Let’s Stop the Clot:

Venous Thromboembolism
Vivian (Wint War) Phyo, PharmD, BCPS
PGY-2 Internal Medicine Pharmacy Resident
Eskenazi Health, Indianapolis, IN

February 12, 2024

The author has no actual or potential conflicts of interest in relation to this presentation
 Objectives
1. Describe the pathophysiology and clinical presentation of venous
thromboembolism (VTE)
2. Implement different risk assessment models to identify appropriate
patients to receive VTE prophylaxis
3. Differentiate oral and parenteral anticoagulants based on safety,
efficacy, and simplicity
4. Design appropriate regimens for VTE prophylaxis and treatment
based on patient specific factors
Background
 Definitions
• Venous thromboembolism (VTE) – formation of
clots that block the flow of blood in the affected vein(s)
• Deep vein thrombosis (DVT) – Clotting in > 1 of the deep
veins in the extremities
• Affects lower extremities more than upper extremities
• Pulmonary embolism (PE) – Clotting in a pulmonary artery

Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738

Virchow’s Triad

• Immobility (confined to bed, prolonged travel)

Stasis • Spinal cord injury (paraplegia/quadriplegia)

• Hereditary thrombophilia
Thrombosis (e.g., protein C or S deficiency,
antithrombin deficiency)
• Drug (e.g., estrogen,
Endothelial Hyper- tamoxifen, chemotherapy)
• Active cancer
• Surgery damage coagulability • Pregnancy
• Trauma
• Obesity
• Indwelling venous catheters
• Smoking
Kumar DR, et al. Clin Med Res. 2010;8(3-4):168-172
VTE Prophylaxis
 Hospital-acquired VTE
Interventions to prevent VTE:
~50% of VTE events • Compression stockings
Mechanical • Intermittent pneumatic compression
occur due to hospital
admission for surgery
or medical illness Chemical • Anticoagulants (e.g., heparin products)

Hospital-acquired DVT
and PE occurred in
1.3% and 0.4% of
hospital admissions,
respectively
DVT: deep vein thrombosis Compression stockings Intermittent pneumatic compression
PE: pulmonary embolism
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 Padua Risk Assessment Model
Risk Factors Points
Previous VTE 3
Active cancer 3
Thrombophilia 3 Padua Score Incidence of VTE Incidence of Bleeding
Reduced mobility 3 0-3 0.3% --
Recent (< 1 month) trauma/surgery 2 >4 11% 1.6%
Age > 70 years 1 Padua Score > 4: pharmacologic prophylaxis warranted
Heart and/or respiratory failure 1 (unless high risk of bleeding)

Acute MI/ischemic stroke 1

Acute infection or rheumatological disorder 1
Obesity (BMI > 30 kg/m2) 1
Ongoing hormonal therapy 1
BMI: body mass index
MI: myocardial infarction
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 IMPROVE Risk Assessment Models
VTE Risk Factor Points Bleeding Risk Factor Points

Previous VTE 3 Active gastroduodenal ulcer 4.5

Active cancer 2 Major bleeding in 3 months before admission 4

Platelet < 50 x 109/L 4
Thrombophilia 2
Age > 85 years 3.5
Lower limb paralysis 2
40-84 years 1.5
Immobilization of > 7 days 1
Hepatic failure (INR > 1.5) 2.5
Age > 60 years 1
Renal failure eGFR < 30 mL/min/m2 2.5
ICU/CCU stay 1 eGFR 30-59 mL/min/m2 1
Score 3-month VTE Risk ICU/CCU stay 2.5
0-1 0.5% Central venous catheter 2
2-3 1.5% Rheumatic disease 2
> 4% 5.7%
Active cancer 2
IMPROVE VTE score > 2: pharmacologic prophylaxis indicated
Male 1
(unless high risk of bleeding)
ICU/CCU: intensive care unit/critical care unit IMPROVE bleeding score > 7: high bleeding risk
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 VTE Prophylaxis Guideline
Recommendation 6: In acutely or critically ill medical patients, the panel suggests using pharmacological
VTE prophylaxis over mechanical prophylaxis (conditional recommendation, very low certainty)

Outcomes Relative effect: RR (95% CI) Absolute risk effect (mechanical vs pharmacological prophylaxis)
Mortality 0.95 (0.42-1.13) 1 fewer death per 1000
PE 1.54 (0.48-4.93) 1 more PE per 1000
Symptomatic DVT 2.20 (0.22-22.09) 2 more DVT per 1000
Major bleeding 0.87 (0.25-3.08) 4 fewer bleeds per 1000

DVT: deep vein thrombosis

PE: pulmonary embolism
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 VTE Prophylaxis Guideline
Recommendation 6: In acutely or critically ill medical patients, the panel suggests using pharmacological
VTE prophylaxis over mechanical prophylaxis (conditional recommendation, very low certainty)

Recommendation 8 and 9: In acutely or critically ill medical patients, the panel suggests either
pharmacological or mechanical prophylaxis alone over combination of pharmacological and mechanical
prophylaxis (conditional recommendation, very low certainty)

Outcomes Relative effect: RR (95% CI) Absolute risk effect (combined vs pharmacological alone)
Mortality 0.50 (0.05-5.30) 4 fewer deaths per 1000
PE 0.35 (0.05-2.22) 1 fewer PE per 1000
Symptomatic DVT 0.13 (0.04-0.40) 2 fewer DVT per 1000
Major bleeding 2.83 (0.30-26.70) 51 more bleeds per 1000

DVT: deep vein thrombosis

PE: pulmonary embolism
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 VTE Prophylaxis Guideline
Recommendation 6: In acutely or critically ill medical patients, the panel suggests using pharmacological
VTE prophylaxis over mechanical prophylaxis (conditional recommendation, very low certainty)

Recommendation 8 and 9: In acutely or critically ill medical patients, the panel suggests either
pharmacological or mechanical prophylaxis alone over combination of pharmacological and mechanical
prophylaxis (conditional recommendation, very low certainty)
Recommendation 11: In acutely ill hospitalized patients, the panel recommends using LMWH over DOACs
as VTE prophylaxis (strong recommendation, moderate certainty)

Outcomes Relative effect: RR (95% CI) Absolute risk effect (DOACs vs LMWH)
Mortality 0.64 (0.21-1.98) 0 fewer deaths per 1000
PE 1.01 (0.29-3.53) 0 fewer PE per 1000
Symptomatic DVT 1.03 (0.34-3.08) 0 fewer DVT per 1000
Major bleeding 1.70 (1.02-2.82) 2 more bleeds per 1000
DOACs: direct oral anticoagulants DVT: deep vein thrombosis
LMWH: low molecular weight heparin PE: pulmonary embolism
VTE: venous thromboembolism Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 Parenteral Anticoagulants

Drug Mechanism Dosing Clinical pearls

Unfractionated Biological molecule that inhibit 5000 units SQ every 8-12 hours Preferred in renal dysfunction
Heparin (UFH) both factor Xa and thrombin CI in history of HIT
Enoxaparin Biological molecule that inhibit 40 mg SQ every 24 hours Renally cleared (require dose reduction)
(preferred*) factor Xa more than thrombin • 30 mg SQ every 24 hours CI in history of HIT
(CrCl < 30 mL/min)
Fondaparinux Synthetic molecule that inhibit 2.5 mg SQ every 24 hours Renally cleared (CI in CrCl < 30 mL/min)
factor Xa only Preferred in history of HIT

*compared to UFH, enoxaparin is associated with fewer mortality and lower incidence of HIT, without difference in the risk of major bleeding

CI: contraindicated CrCl: creatinine clearance

HIT: heparin-induced thrombocytopenia SQ: subcutaneously Schünemann HJ, et al. Blood Adv. 2018;2(22):3198-3225
 Meet CD
78 YOM admitted to the ICU for septic shock secondary to severe skin
and soft tissue infection around the surgical site. He underwent
surgery on his shoulder 1 month ago without major blood loss.
Problem list: CAD s/p stent (2016), HFrEF (20%), history of PE (2019)
CKD III (baseline CrCl ~40)
Treatment (on mechanical ventilation):
• Vancomycin
• Norepinephrine (on peripheral line)
• Hydrocortisone
• Aspirin
Labs: CMP – WNL. CBC – remarkable for elevated WBC
1. What are CD’s Padua and IMPROVE bleeding scores?
 Meet CD – Padua Score
78 YOM admitted to the ICU for septic shock secondary to severe skin
and soft tissue infection around the surgical site. He underwent
surgery on his shoulder 1 month ago without major blood loss.
Problem list: CAD s/p stent (2016), HFrEF (20%), history of PE (2019)
CKD III (baseline CrCl ~40)
Treatment (on mechanical ventilation):
• Vancomycin
• Norepinephrine (on peripheral line)
• Hydrocortisone
• Aspirin
Labs: CMP – WNL. CBC – remarkable for elevated WBC
Padua Score – 11
 Meet CD – IMPROVE Bleeding
78 YOM admitted to the ICU for septic shock secondary to severe skin
and soft tissue infection around the surgical site. He underwent
surgery on his shoulder 1 month ago without major blood loss.
Problem list: CAD s/p stent (2016), HFrEF (20%), history of PE (2019)
CKD III (baseline CrCl ~40)
Treatment (on mechanical ventilation):
• Vancomycin
• Norepinephrine (on peripheral line)
• Hydrocortisone
• Aspirin
Labs: CMP – WNL. CBC – remarkable for elevated WBC
IMPROVE Bleeding Score – 6
 Meet CD
2. Which of the following options would you
recommend for VTE prophylaxis for CD?
a) Direct oral anticoagulant (e.g., apixaban, rivaroxaban)
b) Compression stockings alone
c) Compression stockings + parenteral anticoagulant
d) Parenteral anticoagulant alone
e) No VTE prophylaxis required

VTE: venous thromboembolism

 Meet CD
3. Pick an appropriate VTE prophylaxis regimen
that is also most preferred by the 2018 ASH
Guideline.
a) Apixaban 2.5 mg PO twice a day
b) Heparin 5000 units SQ three times a day
c) Enoxaparin 40 mg SQ daily
d) Enoxaparin 30 mg SQ daily
e) Fondaparinux 2.5 mg SQ daily

ASH: American Society of Hematology

VTE: venous thromboembolism
VTE Treatment
 Clinical Presentation
Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE)
Unilateral more Swelling, Shortness of Chest pain /
common redness/discolored breath, tachypnea tightness (pleuritic)

Tachycardia / Coughing /
Pain / tenderness Warm to touch
palpitation hemoptysis

Diagnostic D-dimer elevation Imaging (e.g., chest

Compression
(non-specific: CT, pulmonary
Tests ultrasound
DVT, PE, or both) angiogram)

CT: computed tomography National Blood Clot Alliance. Blood Clots. July 31, 2018. Accessed February 3, 2024
 Timeline of VTE Treatment

Initial Management Secondary

• First 3 weeks after
Decision Prevention
point
diagnosis • Beyond 6 months

Primary Treatment
• 3-6 months from the
diagnosis

VTE: venous thromboembolism Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738

 Initial Management of DVT
Acute DVT

Phlegmasia High risk of

Uncomplicated
cerulea dolens severe PTS

Phlegmasia cerulea dolens

(PCD)
Thrombolysis /
Anticoagulation + Thrombolysis
Thrombectomy

Anticoagulation Anticoagulation

DVT: deep vein thrombosis

PTS: post thrombotic syndrome Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738
 Initial Management of PE
Acute PE

Submassive
Massive with right ventricular Uncomplicated
with hemodynamic dysfunction without
compromise* hemodynamic compromise*

Thrombolysis / Preferred:
Anticoagulation
Thrombectomy Anticoagulation

2nd line:
Anticoagulation Thrombolysis +
Anticoagulation
PE: pulmonary embolism *SBP < 90 mmHg or decrease of > 40 mmHg from baseline
SBP: systolic blood pressure Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738
 DOACs • 1st line

Anticoagulant - DOACs
Warfarin • 2nd line

Drug Mechanism Dosing Clinical pearls

Apixaban Directly 10 mg PO twice a day x 7 days, DDI with P-gp and strong CYP3A4 inducers/inhibitors
(Eliquis®) inhibits followed by 5 mg PO twice a day No dose adjustment required for reduced renal function
factor Xa Reversal agent: Andexanet alfa
Rivaroxaban 15 mg PO twice a day x 21 days, Take with food to increase bioavailability
(Xarelto®) followed by 20 mg PO daily DDI with P-gp and strong CYP3A4 inducers/inhibitors
Contraindicated in CrCl < 30 mL/min
Reversal agent: Andexanet alfa
Edoxaban 60 mg PO daily – Requires > 5 days For weight < 60 kg or CrCl 15-50 mL/min or concomitant P-gp
(Savaysa®) of pretreatment with parenteral inhibitor: 30 mg PO daily
anticoagulants prior Contraindicated in CrCl < 15 mL/min
Reversal agent: Andexanet alfa (off-label)
Dabigatran Directly 150 mg PO twice a day – Requires DDI with P-gp inducers/inhibitors
(Pradaxa®) inhibits > 5 days of pretreatment with Contraindicated in CrCl < 30 mL/min
thrombin parenteral anticoagulants prior Reversal agent: Idarucizumab
CrCl: creatinine clearance DOACs: direct oral anticoagulants
DDI: drug-drug interaction PO: by mouth Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738
 DOACs • 1st line

Anticoagulant – Warfarin
Warfarin • 2nd line

Mechanism

• Inhibits vitamin K epoxide reductase complex 1 from activating vitamin K. Therefore, indirectly reduce vitamin
K dependent clotting factors (II, VII, IX, X, and protein C and S)

Dosing

• Common starting dose: 5 mg PO daily (consider lower dose of 2.5 mg PO daily in sensitive patients)
• Risk factors for increased sensitivity to warfarin: older age (> 75 years), malnutrition, hepatic disease, heart
failure, etc.
• Dose adjustment based on goal INR of 2-3

Clinical pearl

• Metabolized by CYP2C9, CYP1A2, CYP3A4, CYP2C19 – so always check for DDI!!

• Interaction with food that are rich in vitamin K – key is to have consistent diet
• Long half-life of ~40 hours
• Reversal agents: vitamin K + pro-thrombin complex concentrate (reserved for major bleeding or rapid reversal)

INR: international normalized ratio PO: by mouth Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738
 Anticoagulant – Parenteral
Drug Half-life Dosing Clinical pearls
(hrs)
Unfractionated 1-2 • IV Weight-based: 80 units/kg IV bolus, then *most precise dosing with aPTT or anti-factor Xa
Heparin 18 units/kg/hr infusion adjusted per level* level monitoring
• IV Fixed-dose: 5000 units IV bolus, then Highest risk of developing heparin-induced
1000 units/hr infusion thrombocytopenia (HIT) – 4T probability score
• SQ Fixed-dose: 333 units/kg bolus SQ, then Reversal agent: protamine sulfate
250 units/kg SQ twice a day
Enoxaparin 3-6 • 1 mg/kg SQ every 12 hours Dose reduction required in CrCl < 30 mL/min
• 1.5 mg/kg SQ every 24 hours Consider peak anti-Xa level monitoring (3-5 hours
after at least 3 consecutive doses) in renal
impairment, extremes of weight, infants, pregnancy
Reversal agent: protamine sulfate (neutralizes
60-70% of enoxaparin)
Fondaparinux 17-21 < 50 kg: 5 mg SQ daily Contraindicated in CrCl < 30 mL/min
50-100 kg: 7.5 mg SQ daily Preferred in history of HIT
> 100 kg: 10 mg SQ daily Reversal agent: n/a

CrCl: creatinine clearance Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738

 Timeline of VTE Treatment

Initial Management Secondary

• First 3 weeks after
Decision Prevention
point
diagnosis • Beyond 6 months

Primary Treatment
• 3-6 months from the
diagnosis

VTE: venous thromboembolism Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738

 Timeline of VTE Treatment

Initial Management Secondary

• First 3 weeks after
Decision Prevention
point
diagnosis • Beyond 6 months

Primary Treatment
• 3-6 months from the
diagnosis
Recommendation 12-14: The panel suggests using a shorter course (3-6 months) over a longer course
(6-12 months) of anticoagulation for primary treatment (conditional recommendation; moderate certainty)
VTE: venous thromboembolism Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738
 Timeline of VTE Treatment

Initial Management Secondary

• First 3 weeks after
Decision Prevention
point
diagnosis • Beyond 6 months

Primary Treatment
• 3-6 months from the
diagnosis

VTE: venous thromboembolism Ortel TL, et al. Blood Adv. 2020;4(19):4693-4738

 Secondary Prevention
Transient (risk factors that resolve after development of VTE)
Surgery with general anesthesia (including Cesarean section)
Confined to bed > 3 days VTE event

Leg injury associated with reduced mobility > 3 days

Estrogen therapy (e.g., oral contraceptives) Provoked by Provoked by
Pregnancy and puerperium transient risk chronic risk Unprovoked*
factor(s) factor(s)
Recent hospital admission
Chronic (risk factors that persist after development of VTE) Secondary
No secondary
Active cancer prevention
prevention
Inflammatory bowel disease suggested
*absence of any identifiable transient or chronic risk factors
Autoimmune disorders (e.g., antiphospholipid syndrome)
Chronic infection
Chronic immobility (e.g., spinal cord injury)
VTE: venous thromboembolism
 Meet SM
27 YOF presented to the ED with left leg pain and swelling. Ultrasound
revealed occlusive DVT in popliteal vein.
PMH: ACL reconstruction (2 weeks ago)
Home med: acetaminophen
Vitals/Labs: Unremarkable

1. SM would like avoid needles and injections, if possible. What is the

most appropriate treatment for acute DVT?
a) Dabigatran
b) Edoxaban
c) Rivaroxaban
d) Warfarin
 Meet SM
27 YOF presented to the ED with left leg pain and swelling. Ultrasound
revealed occlusive DVT in popliteal vein.
PMH: ACL reconstruction (2 weeks ago)
Home med: acetaminophen
Vitals/Labs: Unremarkable

2. What duration of rivaroxaban do you recommend for SM?

a) 21 days
b) 3-6 months
c) 6-12 months
d) Indefinitely
 Meet OP
83 YOF was brought to the ED after found down at home for unknown period of time.
PMH: CKD 4, stage 3 lung cancer (on chemotherapy)
Vitals: hypotensive (on pressor), tachycardic, requires 4L nasal canula oxygen
Labs: Elevated CK, D-dimer, SCr (current CrCl ~8 mL/min; baseline: 25 mL/min)
Imaging: Xray showed femur fracture, Chest CT showed segmental left lower lobe PE

1. Open reduction and internal fixation (ORIF) is planned for tomorrow

evening. Which of the following regimen is appropriate to start treatment
of PE today?
a) Unfractionated Heparin
b) Enoxaparin
c) Apixaban
d) Warfarin
 Meet OP
83 YOF was brought to the ED after found down at home for unknown period of time.
PMH: CKD 4, stage 3 lung cancer (on chemotherapy)
Vitals: hypotensive (on pressor), tachycardic, requires 4L nasal canula oxygen
Labs: Elevated CK, D-dimer, SCr (current CrCl ~8 mL/min; baseline: 25 mL/min)
Imaging: Xray showed femur fracture, Chest CT showed segmental left lower lobe PE

2. ORIF was successful and AKI secondary to rhabdomyolysis has also

resolved. Which of the following regimen is the most appropriate for OP?
a) Continue heparin until at least 5 days, then switch to dabigatran
b) Warfarin with heparin bridge
c) Rivaroxaban
d) Apixaban
 Meet OP
83 YOF was brought to the ED after found down at home for unknown period of time.
PMH: CKD 4, stage 3 lung cancer (on chemotherapy)
Vitals: hypotensive (on pressor), tachycardic, requires 4L nasal canula oxygen
Labs: Elevated CK, D-dimer, SCr (current CrCl ~8 mL/min; baseline: 25 mL/min)
Imaging: Xray showed femur fracture, Chest CT showed segmental left lower lobe PE

3. What duration of apixaban do you recommend for OP?

a) 7 days
b) 3-6 months
c) 6-12 months
d) Indefinitely
 Summary
• During hospitalization, assess the need of VTE prophylaxis (mechanical or pharmacological) based on
risk factors for thrombosis and bleeding
Prophylaxis • Padua and IMPROVE risk assessment models can be used to stratify these risks

• Initial treatment of VTE should include a rapid-acting anticoagulant

Initial • Some oral anticoagulants (e.g., warfarin, edoxaban) require parenteral anticoagulant overlap or bridge

• ASH guideline recommends 3-6 months over 6-12 months of anticoagulation for primary treatment
Primary

• Indefinite anticoagulation to prevent recurrence may be appropriate in patients with unprovoked VTE
or chronic risk factor(s).
Secondary

ASH: American Society of Hematology

VTE: venous thromboembolism
 Let’s Stop the Clot:
Venous Thromboembolism
Vivian (Wint War) Phyo, PharmD, BCPS
wintwar.phyo@eskenazihealth.edu

The author has no actual or potential conflicts of interest in relation to this presentation