U.O.D Ematologia Prof.ssa L. Annino IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA.

U.O.D Ematologia

Prof.ssa L. Annino

IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA

NUOVA TEORIA DELLA COAGULAZIONE

IX IXa

TISSUE FACTOR (Tromboplastina)VII/VIIa

Ca

VIIIaPLCA

protrombina trombina

X XaVaPLCA

VIA INTRINSECA

TFTF TFTF TF TF TF TFTFTF TFTF TF TFTF TF

ATTIVAZIONE DELLA TROMBINA

X+V

IX+VIII TF+VIIa

TROMBINA

TF

TF TF

TF PAR TMPC PCa MONONUCLEATO

PAR

IIaTFPAR

FIBRINOGENO FIBRINA

V IXa

VIII XaPIASTRINA

CELL. ENDOTELIALE

V

IXIXaVIIa

V

VIII

IX

IXa

VIIa

Xa


PAR 2 PAR 1 PAR 3 PAR 4

TF

VIIa

TF

VIIaXa

ANGIOGENESI

VEGFPROTEINASI

VEGFPGFHIF-1

AGGREGAZIONEPIASTRINICA EMOSTASI

PROTROMBINA TROMBINA EMOSTASI


Predictors of thromboembolic risk

in medical and surgical patients

Clinical setting Patient risk factors

Clinical Molecular Inherited Acquired

Type/duration of surgery

Type of anaesthesia Stroke MI

Congestive heart failure

Chest infection Intensive care Spinal cord injury Multiple trauma

Previous VTE Varicose veins Malignancy Age > 70 Obesity Prolonged bed rest Level of hydration Severe medical

illness Infection/sepsis Pregnancy/ puerperium

Combined oral contraceptive

Factor V Leiden Prothrombin 20210A mutation Deficiencies: Antithrombin III Protein C Protein S

Lupus anticoagulant

Anticardiolipin antibodies Myeloproliferativedisease

Hyperhomocystei-naemia

Hyperhomocystei-naemia

Classification of level of VTE risk in

surgical patients(6th ACCP Consensus Conference on Antithrombotic Therapy)

Low risk Moderate risk High risk Highest risk

Minor surgery Major surgery Major surgery Major surgery in patientsin patients in patients in patients >40 years plus:<40 years, no risk <40 years, >40 years, Previous VTEfactors no other additional risk Malignancy

risk factors factors or MI Hip or knee surgery Stroke or spinal cord

Minor surgery Non-major injuryand risk surgery in Hip fracturefactors patients Major trauma

>60 years, Hypercoagulable stateNon-major or withsurgery additionalin patients risk factorsaged40-60 years

Geerts et al. Chest 2001

Markers for specific risk classifications

High-risk markers thrombophilia; age >60 years; history of

DVT/PE (certain patients) Moderate-risk markers

age 40–60 years (certain patients) Low-risk markers

age <40 years (in absence of other risk factors)

Nicolaides et al. Int Angiol 1997

Definition of thromboembolicrisk categories

Category Calf-vein Proximal Fatal PE (%) thrombosis (%) vein thrombosis (%)

High risk 40-80 10-30 > 1

Moderate risk 10-40 1-10 0.1-1

Low risk < 10 < 1 < 0.1

Modified from Salzman and Hirsh. In: Colman RW et al, eds. Hemostasis and thrombosis; basic principles and clinical practice. New York: Lippincott, 1982

Nicolaides AN et al. Int Angiol 1997

PE, pulmonary emobolism

Frequency of VTE without prophylaxis

Surgical risk-assessment model from the Paris public assistance hospitals

Chapuis et al. Sang Thromb Vaiss 1995

General/digestive surgery Structure of risk-assessment model

Risk associated Risk Risk associatedwith surgery level with patient

Less than 45 min, 1 No risk factorsno dissection

Moderate dissection, 2 Age >40 years less than 45 min confined to bed >4 days Complicated appendectomy Varicose veins, obesity Inflammatory GI disease

Neoplastic surgery 3 Actual/developing cancer

Previous thromboembolismThrombophilia

Paris public assistance hospitals’recommendations for general surgery

Chapuis et al. Sang Thromb Vaiss 1995

Low

High

Moderate

1

2

3

2

1

3

Surgical risk + Patient risk = Thromboembolic Recommended factors factors risk therapeutic regimen

No treatment

LMWH, UFHor graduated compression stockings (GCS)

LMWH + GCS orUFH + GCS

1

2

3

1

2

3

Laparoscopic surgery and thrombosis

Pneumoperitoneum haemodynamic changes:

Increase in the venous pressure distal to the obstacle Decrease in the blood flow Decrease in the blood venous return in lower limbs

Duration of surgery

Reverse Trendelenburg position

THROMBOSIS


Catheline JM, Int. Surg. Investig. 2000; 2(1):41-47

Thromboembolism prophylaxis and incidence of thromboembolic complications of laparoscopic surgery

Non-oncologic surgery: 2384 pts

8 DVT (0.33%)0 PE




8 DVT

6 Trendelenburg > 1h

Trendelenburg > 3h2




In 6/8 cases the DVT occurs:

after cessation of LWMH delivery after discharge at home before post-operative day 10

Cellula tumorale

Tissue FactorProcoagulant protein

Attività fibrinoliticaT-PA,u-PA,,u-ParTf, PAI-1, PAI-2

Molecole diadesione

Effetto diretto

IL 1, TNF, VEGF

Effetto indiretto

TF PAR TMPC PCa MONONUCLEATO

PAR

IIaTF

FIBRINOGENO FIBRINA

PAR

V IXa

VIII XaPIASTRINA

CELL. ENDOTELIALE

V

IXIXaVIIa

V

VIII

IX

IXa

VIIa

Xa

TF

PC

VIIa

IFNIL 1

CELL. NEOPLASTICA

Complex Relation Between Cancer and VTE

VTE occult cancer Cancer increased risk of VTE

- peri-operatively - in non-surgical patients

Cancer resistance to prophylaxis and treatment

Cancer central catheter thrombosis

Thrombopathogenetic Factorsin Cancer Patients

Hypercoagulability TF expression Endothelial damage tumour invasion,

chemotherapy, radiation, catheters, host response

Platelet dysfunction activation, thrombocytosis

Venous stasis venous obstruction,immobility, increasedblood viscosity

TF, tissue factor

Embolia Polmonare e Mortalità

2a causa di morte nel paziente oncologico

20% delle TVP Paziente con TVP e tumore:

Mortalità a 6 mesi elevata, 3 Mortalità a 6 mesi elevata, 3 volte maggiore di quelli senza volte maggiore di quelli senza tumore e non sempre correlata tumore e non sempre correlata alla gravità del cancroalla gravità del cancro

Hillen HFP: Ann Oncol 2000Hillen HFP: Ann Oncol 2000Levitan et al, Medicine 1999Levitan et al, Medicine 1999Shen & Pollock South Med J 1980Shen & Pollock South Med J 1980

Tasso di trombosi in pazienti neoplastici

Correlazioni

Levitan et al 1999Levitan et al 1999

98

81 7661

110117120

0

20

40

60

80

100

120

140

Ovaio Encefalo Pancreas LinfomaLeucemiaColonPolmone

Tasso di tromboembolismo in base alla localizzazione del tumore

Tasso/10.000 pazienti

Cancer and Post-operative VTE

More extensive surgery Venous trauma Prothrombotic haemostasis Chemotherapy Radiation Indwelling vascular lines Prolonged immobilization

Flordal PA et al. Eur J Surg 1996;162:783–9.

Independent Risk Factors for Major Post-operative Thromboembolism

2,070 patients undergoing elective abdominal surgery

Risk factor OR P Prevalence(%)

Malignant disease 1.7 <0.05 66Duration of surgery >150 min 1.4 <0.05 35Pre-op hospital stay 6 days 1.6 <0.02 24Previous major orthopaedic

event 1.7 <0.02 12Pre-op transfusion >1 unit 2.0 <0.01 7Previous thromboembolism 1.7 <0.04 6Leg ulcer 4.2 <0.001 0.5

Br J Surg 1997;84:1099–103.

ENOXACAN Study

Efficacy and safety of enoxaparin versus unfractionated heparin for

prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial

with venographic assessment

Br J Surg 1997;84:1099–103.

ENOXACAN Study Prophylaxis of VTE in Abdominal

and Pelvic Cancer Surgery

631 evaluable patients

UFH Enoxaparin(n=319) (n=312)

Overall 58 (18.2%) 46 (14.7%)DVT only 56 45PE + DVT 2 0Death 0 1

ENOXACAN Study Blood Loss and Haemorrhagic

Complications 1,115 patients

UFH Enoxaparin(n=560) (n=555)

Intra-op bleeding (ml), median (range) 500 (11–9,670) 500 (22–7,000)

Post-op bleeding (ml), median (range) 434 (2–11,250) 385 (2–6,520)

Major bleeding, n (%) 16 (2.9) 23 (4.1)Discontinued prophylaxis,

n (%) 12 (2.1) 18 (3.2)Injection-site haematoma,

n (%) 11 (2.0) 6 (1.1)

Br J Surg 1997;84:1099–103.

Duration of Thromboprophylaxis

1 weekor

1 monthor?

Ris

k o

f V

TE

Surgery Discharge

Time

?

Risk of VTE over Time

Reasons for Prolonged Prophylaxis

Late DVT Late fatal PE Impaired haemodynamics Proximal-vein injury Poor post-discharge mobilization Change in clinical routines Commercial interests

ENOXACAN II

Duration of prophylaxis against venous thromboembolism with

enoxaparin after surgery for cancer

Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

Inclusion Criteria

Age 40 years Life expectancy 6 months Open, elective, curative

surgery Abdominal/pelvic cancer Duration of surgery 45 min General anaesthesia


Primary Endpoint

Venographically confirmed DVT at Day 28±3

All objectively verified VTE before Day 28±3


Risk Factors at Baseline

Intent-to-treat for efficacy population, n (%) Placebo

Enoxaparin (n=167) (n=165)

History of VTE 4 (2.4) 5 (3.0)Varicose veins 24 (14.4) 17 (10.3)Obesity 23 (13.8) 22 (13.3)Chronic heart failure 6 (3.6) 7 (4.2)Chronic lung disease 4 (2.4) 10 (6.1)Hormone replacement 4 (2.4) 4 (2.4)


Characteristics of Surgical Procedures

Intent-to-treat for efficacy population, n (%) Placebo Enoxaparin

(n=167) (n=165)Location of surgery

Gastrointestinal 137 (82) 141 (86)Gynaecological 11 (7) 17 (10)Urological 17 (10) 11 (7)Others 3 (2) 2 (1)2 sites 11 (7) 9 (6)

Palliative surgery 6 (3.6) 16 (9.7)*Bleeding complications 8 (5) 10 (6)Duration of surgery, h:min 3:05 3:13

median (range) (0:45–11:00) (0:23–9:35)

*P=0.024


Incidence of VTE

Intent-to-treat for efficacy population, n (%)

Placebo Enoxaparin RRR (%) P (n=167) (n=165) (95% CI)In double-blind period

All DVT 20 (12.0) 8 (4.8) 60 (10–82) 0.02Proximal DVT 3 (1.8) 1 (0.6)Distal DVT 17 (10.2) 7 (4.2)PE 1 0

At 3 monthsAll DVT 23 (13.8) 9 (5.5) 60 (17–81) 0.02Proximal DVT 4 (2.4) 2 (1.2)Distal DVT 17 (10.2) 7 (4.2)PE 2* 0

*One fatal

Incidence of Haemorrhage

Placebo Enoxaparin (n=248) (n=253) n (%)

In double-blind period Minor 9 (3.6) 12 (4.7)Major 0 1 (0.4)Total 9 (3.6) 13 (5.1)

At 3 monthsMajor 1 (0.4) 2 (0.8)

Cumulative incidence at 3 monthsMajor 1 (0.4) 3 (1.2)Total 11 (4.4) 18 (7.1)*

*P=0.2


Mortality

Placebo Enoxaparin

(n=167) (n=165)

In double-blind period 0 0At follow-up 6 (3.6%) 3 (1.8%)


EPARINA NON FRAZIONATA

AT III

PROTEINE PLASMATICHE

EPARINA

•SOLO UN TERZO SI LEGA ALL’AT III

•EFFETTO ANTICOAGULANTE NON PREVEDIBILE•TERAPIA CON DOSI PERSONALIZZATE•NECESSARI FREQUENTI ESAMI DI LABORATORIO

PESO MOLECOLARE MEDIO: 15.000 d

EPARINA A BASSO PESO MOLECOLARE

AT III

PROTEINE PLASMATICHE

EPARINA

•ALTA ATTIVITA’ ANTI Xa/BASSA ATTIVITA’ ANTI IIa•MIGLIORE BIODISPONIBILITA’•EMIVITA PIU LUNGA•ATTIVITA’ ANTICOAGULANTE PREVEDIBILE

PESO MOLECOLARE MEDIO: 4.000-5.000 d

PROFILASSI TVP E/O EP

5000 U/ s.c. X 2 o 3 volte/die

EPARINA CALCICA

EPARINE A BASSO PESO MOLECOLARE

ENOXAPARINA 2000-4000 U s.c./dieDALTEPARINA 2500 U s.c./dieNADROPARINA 3000 U s.c./die

•CHIR. NEOPLASTICA•CHIR. ADDOMINALE•CHIR. ORTOPEDICA•SPLENECTOMIA

•APPENDIC. COMPLICATA•CHIR. MALATTIE INFIAMM.COLON /TENUE

•APPENDICECTOMIA•ERNIA INGUINALE•COLECISTECTOMIA

ETA’ < 40aa

ETA’> 40aaALLETTATOOBESITA’POST –PARTUM

CANCROPRECEDENTETVPTROMBOFILIA

PROFILASSI CON:EPARINA NON FRAZIONATAEPARINE A BASSO PESO MOLECOLARE

PROFILASSI PAZIENTI CHIRURGICI

PROFILASSI PAZIENTI NON CHIRURGICI

•ICTUS +PARESI• BPCO CON RESP. MECCANICA

•INFARTO•SCOMPENSO CARDIACO•SEPSI•IMMOBILIZZAZIONE

•CATETERE VENOSO (?)•MALATTIA INFETTIVA

•NO RISCHIO

NO RISCHIO

•V.VARICOSE•TVPFAMILIARE•OBESITA’•PILLOLA

•>65 aa• GRAVIDANZA• S. NEFROSICA

•TROMBOFILIA•TVP PRECED.•CANCRO

PROFILASSI CON:EPARINA NON FRAZIONATAEPARINE A BASSO PESO MOLECOLARE

TERAPIA CON EPARINA SODICA e.v.

TERAPIA TVPTERAPIA EP

TERAPIA DELL’IMA

VANTAGGI:• PER e.v. EFFETTO ANTICOAGULANTE IMMEDIATO• POSSIBILITA’ DI MONITORARE L’EFFETTO ANTICOAGULANTE• BREVE EMIVITA• ESISTENZA DELL’ANTIDOTO

TERAPIA CON EPARINA NON FRAZIONATA

MONITORAGGIO DELL’EFFETTOANTICOAGULANTE

PTT

RANGE TERAPEUTICO:

PTT in secondi paziente

PTT in secondi pool normale=1.5- 2.5

NORMOGRAMMA DI RASCHKE

BOLO DI 5000 U DI EPARINA SODICA EV

IN PAZ A BASSO RISCHIO EMORRAGICO:

1680 U/h (40.000/24 ore)

IN PAZ AD ALTO RISCHIO EMORRAGICO:

1240 U/h (30.000/24 ore)

PRIMO PTT DOPO 6 ORE POI CONTROLLI OGNI 6 ORE

paz. ad alto rischio emorragico:•soggetti > 60 anni•pazienti con gravi patologie intercorrenti di altra natura•pazienti reduci da interventi e/o traumi•alcoolisti•pazienti con storia di emorragia gastrica/ulcera peptica•pazienti con predisposizione emorragica•pazienti con piastrine <150.000/mm3

TERAPIA CON EPARINA NON FRAZIONATA

PTT BOLOEPARINA

SOSPENSIONE VARIAZIONEDOSE EPARINA

<1.2 80 U/Kg + 4 U/kg/h

1.2 - 1.5 40 U/Kg + 2 U/kg/h

1.5 - 2.3

2.3 - 3.0 - 2 U/kg/h

>3 - 3 U/kg/h 1 ora

CONTROLLO DEL PTT OGNI 6 ORE

EPARINA A BASSO PESO MOLECOLARE (LWMH)

INDICAZIONI TERAPEUTICHE

NADROPARINADALTEPARINAENOXAPARINA

TRATTAMENTO DELLA TVP ACUTA

PROFILASSI DELLA COAGULAZIONE IN EMODIALISI

TRATTAMENTO DELL’ANGINA INSTABILE E DELL’IMA NON Q

PROFILASSI DELLA TVP IN CHIRURGIA GENERALE E IN CHIRURGIA ORTOPEDICA

PROFILASSI DELLA TVP IN PAZIENTI NON CHIRURGICI


•NADROPARINA

•ENOXAPARINA

•DALTEPARINA

•ARDEPARINA

•TINZAPARINA

•REVIPARINA

DOSI TERAPEUTICHE NELLA TVP/EP

90U /Kg/ 12 ORE180U /Kg/ 24 ORE

100U /Kg/ 12 ORE

200U /Kg/ 24 ORE

130U /Kg/ 12 ORE

175U /Kg/ 24 ORE

100U /Kg/ 12 ORE


Confronto LWMH /EPARINASTANDARD nella terapia

della TVP e/o EP

• RIDUZIONE RECIDIVE TROMBOEMBOLICHE: 2.7% vs 7%

• RIDUZIONE EVENTI EMORRAGICI MAGGIORI: 0.9% vs 3.2%

• RIDUZIONE MORTALITA’ A LUNGO TERMINE: 4.3% vs 8.1%

INATTIVA:

• 100% EPARINA NON FRAZIONATA(1 mg per 100 U di Eparina)

• 30% ENOXAPARINA• 40% DALTEPARINA• 60% TINZAPARINA

TRATTAMENTODELL’IPERDOSAGGIO DA EPARINA

SOLFATO DI PROTAMINA

PROFILASSI TVP IN PAZIENTI CHIRURGICI

emocromoLWMHLWMH

giornigiorni

-1 1-1 1 2 2 33 4 5 6 4 5 6

INTERVENTO DIMISSIONE

ENOXAPARINA 4000 U s.c./dieDALTEPARINA 2500 U s.c./dieNADROPARINA 3000 U s.c./die

emocromoLWMHLWMH

??

1 mese ?1 mese ?

emocromo

11 22 33 44 55 66 3 a 63 a 6mesimesigiornigiorni

TERAPIA ANTICOAGULANTE DELLA TVP

emocromoemocromo

eparinaeparina

Anticoagulante oraleAnticoagulante orale

INR > 2INR > 2

Terapia/profilassi con anticoagulanti orali nel paziente

neoplastico

Gravata da un maggior numero di

fallimenti:

maggior rischio di recidive

maggior rischio di emorragie

monitoraggio più frequente

AO nei pazienti oncologici

Dieta Farmaci (Interazione) Assorbimento intestinale (vomito) Funzionalità epatica

Causano imprevedibili cambiamenti della dose/risposta

Causano impreviste fluttuazioni dell’ INR con necessità di frequenti monitoraggi e frequenti

sospensioni

Sanguinamento degli AO

Gitter 1995 Neoplastici 10.6% Non neoplastici 5.3%Prandoni 1996 Neoplastici 8.6% (3.4% mag) Non neoplastici 5.3% (3.0% mag)Palareti 2000 Neoplastici 21.6% Non neoplastici 4.5%

EBPM: alternativa agli AO

Vantaggi: non necessita monitoraggio assenza d’ interazione con le piastrine risposta anticoagulante costante (non

interferenza con fattori dietetici o con farmaci concomitanti)

rapidità del meccanismo d’azione più maneggevoli per le interruzioni/ripristino

della terapia anticoagulante (piastrinopenia, manovre invasive)



… all patients will undergo laparoscopy surgery

must be prophylaxed with LWMH…

….continued prophylaxis after discharge should be

considered in individual patients….


ROUTINE ADMINISTRATION OF PHARMACOLOGICAL ANTI DVT

PROPHILAXIS

HEPARIN IS CONTINUED AL LEAST UNTIL THE PATIENT IS FULLY

AMBULANT

AVOIDANCE OF PROLONGED REVERSE TRENDELENBURG POSITION

AVOIDANCE OF HIGH INSUFFLATION PRESSURE

INTERMITTENT RELEASE OF PNEUMOPERITONEUM ESPECIALLY

IN LENGTHY PROCEDURE

EARLY POSTOPERATIVE MOBILIZATION OR DISCHARGE

RECOMMENDATIONS

Meshinkhes 2003

Conclusions

Cancer surgery is a high-risk situation for post-operative thromboembolism

Cancer surgery may be a situation where prolonged thromboprophylaxis is indicated

LWMH for 1 month is significantly better than for 1 week in reducing phlebographically confirmed thrombosis

The benefit is maintained at 3 months The optimal duration is not known The optimal pharmacological substance is

not known

U.O.D Ematologia Prof.ssa L. Annino IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA.

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Transcript of U.O.D Ematologia Prof.ssa L. Annino IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA.