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Migration
PE
Embolus
Thrombus
DVT
Clinical presentations of DVT
DVT occurs when clots form in the deep veins within the muscles of
the leg1
Less commonly, clots may form in the upper extremities as well2
DVT-related symptoms may include:1,3
Leg pain
Tenderness of the leg
Cramping that intensifies over several days
Erythema
Warmth at the site of DVT
Edema
DVT is often asymptomatic, sometimes revealed only after
diagnostic tests4
1. Blann AD, Lip GY. BMJ 2006; 2. Spencer FA. J Gen Intern Med 2006 3. Goldhaber SZ, Morrison RB. Circulation 2002;
4. Anderson FA et al. Center for Outcomes Research, University of Massachusetts Medical Center 1998
Risk factors for VTE
Exposing risk factors Predisposing risk factors
(acute conditions or trauma, surgery) (patient characteristics)
History of VTE
Chronic heart failure
Advanced age
Surgery
Varicose veins
Trauma Cancer Obesity
Acute medical illness
Immobility or paresis
Acute heart failure* Inflammatory
Myeloproliferative disorders
Acute respiratory failure diseases
Pregnancy/peripartum period
Central venous
catheterization Inherited or acquired
thrombophilia
Hormone therapies
Renal insufficiency
Circulatory
Stasis
Left ventricular dysfunction
Immobility or paralysis
Venous insufficiency or varicose veins
Venous obstruction from tumour, obesity or pregnancy
Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856;
Blann AD, Lip GYH. BMJ 2006; Geerts WH et al. Chest 2004; Bennett PC et al. Thromb Haemost 2009
Provoked and unprovoked VTE
Transient/
Continuing/
reversible factors No identifiable
irreversible factors
e.g. surgery or cause
e.g. cancer
hospitalization
Unprovoked
Provoked VTE (idiopathic)
VTE
50
Age
1. Anderson FA, Jr et al. Arch Intern Med 1991; 2. Torbicki A et al. Eur Heart J 2008
Distal or proximal
Proximal
DVT can be:
Distal External iliac
Below the knee in the deep
veins of the calf
Deep femoral
Proximal
Above the knee, primarily in the Great saphenous
popliteal and femoral veins
Popliteal
DVT usually begins distally
Distal
A thrombus may grow and extend to
the proximal veins Anterior tibial
and embolize1 Posterior tibial
1. Anderson FA, et al. Center for Outcomes Research, University of Massachusetts Medical Center; 1998
Potential complications
and goal of treatment
DVT complications:1,2
PE
Damage to valves in the deep veins
Venous reflux
Post-thrombotic syndrome (PTS)
Goal of treatment
Prevent embolization to the lungs
Prevent extension into larger veins
Prevent recurrence
Avoid the chronic complications
1. Kearon C. Circulation 2003; 2. Ginsberg JS, et al. Arch Intern Med 2000
Pulmonary embolism
PE occurs when part of a dislodged thrombus (embolus) passes
into the pulmonary circulation blocking the main artery of the lung
or one of its branches
May lead to increased pulmonary vascular resistance, impaired
gas exchange (alveolar ventilation with hypoperfusion)
Increase in pressure on the right heart can cause dilation,
dysfunction, and ischemia of the right ventricular wall1
PE-related symptoms13
Shortness of breath
Chest pain, tachypnoe, tachycardia
Anxiety
Hemoptysis
Fever Medical Illustration Copyright 2007
Nucleus Medical Art. All rights reserved.
1. Goldhaber SZ. N Engl J Med 1998; 2. Goldhaber SZ, et al. Circulation 2002; 3. Stein PD et al. Chest 2001
Chronic thromboembolic
pulmonary hypertension
Serious complication of PE
Up to 5% of patients with PE are
reported to develop chronic
thromboembolic pulmonary
hypertension (CTPH)1
Initial phase of disease often
asymptomatic and followed by
progressive dyspnoea and
hypoxaemia2
Right heart failure can frequently
occur2
Progressive condition associated
with mortality rates of 420%2
Chest axial with a clot on the left (patients right side); a
tongue of white contrast can be seen extending into the
clot (PE)
Reproduced with permission from Professor AT Cohen
1. Kearon C. Circulation 2003; 2. Torbicki A et al. Eur Heart J 2008
Post-thrombotic syndrome
Occurs in nearly one-third of
patients within 5 years after
idiopathic DVT1
PTS is characterized by:2
Pain
Oedema
Hyperpigmentation
Eczema
Varicose collateral veins
Venous ulceration
Severe PTS can lead to
intractable, painful venous
leg ulcers requiring ongoing
nursing and medical care3
Reproduced with permission from Dr AT Cohen and Dr T Urbanek
1. Prandoni P et al. Ann Intern Med 1996; 2. Kahn SR. J Thromb Thrombolysis 2006;
3. Kahn SR, et al. J Gen Intern Med 2000
VTE is a leading cause of death worldwide
VTE is estimated to cause >500,000 deaths
Europe every year1
An estimated
300,000
VTE-related
deaths occur in
the US VTE is estimated to cause at least
each year2 3 million deaths a year worldwide
1. Cohen AT et al. Thromb Haemost 2007; 2. Heit JA et al. Blood 2005
VTE is a major cause of death in Europe
600,000 Deaths resulting from VTE
543,454
500,000
Number of deaths per annum
400,000
300,000
Combined deaths
209,926
200,000 Transport accident
Prostate cancer
100,000
Breast cancer
AIDS
0
p=0.38
16000 N=14,108
14000 $14,722
p=0.006 $14,146
Total average cost
per patient (US$)
12000
$11,862
10000
$9,805
8000
6000
4000
2000
0
First Recurrent First Recurrent
DVT DVT PE PE
0 5 10 15 20 25
Incidence of DVT per 10,000 hospital patients
(n=315),
Percentage (%)
40
25%
30
Non cancer
(n=932), 75% 26%
20
20%
10
0
Metastatic Prior/ongoing Prior cancer Recurrent VTE
disease chemotherapy surgery
1-year survival in patients with cancer and VTE versus matched controls
50
VTE at the same time
p<0.001
as cancer diagnosis
40
36%
30
20
10 12%
0
1-year survival
Heparin resistance1 aPTT testing does not correlate well with clinical efficacy of
UFH doses >35,000 units/day
*These recommendations are not evidence-based and vary between guidelines (international and national)
1. Rondina MT et al. Thromb Res 2007;119:391402
Diagnostic investigations
(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
Wells score DVT
Factor Points
Active cancer (treatment within last six months or palliative) 1
Calf swelling 3 cm compared to asymptomatic calf (measured 10 1
cm below tibial tuberosity)
Collateral superficial veins (non-varicose) 1
Pitting oedema (confined to symptomatic leg) 1
Swelling of entire leg 1
Localised tenderness along distribution of deep venous system 1
(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
Wells score = DVT likely
Offer
proximal leg vein ultrasound scan (within 4 hours of request), if
negative, a D-dimer test or
if proximal leg vein scan not available within 4 hours, D-dimer test
and an interim 24-hour dose of a parenteral followed by proximal
leg vein ultrasound within 24 hours of request
Repeat proximal leg vein ultrasound scan 68 days later for all patients
with positive D-dimer test and negative proximal leg vein ultrasound
scan
(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
Diagnose DVT and treat patients with positive proximal leg
vein ultrasound
(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
The risk of recurrent VTE
Events occurring subsequent to an acute episode are termed
recurrent VTE, and their prevention is termed secondary prevention
Chance of recurrent VTE in first 3 months
<2% 47%
If adequate anticoagulant response is
achieved1 (2-4% in subsequent 3 months) If proximal DVT inadequately treated1
Idiopathic presentation1,2
Thrombophilia1
Presentation of primary DVT1
Increasing age1
Proximal DVT2
Cancer2
Residual thrombus mass3
Male gender4
1. Prandoni P et al. Haematologica 2007; 2. Hansson PO et al. Arch Intern Med 2000;
3. Prandoni P et al. Ann Intern Med 2002; 4. Eichinger S et al. Circulation 2010
Summary of 2012 ACCP guidelines:
duration of anticoagulant treatment
Condition ACCP recommendation Grade of recommendation
First provoked DVT or PE Therapy for 3 months 1B
2B (nonsurgical risk factor and
low or moderate bleeding risk)
First unprovoked proximal Extended treatment 2B
DVT or PE with low to
moderate risk for bleeding
First unprovoked proximal Therapy for 3 months 1B
DVT or PE with high risk for
bleeding
First unprovoked proximal extended therapy 1B
DVT or PE in cancer patients 2B (high bleeding risk)
with LMWH over VKA 2B
Second unprovoked extended therapy in low to moderate 1B (2B moderate bleeding risk)
VTE bleeding risk
3 months therapy in high bleeding risk 2B
Choice of agent VKA or LMWH over dabigatran or 2B
rivaroxaban
Extended therapy Reassessed at periodic intervals (eg,
annually)
Kearon C et al. Chest 2012
Antithrombotic therapy for VTE disease
In their recent guideline on antithrombotic therapy of VTE disease,
ACCP has considered for the first time treatment with rivaroxaban
The ACCP treatment model is a 3-phase model. The three phases
are initial, long-term and extended treatment
Long-term Extended
Initial (07 days)
(7 days3 months) (3 monthsindefinite)
Phases of anticoagulation
Recommended anticoagulants
0 to ~7 days
Therapeutic
UFH, LMWH,
Up to 3 months >3 months to indefinite with
fondaparinux or
periodic (eg. annual) risk assessment
rivaroxaban
Thrombosis
Narrow
Bleeding
therapeutic
Multiple drugdrug and window
fooddrug interactions
Slow onset/offset of action
Increased risk of bleeding
Dose
Parenteral administration
Injection site reactions (uncommon)
Risk of osteoporosis
Risk of HIT, although relatively rare, may have serious
consequences
Requirement for platelet monitoring
Weight-adjusted dosing and coagulation monitoring
Subcutaneous injection
Injection site problems
Risk of osteoporosis (although less than with UFH)
A lower risk of HIT compared with UFH
Risk of accumulation with renal impairment
Initiation
X IX
Va
Propagation =
Xa IXa
thrombin-generation
phase
Rivaroxaban II Prothrombin
Prothrombinase
Inactive factor apixaban complex
edoxaban
Active factor and others
Dabigatran Thrombin
Transformation IIa
and others
Catalysis
CURRENT
FUTURE
EINSTEIN DVT/PE:
rivaroxaban single drug Rivaroxaban 15 mg bid 3 wks, then 20 mg od
Single-drug approach
EINSTEIN DVT:
primary efficacy outcome time to first event
4.0
Cumulative event rate (%)
Enoxaparin/VKA (N=1718)
3.0
Rivaroxaban (N=1731)
2.0
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk
Rivaroxaban 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266
Enoxaparin/
1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264
VKA
0.1 1 10
10
8 Rivaroxaban (N=1718)
6
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk
Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140
Enoxaparin/
1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118
VKA
Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81
Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85
1. Schulman S. N Engl J Med 2003; 2. Prandoni P et al. Ann Intern Med 1996;
3. Heit JA et al. Arch Intern Med 2000; 4. The EINSTEIN Investigators. N Engl J Med 2010;
5. The EINSTEINPE Investigators. N Engl J Med 2012