2. INTRODUCTION
VTE(VENOUS THROMBOEMBOLISM)=DVT+PE
In 1865-Armand Trousseau first described venous
thrombosis
1
Risk of mortality doubles if cancer pts develop DVT
VTE is the second leading cause of death in
hospitalized cancer patients1
1. J Thromb Haemost 2007;5(3):632.
3. Likelihood of Death After
Hospitalization
1.00
DVT/PE and Malignant Disease
0.80
Probability of Death
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0 20 40 60 80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
5. GENETIC MUTATIONS
TP53 KRAS
TISSUE FACTOR AND TF CONTAINING VESICLES
CANCER CELLS ENDOTHELIAL CELLS
UPREGULATION
VEGF
DOWNREGULATION
THROMBOSPONDIN
HYPERCOAGULABILITY
6. OTHER AGENTS
• Cancer procoagulant----Xa Activation
• PAI
• TNF,1L-1 and 6
• IFNs
• Increased 8-vWF
• Decreased protein C and S,
Antithrombin
7. Risk factors
Patient related Disease related Treatment related
• Age • Site of primary • Surgery
• Race • Brain,lung • Prechemo platelet
• Obesity • Stomach,pancreas count>350000
• Infection • Kidney,ovary • Hormonal therapy-
• Genetic mutations • Lymphomas,mela tamoxifen,OCP
• V leiden noma • Chemo- 6.5 fold risk
• Metastatic disease of DVT-
• Prothrombin
thalidomide,
• h/o DVT
lenalidomide and
• Renal disease bevacizumab
• Pulmonary disease • Erythropoeitin
• Central vein
catheter
8. VTE and Cancer: Epidemiology
Of all cases of VTE:
● About 20% occur in cancer patients
● Annual incidence of VTE in cancer
patients ≈ 1/250
Of all cancer patients:
● 15% will have symptomatic VTE
● As many as 50% have VTE at autopsy
Compared to patients without cancer:
● Higher risk of first and recurrent VTE
● Higher risk of bleeding on anticoagulants
● Higher risk of dying
Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
9. VTE Incidence In Various Tumors
Oncology Setting VTE Incidence
Breast cancer (Stage I & II) w/o further
0.2%
treatment
Breast cancer (Stage I & II) w/ chemo 2%
Breast cancer (Stage IV) w/ chemo 8%
Non-Hodgkin’s lymphomas w/ chemo 3%
Hodgkin’s disease w/ chemo 6%
Advanced cancer (1-year survival=12%) 9%
High-grade glioma 26%
Multiple myeloma (thalidomide + chemo) 28%
Renal cell carcinoma 43%
Solid tumors (anti-VEGF + chemo) 47%
Wilms tumor (cavoatrial extension) 4%
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
10. OCCULT CANCER AND VTE
SOMIT(Screening For Occult Malignancy In Patients
With Symptomatic Idiopathic VTE Trial) concluded
that most cancers are diagnosed within four to six
months of diagnosis of DVT and 40% will have
metastasized
Greatest risk of DVT is within few months of diagnosis
of cancer
No evidence of survival benefit due to screening and
earlier detection
NCCN does not recommend screening VTE pts for
cancer
11. DIAGNOSIS OF DVT/PE
Clinical assessment + D-
dimer assay
False negative rates high for
D-dimer assay
Duplex USG is the
investigation of choice for
lower limb DVT
CT angiogram is the IOC for
PE
CT/MRI is more sensitive for
upper limb DVT
12. Deep vein thrombosis
Common femoral vein
Thrombus
Proximal
Knee
Distal
Veins of the leg
14. DVT – Wells Score
The following were assigned a point value of 1 if
present: Cancer Entire leg swollen
Paralysis or plaster Calf > 3cm larger
immobilization than unaffected leg
Bedrest > 3 d or Pitting edema
surgery in past 4 greater than
wks unaffected leg
Localized Collateral
tenderness superficial veins
• Probability High (≥ 3), Moderate (1-2) or Low (0 or less)
• DVT risk: High – 75%, Moderate – 17%, Low – 3%
Wells PS, Andersen DR, Bormanis J et al. Lancet. 1997;350:1795-8
15. Symptoms of DVT and PE
DVT PE
Swelling Unexplained shortness of
Pain or tenderness -the pain is breath
usually in 1 leg and may only Chest pain and/or palpitations
be present when standing or
walking Anxiety and/or sweating
Warm skin Coughing/coughing up blood
Red or discolored skin Fatigue and/or fainting
Not all people with DVT have signs or symptoms
.
16. Myths of the great masquerader!
Myth
– “Patients with pulmonary embolism are short of
breath and have chest pain!”
Reality:
You can forget about making the diagnosis on
clinical grounds, but wait…don’t plan on completely
ruling it out either!
16
18. Clinical Features
Signs with Angiographically Proven PE
Sign Percent
Tachypnea > 20/min 92
Rales 58
Accentuated S2 53
Tachycardia >100/min 44
Fever > 37.8 43
Diaphoresis 36
S3 or S4 gallop 34
Thrombophebitis 32
Lower extremity edema 24
18
19. Chest X-ray Eponyms of PE
Westermark's sign
– A dilation of the pulmonary vessels proximal to the
embolism along with collapse of distal vessels,
sometimes with a sharp cutoff.
Hampton’s Hump
– A triangular or rounded pleural-based infiltrate
with the apex toward the hilum, usually located
adjacent to the hilum.
19
21. Diagnostic Testing
- CXR’s
Chest X-Ray Myth:
“You have to do a chest x-ray so you can find
Hampton’s hump or a Westermark sign.”
Reality:
Most chest x-rays in patients with PE are
nonspecific and insensitive
21
22. Diagnostic Testing
- CXR’s
Chest radiograph findings in patient with
pulmonary embolism
Result Percent
Cardiomegaly 27%
Normal study 24%
Atelectasis 23%
Elevated Hemidiaphragm 20%
Pulmonary Artery Enlargement 19%
Pleural Effusion 18%
Parenchymal Pulmonary
Infiltrate 17%
22
23. Diagnostic Testing
- Pulse Oximetry
The Pulse Oximetry Myth:
– “ You must do a pulse oximetry reading, since
patients with pulmonary embolism are hypoxemic!”
Reality:
– Most patients with a PE have a normal pulse
oximetry, and most patients with an abnormal pulse
oximetry will not have a PE.
23
24. Diagnostic Testing
- ABG’s
The ABG/ A-a Gradient myth:
– “You must do an arterial blood gas and calculate the alveolar-
arterial gradient. Normal A-a gradient virtually rules out PE”.
Reality:
– The A-a gradient is a better measure of gas exchange than the
pO2, but it is nonspecific and insensitive in ruling out PE.
24
25. So What Do We Do ???
Confusing for Emergency Physician
Do we under diagnose/over diagnose?
Why don’t we have a standardized method of work
up after all these years?
25
26. Ventilation/Perfusion Scan
- “V/Q Scan”
A common modality to image the lung.
Relatively noninvasive and sadly most often
nondiagnostic!
In many centers it remains the initial test of
choice
Preferred test in pregnant patients
50 mrem vs 800mrem (with spiral CT)
26
27. Spiral (Helical) Chest CT
Advantages
– Noninvasive and Rapid
– Alternative Diagnosis
Disadvantages
– Costly
– Risk to patients with borderline renal function
– Hard to detect subsegmental pulmonary emboli
27
29. Pulmonary Angiography
“Gold Standard”
– Performed in an Interventional Cath Lab
Positive result is a “cutoff” of flow or intraluminal
filling defect
“Court of Last Resort”
29
30.
31. Antithrombotic Therapy: Choices
Nonpharmacologic Pharmacologic
(Prophylaxis) (Prophylaxis & Treatment)
Intermittent Elastic Unfractionated Low Molecular
Pneumatic Stockings Heparin (UH) Weight Heparin
Compression (LMWH)
Inferior
Vena Cava Oral
Filter Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
32. ASCO Guidelines
1. Should hospitalised cancer patients receive
anticoagulation for VTE prophylaxis?
2. Should ambulatory cancer patients receive prophylactic
anticoagulation during systemic chemotherapy for VTE?
3. Should patients with cancer undergoing surgery receive
peri-op prophylaxis?
4. What is the best method to treat patients with cancer
with VTE to prevent recurrence?
5. Should patients with cancer receive anticoagulation in
the absence of established VTE to improve survival?
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
33. VTE Prophylaxis Is Underused
in Patients With Cancer
Cancer: Major
100 FRONTLINE Survey1— Surgery2
3891 Clinician
89
90 Respondents
Rate of Appropriate Prophylaxis, %
80
Cancer:
70 Surgical Major Confirmed DVT
ABDominothoracic (Inpatients)5
60 Medical
52 Surgery (Elderly)3
Inpatients4
50
42
40 38
Cancer: 33
30 Medical
20
10 5
0
FRONTLINE FRONTLINE: Stratton Bratzler Rahim DVT FREE
Surgical Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 4. Rahim SA et al. Thromb Res. 2003;111:215-219
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
34. PREVENTION OF DVT IN SURGICAL
PATIENTS
7 fold risk of post-op DVT and 54 fold in first three
months
Risk of VTE as high as 50% without prophylaxis
If LMWH/UFH 7-10 days post-op VTE risk -15% and
bleeding risk is 4%
UFH vs LMWH? No difference in efficacy
15% develop DVT inspite of either
S/c fondaparinux –equivalent efficacy and low incidence of
hit
Graduated Compression Stockings(GCS) and Intermittent
Pneumatic Compression (IPC) devices can be used as an
adjunct but not as a primary prophylaxis unless ACGs are
contraindicated
35. Incidence of VTE in Surgical
Patients
Cancer patients have 2-fold risk of post-operative DVT/PE
and >3-fold risk of fatal PE despite prophylaxis:
No Cancer Cancer
P-value
N=16,954 N=6124
Post-op VTE 0.61% 1.26% <0.0001
Non-fatal PE 0.27% 0.54% <0.0003
Autopsy PE 0.11% 0.41% <0.0001
Death 0.71% 3.14% <0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
36. ENOXACAN II STUDY
ENOXAPARIN
SAME UPTO 31DAYS
40MG/D SC OD FOR
POST OP
FIRST 10D POST-OP
12% DVT
4%
INCIDENCE
3.6% BLEEDING
4.7%
INCIDENCE
8th ACCP GUIDELINES RECOMMENDS EXTENDED LMWH IN CANCER
SURGERY PTS
ENOXACAN Study Group. Br J Surg 1997;84:1099–103
37. Extended Prophylaxis in
Surgical Patients
15%
Incidence of Outcome Event
12.0%
ENOXACAN II
10%
P=0.02 placebo
N=167
5.1% enoxaparin 40 mg
4.8%
5% 3.6% N=165
1.8%
0.6% 0% 0.4% NNT = 14
0%
VTE Prox Any Major
DVT Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
38. SOME SPECIAL SCENARIOS
Prophylaxis in laparascopic surgery-no consensus
CNS tumors and neurosurgery pts-both thrombosis
and bleeding risk high
Extremely cautious use of ACGs and the decision to start
anticoagulation rests with the treating oncologist
Some consider it an absolute contraindication
39. PROPHYLAXIS IN CVC
None of the ACGs are beneficial
Thrombosis rates were similar with or without ACG
but risk of bleeding was high for pts on ACG
Placebo vs. anticoagulants?-No difference
SO 8TH ACCP CONSENSUS guidelines-no routine
prophylaxis to prevent thrombosis secondary to
central venous catheters, including LMWH and fixed-
dose warfarin
40. TREATMENT OF CVC THROMBOSIS
Remove the catheter
Follow the same guidelines as for DVT in any other site
Decisions about duration, dose etc., of therapy rests
with treating oncologist
41. PROPHYLAXIS IN MEDICAL
ONCOLOGY
In myeloma patients receiving thalidomide+dexa
and/or doxorubicin
The reason is not fully understood
NCCN recommends prophylaxis but no clear cut
regimens so far
ACCP –Assume that all inpatients on
chemo/chemoradiation/hormone therapy are at high
risk for VTE and should be considered for ACGs
42. AMBULATORY PATIENTS ON
CHEMO
ACG not routinely recommended(no studies till now)
special consideration for prophylaxis
Prechemo platelet>350000
GIT,lung and lymphoid malignancies
Anemic pts on epoeitin
43. IVC FILTERS
Used if ACGs C/I or in recurrent VTE
Invasive procedure and requires expertise
Paradoxically risk of thrombosis is high
Usually considered as a last resort for recurrent VTE
44. TREATMENT OF DVT
INITIAL TREATMENT
LMWH vs. UFH ?- equivalent efficacy
Fondaparinux – equivalent to LMWH in efficacy but no
RCTs in cancer patients
1 mg/kg BD vs 1.5 mg/kg OD enox?
Recurrence rate 6.4% in BD and 12.2% in OD
OD dosing is approved for inpatients and BD is
preferred for outpatients
45. HOW TO INITIATE THERAPY?
UFH/LMWH ONLY OR WITH WARFARIN
OVERLAP
OVERLAP HEPARIN AND
WARFARIN TILL 2 PT INR VALUES
24 HRS APART ARE IN THE RANGE
OF 2-3 (usually first 5 days)
STOP HEPARIN AND CONTINUE
WARFARIN OR CONTINUE LMWH
FOR MINIMUM 6 MONTHS
REASSESS PERIODICALLY AND CONSIDER
DISCONTINUATION
46. CLOT: Landmark Cancer/VTE Trial
Dalteparin Dalteparin
CANCER PATIENTS WITH ACUTE
DVT or PE Randomization
[N = 677] Dalteparin Oral Anticoagulant
► Primary Endpoints: Recurrent VTE and Bleeding
► Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
47. Landmark CLOT Cancer Trial
Reduction in Recurrent VTE
25 Risk reduction = 52%
Recurrent VTE p-value = 0.0017
Probability of Recurrent VTE, %
20
15 OAC
10
Dalteparin
5
0
0 30 60 90 120 150 180 210
Lee, Levine, Kakkar, Rickles et.al. N Days Post Randomization
Engl J Med, 2003;349:146
48. Bleeding Events in CLOT
Dalteparin OAC P-value*
N=338 N=335
Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27
Any bleed 46 (13.6%) 62 (18.5%) 0.093
* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
49. THE LITE TRIAL(LONG TERM
INNOVATIONS IN TREATMENT)
INITIAL UFH INITIAL
AND THEN TINZAPARIN
WARFARIN 175IU/KG/DAY
CONTINUE
CONTINUE DALTEPARIN FOR
THREE MONTHS
WARFARIN AND SHIFT TO
WARFARIN
AFTER 16% 7%
1 YEAR RECURRENCE RECURRENCE
•N=200 CANCER PATIENTS
•BLEEDING COMPLICATIONS COMPARABLE IN BOTH ARMS
50. DURATION OF TREATMENT
Usually six months for responsive patients without
active cancer or metastatic disease
For patients with active malignancy and metastatic
disease duration is based on the treating physician’s
opinion
If patients tolerate continue LMWH/warfarin
51. THROMBOLYSIS
Used in PE with severe hemodynamic instability
Severe DVT leading to arterial insufficiency
Clinically significant thrombus extension
To maintain patency of occluded CVC
52. SIDE EFFECTS OF LONG TERM
TREATMENT
Bleeding
Decreased bone density –LMWH
Fetal warfarin syndrome
Drug interactions
ACCP recommends LMWH for long term therapy
53. CONTRAINDICATIONS FOR
ANTICOAGULATION
Major active bleed- only absolute contraindication
Recent CNS bleed;recent craniotomy
Bleeding diathesis
Paraspinal tumours
CNS tumors
54. RECURRENCE OF VTE
No guidelines for optimal treatment
Trial evidence lacking for duration of therapy
55. Cancer, clots and consensus
1. Should hospitalised cancer patients receive
anticoagulation for VTE prophylaxis? yes
2. Should ambulatory cancer patients receive prophylactic
anticoagulation during systemic chemotherapy for
VTE?no
3. Should patients with cancer undergoing surgery receive
peri-op prophylaxis? yes
4. What is the best method to treat patients with cancer
with VTE to prevent recurrence? LMWH
5. Should patients with cancer receive anticoagulation in
the absence of established VTE to improve survival? no
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
56. THE JIPMER CONSENSUS
PT INR EVERY
HISTORY/CLINI PT INR
14D FOR A
CAL EXAM --- MONTHLY FOR
MONTH OR
DVT SIX MONTHS
TWO
IF WITHIN
INFORM SOS IF
COMPRESSION TARGET
MAJOR ACTIVE
USG RANGE(ABOVE
BLEED
1.8)
WARN ABOUT
TWICE WEEKLY
LMWH FOR 3D DRUG
PT INR
INTERACTIONS
WARFARIN FOR STABILISE WITH CONSIDER
3D WITH WARFARIN INR PROLONGED
OVERLAP 2-3 (above 1.8) THERAPY?
57. WHERE ALL CAN WE GO WRONG?
PT INR monitoring and target range
Warfarin drug interactions
Warfarin step up dose
Missing a PE
Missing occult bleed-e.g. melaena
Restarting Rx after major bleed-weigh the risk vs.
Benefit
Follow up and patient education
Lab limitations
