VTE/PE Flashcards
(128 cards)
1
Q
Risk Factors for VTE/PE
A
Fractures/trauma Valvular disease or replacement Indwelling catheters Previous DVT/PE Malignancy Surgery (especially orthopedic) Immobility/bed rest/paralysis* Pregnancy Increasing age (> 40) Obesity Protein C deficiency or resistance (factor V Leiden) Protein S deficiency Antiphospholipid antibodies Antithrombin deficiency Pregnancy Estrogen therapy Malignancy
2
Q
• Virchow’s triad: 3 primary factors influencing formation of a pathologic clot
A
o Damage to the vessel wall
o Venous stasis
o Hypercoagulable state
3
Q
• Damage to the endothelium initiates two processes
A
o Platelet adhesion, activation and aggregation
o Activation of the coagulation cascade
4
Q
Describe Blood Clot Formation
A
Platelet adhesion to the surface of the vessel occurs when blood is exposed to subendothelial collagen and von Willebrand factor (vWF)
Platelets become activated and release adenosine diphosphate (ADP), serotonin and thromboxane A2 (TXA2) which stimulate platelet aggregation
Platelet aggregation: glycoprotein IIb/IIIa receptor on platelet surface binds to fibrinogen (binding ligand)
5
Q
Describe the Extrinsic pathway
A
- Tissue factor is released from subendothelial cells present in many organs extrinsic to blood
- Factor VII is activated and converted to factor VIIa when tissue factor binds
- Factor VIIa-tissue factor complex activates factor X at the beginning of the common pathway
6
Q
Describe Intrinsic pathway
A
- Factor XII is activated when it comes into contact with the subendothelial membrane during vessel injury
- A series of reactions leads to activation of factor IXa which activates factor X at the beginning of the common pathway
- Alternatively, the factor VIIa-tissue factor complex activates factor IX in the intrinsic pathway
7
Q
Describe Common pathway
A
• Factor Xa converts prothrombin (factor II) to thrombin (factor IIa)
8
Q
Thrombin plays a central role in clot formation by
A
o Converting fibrinogen to fibrin monomers which begin to precipitate and polymerize to form a fibrin clot
o Activating platelets
o Enhances prothrombin activation on platelets by converting factor V to Va and factor VIII to VIIIa which accelerate the activity of factors Xa and IXa respectively
9
Q
Natural inhibitors of clot formation
A
o Antithrombin o Protein S o Protein C o Tissue factor pathway inhibitor (TFPI) o Plasminogen o Plasmin
10
Q
inhibits thrombin (IIa), factor IXa and factor Xa
A
o Antithrombin
11
Q
cofactor for activation of protein C
A
o Protein S
12
Q
inactivates factors Va and VIIIa
A
o Protein C
13
Q
binds to factor VIIa-tissue factor complex and inhibits activation of factor X
A
o Tissue factor pathway inhibitor (TFPI)
14
Q
Plasminogen is converted to plasmin via:
A
tissue plasminogen activator (t-PA
15
Q
lyses fibrin to form fibrin degradation products
A
o Plasmin
16
Q
Location of clot formation:
A
o Can form in any part of the venous circulation but the muscular veins of the calf or the valve cusp pockets of the deep calf veins are the most common locations
17
Q
Deep vein thrombosis once formed can potentially do what 3 things
A
- Spontaneously lyse
- Extend into more proximal veins
- Embolize to the lungs causing pulmonary embolus
18
Q
Clinical Presentation/symptoms of VTE
A
Unilateral calf or leg swelling Calf pain or tenderness Erythema Warmth Palpable cord \+Homan’s sign
19
Q
Clinical Presentation/symptoms of PE
A
Dyspnea Pleuritic chest pain Anxiety Tachypnea (>20 breaths/min) Tachycardia (>100 beats/min) Cough Hemoptysis Diaphoresis
20
Q
Diagnosis of VTE/PE include
A
- Clinical Presentation/symptoms
- Risk factor assessment
- D-dimer
- Diagnostic testing
21
Q
Explain D-dimer testing
A
o Cross linked fibrin degredation fragment produced during clot dissolution
o Negative predictive value
o Negative = <0.5 mg/L
22
Q
Diagnostic testing for DVT
A
Doppler ultrasonography and B-mode compression ultrasound Contrast venography (Gold standard)
23
Q
Diagnostic testing for PE
A
Ventilation perfusion (V/Q) lung scan
Chest CT with contrast (most commonly used)
Pulmonary angiography (Gold standard but most invasive)
Confirmation of proximal DVT via Doppler or venography
24
Q
Radiographic visualization of the involved vessels with injection of radiocontrast material
A
Contrast venography
25
Perfusion evaluated by radiolabeled albumin and ventilation evaluated by inhalation of radiolabeled particles
Ventilation perfusion (V/Q) lung scan - V/Q mismatch indicates possible PE
26
Injection of radiocontrast dye into the pulmonary artery
Pulmonary angiography
27
Ancillary tests for PE
arterial blood gas, EKG, CXR
28
Acute treatment for DVT/PE
Bridge therapy
o Parenteral agent: provides immediate anticoagulant activity
o Oral Therapy: Warfarin
o Bridge oral and parenteral agents for a minimum of 5 days AND until the INR is ≥ 2 for at least 24 hours
29
Structure of UFH
Heterogeneous mixture of glycosaminoglycan polysaccharide chains with molecular weights ranging from 3000 to 30000 kDa (mean = 1500)
30
MOA of UFH
Binds to antithrombin via a unique pentasaccharide sequence and accelerates its interaction and inactivation of thrombin and factor Xa by 1000-fold
31
Inhibition of thrombin requires
a heparin chain that is at least 18 saccharide units in length
32
Also inhibits Factor IXa, XIa, XIIa
UFH
33
can inhibit factor Xa by binding to antithrombin
Any pentasaccharide-containing heparin
34
Pharmacokinetics of UFH
not absorbed orally
treatment of VTE = continuous infusion, propylaxis of VTE = subcutaneous injection
Clearance: non-linear, dose-dependant
• Rapid saturable binding process
(Intravascular Binding)
• Slower, nonsaturable clearance through the kidneys
• T1/2 = 30-60 min
35
creates variablity and unpredictability in patient response
Intravascular binding
36
Monitoring for UFH
Activated partial thromboplastin time (aPTT)
Platelet counts, hemoglobin/hematocrit
Signs/symptoms of bleeding
37
Clotting time reported in seconds- measures activity of thrombin and factor Xa
aPTT
38
Dosing of UFH
- VTE treatment: IV bolus of 80 units/kg, followed by 18 units/kg/hr continous IV infusion
- VTE prophylaxis: 5000 units SC q 8 hrs
- No renal adjustment
39
Adverse effects
- Bleeding
- Heparin-induced thrombocytopenia
- Heparin-induced osteoporosis
40
How is bleeding that is caused by UFH reversed
o 1 mg of protamine will neutralize 100 units of UFH
o Short half life of heparin allows neutralization of heparin infused in the previous 60 mins
• Transfusion therapy may be required
41
2 types of HIT
* Type 1: transient fall in platelets due to a direct effect of heparin
* Type 2: immune-mediated reaction
42
MOA and onset of type II HIT
o Mechanism: IgG antibodies directed at heparin-platelet factor 4 complexes
o Patients are at an increased risk of thromboembolic events due to excessive thrombin generation, expression of tissue factor by monocytes and endothelial cells and platelet activation
o Onset: 5-14 days
o Platelet counts fall by greater than 50%
43
Treatment of HIT
Direct thrombin inhibitors: FDA approved
• Argatroban (see drug chart)
• Bivalirudin (see drug chart)
Fondaparinux
44
What types of patients are more at risk for Heparin-induced osteoporosis
• Usually only occurs with infusions > 6 months (rare)
45
heterogenous mixture of glycosaminoglycans derived from chemical or enzymatic degradation of UFH - Approximately 1/3 the molecular weight of UFH
• Low Molecular Weight Heparins (LMWH)
46
MOA of LMWHs
Binds to antithrombin via a unique pentasaccharide sequence
- Accelerates inactivation of factor Xa
- Only 25-50% of LMWH molecules inactivate thrombin
47
Pharmacokinetics of LMWHs
SC injection
| - Intravascular binding: much less than UFH = more predictable dose-response relationship
48
2 LMWHs
* Enoxaparin (Lovenox)
| * Dalteparin (Fragmin)
49
Monitoring of LMWHs
Antifactor Xa levels
Assess baseline renal function
Signs and symptoms of bleeding
Platelet counts, hemoglobin/hematocrit
50
Dosing (enoxaparin)
Treatment of VTE: 1 mg/kg SC q 12 hr or 1.5 mg/kg SC q 24 hr
• Renal adjustment: 1 mg/kg SC q 24 hr (CrCl < 30 mL/min)
51
Adverse events of LMWHs
Bleeding
Heparin-induced thrombocytopenia
Perispinal hematoma
52
How is bleeding that is caused by LMWHs reversed
o LMWH administered within 8 hours: 1 mg protamine per 100 antifactor Xa units of LMWH (this is 1 mg of enoxaparin)
o A second dose of 0.5 mg protamine per 100 antifactor Xa units if bleeding continues
o Smaller doses can be used if the LMWH was administered more than 8 hours before the bleeding event
53
When is a patient at an increased risk for perispinal hematoma
when antithrombotic medications are administered concomitantly with neuraxial blockade
54
Dosing of LMWHs in patients with renal dysfunction
* Clinical trials have demonstrated increased exposure to anti-Xa activity with CrCl <30 mL/min
* Measurement of anti-factor Xa levels is reasonable if LMWHs are used in patients with renal dysfunction
55
Dosing adjustments of LMWHs based on weight
* Prescribing information now includes doses for patients up to 190 kg
* Risk of overdosing since intravascular volume does not have a linear relationship with total body weight
* Testing of anti-factor Xa levels is reasonable in patients with a total body weight >150 kg or BMI >50 kg/m2
56
When may UFH be preferred over LMWH
• If patient is obese and Crcl <30 ml/min then UFH may be preferred
57
A synthetic analog of the pentasaccharide sequence that binds to antithrombin - Selectively inhibits factor Xa
• Fondaparinux (Arixtra)
58
Pharmacokinetics of fondaparinux
Subcutaneous injections
Mimimal intravascular binding
Half life = 17 hours
Excreted unchanged in the urine
59
Monitoring of fondaparinux
Assess baseline kidney function
Signs and symptoms of bleeding
Platelet counts and hemoglobin/hematocrit
60
In what patients would you not want to use fondaparinux
Do not use in patients with CrCl <50 kg
61
Dosing of fondaparinux
```
Treatment
• For patients < 50 kg: 5 mg SC q 24 hr
• For patients 50-100 kg: 7.5 mg SC q 24 hr
• For patients >100 kg: 10 mg SC q 24 hr
Prophylaxis: 2.5 mg SC q 24 hr
```
62
Adverse events of fondaparinux
Bleeding (increased risk in patients with smaller weights)
63
inhibits the activation of coagulation factors by inhibiting the vitamin K dependent carboxylation of the factors - inhibits vitamin K oxide reductase enzyme complex (VKORC) therefore inhibiting vitamin K activation (from its inactive form: vitamin K epoxide) which then stops carboxylation
• Warfarin
64
Coagulation factors affected by warfarin
* Factor VII (t1/2 = 6 hours)
* Factor IX ( t1/2 = 21-30 hours)
* Factor X (t1/2 = 27-48 hours)
* Factor II (t1/2 = 60-72)
65
Anticoagulation factors affected by warfarin
* Protein C (t1/2 = 9 hours)
| * Protein S (t1/2 = 60 hours)
66
Structure, pharmacokinetics and pharmacodynamics of warfarin
Racemic mixture of S- and R- isomers
High bioavailability
Highly bound to plasma proteins (primarily albumin)
67
Onset of anticoagulant action of warfarin
• Takes 5-7 days to obtain peak anticoagulant effects
68
Half life of warfarin
36-42 hours, takes 3-5 days to reach steady state
69
warfarin Metabolism
Metabolized in the liver
• S-isomer: CYP 450 2C9
• R-isomer: CYP 450 1A2 and 3A4
70
account for up to 50% of the interindividual variability of warfarin response
• VKORC1 and CYP450 2C9
71
leads to poor metabolism of warfarin (will require lower doses)
• Mutation of CYP 2C9
72
mutations that have shown the highest risk of bleeding
• Mutation of CYP 2C9*2 and CYP 2C9*3 (*2 and *3 refers to the alleles) genetic variations
73
* VKORC1 (vitamin K epoxide reductase complex subunit 1)
* Genotype AA
* Genotype GG
* Genotype AG
o AA: sensitive = need lower dose of warfarin
o GG: resistant = need higher doses of wararin
o AG = usual dose
74
Medications/Drugs/Diseases that increase INR
```
Hepatic dysfunction
Thyroid hormones
Hypermetabolic states (hyperthyroidism, fever)
Broad-spectrum antibiotics
Amiodaroneb,c,d
Isoniazidb
Metronidazolec
Celecoxibc
Grapefruit juiceb,d
Sulfamethoxazolec
Phenytoine
Tobacco smokee
Azole antifungalsb,c
Macrolide antibioticsb
(erythromycin and clarithromycin)
Heparin
LMWH
Thrombolytic agents
```
75
Medications/Drugs/Diseases that decrease INR
```
Vitamin K (drugs/food)a
Methimazole, propylthiouracil
Hypothyroidism
Carbamazepineb
Barbiturateb
Rifampinb
Phenytoine
Tobacco smokee
Cholestyramine
```
76
Monitoring of warfarin
Prothrombin time (PT)
International normalized ratio (INR)
Signs/symptoms of bleeding
77
Accounts for variations in sensitivity of thromboplastin reagents to reductions in vitamin k-dependant clotting factors
International normalized ratio (INR)
78
Goal INR range
2-3
79
Frequency of monitoring warfarin
* Hospitalized patients = daily
* Outpatients = within 3 days of hospital discharge then weekly
* Once a stable response achieved = Every 4 weeks and some patients every 12 weeks
80
Adverse events of warfarin
Bleeding
81
Types of patients initiated on 2.5 mg PO daily of warfarin
Patients > 65 y/o
Significant drug interaction that ↑ INR (especially 2C9 inhibitors)
Patients with congestive heart failure (CHF)
Liver disease
Malnourished (low albumin state)
High risk of bleeding
Baseline INR > 1.5
82
Types of patients initiated on 7.5 - 10 mg PO daily of warfarin
```
Younger patients (< 60 y/o)
No interacting medications
Low bleeding risk
```
83
For patients treated in the outpatient setting what loading dose would be used of warfarin
loading dose of 10 mg for the first 2 days of therapy
84
```
Goal INR 2.5 (Range 2.0-3.0):
dose adjust for INR < 1.5
or
Goal INR 3.0 (Range 2.5-3.5) (mechanical valves)
dose adjust for INR < 2.0
```
↑ total weekly dose by 10 – 20%
85
```
Goal INR 2.5 (Range 2.0-3.0):
dose adjust for INR 1.5 – 1.9
or
Goal INR 3.0 (Range 2.5-3.5) (mechanical valves)
dose adjust for INR 2.0 – 2.4
```
Continue current dose and recheck in 1-2 weeks
86
```
Goal INR 2.5 (Range 2.0-3.0):
dose adjust for INR 3.1 – 3.5
or
Goal INR 3.0 (Range 2.5-3.5) (mechanical valves)
dose adjust for INR 3.6 – 4.0
```
Continue current dose and recheck in 1-2 weeks
87
```
Goal INR 2.5 (Range 2.0-3.0)
dose adjust for INR 3.6 – 4.5
or
Goal INR 3.0 (Range 2.5-3.5) (mechanical valves)
dose adjust for INR 4.1 – 4.5
```
Hold 1 – 2 doses; when resume ↓ total weekly dose by 10 – 20%
88
Intervention for INR > 4.5, but < 10, no significant bleeding
Hold warfarin until INR close to goal
Monitor more frequently and resume therapy at lower dose as above when close to goal INR
-If rapid reversal for surgery required administer vitamin K PO < 5 mg and hold warfarin.
- Expect INR ↓ in 24 hours. If still elevated administer another 1 – 2 mg of vitamin K orally
89
Intervention for INR > 10, no significant bleeding
Hold warfarin therapy and administer Vitamin K 2.5 – 5 mg PO. Expect INR ↓ in 24 – 48 hrs. Resume therapy at lower dose as above when close to goal INR.
90
Intervention for Serious bleeding at any elevated INR
Hold warfarin therapy and give Vitamin K 10 mg slow IV infusion. May repeat Vitamin K q12h for persistent elevated INR.
-Supplement with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa in
life threatening situations such as intracranial hemorrhage
91
What would happen if doses of Vitamin K greater than recommended were given
could result in warfarin resistance for up to 1 week
92
Non Bridge Therapy
* Rivaroxaban (Xarelto)
| * Dabigatran (Pradaxa)
93
Selectively blocks the active site of factor Xa without requiring a cofactor (like AT)
• Inhibits factor Xa in both the intrinsic and extrinsic pathways
• Inhibition of clot bound factor Xa
• Rivaroxaban (Xarelto)
94
Pharmacokinetics of rivaroxaban
• 15 mg and 20 mg tablets should be taken with food to increase bioavailability 90% bound to plasma proteins
Half life: 5-9 hours
Hepatic metabolism (3A4, 2J2), excreted in urine and feces
95
Monitoring of rivaroxaban
Assess baseline kidney function and hepatic function
Signs and symptoms of bleeding
Platelet counts and hemoglobin/hematocrit
96
Drug-drug interactions with rivaroxaban
strong 3A4 and P-glycoprotein inhibitors
97
Dosing of rivaroxaban
15 mg twice daily with food for the first 21 days, then 20 mg once daily with food
98
Rivaroxaban is contraindicated in which patients
• Avoid use in patients with Crcl <15 ml/min (for Afib patients)
99
Adverse effects of rivaroxaban
Bleeding
100
Clinical Trials associated with rivaroxaban
VTE: Einstein DVT, Einstein PE
101
not orally bioavailable due to its highly polar structure - is a prodrug
• Dabigatran (Pradaxa)
102
MOA of dabigatran
A direct thrombin inhibitor- inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation
103
Pharmacokinetics of dabigatran
Rapid absorption: peak concentration reached within 2 hours
Not metabolized by CYP enzymes to any significant extent
Renal elimination (~80% of total clearance)
Half life: 12-17 hours
104
Monitoring of dabigatran
Renal function
Platelet counts and hemoglobin/hematocrit
Signs and symptoms of bleeding
105
Drug interactions with dabigatran
• P-glycoprotein inhibitors: may increase concentration of dabigatran
o Drugs: amiodarone, dronedarone, verapamil, ketoconazole
106
Indication/dosing of dabigatran
VTE treatment after the patient has received a parenteral anticoagulant for 5-10 days
• Dosing: 150 mg twice daily for CrCl > 30 ml/min, Crcl <30 mL/min no doing recommendations provider per PI
FDA approval for nonvalvular atrial fibrillation
107
AE of dabigatran
Bleeding
| GI effects: dyspepsia
108
In patients with CrCl 30-50 mL/min and concomitant use of P-gp inhibitor dronedarone or ketoconazole what would the dose of dabigatran be
consider reducing the dose to 75 mg twice daily
109
Converting from parenteral anticoagulant to dabigatran when would dabigatran be started
start dabigatran 0-2 hours before the time that the next dose of the parenteral drug would be administered or at the time of discontinuation of IV heparin
110
Clinical Trials for dabigatran
VTE: RECOVER, RECOVER II, RE-MEDY and RE-SONATE trials
111
Duration of treatment for dabigatran
1st episode of DVT or PE secondary to a reversible risk factor = Treatment for 3 months
1st episode of idiopathic (unprovoked) DVT or PE = Treatment for at least 3 months (then evaluate risk-benefit ratio for extended therapy)
DVT or PE in patients with cancer = LMWH for 3 months, continue therapy indefinitely with wafarin or LMWH or until cancer is resolved
Two or more episodes of DVT or PE = Indefinite treatment
112
Risk factors for bleeding
age >65, previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, diabetes, previous stroke, anemia, recent surgery, frequent falls, alcohol abuse
113
Additional therapy options for DVT/PE
```
o Thrombolysis (Streptokinase, Urokinase, Rt-PA)
o Inferior vena cava filter
```
114
Situations to consider thrombolysis
* Risk of limb gangrene secondary to venous occlusion (seen with massive ileofemoral thrombosis)
* Massive PE in hemodynamically unstable patients
115
Situations to consider inferior vena cava filter
patients with contraindications to anticoagulation, patients with recurrent thromboembolism despite adequate anticoagulation
116
Risk factors for VTE in hospitalized patients
- previous VTE
- reduced mobility
- thromboembolic condition
- trauma or surgery within 3 months
- 70 y/o and above
- heart and/or respiratory failure
- acute MI or ischemic stroke
- acute infection or rheumatologic disorder
- obesity (BMI 30 and greater)
- ongoing hormonal treatment
117
Uses of mechanical methods for VTE
* In patients who are at high risk of bleeding
| * As an adjunct to anticoagulant-based prophylaxis
118
Types of mechanical methods
* Ambulation and physical therapy
* Graduated compression stockings (GCS) or elastic stockings (ES)
* Intermittent pneumatic compression (IPC) devices
* Venous foot pump (VFP)
119
Pharmacologic methods for General surgery or acutely ill medical patients
• UFH, enoxaparin, or fondaprinux
120
Pharmacologic methods for Orthopedic surgery - Total hip replacement
o DOC: enoxaparin 40 mg SC q 24 hr or enoxaparin 30 mg SC q 12 hr (crcl <30 use enoxaparin 30 SC q 24 hr)
o Other agents: fondaparinux 2.5 mg SC q 24 hr, rivaroxaban 10 mg po q 24 hr, or warfarin (INR goal 2-3), apixaban 2.5 mg po twice daily, dabigatran (recommended in CHEST but not FDA approved), aspirin
121
Pharmacologic methods for Orthopedic surgery -Total knee replacement
o DOC: enoxaparin 30 mg SC q 12 hr (crcl <30 enoxaparin 30 mg SC q 24 hr)
o Other agents: fondaparinux 2.5 mg SC q 24 hr, rivaroxaban 10 mg po q 24 hr, warfarin (INR goal 2-3), apixaban 2.5 mg po twice daily, dabigatran (recommended in CHEST but not FDA approved), aspirin
122
MOA of apixaban
Direct factor Xa inhibitor: inhibits both free and clot-associated factor Xa activity
123
Pharmacokinetics of apixaban
Oral administration
• Absorption not affected by food
Prolonged absorption therefore half life is ~12 hours with repeat dosing
• Onset 3-4 hours
Metabolized by CYP enzymes (mainly 3A4)
• Avoid strong 3A4 inhibitors
Elimination: urine (25%) and feces
124
Monitoring of apixaban
Hemoglobin/hematocrite and platelet counts
Signs and symptoms of bleeding
Renal function, body weight (dose adjustment)
125
Drug-Drug interactions for apixaban
• 5 mg dose should be reduced to 2.5 mg twice dialy when coadministrated with strong CYP3A4 and P-gp inhibitors like ketoconazole, itraconazole, ritonavir, or clarithromycin
126
Indication for apixaban
FDA approved for nonvalvular atrial fibrillation
| VTE prophylaxis for post-hip or knee replacement
127
Adverse events of apixaban
Bleeding
128
Clinical Trial for apixaban
VTE: AMPLIFY-EXT
