1. PRESENTER:DR.SATHISH,JR,RT
MODERATOR:DR.SHYAMA(ASSISTANT PROFESSOR
OF RADIOTHERAPY)

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

4. PATHOPHYSIOLOGY
 VIRCHOW’S TRIAD
VESSEL
STASIS INJURY
HYPERCOAGULABILITY

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

13. Post-thrombotic syndrome
 Pain
 Oedema
 Discoloration
 Varices
 Ulceration
Symptoms of post-thrombotic syndrome – long
“lag-phase” (years)

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

17. Clinical Features
Symptoms in Patients with Angio Proven PTE
Symptom Percent
Dyspnea 84
Chest Pain, pleuritic 74
Anxiety 59
Cough 53
Hemoptysis 30
Sweating 27
Chest Pain, nonpleuritic 14
Syncope 13
17

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

20. Radiographic Eponyms
- Hampton’s Hump, Westermark’s Sign
Westermark’s Sign
Hampton’s Hump
20

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

28. CT revealing emboli in pulmonary artery.

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

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

58. THANK YOU