1) Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), affects over 900,000 Americans each year and can be fatal. The risk of recurrence of VTE is 17-30% over time without continued anticoagulation treatment. 2) The risk of recurrent VTE depends on factors like whether the initial VTE was provoked by surgery or other transient risk factors, whether the patient has active cancer, and whether it is a first or subsequent episode of VTE. Hereditary thrombophilias alone do not strongly determine recurrence risk. 3) Treatment options for VTE include anticoagulants like warfar

1. Management of Venous
Thromboembolism
Yu-Min Shen, MD, FACP
Associate Professor
Division of Hematology/Oncology
University of Texas Southwestern Medical Center

2. 2
VTE: Incidence and Impact
• Approximately >900,000 VTEs occur every year
• Each year 1 person in 1000 will experience his/her first VTE in the US
– One third manifest pulmonary embolism (PE, with or without DVT)
• Death within 1 month of diagnosis:
– 6% of DVT cases
– 12% of PE cases
• >100,000 deaths attributable to VTE each year
• Recurrent DVT:
– 17% of DVT patients 2 years after initial treatment
– 30% of DVT patients 8 to 10 years after initial treatment
• ~550,000 hospitalizations annually
• Health care costs up to $10 billion annually
1. CDC data
2. Heit, Arterioscler Thromb Vasc Biol 2008; 28: 370-372
3. Heit et al, Blood 2005; 106: 267A
4. American Heart Association. Heart Disease and Stroke Statistics – 2004 Update.
5. Prandoni P et al. Haematologica. 1997;82:423-428.
6. Pengo V et al. N Engl J Med. 2004;350:2257-2264.

3. Heit, J; J of Thrombosis & Haemostasis 2005, 3:1611-1617

4. Thrombosis
Genetic or Acquired
Risk Factors
Predisposing Event
Thrombus

5. Major Risk Factors for 1st Lifetime VTE
• Persistent fixed
– Age
– Inherited thrombophilia
• Persistent variable
– Cancer
– Myeloproliferative disorders
– Inflammatory bowel disease
– Obesity
– Antiphospholipid antibodies
• Transient
– Surgery
– Trauma
– OCP use or pregnancy
– Travel
– Infection
Cannegieter and Van Hylckama Vlieg, JTH 2013, 11(Suppl 1):161-169

6. Risk Factors for 1st Lifetime VTE
21.7
12.7
8.0
6.5
4.0
5.6
3.0
4.3
4.2
Heit et al, Arch Intern Med 2000, 260:809-815

7. Heit et al, Arch Intern Med 2002, 162:1245-1248

8. Seligsohn, U. et al. N Engl J Med 2001;344:1222-1231
Inherited Thrombophilia
Common
G1691A mutation in factor V gene (Leiden mutation)
G20210A mutation in prothrombin gene
C677T mutation in MTHFR gene
Rare
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Very rare
Dysfibrinogenemia
Homozygous homocysteinuria
Probably
inherited
Increased factor VIII, IX, XI, or fibrinogen
**Factor VIII and fibrinogen are acute phase reactants

9. Inherited Thrombophilia
Lijfering et al, Blood 2009, 113:5314-5322

10. Relative Contribution of Inherited
Thrombophilia to VTE Incidence
FVL PGM PC PS AT
% of general population 4.80 2.70 0.20 0.03 0.02
Relative risk of VTE 4 2 8 8 8
Expected pts with VTE per year 14400 6600 4200 630 1020
% of pts with VTE per yr with
particular defect
(based on 1/1000 incidence and
331,800,000 population)
4.34 1.99 1.27 0.19 0.31
De Stefano V et al. Semin Thromb Hemost. 2006;32(8):767-80
De Stefano V et al. Haematologica. 2002;87(10):1095-108

11. Treatment of Venous
Thromboembolism
Risk of Recurrent
or Progressive VTE
Risk of Bleeding on
Anticoagulation RX

12. Treatment of Venous
Thromboembolism
• Initial (1st week): prevent progression/embolization
• Long term (1st 3 months): resolution of the clot
• Extended (after 3 months): prevention of new clots

13. Options for the Initial Treatment of VTE
Drug Route Dose HIT Risk
Major Bleeding
Risk
Unfractionated
Heparin
IV
Loading: 80 IU/kg
Infusion: 18 IU/kg/hr
2.7% 1.9%
SC Loading: 333 IU/kg then 250 IU/kg q12 hrs 1.1%
Enoxaparin SC 1 mg/kg BID or 1.5mg/kg daily <1% ~1%
Dalteparin SC 100 IU/kg BID or 200 IU/kg daily <1% ~1%
Tinzaparin SC 175 IU/kg daily <1% ~1%
Fondaparinux SC
5mg for <50kg; 7.5mg for 50-100kg; 10mg
for >100kg
0%? 1.1-1.3%
Rivaroxaban PO 15mg twice daily x 21 days 0% 1%
Apixaban PO 10mg twice daily x 7 0% 0.6%

14. Hetzel G R , Sucker C; Nephrol. Dial. Transplant. 2005;20:2036-2042

15. Anti-Xa vs Anti-IIa
Ansell, J; JTH 2007; 5(suppl 1): 60-64
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
Ximelogatran

16. Additional Initial Treatments
• In select patients with the following:
– Iliofemoral DVT
– Symptoms <14 days
– Good functional status
– Life expectancy ≥1 yr
– Low risk of bleeding
• Additional treatments to consider:
– Pharmacomechanical catheter-directed thrombolysis
followed by balloon angioplasty and stents
– Systemic thrombolysis if above not available
– Operative venous thrombectomy
Kearon et al, Chest 2008; 133:454S-545S

17. Therapies that were Recommended
Against for Initial Treatment!
• Percutaneous venous thrombectomy alone
• Routine use of a vena cava filter in addition to
anticoagulants
– Consider IVC filter for pts with acute proximal DVT
only if anticoagulant therapy is not possible
– Should subsequently receive conventional course
of anticoagulation therapy if risk of bleeding
resolves
Kearon et al, Chest 2008; 133:454S-545S

18. 8-yr follow up of
PREPIC study
PREPIC study group, Circulation 2005; 112:416-422

19. Longer term treatment of VTE
• Vitamin K antagonist: Warfarin INR 2-3
• Factor Xa inhibitor
– Rivaroxaban 20mg daily
– Apixaban 5mg bid
– Edoxaban 60mg daily;
• 30mg daily for CrCl 30-50, wt <60kg, on p-gp inhibitor
• Direct thrombin inhibitor:
– Dabigatran 150mg BID
• Weight based UFH/LMWH/fondaparinux

20. Risk of Recurrent VTE
Largely Determined by
• Whether the acute episode of VTE has been
effectively treated
• The patient’s intrinsic risk of having a new
episode of VTE

21. Risks of Recurrent VTE
Heit et al, Arch Intern Med 2000, 160:761-768

22. Risks of Recurrent VTE
Prandoni et al, Hematologica 2007; 92: 199-205

23. Risks of Recurrent VTE
Prandoni et al, Hematologica 2007; 92: 199-205

24. Primary Factors for Estimating Risk of
Recurrent VTE
Risk Category 1 yr cumulative risk 5 yr cumulative risk
Provoked by surgery 1% 3%
Provoked by nonsurgical
reversible risk factors
5% 15%
Unprovoked 10% 30%
Cancer associated
15% per year; variable with stage, chemotherapy,
pace of disease progression; difficult to estimate
with high mortality in pts with VTE and cancer.
Kearon et al, Chest 2012; 141: e419S-e494S

25. Secondary Factors for Estimating Risk of
Recurrent VTE
• Whether DVT was confined to distal veins (isolated distal
recurrence rate half compared to that of proximal DVT and
PE)
• Whether VTE was 2nd or subsequent episode (50% higher
risk of recurrence compared with a 1st VTE)
• Additional factors not strongly or consistently enough to
influence recommendations
– Residual thrombosis in proximal veins (RR ~1.5)
– Negative d-dimer 1 months after stopping warfarin (RR ~0.4)
– Antiphospholipid antibody (RR ~2)
– Hereditary thrombophilia (RR ~1.5-1.8)
– Male vs. females (RR ~2)
– Asian ethnicity (RR ~0.8)
Kearon et al, Chest 2012; 141: e419S-e494S

26. Residual Thrombus and Recurrence
Young et al., J Thrombosis & Haemostasis 2006; 4:1919-1924
Residual thrombus present
Residual thrombus absent

27. Palareti G et al. N Engl J Med 2006;355:1780-1789
D-Dimer and Recurrence

28. Recurrent VTE According to
Presence of ≥1 Thrombophilias
Kearon et al, Blood 2008; 12: 4432-4436

29. Copyright restrictions may apply.
Christiansen, S. C. et al. JAMA 2005;293:2352-2361.
Cumulative Incidence of Recurrent Thrombotic Events

30. Copyright ©2000 American Society of Hematology. Copyright restrictions may apply.
Simioni et al, Blood 2000;96:3329-3333
Recurrent VTE in Patients after 1st Episode Unprovoked DVT With or
Without Factor V Leiden or Prothrombin Mutation

31. Recurrent VTE with Thrombophilia
Prandoni et al, Hematologica 2007; 92: 199-205
Predictor
Adjusted
HR
Unprovoked 2.30
Thrombophilia 2.02
Primary DVT 1.44
Shorter anticoagulation 1.39
Aging 1.14

32. Cohn, Roshani, Middledorp, Semin Thromb Hemost 2007; 33: 573-581

33. Thrombophilia
Annual Recurrence
Rate
2 yr Cumulative
Recurrence
5 yr Cumulative
Recurrence
10 yr Cumulative
Recurrence
AT/PC/PS 6.23% 19% 40% 55%
FVL/PT/FVIII 2.25% 7% 11% 25%
Risk of Recurrence with Inherited Thrombophilias
Lijfering et al, Blood 2009, 113:5314-5322

34. Risk Factors for Bleeding with
Anticoagulant Therapy
• Age >65
• Age >75
• Previous bleeding
• Cancer
• Metastatic cancer
• Renal failure
• Liver failure
• Thrombocytopenia
• Previous stroke
• Diabetes
• Anemia
• Antiplatelet therapy
• Poor anticoagulant
control
• Comorbidity and reduced
functional capacity
• Recent surgery
• Frequent falls
• Alcohol abuse
Kearon et al, Chest 2012; 141: e419S-e494S

35. Estimated Absolute Risk of Major Bleeding
on Anticoagulation
Category
Low risk
(0 risk factors)
Moderate Risk
(1 risk factor)
High Risk
(≥2 risk factors)
Anticoagulation
0-3mos
Baseline risk 0.6% 1.2% 4.8%
Increased risk 1.0% 2.0% 8.0%
Total risk 1.6% 3.2% 12.8%
Anticoagulation
after1st3mos
Baseline risk 0.3%/yr 0.6%/yr ≥2.5%/yr
Increased risk 0.5%/yr 1.0%/yr ≥4.0%/yr
Total risk 0.8%/yr 1.6%/yr ≥6.5%/yr
Kearon et al, Chest 2012; 141: e419S-e494S

36. Balancing the Reduction in Risk of Recurrent VTE
against Bleeding with Long-Term Anticoagulation
• Risk of recurrent VTE
– With major transient risk factor: 3% in 1st yr and 10% over 5 yrs
– Unprovoked: 10% in 1st yr and 30% over 5 yrs
• Risk reduction of recurrent VTE with long-term VKA
– 80% when INR is 1.5-2.0
– 95% when INR is 2.0-3.0
• Case fatality rate of recurrent VTE
– 10% after PE
– 5% after DVT
• Risk of major bleeding: 1-2% annually
• Case fatality rate of major bleeding: 10% (higher for h/o CVA)
→ Annual risk of VTE must exceed 1.5% after PE and 3% after DVT to offset
bleeding
Kearon, Circulation 2004; 110(suppl I):I10-I18

37. 9th ACCP Consensus Recommendations
• Proximal DVT secondary to a transient (reversible) risk factor
– Recommend Rx for 3 months over shorter or longer period if provoked by surgery
– Recommend Rx for 3 months over shorter or longer period if provoked by nonsurgical factors if high
bleeding risk; suggest 3 months over extended therapy if bleeding risk low or moderate
• Isolated distal DVT provoked by transient risk factor
– Suggest Rx for 3 months over shorter period
– Recommend Rx for 3 months over longer period
• Unprovoked DVT
– Recommend Rx for at least 3 months over shorter duration and evaluate for risk-benefit ratio of
extended therapy
– 1st unprovoked VTE with low or moderate bleeding risk, suggest extended Rx
– 1st unprovoked VTE with high bleeding risk, recommend 3 months over extended Rx
– 1st unprovoked isolated distal DVT suggest 3 months over extended Rx with low or moderate
bleeding risk; recommend 3 months in those with high bleeding risk
– 2nd episode of unprovoked VTE recommend extended Rx over 3 months with low bleeding risk;
suggest extended Rx in those with moderate bleeding risk
– 2nd episode of unprovoked VTE with high bleeding risk, suggest 3 months over extended Rx
• DVT and active cancer
– Recommend extended Rx over 3 months if bleeding risk not high; suggest extended Rx if high
bleeding risk
• In all pts who receive extended Rx the continuing use of Rx should be reassessed at periodic
intervals (eg annually)
Kearon et al, Chest 2012; 141: e419S-e494S

38. Questions to Ask when Deciding Duration of
Anticoagulation Therapy
• Was the VTE provoked? Reversible risk factors:
– Surgical
– Nonsurgical: trauma, estrogen therapy, pregnancy, prolonged travel (>8
hrs)
• Does the patient have active cancer?
– What is the stage of the cancer?
– Is the patient receiving chemotherapy?
• Additional considerations:
– Whether DVT was confined to the distal veins
– Whether the DVT was a 1st episode or 2nd or subsequent episode of VTE
• Presence of hereditary thrombophilia is NOT a major determinant
of risk of recurrence, at least not in addition to the major
determinants above.

39. Individualized duration of oral anticoagulant
therapy for DVT based on a decision model
Vink et al., J of Thrombosis & Haemostasis 2003; 1:2523-2530

40. Predicting Recurrent VTE
in Your Individual Patient
Can we identify low risk patients in
whom anticoagulation therapy can
be stopped?

41. Identifying Women at
Low Risk of VTE Recurrence
Rodger et al, CMAJ 2008; 179(5):417-426

42. Rodger et al, CMAJ 2008; 179(5):417-426
Annual risk of
recurrent VTE
1.6%
14.1%
HER DOO 2 Clinical Prediction Rule

43. DASH Score
Predicting Recurrence in Patient with
Previous Unprovoked VTE
Tosetto et al, JTH 2012; 10: 1019-1025

44. DASH Score
Predicting Recurrence in Patient with
Previous Unprovoked VTE
Tosetto et al, JTH 2012; 10: 1019-1025

45. Thrombophilia Testing
• Does presence of thrombophilia lead to a
different treatment intensity? No
– Studies addressing varying intensity after first VTE
showed increased recurrence rate with reduced
intensity, regardless of thrombophilia
– Risk reduction of recurrence is 95% when INR 2-3
– Higher INR intensity in APS patients showed no
reduction in recurrence risk and increased bleeding
risk
• Whether clinical outcome is improved in VTE
patients with thrombophilia with longer duration
of anticoagulation has never been investigated
Cohn, Roshani, Middledorp, Semin Thromb Hemost 2007; 33: 573-581

46. Thrombophilia Testing
Cohn, Roshani, Middledorp, Semin Thromb Hemost 2007; 33: 573-581

47. Thrombophilia Testing
• What is the purpose of testing?
– May help fine tune (not determine) the risk of recurrent
thrombosis
– To help counsel family members
• When is the best time to test?
– Ideally, off of anticoagulants
– Not at the time of the acute thrombotic event (does not
determine whether to treat the clot)
– When the results will have an impact on decision making
(duration of anticoagulation??)
• Positive findings should be repeated for confirmation
(except for genetic tests)

48. New Anticoagulants Now Available or
Soon to be Available
• Factor Xa inhibitors
– Rivaroxaban (Xarelto®)
– Apixaban (Eliquis®)
– Edoxaban (Lixiana®)
– LY517717 (Ely Lilly)
– Otamixaban (Sanofi)
– Betrixaban (Portola)
– TAK-442 (Takeda)
• Factor IIa inhibitors
– Dabigatran (Pradaxa®)
– AZD0837 (Astra-Zeneca)
• Warfarin analog
– Tecarfarin (ARYx)

49. renal
Weitz et al, Chest 2012; 141: e120S-e151S