Weber Recorded Lecture Flashcards
Where do venous thrombi (blood clots) form?
Areas of slow/disturbed blood flow
*promoted by stasis blood
What affect does stasis blood have on clotting factors?
Stasis blood decreases clotting factor clearance
What is the connection between PE’s and DVT’s?
All PE’s come from DVT’s
BUT
Not all DVT’s come from PE’s
What is Virchow’s triad and what are its 3 components?
Virchow’s triad consists of the 3 main things that contribute to the development of a blood clot
(nearly all patients who develop a blood clot will have one or more of these, but not all patients with these will develop a blood clot)
- Hypercoagulable state
(abnormal clotting components, seen in pregnancy and cancer) - Circulatory Stasis
(abnormalities in blood flow, seen in long periods of immobility and afib) - Endothelial injury
(abnormal surfaces in contact with blood flow, seen when blood vessels are injured such as during surgery or after traumatic injury)
What is the pathway for blood clot formation and degradation?
Vessel Wall Injury (Endothelium becomes exposed)
Platelet Adhesion and Aggregation
Coagulation Cascade Activation
Thrombin
Fibrin Formation
Stabilized Fibrin Clot
Fibrinolysis and Clot Degradation
Recanalization and Healing
What is the role of Von Willebrand Factor?
ACTIVATES platelet adhesion and aggregation to the endothelium after injury occurs
What is the role of:
Tissue Factor
Factor VIIa (7)
Factor Xa (10)
Factor XIIa (12)
Thrombin (Factor II)?
ACTIVATE the formation of thrombin through the coagulation cascade
What is the role of Factor XIIIa (13)?
ACTIVATES formation and stabilization of the fibrin clot
What is the role of Tissue Plasminogen Activator?
**This is the exception to the activators
Activates clot degradation
What is the role of Heparin and Thrombomodulin?
INHIBIT platelet adhesion and aggregation to the endothelium
(Opposite of Von Willebrand factor)
What is the role of:
Antithrombin
Protein C
Protein S
Tissue Factor Pathway inhibitor?
INHIBIT the formation of thrombin through the coagulation cascade
What is the role of Plasminogen activator Inhibitor-1?
*This is the exception of the inhibitors and the opposite of Tissue Plasminogen Activator
Inhibits clot degradation
What happens during the “Initiation” phase of the coagulation cascade?
Trace amounts of thrombin develop
What happens during the “Amplification” phase of the coagulation cascade?
Trace amounts of thrombin from the Initiation phase leads to more thrombin being produced
-This leads to the activation of clotting factors
What happens during the “Propagation” phase of the coagulation cascade?
A large amount of thrombin is produced
-This leads to fibrinogen being converted to fibrin
-The fibrin clot forms
What Factor # is thrombin?
IIa
What Factor # is prothrombin?
II
*not the active form
What is postthrombotic syndrome?
A long-term complication of DVT
*caused by damage to venous valves
What must we do before diagnosing postthrombotic syndrome?
Rule out recurrent thrombosis
What are 4 non-pharmacological treatment options for DVT?
-Bed Rest
-Elevation of Feet
-Pain Management
-Compression Stockings
What are 3 non-pharmacological treatment options for PE?
-Oxygen
-Mechanical Ventilation
-Compression Stockings
What is a PE?
A blood clot that blocks and stops blood flow to an artery in the lung
Is unfractionated heparin (UFH) long-acting or rapid?
Rapid
How is UFH administered?
Given as a continuous infusion
True or False: UFH has a variable dose response
True
What is aPTT monitoring?
The monitoring system put into place for UFH
-Stands for: activated Partial Thromboplastic Time
**Monitors how long blood takes to clot
What is the goal for aPTT monitoring?
1.5-2.5 x Control
(will be given what control is)
How is UFH dosed?
*Based on weight and has two parts:
80 units/kg IV bolus
and
18 units/kg/hr infusion
What are the adverse effects associated with UFH?
-Bleeding
-Thrombocytopenia
How often should aPTT monitoring occur?
-At baseline
-6 hours after dose or with each dosage change (for first 24 hours)
-Check daily after first day (and if in goal)
What are some key differences between Heparin Associated Thrombocytopenia (HAT) and Heparin Induced Thrombocytopenia (HIT)?
HAT:
-AKA: HIT-Type 1
-Non-immune mediated
-Mild decrease in platelets (remain > 100,000)
-Occurs 48-72 hours after heparin administration (early onset)
-Transient (lasts short time)
-DO NOT NEED TO DISCONTINUE HEPARIN
HIT:
-Immune mediated
-Thrombotic complications
-Occurs 7-14 days after heparin administration (late-onset)
-Can occur up to 9 days after stopping therapy
-Platelets drop >50% from baseline (<100,000)
For which heparin-associated complication do we need to stop ALL heparin products? (HIT or HAT)
HIT
(heparin induced thrombocytopenia)
What platelet levels are indicative of HIT?
Platelet levels that drop > 50% from baseline or are < 100,000/mm^3
Which of the heparin-associated complications has a quick onset (HIT or HAT)?
HAT
(occurs around 48-72 hours after administration)
When a patient develops HIT how should it be managed?
-Stop all heparin products
-Give alternative anti-coagulant (lepirudin, argatroban, bivaliruden, or fondaparinux)
-Evaluate for thrombosis
Should platelet infusions be given when a patient develops HIT?
NO (even though platelet count is low)
At what platelet count are we able to give a patient warfarin after they develop HIT?
We can give a patient warfarin once their platelet count reaches > 150,000
What are the advantages of LMWH over UFH?
-Reduced protein binding (good bioavailability, predictable dose response, no resistance)
-Predictable dose response (fixed or weight-based dosing, no monitoring required)
-Longer plasma half-life (once or twice daily dosing)
-Smaller molecule (improved subq absoprtion)
-Less effect of platelets and endothelium (reduced HIT and possibly bleeding)
What is the dosing of enoxaparin (Lovenox) for prophylaxis?
Surgery: 30mg subQ every 12 hours
Medical: 40mg subQ daily
What is the dosing of enoxaparin (Lovenox) for treatment?
Every 12 hours: 1 mg/kg subQ
Daily: 1.5 mg/kg subQ
What is the dosing of enoxaparin (Lovenox) for renal dysfunction (CrCl <30)?
Prophylaxis: 30 mg subQ daily
Treatment: 1 mg/kg subQ daily
What is the monitoring parameter for LMWH?
*Routine monitoring is not generally recommended (Unlike with UFH)
*Monitoring of Anti Xa Levels only done in special populations
What populations should have their Anti Xa Levels monitored when receiving LMWH treatment?
Children
Severe Kidney Failure
Obesity
Long Courses of treatment
Pregnancy
How are Anti Xa levels monitored in special populations?
Twice Daily Dosing:
—Goal: 0.6-1 units/mL
(obtained 4 hours post-dose) [This is the peak]
Once Daily Dosing:
—Goal: 0.1-0.3 units/mL
(obtained immediately before dose is given) [This is the trough]
What is the one INJECTABLE (IV) Factor Xa Inhibitor?
Fondaparinux
When would we use Fondaparinux?
-Prophylaxis following: THA, TKA, Hip replacement (hip and knee surgeries), abdominal surgery
-Treatment of DVT and PE
HIT
What is the dosing used for Fondaparinux?
Prophylaxis: 2.5mg subQ once daily (for knee, hip, or abdominal surgery)
Treatment (HIT):
<50 kg: 5mg subQ once daily
50-100kg: 7.5mg subQ once daily
> 100kg: 10mg subQ once daily
When should Fondaparinux not be used?
Renal dysfunction (CrCl <30 mL/min)
Prophylaxis with low body weight (<50 kg)
What is the monitoring procedure for Fondaparinux?
No routine monitoring for efficacy
(but can monitor anti-Xa levels similar to LMWH)
Is Fondaparinux safe in pregnancy?
YES
What are the IV direct thrombin inhibitors?
Lepirudin
Bivalirudin (Angiomax)
Argatroban
When are the IV direct thrombin inhibitors mainly used?
HIT treatment
What considerations should be made when taking Argatroban with warfarin?
Argatroban elevates INR
-Treatment should be overlapped with warfarin until the INR reaches greater than or equal to 4
Which IV direct thrombin inhibitor should be adjusted for hepatic impairment?
Argatroban
**Change from 2mcg/kg/min to 0.5 mcg/kg/min
*Use caution in hepatic dysfunction
What are the 2 brand names for warfarin?
-Coumadin
-Jantoven
What strengths of warfarin tablets are available?
1 mg
2 mg
2.5 mg
3 mg
4 mg
5 mg
6 mg
7.5 mg
10 mg
What organ does warfarin work in?
Liver
What is the mechanism of action of warfarin?
Warfarin has two enantiomers (S and R) that are metabolized by different CYP’s
The S enantiomer is 5x more potent than R
These enantiomers block the Vitamin K Reductase Enzyme (VKORC1) which is used to reduce Vitamin K
Reduced Vitamin K is used to create clotting factors, so without it, vitamin K dependent clotting factors are not made
This reduces overall blood clotting
What CYP metabolizes the S (more potent) enantiomer of warfarin?
CYP 2C9
What CYPs metabolize the R (less potent) enantiomer of warfarin?
CYP 1A2
CYP 3A4
What clotting factors have inhibited synthesis with the use of warfarin?
Factors II, VII, IX, and X
Protein C and S
Does warfarin affect circulating clotting factors?
NO, only blocks the synthesis of new clotting factors
If a patient has a sudden increase in their Vitamin K intake, what affect will this have on warfarin?
An increase in Vitamin K levels will decrease the effect of warfarin
How long does it take for warfarin to reach its peak effect?
72-96 hours
*but there will be some anticoagulant effects within 24 hours
How long is the duration of action of warfarin? (of a single dose)
2-5 days
Why is the peak effect of warfarin so delayed?
Warfarin does not effect circulating clotting factors. Therefore, warfarin cannot reach peak effect until these circulating factors reach their half-lives. The half-lives of these clotting factors range from hours to days which delays warfarin’s effects.
*factor X: half life is 24-40 hours
What is CYP2C9?
The primary CYP responsible for metabolism of the S enantiomer of warfarin
What is CYP2C9*1?
The wild type CYP2C9 with normal activity
How does having the CYP2C92 and CYP2C93 genetic variances affect the way a patient metabolizes warfarin?
CYP2C9*2: Decreases S-warfarin clearance by 40-70%
CYP2C9*3: Decreases S-warfarin clearance by 90%
**both of these lead to patients requiring a lower dose of warfarin
For patients with both the CYP2C9 *1 and *2 variances, how does their warfarin dose need to be adjusted?
20% lower warfarin dose requirement
For patients with both the CYP2C9 *2 and *3 OR *1 and *3 combinations, how does their warfarin dose need to be adjusted?
35% lower dose requirement
For patients with a combination of CYP2C9 3/3, how does their warfarin dose need to be adjusted?
80% lower dose requirement
How do CYP2C9 *5, 6,8, and *11 variances affect the required warfarin dosing of a patient?
Correlate with a lower dose requirement
**Potential increased bleeding risk and longer time to goal
What is VKORC1?
The reductase enzyme that is inhibited by warfarin and which forms the active form of Vitamin K
-converts active vitamin K into clotting factors
What do the genetic variances 1639A and 1173T in VKORC1 lead to?
Decreased VKOR production
What affect does the 1639A variance in VKORC1 have on warfarin sensitivity and dosing?
Causes increased warfarin sensitivity
-Lower dosing of warfarin needed
-Average daily dose: 3mg
What affect does the 1639G variance in VKORC1 have on warfarin sensitivity and dosing?
Leads to increased warfarin resistance
-Higher dose of warfarin required
-Average daily dose: 6mg
In VKORC1 genetic variance, what does having more “G” present signify?
More resistance to warfarin
In CYP2C9 genetic variance, what does having more/higher “*” signify?
Increased sensitivity to warfarin
What 3 requirements MUST be met for a patient to need to be tested for genetic variances in CYP2C9 and VKORC1?
- Patient must be warfarin naive
- Genetic test results must be able to be made available before the patient receives their 6th warfarin dose
- Patient must be at high risk of bleeding with elevated INR
What medications have a drug interaction with warfarin that would cause them to INCREASE a patient’s INR?
-Metronidazole
-Fluconazole
-Bactrim
-Ciprofloxacin
-Amiodarone
-Propafenone
What medications have a drug interaction with warfarin that would cause them to DECREASE a patient’s INR?
Rifampin
What drugs increase a patient’s risk for bleeding when on metformin, but do not affect INR?
-Aspirin
-NSAIDs
What affect does alcohol have on a patient’s INR?
Alcohol can either decrease or increase the INR
True or False: A patient should not eat Vitamin K containing foods while on warfarin.
FALSE, a patient can still eat Vitamin K containing foods, but they should remain consistent in how much they are eating and avoid major increases or decreases
What is the effect of acute alcohol consumption (binge drinking) on warfarin?
Acute alcohol consumption increases the anticoagulation effect of warfarin
[Increases INR]
(does this by inhibiting metabolism of warfarin)
What is the effect of chronic alcohol consumption without liver damage on warfarin?
Chronic alcohol consumption w/o liver damage decreases the effect of warfarin
[Decreases INR]
(does this by enhancing warfarin metabolism by inducing hepatic enzymes)
What is the effect of chronic alcohol consumption w/ liver damage on warfarin?
Chronic alcohol consumption w/ liver damage increases the anticoagulation effects of warfarin
[Increases INR]
(this occurs because there is a lack of hepatic enzymes)
What are the 2 classes of anti-platelet medications that have a clinical role in VTE?
COX-1 inhibitors (aspirin)
Phosphodiesterase-3 Inhibitors (dipyridamole)
What role do antiplatelets play in VTE?
Aspirin: considerations for CHADS-VASc score 1
Dipyridamole: consider concomitant use with warfarin when used for prosthetic heart valves
**Concomitant use with anticoagulants increases risk of bleeding
*Limited role in therapy
What products can be used (besides antidotes) to help get bleeding under control when on anti-coags?
-Activated charcoal when < or = 2 hours of bleeding (bind up leftover medication in the stomach)
-Hemodialysis (dabigatran only!)
-Tranexamic acid (clear medication from the blood)
What is the reversal product used in bleeding management for UFH and LMWH?
Protamine Sulfate
What is the reversal product used in bleeding management for Dabigatran (Pradaxa)?
Idarucizumab (Praxbind)
What is the reversal product used in bleeding management for Factor Vz inhibitors?
andexanet alfa
How is Protamine Sulfate dosed to function as an antidote for UFH?
1mg protamine/ 100 units UFH given over the past 3 hours
How is Protamine Sulfate dosed to function as an antidote for LMWH?
Within 8hours of last LMWH dose:
- 1mg per 100 anti-factor Xa units
- 1 mg per 1 mg enoxaparin
> 8 hours:
- 0.5 mg per 100 anti-factor Xa units
- 0.5 mg per 1 mg enoxaparin
What are the side effects associated with protamine sulfate treatment?
Hypotension
Bradycardia (related to the rate of infusion, want to slow down the infusion rate)
What is the maximum dose of protamine sulfate that can be given?
50 mg over 10 minutes
What is the mechanism of action of Idarucizumab (Praxbind)?
-Acts as the antidote to dabigatran
-Directly binds dabigatran and has a higher affinity for thrombin that dabigatran does
What is the dose of Idarucizumab (Praxbind) given for bleeding management?
5 g IV
(given as 2 separate 2.5g doses given no more than 15 min apart)
How is Idarucizumab monitored when being used for bleeding management?
Baseline aPTT taken
–> Repeat in 2 hours
–> Repeat every 12 hours until normal
What DOACs are andexanet alfa (Andexxa) approved to act as the antidote for?
ONLY: Rivaroxaban and Apixaban
What is the dosing of andexanet alfa (Andexxa) for bleeding control with Rivaroxaban and Apixaban?
Dosing <8 hours or Unknown:
Apixa:
< or = 5mg : Low Dose
> 5mg/Unknown : High Dose
Rivar:
< or = 10mg : Low dose
>10mg or Unknown: High dose
Dosing > or = 8 hours:
*Always Low Dose
Low Dose: 400mg IV bolus at 30 mg/min
Followed 2 min later by: 4 mg/min IV infusion for 120min
High Dose: 800mg IV bolus at 30mg/min
Followed 2 min later by 8 mg/min infusion for 120min
How is andexanet alfa (Andexxa) treatment for bleeding with DOACs monitored?
NO MONITORING
How is bleeding with warfarin treatment managed?
Vitamin K is the main antidote to warfarin
Also can use:
-Fresh frozen Plasma (FFP)
-Prothrombin Complex Concentrate (PCC)
What dose of Vitamin K is used to counteract warfarin during bleeding?
Oral: 5 mg tablets (preferred)
Parenteral: Do not exceed 1 mg/min (anaphylaxis risk)
When should Vitamin K be administered for warfarin bleeding management?
If INR>10 and No evidence of bleeding
If a patient is experiencing MAJOR BLEEDING and is taking warfarin, what medication should they be started on and why?
PCC (Prothrombin Complex Concentrate) is preferred over FFP (Fresh frozen Plasma)
*This is because PCC provides a complete reversal of warfarin’s activity
**may also add Vitamin K 5-10mg as well
What is the fastest anti-warfarin medication available?
PCC (Prothrombin Complex Concentrate)
*works in 10-15 minutes
How fast does Vitamin K work to reverse the effects of warfarin when bleeding risk is high?
IV Vitamin K: 4-6 hours
Oral Vitamin K: Within 24 hours
What is the slowest approach you can take to reverse the effects of warfarin?
To simply omit warfarin
*Takes 3-5 days
What is the incidence of VTE in MEDICAL patients who do not undergo prophylaxis?
5-15%
What is the incidence of VTE in SURGICAL patients who do not undergo prophylaxis?
40-80%
What are the 4 available drug classes that can be used for VTE prophylaxis?
- Unfractionated Heparin (UFH)
- Low-Molecular Weight Heparin (LMWH)
- Factor Xa Inhibitors (your “bans,” and also the IV form)
- Vitamin K Antagonists (warfarin)
What classifies a patient at “Low Risk” for a VTE?
VTE risk < 10%
-minor surgery patients
-fully ambulatory medical patients (walking)
-No specific pharmacological therapy needed
-early and aggressive ambulation (movement)
What classifies a patient at “Moderate Risk” for a VTE?
VTE Risk: 10-40%
-Non-orthopedic surgery patients
-Acutely ill medical patients with limited mobility
What classifies a patient at “High Risk” for a VTE?
VTE Risk: 40-80%
-Major orthopedic surgery (ex: joint replacement)
-Major trauma
-Spinal cord injury
In general surgery patients at Moderate VTE Risk, what drugs are recommended for prophylaxis?
UFH
LMWH
Factor Xa Inhibitor (use IV form: fondaparinux)
How long should prophylaxis be continued in general surgery patients at Moderate VTE Risk?
Up to 28 days after hospital discharge
In acutely ill medical patients at Moderate VTE Risk, what drugs are recommended for prophylaxis?
UFH
LMWH
Fondaparinux
*Rivaroxaban
How long should prophylaxis be continued in acutely ill medical patients at Moderate VTE Risk?
UFH, LMWH, Fondaparinux: no specific recommendations
Rivaroxaban: 31-39 days total treatment
In orthopedic surgery (TKA or THA) patients at High VTE Risk, what drugs are recommended for prophylaxis?
UFH
LMWH
Fondaparinux
Rivaroxaban
*Apixaban
*Dabigatran (hip)
*Vitamin K Antagonist (warfarin)
How long should prophylaxis be continued in orthopedic surgery patients at High VTE Risk?
> or = 10-14 days postop
(Consider up to 35 days)
What is the preferred prophylaxis treatment for patients at a high bleeding risk?
Mechanical prophylaxis
–Intermittent pneumatic compression devices
–Venous foot pumps
–Compression stockings
If a patient has:
-PE with severe cardiopulmonary compromise
OR
-DVT with high risk of limb loss
How would you treat them? (Rare)
Thrombolytic therapy
-followed by anticoagulation with UFH or LMWH
If a patient has:
-Active bleeding
OR
-Contraindication to anticoagulation
WITH
-A lower extremity DVT
How would you treat them?
-Place IVC filter
-Initiate anticoag when bleeding or contraindication resolves
-Remove IVC filter as soon as acceptable
If a patient has:
-PE with a poor prognosis
OR
-DVT unsuitable for outpatient treatment
WITH
-CrCl < 30mL/min
How would you treat them?
-Hospitalize for VTE treatment
-Give UFH for 5 days and overlap with warfarin and INR > 2
If a patient needed outpatient VTE treatment, how would you treat them?
With one of these options:
-Rivaroxaban
-Apixaban
-LMWH/fondaparinux for 5 days then dabigatran or edoxaban
-LMWH/fondaparinux for 5 days OVERLAP with warfarin and INR > 2
