Venous thromboembolism (VTE) is common in patients with malignancy and carries a high risk of morbidity and mortality. Approximately 15% of cancer patients will develop symptomatic VTE, and VTE is the second leading cause of death among hospitalized cancer patients. The risk of VTE is increased by certain tumor types, advanced stage, chemotherapy, and surgery. The pathophysiology involves stasis, endothelial injury, and a hypercoagulable state induced by tumor-derived procoagulants and cytokines. Prevention includes pharmacological prophylaxis with low molecular weight heparin for high-risk patients. Treatment of VTE involves initial parenteral anticoagulation followed by long-term therapy typically

1. VENOUS THROMBOEMBOLISM IN
MALIGNANCY PATIENT
MUSTAKIM.MD
Resident at Clinical Pathology Division Hasanuddin University
Makassar, Indonesia

2. CONTENTS
CONTENT
INTRODUCTION
PREVENTION
EPIDEMIOLOGY
AND RISK FACTOR
PATOPHYSIOLOGY
TREATMENT
PROGNOSIS
SUMMARY

3. Thrombosis is a general term for
the formation or presence of a
thrombus (a clot of coagulated
blood) in a blood vessel
Thrombus can develop in
vein,artery,heart &
microcirculation
Thrombosis is much more
prevalent in patients
w/malignancy & predominantly
of the venous circulation

4. 1823
Bouillard;
recognised
deep vein
Thrombosis
in patients
w/malignancy
1865
Armand Trousseau
Describing the
relationship
between VTE
& malignancy

5. Occult cancer
in patients w/
idiopathic venous
thromboembolism
Thrombophlebitis
in patients
w/ malignancy
TROUSSEAU
SYNDROME

6. CONTENTS
CONTENT
INTRODUCTION
PREVENTION
EPIDEMIOLOGY
AND RISK
FACTOR
PATOPHYSIOLOGY
TREATMENT
PROGNOSIS
SUMMARY

7. VTE and malignancy : Epidemiology
• Of all cases of VTE:
– About 18% occur in malignancy patients
– About 10-17% patients ,in which no underlying cause
of VTE, will go on to have the diagnosis of a new
malignancy within two years
• Of all patients w/ malignancy
– 15% will have symptomatic VTE
– As many as 30- 50% have VTE at autopsy
• Compared to patients without malignancy:
– Higher risk of first and recurrent VTE (about 7- fold
increased )
– In certain malignancy risk for VTE increased 28-fold

8. VTE AND RISK FACTOR
PATIENT RELATED FACTOR
Age,sex,ethnicity,comorbid condition &
prothrombotic mutation
TUMOR RELATED FACTOR
type, site, stage & duration of malignancy

9. VTE AND RISK FACTOR ( CONT…)
TREATMENT RELATED FACTOR
 Pharmacologic therapy
 Chemotherapeutic agent


10. Predictive model for chemotherapy associated
VTE

11. VTE AND RISK FACTOR ( CONT…)
TREATMENT RELATED FACTOR
 Hormonal agent
 Antiangiogenic agent
 Erythropoiesis-stimulating agent
Mechanical therapy


12. CONTENTS
I. INTRODUCTION
II.EPIDEMIOLOGY AND RISK FACTOR
III.PATOPHYSIOLOGY
IV.PREVENTION
V.TREATMENT
VI.PROGNOSIS
VII.SUMMARY

14. Pathogenesis of Thrombosis in malignancy
patient
1.
Stasis
A Modification of Virchow’s Triad
– Prolonged bed rest
– Extrinsic compression of blood vessels by tumor
2. Vascular Injury
– Direct invasion by tumor
– Prolonged use of central venous catheters
– Endothelial damage by chemotherapy drugs
– Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability
– Tumor-associated procoagulants & cytokines (tissue
factor, CP, TNF , IL-1 , VEGF, etc.)
– Impaired endothelial cell defense mechanisms (APC
resistance; deficiencies of AT, Protein C and S)
– Enhanced selectin/integrin-mediated, adhesive
interactions between tumor cells,vascular endothelial
cells, platelets & host macrophages

15. VTE: PATHOPHYSIOLOGY Cont…….
 The PRINCIPAL prothrombotic properties
of tumor cell :
Capacity of tumor cell to interact w/ host
blood cells; endothelial, leukocytes &
platelet.
Capacity of tumor cell to produce & release
its own procoagulant & fibrinolytic activities,
beside proinflammatory cytokines

16. Tumor cells
Angiogenesis,
Basement
matrix
degradation.
Fibrinolytic
activities:
t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant
Activities
IL-1, TNFVEGF
PMN leukocyte
Activation of
coagulation
FIBRIN
Platelets
Monocyte
Endothelial cells

18. CONTENT
I. INTRODUCTION
II.EPIDEMIOLOGY AND RISK FACTOR
III.PATOPHYSIOLOGY
IV.PREVENTION
V.TREATMENT
VI.PROGNOSIS
VII.SUMMARY

19. VTE : PREVENTION
PRIMARY PREVENTION
AMBULATORY PATIENT W/ CHEMOTHERAPY
MEDICAL INPATIENT W/ CHEMOTHERAPY
MALIGNANCY PATIENT W/ SURGERY

20. • Ambulatory Patient with Chemotherapy
NCCN Recommended VTE prophylaxis in
high risk setting :
Patient receiving highly thrombotic
antiangiogenic therapy (i.e., thalidomide/
lenalidomide in combination w/ high dose
dexamethasone
Myeloma patients w/ 2 or more
individual or myeloma risk factors

21. Ambulatory Patient (Cont….)
Modality for prophylaxis:
 Low dose warfarin (1mg
for 6 weeks ) adjusted to INR
1,3-1,9
Enoxaparin 1mg/kg SC
every 24 hour for at least 3
months.
Apixaban

22. VTE : PREVENTION
PRIMARY PREVENTION
AMBULATORY PATIENT W/ CHEMOTHERAPY
MEDICAL INPATIENT W/ CHEMOTHERAPY
CANCER SURGERY PATIENT

23. Medical Inpatient with chemotherapy
NCCN recommended :
• Enoxaparin, 40 mg sc daily
• Tinzaparin, 4500 units (fixed dose) sc daily or
75 units/kg sc daily
• Dalteparin, 5000 units sc daily
• Fondaparinux ; 2.5 mg sc daily
• Unfractionated heparin:5000 units sc 3 times
daily
• Warfarin (adjusted to INR 2-3)

24. VTE : PREVENTION
PRIMARY PREVENTION
AMBULATORY PATIENT W/ CHEMOTHERAPY
MEDICAL NPATIENT W/ CHEMOTHERAPY
MALIGNANCY PATIENT W/ SURGERY

25. CANCER SURGERY INPATIENT
Mechanical prophylaxis
•
•
•
•
electrical calf stimulation
intermitten pneumatic compression devices
graduated compression stocking
venous foot pump devices

26. Malignanct inpatient w/ surgery ( cont…)
pharmacological
• Modality prophylaxis for malignancy
patient w/ surgery is not
significantly different w/ medical in
patient w/ chemotherapy

27. VTE PREVENTION
SECONDARY PREVENTION
Warfarin
●Difficulty maintaining tight therapeutic
control, due to anorexia, vomiting, drug
interactions
●Frequent interruptions for
thrombocytopenia & procedures
●Difficulty in venous access for
monitoring
● Increased risk of both recurrence &
bleeding
Low molecular weight heparin

28. CONTENT
I. INTRODUCTION
II.EPIDEMIOLOGY AND RISK FACTOR
III.PATOPHYSIOLOGY
IV.PREVENTION
V.TREATMENT
VI.PROGNOSIS
VII.SUMMARY

29. THERAPY
Goals therapy
(1)Preventing fatal PE
(2) Reducing short-term morbidities
associated w/ acute leg or lung
thrombus
(3) Preventing recurrent VTE
(4) Preventing the long-term sequelae of
VTE

30. VTE in Cancer : Therapy
Anticoagulant Therapy
Acute Management
 Dalteparin (200 units/kg subcutaneous daily
Enoxaparin (1 mg/kg subcutaneous every 12
hours) (4-5 days,continuated with warfarin if INR
>2,0.
Tinzaparin :175 u/kg sc daily
 Fondaparinux (5 mg [< 50 kg]; 7.5 mg [50-100 kg];
10 mg [> 100 kg] subcutaneous daily)
 Unfractionated Heparin : 5000 IU load,or 80 U/kg
load, then 18 U/kg/h (aPTT 0f 2-2,5Xcontrol)

31. Therapeutic Anticoagulation Failure
Therapeutic
INR
Patient
on
warfarin
Switch to heparin
(LMWH preferred)
or fondaparinux
Check
INR
Subtherapeutic
INR
Increase warfarin dose
and treat with
parenteral agent until
INR target achieved or
consider switching to
heparin (LMWH
preferred) or
fondaparinux

32. Therapeutic Anticoagulation Failure
Therapeutic
aPTT
Patient
on
heparin
Increase dose of heparin or
Switch to LMWH or Switch
to fondaparinux&Consider
placement of IVC filter &
Consider HIT
Check
aPTT
levels
Subtherapeutic
aPTT
Increase dose of heparin
to reach therapeutic
level

33. CONTENT
I. INTRODUCTION
II.EPIDEMIOLOGY AND RISK FACTOR
III.PATOPHYSIOLOGY
IV.PREVENTION
V.TREATMENT
VI.PROGNOSIS
VII.SUMMARY

34. PROGNOSIS
►Survival after VTE is lower than expected in
malignancy patients.
►VTE : 2nd most common cause of death in
hospitalized patients w/ malignancy(tied
with infection)
►Survival among active cancer patients with
VTE differs by gender.

35. CONTENT
I. INTRODUCTION
II.EPIDEMIOLOGY AND RISK FACTOR
III.PATOPHYSIOLOGY
IV.PREVENTION
V.TREATMENT
VI.PROGNOSIS
VII.SUMMARY

36. SUMMARY
►VTE : 2nd most common cause of death
in hospitalized malignancy patient
► Risk factors for VTE in the setting of
malignancy have been well characterized:
solid tumors, chemotherapy, surgery,
thrombocytopenia
► Long-term secondary prevention w/ LMWH
has been shown to produce better outcomes
than warfarin
► malignancy patients are under-prophylaxed
for VTE

37. SUMMARY (Cont….)
 Effective VTE prophylaxis in malignancy
patients usually requires anticoagulation
w/ LMWH but when bleeding risk is too
high, use mechanical measures.
 VTE prophylaxis in malignancy patients is
under-utilized & requires increased
vigilance and prophylaxis-focused
intervention

38. that
THANK
YOU

43. Trombosis lebih sering pada vena dibanding
arteri because:
• Aliran darah pada vena lebih lambat
dibandingkan arteri.
• Trombus pada arteri : trombus putih karena
terdiri dari trombin bersifat lebih kuat tidak
mudah lepas,pada vena trombus merah
terbentuk dari fibrin mudah lepas menjadi
emboli.

44. • APC resistance = Activated Protein C resisten
adalah kegagalan protein C aktiv merubah FVa
menjadi FV,sehingga FVa menjadi bertumpuk
yang memudahkan trombosis.