VENOUS THROMBOEMBOLISM IN MALIGNANCY PATIENT

MUSTAKIM.MD

Resident at Clinical Pathology Division Hasanuddin University

Makassar, Indonesia

CONTENTS

INTRODUCTION

EPIDEMIOLOGY AND RISK FACTOR

PATOPHYSIOLOGY

PREVENTION

TREATMENT PROGNOSIS

SUMMARY

CONTENT

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

Armand TrousseauDescribing the relationship between VTE & malignancy

Bouillard;recognised deep vein

Thrombosis in patients

w/malignancy

1823 1865

TROUSSEAU SYNDROME

Occult cancer in patients w/

idiopathic venous thromboembolism

Thrombophlebitis in patients

w/ malignancy

CONTENTS

INTRODUCTION

EPIDEMIOLOGY AND RISK FACTOR

PATOPHYSIOLOGY

PREVENTION

TREATMENT PROGNOSIS

SUMMARY

CONTENT

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

VTE AND RISK FACTOR

Age,sex,ethnicity,comorbid condition & prothrombotic mutation

type, site, stage & duration of malignancy

PATIENT RELATED FACTOR

TUMOR RELATED FACTOR

VTE AND RISK FACTOR ( CONT…)

Pharmacologic therapy Chemotherapeutic agent

TREATMENT RELATED FACTOR

Predictive model for chemotherapy associated VTE

VTE AND RISK FACTOR ( CONT…)

Hormonal agent Antiangiogenic agent Erythropoiesis-stimulating agent

Mechanical therapy

TREATMENT RELATED FACTOR

CONTENTSI. INTRODUCTION

II.EPIDEMIOLOGY AND RISK FACTOR

III.PATOPHYSIOLOGY

IV.PREVENTION

V.TREATMENT

VI.PROGNOSIS

VII.SUMMARY

Pathogenesis of Thrombosis in malignancy patientA Modification of Virchow’s Triad

1. Stasis– 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

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

Fibrinolytic activities:t-PA, u-PA, u-PAR, PAI-1, PAI-2

Procoagulant Activities

FIBRIN

Endothelial cells

IL-1, TNF-, a VEGF

Tumor cells

Monocyte

PMN leukocyte

Activation of coagulation

Platelets

Angiogenesis,Basement matrix degradation.

CONTENTI. INTRODUCTION

II.EPIDEMIOLOGY AND RISK FACTOR

III.PATOPHYSIOLOGY

IV.PREVENTION

V.TREATMENT

VI.PROGNOSIS

VII.SUMMARY

VTE : PREVENTION

AMBULATORY PATIENT W/ CHEMOTHERAPY

MEDICAL INPATIENT W/ CHEMOTHERAPY

MALIGNANCY PATIENT W/ SURGERY

PRIMARY PREVENTION

• 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 dexamethasoneMyeloma patients w/ 2 or more individual or myeloma risk factors

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

VTE : PREVENTION

AMBULATORY PATIENT W/ CHEMOTHERAPY

MEDICAL INPATIENT W/ CHEMOTHERAPY

CANCER SURGERY PATIENT

PRIMARY PREVENTION

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)

VTE : PREVENTION

AMBULATORY PATIENT W/ CHEMOTHERAPY

MEDICAL NPATIENT W/ CHEMOTHERAPY

MALIGNANCY PATIENT W/ SURGERY

PRIMARY PREVENTION

CANCER SURGERY INPATIENT

• electrical calf stimulation• intermitten pneumatic compression devices• graduated compression stocking• venous foot pump devices

Mechanical prophylaxis

Malignanct inpatient w/ surgery ( cont…)

• Modality prophylaxis for malignancy patient w/ surgery is not significantly different w/ medical in patient w/ chemotherapy

pharmacological

VTE PREVENTIONSECONDARY 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 &

bleedingLow molecular weight heparin

CONTENTI. INTRODUCTION

II.EPIDEMIOLOGY AND RISK FACTOR

III.PATOPHYSIOLOGY

IV.PREVENTION

V.TREATMENT

VI.PROGNOSIS

VII.SUMMARY

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

Goals therapy

VTE in Cancer : 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)

Anticoagulant Therapy

Therapeutic Anticoagulation Failure

Therapeutic INR

Switch to heparin (LMWH preferred)

or fondaparinux

Increase warfarin dose and treat with

parenteral agent until INR target achieved or consider switching to

heparin (LMWH preferred) or fondaparinux

Patient on

warfarin

Check INR

Sub-therapeutic

INR

Therapeutic Anticoagulation Failure

Therapeutic aPTT

Increase dose of heparin or Switch to LMWH or Switch to fondaparinux&Consider placement of IVC filter & Consider HIT

Increase dose of heparin to reach therapeutic

level

Patient on

heparin

Check aPTT levels

Sub-therapeutic

aPTT

CONTENTI. INTRODUCTION

II.EPIDEMIOLOGY AND RISK FACTOR

III.PATOPHYSIOLOGY

IV.PREVENTION

V.TREATMENT

VI.PROGNOSIS

VII.SUMMARY

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.

CONTENTI. INTRODUCTION

II.EPIDEMIOLOGY AND RISK FACTOR

III.PATOPHYSIOLOGY

IV.PREVENTION

V.TREATMENT

VI.PROGNOSIS

VII.SUMMARY

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

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

thatTHANK YOU

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.

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