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Venous Thromboembolism
Anthony Battad CD, MD, MSc., MPH, FRCPCDirector // DirecteurAmbulatory Care, St. Boniface Hospital // Soins ambulatoire, Hôpital St. BonifaceMedical Director //Directeur médicalMaster of Physician Assistant Studies // Mâitre d’études assitants-médicineUniversity of Manitoba // Université du Manitoba
Disclosure
• Conference expenses paid for by University of Manitoba• No financial conflicts to disclose
Case # 162 year old male with PMHx:• Prostate Ca• HTN
Noticed unilateral right leg swelling and pain over the last 3 days
Recently returned from a 16 hour bus tour
Case # 254 year old female with PMHx:• HTN, controlled• Anxiety
Presents with SOBOE, worsening over the past 2 weeks
Denies any infectious symptoms
Case # 328 year old male• In a walking cast for 2
weeks because of 3o ankle sprain
• Now has unilateral right swelling
Objectives
• Know the impact of VTE disease on health
• Describe the pathogenesis of VTE (DVT and PE)
• Recognize the risk factors for VTE
• Name the signs and symptoms of DVT and PE
• Identify the appropriate diagnosis and treatment of VTE
VTE is a prevalent and severe disease compared with other public health burdens
500 000
VTE-related deaths
Breast cancer
Prostatecancer
Transport accidents
AIDS
400 000
300 000
200 000
100 000
600 000Annual mortality rate in Europe
(25 member-state countries)
Adapted from Cohen et al. Thromb Haemost 2007;98:756-64
543 454
86 83163 636 53 599
5860
0
Annu
al n
o. o
f dea
ths
VTE is a Major International Health Problem: Millions of Cases Annually
0100,000200,000300,000400,000500,000600,000700,000800,000
Nonfatal DVT Nonfatal PE Fatal VTEPa
tient
s pe
r Yea
r With
VTE
Patie
nts
per Y
ear W
ith V
TE
0
100,000
200,000
300,000
400,000
Nonfatal DVT Nonfatal PE Fatal VTE
~900,000 VTE events occur each year in the US
~1.6 million VTE events occur each year in the EU
VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism.Heit JA et al. Abstract #910 appears in Blood. 2005;106.
Adapted from Cohen AT et al. Thromb Haemost. 2007;98:756-764.
• ~ 45,000 patients in Canada are affected by deep vein thrombosis (DVT) each year1
• Among those who develop DVT2:• One-third will have long term complications such as chronic lower leg
edema, post-phlebitic syndrome, pain, pigment changes • One-third will develop a recurrent event within 10 years
• Despite adequate therapy, 1% to 8% of patients in whom pulmonary embolism develops, will die2
1. Thrombosis Canada, 2013, Clinical Guides, Venous Thromboembolism; http://thrombosiscanada.ca/ 2. Scarvelis et al, CMAJ 2006; 175(9) 1087-92
Incidence of VTE in Canada
Annual Event Rates of Recurrent VTE• Patients with unprovoked VTE had the highest risk of recurrence
10
Duration of Follow-Up
Provoked bySurgery
Provoked byNonsurgical Factor
Unprovoked(idiopathic)
12 months 1.0%/yr 5.8%/yr 7.9%/yr
24 months 0.7%/yr 4.2%/yr 7.4%/yr
Data from Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710–1716.
Kaatz S et al. Cleve Clin J Med. 2011;78(9):609-618.
Pathophysiology of VTE
11
Virchow’s
Triad
Hypercoagulability
Endothelial InjuryStasis of Venous
Blood Flow
Adapted from Kyrle PA et al. Blood 2009; 114: 1138-1139
VTE: Clot Formation Within the Venous Circulation
Pulmonary embolism (PE)
Deep vein thrombosis (DVT)
MigrationEmbolus
1
2
Tapson VF. N Engl J Med. 2008;358:1037-1052.Image adapted from Tapson VF.
Thrombus
12
Clinical-setting–related Risk Factors
Patient-related Risk FactorsClinical Inherited Acquired
Type or duration of surgery
Orthopedic surgery Pelvic or hip fracture Type of anesthesia Congestive heart
failure Intensive care Multiple trauma
Previous VTE Varicose veins Age >70 years Obesity Prolonged bed rest Level of hydration Severe medical illness Cancer Infection or sepsis Pregnancy or childbirth Combined oral
contraceptives Stroke Myocardial infarction
Activated protein C resistance
Deficiencies in: antithrombin, heparin cofactor II, protein C, protein S
Prothrombin mutation
Hyperhomo-cysteinemia
Lupus anticoagulant Anticardiolipin
antibodies Myeloproliferative
disease Hyperhomo-
cysteinemia
Arcelus JI et al. Orthopedics. 2006;29(6):506-516.13
Anatomy Review
Image from Thrombosis Adviser. http://www.thrombosisadviser.com/en/resources/image-library/index.php. Accessed September, 2015
Proximal vs. Distal DVT
Proximal DVT• > 90% of acute PE due to
proximal DVT• Iliac, femoral, and popliteal veins• Associated with chronic risk
factors:• Active malignancy, CHF, age > 75,
chronic respiratory disese• ~ 50% untreated DVT PE within
3 months• Higher 3 month mortality than
distal DVT
Distal DVT• Small veins of the calf• Associated with transient risk
factors:• Recent surgery• Immobilization• Travel
• 25% - 33% of untreated and symptomatic distal DVT extend proximally
• Proximal extensions treated as if they originated in proximal vein
Upper Extremity DVT
• 4% to 11% of all DVT 1
• Risk Factors• CVL placement• Malignancy• Hospitalization
• Less incidence of pain• Less likely to have PE at time of diagnosis• Rates of recurrent VTE and death similar to lower extremity VTE
1. Muñoz FJ et al. Chest. 2008;133(1):143-148. http://dx.doi.org/10.1378/chest.07-1432 2. Joffe HV et al. Circulation. 2004;110:1605-1611.3. Mai C, Hunt D. Am J Med. 2011;124(5):402-407.
Clinical Presentation: Signs and Symptoms1-4
DVT• Pain• Swelling• Tenderness• Discoloration• Pitting edema
PE• Shortness of breath• Cough• Chest pain• Tachycardia• Hypotension• Low-grade fever
1. Moll S. Arterioscler Thromb Vasc Biol. 2008;28(3):373-379.2. Pai M et al. http://www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics Accessed September 20153. Thompson et al. http://www.uptodate.com/contents/pulmonary-embolism-beyond-the-basics Accessed September 20154. Goldhaber SZ. Pulmonary Embolism. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed.
Philadelphia, PA: Elsevier, 2012.
17
Left image from National Blood Clot Alliance. http://www.stoptheclot.org/learn_more/learn_thrombosis.htm. Accessed September 2015.Right image from University of Maryland Medical Center. http://www.umm.edu/patiented/articles/000583.htm. Accessed September, 2015
Image from Medic Scientist. http://medicscientist.com/chest-pain-differential-diagnosis. Accessed September, 2015.
Clinical Feature ScoreActive cancer (ongoing Rx or within 6 months or palliative 1
Paralysis, paresis, or recent immobilization (cast) of lower extremity 1
Recently bedridded > 3 days or major surgery within 4 weeks 1
Localized tenderness along the distribution of the deep venous system 1
Entire swelling of the leg (thigh to foot) 1
Calf swelling > 3 cm as compared to asymptomatic leg 1
Pitting edema worse in the affected leg 1
Collateral superficial veins (non-varicose) 1
Alternative diagnosis as likely or more likely than DVT -2
Previously documented DVT 1
Modified Wells Criteria for DVT
Adapted from:Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350:1795Wells PS, Anderson,DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349:1227
Modified Wells Scoring
• 2 or greater DVT likely
• 1 or less DVT unlikely
• Modified Wells score takes into account D-Dimer
• (eg) if DVT unlikely (score 1 or less), negative D-Dimer rules out DVT
Diagnosis
DVT1
• D-dimer measurements• Venous ultrasonography• Contrast venography
•PE2
• ECG• Chest radiograph• CT angiogram
• Ventilation-perfusion (V/Q) scan3
• Pulmonary angiogram
1. Bates SM et al. Chest. 2012;141(2 Suppl):e351S-e418S.2. Tapson VF. N Engl J Med. 2008;358:1037-1052.3. Schümichen C. Respiration. 2003;70(4):329-342.
4. Sidhu PS, et al. Br J Radiol. 2007;80(959):859-865.20
Image from Phlebologia. http://www.phlebologia.com/en/anatomie_classique_04.asp. Accessed September, 2015.
Image courtesy of RF Schneider, Pfizer
Image from Schümichen C.
Upper calf image from Sidhu PS et al.4
Phases of Anticoagulation Treatment for VTE
Vitamin K antagonist (VKA) or other agent†Parenteral
Initial1
(0 to ~7 days)Long-term
(~7 days to ~3 months)Extended
(~3 months to indefinite)
Treatment
Secondary preventionRisk
of R
ecur
rent
VTE
Time since starting treatment
Start of treatmentand secondary prevention2 Completion of treatment
1. Kearon C et al. Chest. 2012;141(2 Suppl):e419s-e494s.2. Kearon C. J Thromb Haemost. 2012;10:507-511. 21
Phases of Anticoagulation Treatment for VTE
NOAC/DOAC or Vitamin K Antagonist
Initial1
(0 to ~7 days)Long-term
(~7 days to ~3 months)Extended
(~3 months to indefinite)
Treatment
Secondary preventionRisk
of R
ecur
rent
VTE
Time since starting treatment
Start of treatmentand secondary prevention2 Completion of treatment
1. Kearon C et al. Chest. 2012;141(2 Suppl):e419s-e494s.2. Kearon C. J Thromb Haemost. 2012;10:507-511. 22
• Do not delay treatment while waiting for diagnostics
• Prevent clot extension
• Prevent the development of PE
• Reduce the risk of recurrence
• Limit the development of late complications
Treatment Rationale
High probability or
Confirmed VTE
No Treatment
Bleeding Risk
< 3%High Risk
Clot
Severe Symptoms 1
Inpatient Treatment
Outpatient Treatment
1Severe Symptoms
• Symptomatic PE• Severe leg swelling limiting
mobility• Cerulea phlegmasia dolens
NO
YES
NOYES
NO
YES
YES
HAS-BLED Score
Courtesy of mayoclinic.org, Accessed October, 2015
• Unfractionated heparin• Fallen out of favour – reserved for patients with decreased renal function
• Low molecular weight heparin (LMWH)• Dalteparin
• Fondiparinox – synthetic Xa inhibitor• Used in patients with HIT (heparin induced thrombocytopenia)
• If using warfarin, start at the same time and overlap for 2 days of therapeutic INR (2 – 3)
Inpatient Treatment
• LMWH plus warfarin• Overlap 2 days within therapeutic INR range (2-3)
• New Oral Anticoagulants (NOAC)• Dabigatran – direct thrombin inhibitor• Rivoroxiban – Xa inhibitor• Apixiban – Xa inhibitor
• Avoid NOACs in patients with impaired renal function (eGFR < 30)
Outpatient Treatment
A Few Words About NOACs
• Advantages
• Rapid onset and offset• No monitoring• Reliable and predictable
pharmakokinetics• Less incidence of major bleeding
(compared to warfarin)• Non-inferior to warfarin
• Disadvantages
• Expensive• Can’t use in patients with poor
renal function• No “anti-dote”
Using current criteria for approval, warfarin
would NEVER be approved for use today.
• 1st provoked DVT – 3 months
• 2nd provoked DVT – 6 months
• 1st unprovoked DVT – 3-6 months (depending on risk of bleeding)
• 2nd unprovoked DVT – indefinite
• Documented PE treated for 6 months• 2nd PE – indefinite anticoagulation
Duration of Treatment
• Post-thrombotic syndrome (PTS)1
• Can occur within 1-2 years after DVT in 20% to 50% of all patients• Severe PTS occurs in 25-33% of patients with PTS
• Can lead to deep vein insufficiency and leg ulcers
• Chronic thromboembolic pulmonary hypertension (CTPH)• Can occur after PE and is associated with significant
morbidity and mortality2
• Frequency3
• 1.0% at 6 months• 3.1% at 1 year• 3.8% at 2 years
Secondary Complications of VTE
1. Kahn SR, Ginsberg JS. Arch Intern Med. 2004;164:17-26.2. McNeil K, Dunning J. Heart. 2007;93:1152-1158.3. Pengo V et al. N Engl J Med. 2004;350(22):2257-2264 30
Image from UpToDate. http://www.uptodate.com/contents/diagnostic-evaluation-of-chronic-venous-insufficiency. Accessed September 1, 2012.
Image from McNeil K. Heart. 2007;93:1152-1158.
• Age appropriate screening acceptable
• Multi-phase CT of chest, abdomen, pelvis
Malignancy Screening
Back to the cases
Case # 162 year old male with pMHx:
• Prostate Ca
• HTN
Noticed unilateral right leg swelling and pain over the last 3 days
Recently returned from a 16 hour bus tour
Case # 254 year old female with PMHx:
• HTN, controlled
• Anxiety
Presents with SOBOE, worsening over the past 2 weeks
Denies any infectious symptoms
Case # 328 year old male• In a walking cast for 2
weeks because of 3o ankle sprain
• Now has unilateral right swelling
