life

Answer 50

30 minutes

Question 51

Monitoring of Bivalirudin

Answer 51

ACT and aPTT

Question 52

Clearance of Bivalirudin

Answer 52

Renal and hepatic

Question 53

Anticoagulants with no specific antidote

Answer 53

Bivalirudin Argatroban

Question 54

A small-molecule arginine derivative that reversibly and directly inhibits thrombin by binding to the active catalytic site of the enzyme with a Ki of 3.9 × 10−8 mol/L.

Answer 54

Argatroban

Question 55

Argatroban: half-life

Answer 55

39 to 51 minutes

Question 56

Monitoring of Argatroban

Answer 56

aPTT or ACT

Question 57

Clearance of Argatroban

Answer 57

Hepatic

Question 58

A DOC which is is a thrombin-inhibitor prodrug with a bioavailability of approximately 6% after oral administration

Answer 58

Dabigatran etexilate

Question 59

Dabigatran: half-life

Answer 59

12 hours

Question 60

Monitoring of Dabigatran

Answer 60

Dilute thrombin time and ecarin clotting time

Question 61

Dabigatran is dependent on the efflux transporter _________for enteral elimination

Answer 61

P-glycoprotein (P-gp) Strong P-gp inducers (ie, rifampicin, carbamazepine, phenytoin, phenobarbital) will reduce the effect Strong P-gp inhibitors (ie, ketoconazole, itrakonazole, HIV-protease inhibitors, dronedarone) will increase the effect

Question 62

Can inhibit both free- and thrombus-associated factor Xa

Answer 62

Rivaroxaban

Question 63

Clearance of Rivaroxaban

Answer 63

Renal, hepatic, P-gp transport

Question 64

Rivaroxaban: half-life

Answer 64

5.7–9.2 hours

Question 65

Monitoring of Rivaroxaban

Answer 65

Rivaroxaban-calibrated anti-Xa assay PT is more accurate than the aPTT

Question 66

Reversal agent for Rivaroxaban

Answer 66

Andexanet alfa

Question 67

Clearance of Apixaban

Answer 67

Renal, hepatic, P-gp transport

Question 68

Apixaban: half-life

Answer 68

12 hours

Question 69

Monitoring of Apixaban

Answer 69

Apixaban-specific anti-Xa assays PT is more sensitive than aPTT

Question 70

Edoxaban : half-life

Answer 70

8 hours.

Question 71

Clearance of Edoxaban

Answer 71

Renal, P-gp transport

Question 72

Monitoring of Edoxaban

Answer 72

Edoxaban-specific anti-Xa assays Partial thromboplastin time

Question 73

It has the lowest renal excretion of all direct oral anticoagulants, 11%, and is metabolized by non CYP-hydrolysis.

Answer 73

Betrixaban

Question 74

Betrixaban : half-life

Answer 74

19–27 hours

Question 75

Uses of fibrinolytic therapy

Answer 75

Venous and arterial thrombosis Acute myocardial infarction Thrombosis of peripheral arteries, bypass grafts, and catheters Pulmonary emboli causing hemodynamic compromise

Question 76

The first plasminogen activator used clinically

Answer 76

Streptokinase

Question 77

TRUE OR FALSE Streptokinase has no enzymatic activity, but it combines with plasminogen to form an equimolar streptokinase– plasminogen complex that can then convert other plasminogen molecules to plasmin.

Answer 77

TRUE Streptokinase has no enzymatic activity, but it combines with plasminogen to form an equimolar streptokinase– plasminogen complex that can then convert other plasminogen molecules to plasmin.

Question 78

Streptokinase has a rapid plasma clearance with a half-life of approximately _____ minutes, but the duration of the proteolytic effect is more prolonged.

Answer 78

20 minutes

Question 79

Streptokinase is antigenic, and high-titer antibodies develop ______weeks after use, precluding retreatment until the titer declines.

Answer 79

1–2 weeks

Question 80

A naturally occurring plasminogen activator that is structurally and immunologically distinct from urokinase

Answer 80

Tissue-type plasminogen activator (t-PA)

Question 81

Recombinant tissue-type plasminogen activator (t-PA)

Answer 81

Alteplase

Question 82

The half-life of t-PA after intravenous administration is approximately ______ minutes, which requires a constant infusion to maintain therapeutic plasma levels.

Answer 82

5 minutes

Question 83

Has enhanced fibrin specificity and a significantly longer half-life of 15 minutes compared with 4 minutes with t-PA, so it can be administered as an intravenous bolus rather than as a continuous infusion

Answer 83

Reteplase

Question 84

Useful for prehospital administration in remote areas, or areas with limited access to primary percutaneous coronary interventions

Answer 84

Reteplase

Question 85

It has a half-life of more than 30 minutes and can be administered as a single IV bolus.

Answer 85

Tenecteplase (TNK)

Question 86

Substance that recruits platelets

Answer 86

Adenosine diphosphate (ADP) Thromboxane A2

Question 87

TRUE OR FALSE The role of platelets in initiating thrombosis is greater in the arterial circulation than in the venous circulation because higher shear forces that are present in arteries activate platelets.

Answer 87

TRUE The role of platelets in initiating thrombosis is greater in the arterial circulation than in the venous circulation because higher shear forces that are present in arteries activate platelets.

Question 88

CYCLOOXYGENASE INHIBITORS

Answer 88

Aspirin

Question 89

AGENTS THAT INCREASE cAMP

Answer 89

Dipyridamole Pentoxifylline Cilostazol

Question 90

ADP RECEPTOR BLOCKERS

Answer 90

Ticlopidine Clopidogrel Prasugrel Ticagrelor

Question 91

ADP mimetic

Answer 91

Cangrelor

Question 92

αIIbβ3 inhibitors

Answer 92

Abciximab Eptifibatide Tirofiban

Question 93

THROMBIN RECEPTOR BLOCKER

Answer 93

Vorapaxar

Question 94

It converts arachidonic acid released from membrane phospholipids by phospholipase A2 or phospholipase C and diacylglycerol to prostaglandin (PG) G2

Answer 94

Cyclooxygenase (COX)-1

Question 95

A potent inhibitor of platelet function, through an increase in intraplatelet cyclic adenosine monophosphate (cAMP)

Answer 95

Prostacyclin

Question 96

Aspirin cause (reversible or irreversible) enzyme inhibition

Answer 96

Irreversible

Question 97

Two phosphodiesterase inhibitors that are used primarily in patients with peripheral vascular disease

Answer 97

Pentoxifylline and cilostazol

Question 98

Thienopyridines ADP blockers

Answer 98

Ticlopidine, clopidogrel, and prasugrel

Question 99

Nonthienopyridines ADP blockers

Answer 99

Ticagrelor and cangrelor

Question 100

There are three ADP receptors on platelet membranes, with the thienopyridines inhibiting one of them, the ________receptor.

Answer 100

P2Y12 receptor

Question 101

Thienopyridines associated with increased risk of thrombocytopenia and neutropenia.

Answer 101

Ticlopidine

Question 102

A “third-generation” P2Y12 blocking agent Can be converted to its active metabolite via esterases present in either the liver or the gut.

Answer 102

Prasugrel

Question 103

Agent that reversibly inhibit the P2Y12 platelet receptor

Answer 103

Ticagrelor

Question 104

The first parenteral ADP receptor blocker

Answer 104

Cangrelor

Question 105

αIIbβ3 blocker: a cyclic heptapeptide based on a rattlesnake venom peptide

Answer 105

Eptifibatide

Question 106

αIIbβ3 blocker: a nonpeptide derivative of tyrosine

Answer 106

Tirofiban

Question 107

TRUE OR FALSE Prohemostatic agents may, at least theoretically, predispose for thrombotic complications.

Answer 107

TRUE Prohemostatic agents may, at least theoretically, predispose for thrombotic complications.

Question 108

A vasopressin analogue that, despite minor molecular differences, has retained its antidiuretic properties but has much fewer vasoactive effects. Induces release of the contents of the endothelial cell–associated Weibel–Palade bodies, including von Willebrand factor

Answer 108

De-amino D-arginine vasopressin (DDAVP, desmopressin)

Question 109

A rare but important adverse effect of DDAVP is the occurrence of_________ , probably a result of the remaining vasoactive effect of the drug.

Answer 109

Acute coronary syndromes

Question 110

A 58-amino-acid polypeptide, mainly derived from bovine lung, parotid gland, or pancreas Directly inhibits the activity of various serine proteases, including plasmin, coagulation factors or inhibitors, and constituents of the kallikrein-kinin and angiotensin system

Answer 110

Aprotinin

Question 111

Lysine analogues that competitive bindst o the lysine-binding sites of a fibrin clot

Answer 111

ε-aminocaproic acid and tranexamic acid **tranexamic acid (Cyklokapron) is at least 10 times more potent than ε-aminocaproic acid (Amicar)

Question 112

The use of lysine analogues is contraindicated in

Answer 112

Ongoing systemic activation of coagulation (such as in disseminated intravascular coagulation) In cases of macroscopic hematuria, because the inhibition of urinary fibrinolysis caused by the high concentrations of the antifibrinolytic agent in the urine may result in deposition of urinary tract–obstructing clots.

Question 113

The most significant contraindication of tranexamic acid

Answer 113

macroscopic hematuria