Venous Thromboembolism Therapeutics

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1

List the two types of Venous Thromboembolisms (VTE)

  • Deep Venous Thrombosis
  • Pulmonary Embolism
2

What is a VTE?

Fibrin clot formation w/in the venous system

3

List factors that could contribute to a VTE

  • Venous stasis
  • Vessel wall injury
  • Hypercoagulability
4

Which kind of thrombosis is a formation of a clot in a deep vein of the body/

DVT

5

Veins located where are the most commonly affected by DVT

Legs

6

What are the most common veins w/in the leg that are affected by DVT?

Proximal (femoral, popliteal, and iliac veins)

7

Which distal veins in the leg can be affected by DVT?

Calf veins

8

Blockage of a main artery of the lung or one of its branches is known as _______

Pulmonary Embolism (PE)

9

PE most commonly results from __________ that breaks off and migrates to the lungs

DVT

10

What is a common symptoms of a PE?

SOB

11

T/F: Incidence of VTE triples each decade over 45

False

12

Describe the pathophysiology of a VTE

  • Vascular injury --> hemostatic plug forms and seals wall --> prevent further blood loss
  • Disruption of system = inappropriate clot formation
    • Obstructs BF
    • Embolizes to distant vascular bed
13

What are the parts of Virchow's Triad?

  • Venous stasis
  • Vessel wall injury
  • Hypercoagulability
14

Risk factors of VTE

  1. Age (>50)
  2. History of VTE
  3. Hypercoagulable states
  4. Venous stasis
  5. Vascular injury
  6. Medications
15

List examples of hypercoagulable states:

  1. Pregnancy
  2. Malignancy
  3. Activated ptn C resistance factor/factor V Leiden
  4. Prothrombin (G20210A) gene mutation
  5. Ptn C or S deficiency
  6. Anti-thrombin deficiency
  7. Anti-phospholipid antibodies
16

List examples of venous stasis that could increase risk of blood clot

  1. Acute medical illness
  2. Surgery
  3. Paralysis
  4. Immobility
  5. Obesity
17

List examples of vascular injury that could increase risk of blood clot

  1. Major orthopedic surgery
  2. Trauma
  3. Central venous catheter
18

List examples of medication that could increase risk of blood clot

  1. Oral contraceptive
  2. Estrogen replacement therapy
  3. Selective estrogen receptor modulators (SERMs)
  4. Chemotherapy
  5. Heparin (HIT)
19

T/F: Most DVT pts have no symptoms. If they do have symptoms, typically the s/sx are bilateral and non-specific.

False

20

List symptoms of DVT

  • Leg pain
  • Swelling
  • Warmth
  • Redness
21

List the signs of DVT

  • Dilated superficial veins
  • Palpable cord
  • Homan's sign
  • Low-grade fever
22

T/F: When assessing for a DVT, we use the symptoms more than signs (signs are not super specific and we don't usually look for those)

True

23

T/F: D-dimer is a diagnostic blood test used to evaluate for VTE. It is a screening tool only (not used for diagnosis)

True

24

D-dimer <500ng/mL =

rule out VTE

25

D-dimer >500 ng/mL =

Possible VTE

26

D-dimer has high ___________(sensitivity/specificity) and low ___________(sensitivity/specificity)

Sensitivity; specificity

27

T/F: D-dimer levels are decreased in acute thrombosis

False

28

__________ is a degradation product of a fibrin clot used as a screening tool for VTE

D-dimer

29

T/F: A higher score on the Well's criteria for DVT = higher risk for DVT

True

30

What is the most common way to diagnose a DVT?

Duplex Ultrasonography ("dopplers")

31

What does Duplex Ultrasonography ("dopplers") do in regards to DVT?

  • Measures rate and direction of BF
  • Visualizes clot in proximal veins of legs
32

What is the gold standard (but last line) way to diagnose DVT?

Venography

33

Why is venography last line for DVT diagnosis?

  • Invasive and expensive
  • Pt anesthetized and dye injected (anaphylactic risk) to show where clot is
34

List the complications of DVT

  • PE
  • Post-thrombotic syndrome
35

Describe post-thrombotic syndrome

  • Long term complication of DVT
  • Damage to venous valves after DVT is treated
36

Symptoms of post-thrombotic syndrome:

  • Chronic lower extremity edema
  • Pain
  • Tenderness
  • Skin discoloration
  • Ulceration
37

T/F: Many pts w/ PE may present w/ symptomatic DVT

True

38

S/Sx of PE depend on what?

Massive vs. submassive PE

39

Symptoms of PE:

  • Cough
  • CP, chest tightness, palpitations
  • SOB
  • Hemoptysis
  • Dizziness, lightheadedness, syncope
40

Signs of PE

  • Tachypnea
  • Tachycardia
  • Diaphoresis
  • Cyanosis, hypoxia
  • Hypotension
  • Circulatory shock
  • Low-grade fever
41

What is the most common tool for diagnosing PE?

Computerized Tomography (CT)

42

How does a CT work?

  • IV injection of iodine-contrast agent (dye)
  • Contrast filling defects occur when emboli is present w/in pulmonary arteries
43

T/F: CT iodine-contrast agent is less likely to cause anaphylaxis by dye (compared to venography)

True

44

What is the second line diagnosis tool for PE?

Ventilation/Perfusion (VQ)

45

How does Ventilation/Perfusion (VQ) work?

  • Measures distribution of blood and air flow in the lungs
  • Large mismatch = high probability of PE
46

What is the third line diagnosis tool for PE?

Duplex Ultrasonography ("dopplers") of lower extremities

47

What is the gold standard (but last line) diagnostic tool for PE?

Pulmonary angiography

48

Why is Pulmonary angiography last line for PE diagnosis?

  • Invasive and expensive
  • Anaphylactic risk ~15%
49

T/F: Diagnosis of PE is associated w/ significant morbidity and mortality

True

50

T/F: Sudden death is the first symptom in ~25% of pts who have a PE

True

51

Goals of therapy for DVT:

  • Prevent thrombus embolization/extension
  • Prevent recurrence
  • Prevent post-thrombotic syndrome
52

Goals of therapy for PE

  • Prevent recurrence
  • Decrease mortality
53

Orthopedic pts need to b on what additional therapy?

Blood thinner and anti-coagulant

54

List the initial VTE therapy options:

  1. Warfarin (+LMWH / UFH / Fondaparinux for first 5d)
  2. Rivaroxaban, Apixaban, Edoxaban, Dabigatron
  3. LMWH or Fondaparinux (select pts only)
55

How long should warfarin therapy overlap w/ either LMWH/UFH/Fondaparinux?

Minimum 5d until INR is >2.0 for at least 24 hrs (2 consecutive readings)

56

Which pts can use the injectable products LMWH or Fondaparinux?

  • Cancer pts
  • Pregnant pts
57

Why must therapy with warfarin and a parenteral anticoagulant be overlapped?

Hypercoagulable state develops in first 24 hrs bc ptn C has a short t1/2 and warfarin inhibits it = leaves body fastest. W/o this natural anticoagulant = increased risk of clot until therapeutic warfarin level reached.

58

Duration of therapy for first provoked VTE

3 mo

59

Duration of therapy for idiopathic VTE

3 mo, re-evaluate for extended therapy

60

Duration of therapy for 2 or more VTE

Indefinite

61

Duration of therapy for VTE w/ active cancer

Indefinite (as long as cancer is present)

62

Duration of therapy for:

  • Anti-phospholipid antibodies
  • Factor V leiden
  • Prothrombin mutation

Indefinite

63

Non-pharm therapy for VTE

  • Ambulation
  • Mechanical
    • Graduated compression stockings (GCS)
    • Intermittent pneumatic compression devices (IPC)
    • inferior vena cava (IVC) filters
64

Indications for UFH therapy

  • VTE prophylaxis
  • Trtmt of VTE (hospital setting)
65

MOA of UFH:

  • Enhances anti-thrombin
  • Inhibits platelet aggregation
  • Prevents growth and propagation of a formed thrombosis
66

Administration of UFH

  • SQ (VTE prophylaxis)
  • IV (VTE trtmt)
67

UFH t1/2 :

30-90 min

68

UFH elimination

Enzymatically inactivated by heparinases and desulfatases

69

T/F: Prophylaxis UFH should be monitored w/ aPTT

False

70

LD of IV UFH for VTE treatment:

80 u/kg

71

Max LD of IV UFH

10,000 u

72

Initial maintenance dose of IV UFH for VTE treatment:

18 u/kg/hr

73

Subsequent maintenance dose of IV UFH for VTE treatment

Adjusted based on lab monitoring to achieve therapeutic anti-coagulation

74

Goal aPTT for IV UFH for VTE treatment

1.5-2.5 * control

75

Goal anti-factor Xa for IV UFH for VTE treatment

0.3-0.7 u/mL

76

Lab monitoring for IV UFH for VTE treatment

  • aPTT
    Anti-factor Xa
77

Which monitoring test for UFH is sensitive to changes in the intrinsic and common coagulation pathways?

aPTT

78

How is the aPTT test performed?

Measuring time required for clot formation after the addition of phospholipid, an activator (silica, celite, kaolin, ellagic acid), and Ca to citrated plasma

79

T/F: aPTT can vary based on the reagent used to test the sample

True

80

When would aPTT be measured?

  • Baseline
  • 6 hrs after UFH initiation
  • 6 hrs after UFH dose change
  • Q24hrs when stable
81

AE of UFH

  • Major Bleeding
    • GI
    • soft tissues
    • Urinary tract
  • Minor bleeding
    • Epistaxis
    • Gingival bleeding
    • Prolonged bleeding from cuts
    • Bruising
82

UFH monitoring:

  • aPTT/antifactor Xa levels
  • Hgb/Hct
  • Platelets
83

UFH antidote:

IV protamine sulfate

84

Additional UFH AEs

  • Injxn site rxns
  • HIT
  • LT effects (priapism, alopecia, osteoporosis, suppressed aldosterone synthesis)
85

SQ UFH monitoring:

none

86

T/F: Renal dose adjustment is required for renal insufficiency

False

87

UFH pregnancy category

C

88

T/F: We cannot use UFH in pregnant pts, but we can use it in children

False

89

Hepatic insufficiency means there will be enhanced anticogulant effects. Do we need hepatic dose adjustment for UFH?

No

90

Which LMWH is most commonly used for prophylaxis, VTE treatment, and VTE treatment in cancer and pregnant patients?

Enoxaparin (Lovenox)

91

MOA of LMWH

  • Enhances effects of anti-thrombin
  • Prevents growth and propagation of a formed thrombus
92

Elimination of LMWHs:

Renal (requires renal dose adjustment)

93

Which LMWHs are used as prevention of VTE in cases of acute medical illness?

Enoxaparin and Dalteparin

94

Monitoring for LMWH in prevention (acute medical illness)

none

95

Normal dose and freq of enoxaparin

1 mg/kg SQ q12h

96

Dose and freq for enoxaparin if CrCl <30 mL/min

1 mg/kg SQ q24h

97

What will always need to be monitored with LMWH?

CBC

98

How often should CBC be measured with LMWH?

  • Baseline
  • q5-10 days for first 2 wks
  • q2-4 weeks for duration of therapy
99

Under what circumstances should anti-Xa levels be measured for a pt on LMWH?

  • CrCl <30 mL/min
  • BW <50 kg or >100 kg
  • Prolonged therapy
  • Pregnant females
  • pediatric pts
  • high risk for bleeding
100

Anti-Xa goal level:

0.6-1.0 u/mL

101

If a pt who is on LMWH is determined to need anti-Xa monitoring, when would you need to monitor?

4 hrs after 3rd dose

102

Antidote for LMWH

IV protamine

103

BBW for LMWH

Spinal hematoma that could lead to paralysis if given w/ epidural

104

Major and minor AE for LMWH

  • Major: bleeding (less so than heparin)
  • Minor: injxn site rxn
105

T/F: If pt previously experienced HIT, you can not use LMWH.

True

106

T/F: There is less incidence of HIT/long term effects with LMWH compared to UFH

True

107

T/F: LMWH is safe to use in pregnant pts, but not pediatrics

False

108

If a pt has severe rheumatoid arthritis in their hands, would LMWH be a good recommendation for them?

No, they will struggle to give themselves the injection

109

Advantages of LMWH over UFH

  • Predictable anticoagulation dose response
  • Improved SQ bioavailability
  • Dose-dependent clearance
  • Longer half-life
  • Lower incidence of HIT
    Reduced monitoring need
  • Outpt management of VTE
110

Fondaparinux brand

Arixtra

111

Rivaroxaban brand

Xarelto

112

Apixaban brand

Eliquis

113

Edoxaban brand

Savaysa

114

Betrixaban brand

Bevyxxa

115

List the factor Xa inhibitors

  • Fondaparinux
  • Rivaroxaban
  • Apixaban
  • Edoxaban
  • Betrixaban
116

Which factor Xa inhibitors are first line?

Oral ones

117

T/F: Fondaparinux is used for the treatment and prevention of VTE and is weight based dosing

True

118

Antidote for fondaparinux

none

119

T/F: Fondaparinux cannot be used for management of HIT

False

120

Fondaparinux is contraindicated in:

CrCl <30 mL/min

121

Describe the dosing for Rivaroxaban in the treatment of VTE (initial and after initial treatment)

  • Initial: 15 mg PO BID with food x21d
  • After: 20 mg PO daily with food
122

Rivaroxaban monitoring

CBC (baseline then periodically)

123

Why must rivaroxaban be taken with food?

Bioavailability drops to 0 without food (~200 calories)

124

Rivaroxaban/apixaban antidote

Andexxa

125

Rivaroxaban is contraindicated in:

CrCl <30 mL/min

126

Rivaroxaban/apixaban drug interactions

Cyp3A4 inhibitors/inducers

127

Describe the dosing for Apixaban in the treatment of VTE (initial and after initial treatment)

  • Initial: 10 mg PO BID with food x7 days
  • After: 5 mg PO BID
128

T/F: Rivaroxaban and Apixaban are contraindicated in pts with CrCl <30 mL/min

False

129

Describe treatment of VTE with Edoxaban

  • Initial: At least 5-10 d of pernteral anticoagulant
  • THEN start edoxaban (i.e. on day 6)
130

Antidote for edoxaban

none

131

Betrixaban is used for:

Prevention of VTE

132

Direct thrombin inhibitors are used primarily for:

HIT

133

Dabigatran brand

Pradaxa

134

Dabigatran MOA

Selectively inhibits factor IIa (thrombin)

135

T/F: If a patient is starting dabigatran, they would need to be on a parenteral anticoagulant for 5-10d, THEN can start dabigatran on day 6

True

136

Unique AE of pradaxa

dyspepsia

137

Antidote of Dabigatran

Idarucizumab (Praxbind)

138

Warfarin brand

Coumadin

139

T/F: Rivaroxaban, Apixaban, dabigatron, and warfarin are all first line

False

140

Warfarin dosing:

  • 5-10 mg PO daily
  • 2.5 mg PO daily: >65 yo, malnourished, liver dz, heart failure, concurrent use of interacting meds
141

Warfarin is metabolized by:

CYP 1A2, 2C19, 3A4, and 2C9

142

Warfarin dose changes should not be made more frequently than:

q3d

143

Goal for INR for warfarin

2-3

144

INR <2 means

Increased risk for blood clot

145

INR >3 means

Increased risk for bleeding

146

How often is INR monitored?

  • Baseline
  • q3d during first week
  • q7-14d until stabilized
  • q4wks thereafter
  • Can extend to q 12 weeks in pts w/ consistent/stable INR
147

Why should you give a pt one strength of warfarin (even if the dose varies throughout the week)?

Minimize chance for pt to make an error in which dose they're taking. (i.e. so they don't accidentally take a much higher/lower dose than they were supposed to)

148

AE of warfarin

  • Bleeding
  • purple toe syndrome
  • Warfarin-induced skin necrosis (very rare)
149

Management of supratherapeutic warfarin: INR above therapeutic range but < 4.5; no significant bleeding

Reduce/skip warfarin dose, monitor INR. Resume warfarin when therapeutic

150

Management of supratherapeutic warfarin: INR bw 4.5-10; no significant bleeding

Hold 1-2 doses of warfarin. Monitor INR. Resume at lower dose when INR is therapeutic

151

Management of supratherapeutic warfarin: INR >10; no significant bleeding

Hold warfarin and give oral vitamin K. Monitor INR and resume when therapeutic

152

Management of supratherapeutic warfarin with major bleed

Hold warfarin. admin prothrombin complex concentrate and vitamin K by slow IV infusion

153

If a pt is having a scheduled surgery, warfarin should be stopped for _____ d before the surgery, and resumed ~_______ after surgery?

5d; 12-24 hrs

154

T/F: If a pt is having a scheduled surgery and stops their warfarin, they do not need a bridge therapy since it is only a temporary pause in the warfarin

False

155

Warfarin pregnancy category

X

156

T/F: Warfarin can be used in peds, pts with renal insufficiency, and pts with hepatic insufficiency

True

157

Examples of drugs warfarin interacts with

  • NSAIDS (increase bleed risk)
  • Aspirin (increase bleed risk)
  • Amiodarone (increases warfarin levels)
158

Warfarin important pt counseling:

  • Take every day
  • Maintain consistent vitamin K intake
  • Attend follow-up for INR
  • No alcohol (or NMT 1 12oz beer/d)
159

Anticoagulants to use in pregancy:

  • UFH
  • LMWH
160

Anticoagulants to use in peds

  • UFH/LMWH
  • Warfarin
161

Anticoagulants to use in cancer pts

LMWH