Therapy of Venous Thromboembolism Flashcards
Venous thromboembolism (VTE) results from:
Clot formation within the venous circulation
Venous thromboembolism (VTE) is manifested as:
1) Deep vein thrombosis (DVT)
2) Pulmonary embolism (PE)
Pharmacologic prevention significantly reduces the risk of VTE following:
1) Hip and knee replacement
2) Hip fracture repair
3) Major general surgery
4) Myocardial infarction
5) Ischemic stroke
Hospitalized and acutely ill medical patients at high-VTE-risk and low-bleeding-risk should receive pharmacologic prophylaxis with __, __, or __ during hospitalization or until fully ambulatory
1) Low dose unfractionated heparin (UFH)
2) Low molecular weight heparin (LMWH)
3) Fondaparinux
Routine pharmacologic prophylaxis is NOT indicated in which patients?
Low-VTE-risk medical patients
How should you prevent VTE following non-orthopedic surgery?
1) Low dose UFH
2) LMWH
How should you prevent VTE following following high risk orthopedic surgery (such as joint replacement surgery)?
1) Aspirin
2) Adjusted-dose warfarin
3) UFH
4) LMWH
5) Fondaparinux
6) Dabigatran
7) Apixaban
8) Rivaroxaban
How long should patients take VTE prophylactics following high risk orthopedic surgery (such as joint replacement surgery)?
At least 10 days post-surgery
What is the mainstay of VTE
(DVT & PE) treatment?
Anticoagulation therapy (Rapid-acting)
We should establish an accurate VTE diagnosis in order to avoid:
Bleeding
Traditionally, specific VTE therapy is started with:
LMWH or UFH overlapped with warfarin for 5 days, then the patient is maintained on warfarin
The appropriate initial duration of therapy to effectively treat an acute first episode of VTE for all patients is:
3 months
Which factors determine extending post-VTE anticoagulation therapy beyond 3 months?
1) Circumstances surrounding the initial thromboembolic event
2) Presence of ongoing thromboembolic risk factors
3) Bleeding risk
4) Patient preference
What are some clinically important bleeding risk factors?
1) Age more than 75 years
2) Previous non-cardioembolic stroke
3) History of GI bleeding
4) Renal or hepatic impairment
5) Anemia
6) Thrombocytopenia
7) Concurrent antiplatelet administration
8) Noncompliance
9) Poor anticoagulant control (for patients on warfarin)
10) Serious acute or chronic illness
11) The presence of structural lesions (tumor, recent surgery) that could bleed
How may Unfractionated Heparin (UFH) be given?
1) Subcutaneous injection
2) Continuous IV infusion
Response to UFH is:
Highly variable
UFH dose should be adjusted based on:
Activated partial thromboplastin time (aPTT)
Both __ and __ produce similar clinical outcomes.
Weight-based and Fixed-UFH-dosing
Traditional IV UFH in the acute treatment of VTE may be replaced by:
1) LMWH
2) Fondaparinux
Elimination of LMWH and fondaparinux is dependent on:
Renal function
Can you give UFH to acute VTE patients with CrCL < 30 mL/min?
YES
Why did Low-Molecular-Weight Heparin (LMWH) replace UFH for initial VTE treatment?
1) Improved pharmacokinetic and pharmacodynamic profiles
2) Ease of use
How is LMWH given?
Subcutaneously in fixed or weight-based doses
Is LMWH given subcutaneously in fixed or weight-based doses as effective as UFH given
intravenously for the treatment of VTE?
YES
LMWHs have reduced need for:
Laboratory monitoring
LMWH monitoring is indicated in:
1) Obesity
2) Pregnancy
3) Children
How is LMWH monitored?
By anti–factor Xa activity
Anti–factor Xa goal levels are 0.5 - 1.0 unit/mL __-__ hours following subcutaneous LMWH injection.
4 - 6 hours
Can LMWH be used on an outpatient basis for stable low-risk patients?
YES
In patients without cancer, acute treatment with LMWH is generally transitioned to long-term warfarin therapy after about:
5 - 10 days
_____ is preferred if thrombolytic therapy or embolectomy is anticipated.
Rapidly reversible UFH
Fondaparinux is dosed ___ via weight-based subcutaneous injection.
Once daily
When is Fondaparinux contraindicated?
If CrCL < 30 mL/min
Can we give Warfarin monotherapy for acute VTE treatment? Why or why not?
NO, because the slow onset of action is associated with high incidence of recurrent thromboembolism.
Warfarin is effective in the long-term VTE management IF:
It is started concurrently with rapid-acting parenteral anticoagulant
The initial dose of Warfarin is:
5-10 mg for most patients
Warfarin is periodically adjusted to achieve and maintain an INR between:
2-3
Which direct oral anticoagulants can be started as single-drug therapy?
1) Rivaroxaban
2) Apixaban
How are Rivaroxaban and Apixaban monitored?
None, they don’t need to be monitored.
Which direct oral anticoagulants require prior parenteral anticoagulation?
1) Dabigatran
2) Edoxaban
Can patients with CrCL < 30 mL/min take Edoxaban?
Yes, at half the dose.
Can patients with CrCL < 30 mL/min receive Dabigatran?
NO
Most VTE cases require only ___ therapy.
Anticoagulation
What are Thrombolytic agents?
Proteolytic enzymes
What do Thrombolytic agents do?
Enhance conversion of plasminogen to plasmin, which lyses the thrombus.
Thrombolytic therapy improves:
Early venous patency
Does Thrombolytic therapy improve long-term outcomes?
NO
How should you adjust anticoagulation therapy duration and intensity for DVT patients receiving thrombolysis?
No change
Patients with DVT involving the iliac and common femoral veins are at highest risk of:
Post-thrombotic syndrome
Patients at high risk for post-thrombotic syndrome may benefit from:
Thrombus removal
Which patients are at highest risk for post-thrombotic syndrome?
Patients with DVT involving the iliac and common femoral veins
In acute PE management, successful clot dissolution with thrombolytic therapy:
1) Reduces elevated pulmonary artery pressure
2) Improves right ventricular dysfunction
For thrombolytic therapy to be used, the risk of ___ should outweigh the risk of ___ from thrombolytic therapy.
Death from PE; Serious bleeding
Prior to initiating Thrombolytic therapy, what should patients be screened carefully for?
Contraindications related to bleeding risk
Which anticoagulant crosses the placenta?
Warfarin
Which anticoagulants are preferred in pregnancy?
1) UFH
2) LMWH
What are the complications of taking Warfarin during pregnancy?
1) Fetal bleeding
2) CNS abnormalities
3) embryopathy
Pregnant women with a history of VTE should receive VTE prophylaxis for how long after
delivery?
6-12 weeks
Which anticoagulants are safe during breast-feeding?
1) Warfarin
2) UFH
3) LMWH
VTE in pediatric patients is increasing secondary to:
1) Prematurity
2) Cancer
3) Trauma
4) Surgery
5) Congenital heart disease
6) SLE
Pediatric patients rarely experience ___(provoked/unprovoked) VTE
Unprovoked
Pediatric patients often develop DVT associated with:
Indwelling central venous catheters
How do you give pediatric patients anticoagulation with UFH and warfarin?
Similar to that of adults
Why is obtaining blood from pediatric patients for coagulation monitoring tests problematic?
Because of poor venous access
Which anticoagulant is preferred in pediatric patients?
LMWH
Why is LMWH preferred in pediatric patients?
1) Low drug interaction potential
2) Less frequent lab testing
Warfarin should be continued in pediatric patients for at least ____ for provoked VTE.
3 months
Warfarin should be continued in pediatric patients for at least ____ for unprovoked VTE.
6 months
Is routine use of thrombolysis and thrombectomy recommended in children?
NO
Cancer-related VTE is associated with:
1) Higher rates of recurrent VTE
2) Higher rates of bleeding
3) More resistance to standard warfarin-based therapy
Warfarin therapy in cancer patients is often complicated by:
1) Drug interactions (chemotherapy and antibiotics)
2) The need to interrupt therapy for invasive procedures
Why is maintaining a stable INR difficult in cancer patients?
1) Nausea
2) Anorexia
3) Vomiting
________ for cancer-related VTE decreases recurrent VTE rates without increasing bleeding risks compared with warfarin-based therapy.
Long-term LMWH monotherapy
LMWH therapy for cancer-related VTE should be used for at least the first ___ of long-term treatment
3 - 6 months
Anticoagulation therapy for cancer-related VTE should continue for as long as:
1) The cancer is “active”
2) While the patient is receiving chemotherapy
__ is preferred for acute VTE treatment in renal dysfunction.
UFH
Why can’t LMWH, fondaparinux, and direct-acting anticoagulants (DOACs) be used in renal dysfunction?
Because they accumulate
Patients with chronic kidney disease are at increased risk of __ from other causes.
Bleeding
Unfractionated heparin is a heterogeneous mixture of ___ of variable lengths.
Sulfated mucopolysaccharides
How is the anticoagulant effect of UFH mediated?
Through a specific pentasaccharide sequence that binds to antithrombin.
UFH accelerates the anticoagulant action of ___ 100 - 1,000 times.
Antithrombin
Antithrombin inhibits factors:
2, 9, 10, 12
UFH prevents:
Thrombus growth and propagation
UFH prevents thrombus growth and propagation allowing:
Endogenous thrombolytic systems to dissolve the clot.
Which 2 factors are most sensitive to UFH–antithrombin complex inhibition?
2 (Thrombin) and 10
In order to inactivate thrombin (IIa), the heparin molecule must first form what?
A ternary complex bridging between antithrombin and thrombin
The inactivation of factor Xa requires UFH binding to antithrombin via:
The specific pentasaccharide sequence
The onset of action of UFH after SC injection is:
1-2 hours
The action of UFH peaks at:
3 hours
Why should intramuscular UFH be avoided?
Because of the risk of bleeding and hematomas
UFH has a dose-dependent half-life of:
30-90 minutes
UFH’s elimination follows __(zero/first) order kinetics.
Zero
What are the Adverse Effects of UFH?
1) Bleeding
2) Heparin-induced thrombocytopenia (HIT)
3) Significant bone loss and osteoporosis
What can you give to reverse the anticoagulant effects of UFH?
Protamine sulfate
How quickly does Protamine sulfate act?
5 minutes
What is Heparin-induced thrombocytopenia (HIT) caused by?
Pro-thrombotic antibodies that bind to complexes of heparin and platelet factor 4 (PF4)
Heparin-induced thrombocytopenia (HIT) leads to:
Arterial thromboembolic events
Heparin-induced thrombocytopenia (HIT) occurs ____ after initiation of UFH.
5-10 days
What alternative anticoagulants can be given if the patient experiences Heparin-induced thrombocytopenia (HIT)?
Direct thrombin inhibitors
What represents vaccine-related variant of HIT?
Vaccine-induced immune thrombotic thrombocytopenia (Ex. Thrombosis seen with some Covid-19 vaccines is similar to HIT)
When used for more than 6 months, such as in pregnancy, UFH can cause:
Significant bone loss and osteoporosis
Which drugs can’t be used with UFH out of fear of increased bleeding?
1) Anticoagulants
2) Thrombolytics
3) Antiplatelet agents
4) Aspirin
5) NSAIDs
How is LMWH produced?
By depolymerization of UFH
Which is lighter in weight: LMWH or UFH?
LMWH
Advantages of LMWH?
1) Predictable anticoagulation dose response
2) Improved subcutaneous bioavailability
3) Dose-independent elimination (first-order)
4) Longer half-life
5) Reduced need for routine laboratory monitoring
Which drugs are LMWH?
1) Enoxaparin
2) Dalteparin
How does Low-molecular-weight heparin (LMWH) prevent thrombus growth and propagation?
By enhancing and accelerating the activity of antithrombin against factor Xa
Because of smaller chain lengths, LMWH has limited activity against:
Activated thrombin (IIa)
The bioavailability of LMWH is __% after SC injection.
90%
The peak anticoagulation of LMWH is between __-__ hours.
3 - 5
LMWH is mainly eliminated by:
Renal excretion
Adverse Effects of LMWH?
1) Bleeding
2) HIT
3) Osteoporosis and osteopenia
Antidote for LMWH?
IV protamine sulfate
HIT in LMWH is three times __(higher/lower) than that observed with UFH.
Lower
LMWH should be avoided in patients with __, because of cross reactivity with antibodies.
HIT
Which drugs can’t be used with LMWH because of drug-drug interactions (increased bleeding)?
1) Anticoagulants
2) Thrombolytics
3) Antiplatelet agents
4) Aspirin
5) NSAIDs
6) Dipyridamole
7) Sulfinpyrazone
Fondaparinux is a synthetic molecule consisting of the active pentasaccharide units that bind __(irreversibly/reversibly) to antithrombin.
Reversibly
Fondaparinux is a synthetic molecule consisting of the active pentasaccharide units that bind reversibly to ___.
Antithrombin
Fondaparinux inhibits:
Factor Xa activity ONLY
Fondaparinux is eliminated __(unchanged/changed) in the urine.
Unchanged
Elimination half-life of Fondaparinux is:
19 hours
The anticoagulant effect of Fondaparinux persists for ___ following discontinuation of the drug in patients with normal renal function.
2 to 4 days
Adverse Effects of Fondaparinux?
1) Bleeding
2) Rare cause of HIT
Fondaparinux antidote?
NONE
Which drugs can’t be used with Fondaparinux because of drug-drug interactions (increased bleeding)?
1) Anticoagulant
2) Fibrinolytics
3) Antiplatelets
Hirudin is derived from ___.
Leech
Lepirudin is from:
Recombinant DNA technology
What is Lepirudin?
Irreversible inhibitor, inactivates fibrin-bound thrombin.
How is Lepirudin given?
1) IV
2) SC
Lepirudin is monitored by:
aPTT
How is Lepirudin eliminated?
1) Hepatic metabolism
2) Renal excretion
Lepirudin should not be given in:
Renal failure
Lepirudin is used for:
Thrombosis related to HIT
Antidote for Lepirudin?
NONE
What is Bivalirudin?
Direct thrombin inhibitor
Bivalirudin is a synthetic congener of the naturally occurring anticoagulant ___.
Hirudin
How is Bivalirudin given?
IV bolus followed by infusion
How is Bivalirudin eliminated?
1) Hepatic elimination
2) Renal elimination
3) Proteolytic cleavage
Bivalirudin __(reversibly/irreversibly) inhibits both circulating and clot-bound thrombin.
Reversibly
Bivalirudin inhibits:
1) Circulating thrombin
2) Clot-bound thrombin
3) Thrombin-mediated platelet activation and aggregation
Does Bivalirudin have a higher or lower bleeding risk than r-hirudins?
Lower
Bivalirudin is used in:
1) Percutaneous coronary intervention (PCI)
2) HIT
How is Bivalirudin monitored?
Thrombin Inhibitor Assay
Why is Thrombin Inhibitor Assay better than aPTT?
Because it is NOT affected by antiphospholipid antibodies
Bivalirudin is contraindicated in:
Severe renal impairment
Vitamin K in its reduced form is required for vitamin K-dependent carboxylation of:
1) Factors 2, 7, 9, and 10
2) Proteins C and S
What does Warfarin do?
Inhibits the reduction of vitamin K epoxide = Impairs the formation of complete functioning clotting factors
How long does it take for Warfarin to achieve its full antithrombotic effect?
6 days
Why does it take so long for Warfarin to work?
Because it has NO effect on pre-formed clotting factors
The time required for warfarin to achieve its pharmacologic effect is dependent on:
Coagulation protein elimination half-lives (6 hours for factor 7 and 72 hours for prothrombin (2))
Half-life of Factor 2? (Two)
72 hours (Too long)
Half-life of Factor 7? (Seven)
6 hours (Short)
Half-life of Factor 9?
24 hours
Half-life of Factor 10?
40 hours
Half-life of Protein C?
8 hours
Half-life of Protein S?
30 hours
Warfarin has a __(wide/narrow) therapeutic index.
Narrow
Adverse Effects of Warfarin?
1) Bleeding
2) Purple Toe Syndrome
3) Warfarin-induced skin necrosis
Warfarin antidote?
Vitamin K
In case of bleeding, warfarin should be:
1) Temporarily stopped
2) Dose reduced
What causes Purple Toe Syndrome?
Cholesterol microembolization into the arterial circulation of the toes
Which areas of the body are most commonly affected by Warfarin-induced skin necrosis?
Areas rich in subcutaneous fat:
1) Breasts
2) Thighs
3) Buttocks
4) Abdomen
How is Warfarin monitored?
INR
Which drugs cause pharmacodynamic interactions with Warfarin?
1) Aspirin/NSAIDs
2) Clopidogrel/Ticlopidine
3) Tramadol
4) Levothyroxine
5) Vitamin K containing foods/supplements
What does Tramadol do when given with Warfarin?
Elevates INR
What does Levothyroxine do when given with Warfarin?
Increases catabolism of clotting factors
Which drugs elevate the INR when given with Warfarin?
1) Amiodarone
2) Fluoroquinolones
3) Trimethoprim/Sulfamethoxazole
4) Metronidazole
5) Azole antifungals
6) Statins
7) Isoniazid
8) NSAIDs
9) Sertraline
10) Gemfibrozil
11) Ethanol
12) Macrolides
13) Cimetidine
14) Omeprazole
15) Fluorouracil
16) Garlic!!
17) Gingko
18) Vitamin E
Which drugs reduce the INR when given with Warfarin?
1) Rifampin
2) Barbiturates
3) Carbamazepine
4) Phenytoin
5) St. John’s Wort
6) Smoking
7) Cholestyramine (Bile Binding Resins)
8) OCPs (Estrogen)
9) Ginseng
10) Green tea
11) Avocado
12) Leafy greens
Which enzyme metabolizes Warfarin?
CYP2C9
Why does warfarin exhibit dose variability between patients?
Polymorphisms in:
1) CYP2C9
2) The gene coding for VKOR (Vitamin K Epoxide Reductase)
Which metabolizer subtypes have been associated with increased risk of bleeding on Warfarin?
Poor metabolizers
Warfarin resistance can be due to:
Mutations in the receptor gene
Which drugs are Direct Oral Anticoagulants?
1) Rivaroxaban
2) Apixaban
3) Edoxaban
4) Dabigatran
What do Rivaroxaban, Apixaban, and Edoxaban do?
Selectively inhibit both free and clot-bound factor Xa.
True or False: Rivaroxaban, Apixaban, and Edoxaban require antithrombin to exert their anticoagulant effect.
FALSE; THEY DO NOT REQUIRE IT.
What is Dabigatran?
A selective, reversible, prodrug that directly inhibits factor IIa (Thrombin)
Direct Oral Anticoagulants should be avoided in:
Renal failure (CrCl < 30 mL/min)
Which last longer: Factor 10 inhibitors or Dabigatran?
Dabigatran
Rivaroxaban and apixaban are substrates of:
1) Cytochrome CYP3A4
2) P-glycoprotein
Indications for using Rivaroxaban and Apixaban?
1) Prevent VTE following hip or knee replacement surgery
2) Extended VTE treatment after the first 6 months of anticoagulant therapy
Which drugs are substrates of Cytochrome CYP3A4 and P-glycoprotein?
1) Rivaroxaban
2) Apixaban
Indications for using Dabigatran?
Extended VTE treatment after the first 6 months of anticoagulant therapy
Adverse Effects of Direct Oral Anticoagulants?
1) GI complaints
2) Bleeding
Antidote for Dabigatran?
1) Idarucizumab
2) Hemodialysis
Antidote for Direct Oral Anticoagulants?
Activated charcoal within 2 hours of presentation
How does Idarucizumab work to stop the effects of Dabigatran?
It binds to dabigatran and its acylglucuronide with higher affinity than that of dabigatran to thrombin.
When is Idarucizumab used?
Dabigatran severe side effects:
1) Life-threatening bleeding
2) When there is need for urgent surgical intervention
ALL Direct Oral Anticoagulants should not be given with:
1) P-glycoprotein inducers
2) P-glycoprotein inhibitors
Rivaroxaban and Apixaban should not be given with:
1) CYP3A4 inducers
2) CYP3A4 inhibitors
What should we assess when giving Direct Oral Anticoagulants?
Renal function
___ dosing should be reduced in patients with CrCL 15 - 50 mL/min
Edoxaban
