32 Antithrombotic Therapy Flashcards
The most common adverse effect of antithrombotics
Bleeding
Decrease fibrin formation by inhibiting
thrombin or thrombin formation
Anticoagulant
Inhibit platelet function
Antiplatelet
Activate plasminogen and accelerate clot
lysis
Fibrinolytic agents
Competitive inhibitors of vitamin K
Coumarins or VKAs
VKAs MOA: inhibit γ-carboxylation reactions in the posttranslational modification of the coagulation factors ______________as well as the natural inhibitors ___________
Coagulation factors II, VII, IX, and X
Proteins C and S
VKA: water soluble and rapidly absorbed after oral administration, reaching a peak concentration after _________ minutes
60–90 minutes
Warfarin is metabolized through the _____________-system, the activity of which is influenced by environmental factors and genetic polymorphisms.
Cytochrome P450 (CYP) system
Hereditary resistance to warfarin has been described and is related to specific mutations in ______________.
Vitamin K epoxide reductase
Potentiate effect of VKA
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
Depress effect of VKA
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
Coagulation half life (shortest to longest)
- Factor VII - 5 hours
- Factors X and IX- 24 hours)
- Factor II (prothrombin) (72 hours)
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.
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.
Smaller amounts of Warfarin should be used for
- Frail
- Elderly
- Poorly nourished patients
- Those with an increased bleeding risk
During initiation of therapy, the INR is checked every_____________ until a stable therapeutic effect is achieved.
Every 2–3 days for 1–2 weeks
VKA: The target INR for most indications is _______, with a desirable therapeutic range from ________.
2.5
2 to 3
The clearance of warfarin is the result of hepatic metabolism, and _________is the most important enzyme mediating its clearance.
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.
Converts oxidized vitamin K to the active reduced form as required for posttranslational carboxylation
The target of warfarin, which functions as a competitive inhibitor.
VKORC1
Score for Predicting Bleeding Risk on Warfarin
HAS-BLED Score
Variable included in HAS-BLED Score
- Hypertension
- Abnormal renal or liver function
- Stroke
- Prior bleeding complications
- Labile INR
- Age older than 65 years
- Drug or alcohol abuse
The most important predictor of bleeding risk (HASBLED)
INR
Cause of skin necrosis in with warfarin use
Disproportionately rapid reduction in proteins C and S
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.
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.
TRUE OR FALSE
Vitamin K antagonists are safe during lactation
TRUE
Vitamin K antagonists are safe during lactation
Reversing Warfarin Therapy
INR <6
Lower the dose, consider withholding 1 or more doses
Recheck in 3–7 days
Reversing Warfarin Therapy
INR 6-10
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
Reversing Warfarin Therapy
INR >10
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
INR >1.5 and serious bleeding
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
TRUE OR FALSE
Heparin has direct anticoagulant effect and serves to activate plasma antithrombin (AT), a serine protease inhibitor.
FALSE
Heparin has no direct anticoagulant effect but serves to activate plasma antithrombin (AT), a serine protease inhibitor.
Half life of heparin
1–2.5 hours
Monitoring for heparin
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
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,
Heparin resistance
Usually caused by an acute-phase response that results in high levels of procoagulant proteins, including factor VIII.
TRUE OR FALSE
Monitoring is recommended when low doses of heparin are used for prophylaxis of venous thromboembolic disease
FALSE
No monitoring is recommended when low doses of heparin are used for prophylaxis of venous thromboembolic disease
Reversal agent for heparin
Protamine sulfate
Dosage of protamine sulfate
1 mg to neutralize 100 units of heparin
An immune-mediated platelet consumption caused by an antibody directed against a complex of heparin and platelet factor 4
HIT
Scoring used for HIT
“4T’ score
Vitamin K antagonists should be given only after the platelet count has risen to higher than ______________-
150,000/μL
Difference of LMWH from UFH
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
Plasma half-life of Danaparoid
24 hours
Clearance of Danaparoid
Renal
Monitoring of Danaparoid
Anti– factor Xa assays
A unique heparinlike anticoagulant with highly selective AT-dependent anti–factor Xa activity
Fondaparinux
TRUE OR FALSE
Fondaparinux is synthesized in a structurally homogenous form containing no animal products.
Consequently, fondaparinux does not induce allergic responses.
TRUE
Fondaparinux is synthesized in a structurally homogenous form containing no animal products.
Consequently, fondaparinux does not induce allergic responses.
Fondaparinux: maximum plasma levels are reached approximately ______ hours after subcutaneous administration
Two hours
Fondaparinux: half-life
17 hours
Clearance of Fondaparinux
Renal
Monitoring of Fondaparinux
Anti–factor Xa assay
But there is no effect on other coagulation assays including the activated clotting time (ACT), aPTT, or thrombin clotting time
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.
Bivalirudin
Bivalirudin: half-life
30 minutes
Monitoring of Bivalirudin
ACT and aPTT
Clearance of Bivalirudin
Renal and hepatic
Anticoagulants with no specific antidote
Bivalirudin
Argatroban
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.
Argatroban
Argatroban: half-life
39 to 51 minutes
Monitoring of Argatroban
aPTT or ACT
Clearance of Argatroban
Hepatic
A DOC which is is a thrombin-inhibitor prodrug with a bioavailability of approximately 6% after oral administration
Dabigatran etexilate
Dabigatran: half-life
12 hours
Monitoring of Dabigatran
Dilute thrombin time and ecarin clotting time
Dabigatran is dependent on the efflux transporter _________for enteral elimination
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
Can inhibit both free- and thrombus-associated factor Xa
Rivaroxaban
Clearance of Rivaroxaban
Renal, hepatic, P-gp transport
Rivaroxaban: half-life
5.7–9.2 hours
Monitoring of Rivaroxaban
Rivaroxaban-calibrated anti-Xa assay
PT is more accurate than the aPTT
Reversal agent for Rivaroxaban
Andexanet alfa
Clearance of Apixaban
Renal, hepatic, P-gp transport
Apixaban: half-life
12 hours
Monitoring of Apixaban
Apixaban-specific anti-Xa assays
PT is more sensitive than aPTT
Edoxaban : half-life
8 hours.
Clearance of Edoxaban
Renal, P-gp transport
Monitoring of Edoxaban
Edoxaban-specific anti-Xa assays
Partial thromboplastin time
It has the lowest renal excretion of all direct oral anticoagulants, 11%, and is metabolized by non CYP-hydrolysis.
Betrixaban
Betrixaban : half-life
19–27 hours
Uses of fibrinolytic therapy
Venous and arterial thrombosis
Acute myocardial infarction
Thrombosis of peripheral arteries, bypass grafts, and catheters
Pulmonary emboli causing hemodynamic compromise
The first plasminogen activator used clinically
Streptokinase
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.
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.
Streptokinase has a rapid plasma clearance with a half-life of approximately _____ minutes, but the duration of the proteolytic effect is more prolonged.
20 minutes
Streptokinase is antigenic, and high-titer antibodies develop ______weeks after use, precluding retreatment until the titer declines.
1–2 weeks
A naturally occurring plasminogen activator that is structurally and immunologically distinct from urokinase
Tissue-type plasminogen activator (t-PA)
Recombinant tissue-type plasminogen activator (t-PA)
Alteplase
The half-life of t-PA after intravenous administration is approximately ______ minutes, which requires a constant infusion to maintain therapeutic plasma levels.
5 minutes
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
Reteplase
Useful for prehospital administration in remote areas, or areas with limited access to primary percutaneous coronary interventions
Reteplase
It has a half-life of more than 30 minutes and can be administered as a single IV bolus.
Tenecteplase (TNK)
Substance that recruits platelets
Adenosine diphosphate (ADP)
Thromboxane A2
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.
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.
CYCLOOXYGENASE INHIBITORS
Aspirin
AGENTS THAT INCREASE cAMP
Dipyridamole
Pentoxifylline
Cilostazol
ADP RECEPTOR BLOCKERS
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
ADP mimetic
Cangrelor
αIIbβ3 inhibitors
Abciximab
Eptifibatide
Tirofiban
THROMBIN RECEPTOR BLOCKER
Vorapaxar
It converts arachidonic acid released from membrane phospholipids by phospholipase A2 or phospholipase C and diacylglycerol to prostaglandin (PG) G2
Cyclooxygenase (COX)-1
A potent inhibitor of platelet function, through an increase in intraplatelet cyclic adenosine monophosphate (cAMP)
Prostacyclin
Aspirin cause (reversible or irreversible) enzyme inhibition
Irreversible
Two phosphodiesterase inhibitors that are used primarily in patients with peripheral vascular disease
Pentoxifylline and cilostazol
Thienopyridines ADP blockers
Ticlopidine, clopidogrel, and prasugrel
Nonthienopyridines ADP blockers
Ticagrelor and cangrelor
There are three ADP receptors on platelet membranes, with the thienopyridines inhibiting one of them, the ________receptor.
P2Y12 receptor
Thienopyridines associated with increased risk of thrombocytopenia and neutropenia.
Ticlopidine
A “third-generation” P2Y12 blocking agent
Can be converted to its active metabolite via esterases present in either the liver or the gut.
Prasugrel
Agent that reversibly inhibit the P2Y12 platelet receptor
Ticagrelor
The first parenteral ADP receptor blocker
Cangrelor
αIIbβ3 blocker: a cyclic heptapeptide based on a rattlesnake venom peptide
Eptifibatide
αIIbβ3 blocker: a nonpeptide derivative of tyrosine
Tirofiban
TRUE OR FALSE
Prohemostatic agents may, at least theoretically, predispose for thrombotic complications.
TRUE
Prohemostatic agents may, at least theoretically, predispose for thrombotic complications.
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
De-amino D-arginine vasopressin (DDAVP, desmopressin)
A rare but important adverse effect of DDAVP is the occurrence of_________ , probably a result of the remaining vasoactive effect of the drug.
Acute coronary syndromes
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
Aprotinin
Lysine analogues that competitive bindst o the lysine-binding sites of a fibrin clot
ε-aminocaproic acid and tranexamic acid
**tranexamic acid (Cyklokapron) is at least 10 times more potent than ε-aminocaproic acid (Amicar)
The use of lysine analogues is contraindicated in
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.
The most significant contraindication of tranexamic acid
macroscopic hematuria
