U.O.D Ematologia

1
IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA
Prof.ssa L. Annino
U.O.D Ematologia
2
NUOVA TEORIA DELLA COAGULAZIONE
3
ATTIVAZIONE DELLA TROMBINA
TROMBINA
4
ATTIVAZIONE DELLA TROMBINA
IIa
CELL. ENDOTELIALE
5
ATTIVAZIONE DELLA TROMBINA
PAR 1
PAR 3
PAR 4
PAR 2
6
Predictors of thromboembolic riskin medical and
surgical patients
Clinical setting

Patient risk factors



Clinical
Molecular



Inherited

Acquired

Type/duration of
Previous VTE

Factor V Leiden

Lu
pus
surgery

Varicose veins

Prothrombin
anticoagulant

Type of
Malignancy

20210A mutation

Anticardiolipin
anaesthesia

Age gt 70

Deficiencies

antibodies

Stroke

Obesity

Antithrombin III

Myeloproliferative
MI

Prolonged bed rest

Protein C

disease

Hyperhomocystei- naemia
Congestive heart
Level of hydration

Protein S

Hyperhomocystei- naemia
failure

Severe medical
Chest infection

illness

Intensive care

Infection/sepsis

Spinal cord injury

Pregnancy/
Multiple trauma

puerperium

Combined oral
contraceptive


7
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 gt40 years pluslt40
years, no risk lt40 years, gt40 years, Previous
VTE factors no other additional risk
Malignancy risk factors factors or MI Hip
or knee surgery Stroke or spinal cord
Minor surgery Non-major injury and risk
surgery in Hip fracture factors
patients Major trauma gt60 years,
Hypercoagulable state Non-major or
with surgery additional in patients risk
factors aged 40-60 years
Geerts et al. Chest 2001
8
Markers for specific risk classifications

• High-risk markers
• thrombophilia age gt60 years history of DVT/PE
  (certain patients)
• Moderate-risk markers
• age 4060 years (certain patients)
• Low-risk markers
• age lt40 years (in absence of other risk factors)

Nicolaides et al. Int Angiol 1997
9
Definition of thromboembolicrisk categories
Frequency of VTE without prophylaxis
Category Calf-vein Proximal Fatal PE ()
thrombosis () vein thrombosis () High
risk 40-80 10-30 gt 1 Moderate risk 10-40 1-10 0.1-
1 Low risk lt 10 lt 1 lt 0.1
Modified from Salzman and Hirsh. In Colman RW et
al, eds. Hemostasis and thrombosis basic
principles and clinical practice. New York
Lippincott, 1982Nicolaides AN et al. Int Angiol
1997
PE, pulmonary emobolism
10
Surgical risk-assessment model from the Paris
public assistance hospitals
Chapuis et al. Sang Thromb Vaiss 1995
11
Paris public assistance hospitalsrecommendations
for general surgery
Surgical risk Patient risk Thromboembolic R
ecommended factors factors risk therapeutic
regimen
Low
No treatment
1 2 3
1
LMWH, UFH or graduated compression stockings (GCS)
Moderate
1 2 3
2
1 2 3
LMWH GCS or UFH GCS
High
3
Chapuis et al. Sang Thromb Vaiss 1995
12
Laparoscopic surgery and thrombosis
13
Laparoscopic surgery and thrombosis
Thromboembolism prophylaxis and incidence of
thromboembolic complications of laparoscopic
surgery
Catheline JM, Int. Surg. Investig. 2000
2(1)41-47
8 DVT (0.33) 0 PE
14
Laparoscopic surgery and thrombosis
Thromboembolism prophylaxis and incidence of
thromboembolic complications of laparoscopic
surgery
6
Trendelenburg gt 1h
2
Trendelenburg gt 3h
Catheline JM, Int. Surg. Investig. 2000
2(1)41-47
15
Laparoscopic surgery and thrombosis
Thromboembolism prophylaxis and incidence of
thromboembolic complications of laparoscopic
surgery
Catheline JM, Int. Surg. Investig. 2000
2(1)41-47
16
Tissue Factor Procoagulant protein
Attività fibrinolitica T-PA,u-PA,,u-Par Tf,
PAI-1, PAI-2
Cellula tumorale
Molecole di adesione
IL 1, TNF, VEGF
Effetto diretto
Effetto indiretto
17
PAR
IX
VIIa
TF
IIa
IXa
Xa
IX
IXa
MONONUCLEATO
VIIa
CELL. ENDOTELIALE
18
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

19
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,
  increased blood viscosity

TF, tissue factor
20
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 volte maggiore di
quelli senza tumore e non sempre correlata alla
gravità del cancro
Hillen HFP Ann Oncol 2000 Levitan et al,
Medicine 1999 Shen Pollock South Med J 1980
21
Tasso di trombosi in pazienti neoplastici
Correlazioni
Levitan et al 1999
22
Cancer and Post-operative VTE

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

23
Independent Risk Factors for Major Post-operative
Thromboembolism

• 2,070 patients undergoing elective abdominal
  surgery
• Risk factor OR P Prevalence ()
• Malignant disease 1.7 lt0.05 66
• Duration of surgery gt150 min 1.4 lt0.05 35
• Pre-op hospital stay ?6 days 1.6 lt0.02 24
• Previous major orthopaedic event 1.7 lt0.02 12
• Pre-op transfusion gt1 unit 2.0 lt0.01 7
• Previous thromboembolism 1.7 lt0.04 6
• Leg ulcer 4.2 lt0.001 0.5

Flordal PA et al. Eur J Surg 19961627839.
24
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 1997841099103.
25
ENOXACAN Study Prophylaxis of VTE in Abdominal
and Pelvic Cancer Surgery

• 631 evaluable patients
• UFH Enoxaparin (n319) (n312)
• Overall 58 (18.2) 46 (14.7)
• DVT only 56 45
• PE DVT 2 0
• Death 0 1

Br J Surg 1997841099103.
26
ENOXACAN Study Blood Loss and Haemorrhagic
Complications

• 1,115 patients
• UFH Enoxaparin (n560) (n555)
• Intra-op bleeding (ml), median (range) 500
  (119,670) 500 (227,000)
• Post-op bleeding (ml), median (range) 434
  (211,250) 385 (26,520)
• 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 1997841099103.
27
Duration of Thromboprophylaxis

• 1 week
• or
• 1 month
• or
• ?

28
Risk of VTE over Time
Risk of VTE
?
Time
Surgery
Discharge
29
Reasons for Prolonged Prophylaxis

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

30
ENOXACAN II

• Duration of prophylaxis against venous
  thromboembolism with enoxaparin after surgery for
  cancer

Bergqvist D et al. N Engl J Med
2002346(13)97580.
31
Inclusion Criteria

• Age ?40 years
• Life expectancy ?6 months
• Open, elective, curative surgery
• Abdominal/pelvic cancer
• Duration of surgery ?45 min
• General anaesthesia

Bergqvist D et al. N Engl J Med
2002346(13)97580.
32
Primary Endpoint

• Venographically confirmed DVT at Day 283
• All objectively verified VTE before Day 283

Bergqvist D et al. N Engl J Med
2002346(13)97580.
33
Risk Factors at Baseline

• Intent-to-treat for efficacy population, n ()
• Placebo Enoxaparin (n167) (n165)
• 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)

Bergqvist D et al. N Engl J Med
2002346(13)97580.
34
Characteristics of Surgical Procedures

• Intent-to-treat for efficacy population, n ()
• Placebo Enoxaparin
• (n167) (n165)
• 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, hmin 305 313
• median (range) (0451100) (023935)
• P0.024

Bergqvist D et al. N Engl J Med
2002346(13)97580.
35
Incidence of VTE

• Intent-to-treat for efficacy population, n ()
• Placebo
  Enoxaparin RRR () P
• (n167)
  (n165) (95 CI)
• In double-blind period
• All DVT 20 (12.0) 8 (4.8) 60 (1082) 0.02
• Proximal DVT 3 (1.8) 1 (0.6)
• Distal DVT 17 (10.2) 7 (4.2)
• PE 1 0
• At 3 months
• All DVT 23 (13.8) 9 (5.5) 60 (1781) 0.02
• Proximal DVT 4 (2.4) 2 (1.2)
• Distal DVT 17 (10.2) 7 (4.2)
• PE 2
  0
• One fatal

36
Incidence of Haemorrhage

• 
  Placebo Enoxaparin
  (n248) (n253)
  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 months
• Major 1 (0.4) 2 (0.8)
• Cumulative incidence at 3 months
• Major 1 (0.4) 3 (1.2)
• Total 11 (4.4) 18 (7.1)
• P0.2

Bergqvist D et al. N Engl J Med
2002346(13)97580.
37
Mortality

• Placebo Enoxaparin
• (n167) (n165)
• In double-blind period 0 0
• At follow-up 6 (3.6) 3 (1.8)

Bergqvist D et al. N Engl J Med
2002346(13)97580.
38
EPARINA NON FRAZIONATA
PESO MOLECOLARE MEDIO 15.000 d

• SOLO UN TERZO SI LEGA ALLAT III
• EFFETTO ANTICOAGULANTE NON PREVEDIBILE
• TERAPIA CON DOSI PERSONALIZZATE
• NECESSARI FREQUENTI ESAMI DI LABORATORIO

39
EPARINA A BASSO PESO MOLECOLARE
PESO MOLECOLARE MEDIO 4.000-5.000 d

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

40
PROFILASSI TVP E/O EP
EPARINA CALCICA
5000 U/ s.c. X 2 o 3 volte/die
EPARINE A BASSO PESO MOLECOLARE
41
PROFILASSI PAZIENTI CHIRURGICI

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

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

• APPENDICECTOMIA
• ERNIA INGUINALE
• COLECISTECTOMIA

ETAgt 40aa ALLETTATO OBESITA POST PARTUM
CANCRO PRECEDENTE TVP TROMBOFILIA
ETA lt 40aa
42
PROFILASSI PAZIENTI NON CHIRURGICI
43
TERAPIA CON EPARINA SODICA e.v.
TERAPIA TVP TERAPIA EP TERAPIA DELLIMA
44
TERAPIA CON EPARINA NON FRAZIONATA
PTT in secondi paziente

1.5- 2.5
PTT in secondi pool normale
45
TERAPIA CON EPARINA NON FRAZIONATA
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 gt 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 lt150.000/mm3

46
CONTROLLO DEL PTT OGNI 6 ORE
PTT
BOLO EPARINA
SOSPENSIONE
VARIAZIONE DOSE EPARINA
lt1.2
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
gt3
- 3 U/kg/h
1 ora
47
EPARINA A BASSO PESO MOLECOLARE (LWMH)
INDICAZIONI TERAPEUTICHE
NADROPARINA
DALTEPARINA
ENOXAPARINA
48
EPARINA A BASSO PESO MOLECOLARE (LWMH)
DOSI TERAPEUTICHE NELLA TVP/EP

• NADROPARINA
• ENOXAPARINA
• DALTEPARINA
• ARDEPARINA
• TINZAPARINA
• REVIPARINA

90U /Kg/ 12 ORE 180U /Kg/ 24 ORE
100U /Kg/ 12 ORE
200U /Kg/ 24 ORE
130U /Kg/ 12 ORE
175U /Kg/ 24 ORE
100U /Kg/ 12 ORE
49
EPARINA A BASSO PESO MOLECOLARE (LWMH)

• 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

50
TRATTAMENTO DELLIPERDOSAGGIO DA EPARINA
SOLFATO DI PROTAMINA

• INATTIVA
• 100 EPARINA NON FRAZIONATA
• (1 mg per 100 U di Eparina)
• 30 ENOXAPARINA
• 40 DALTEPARINA
• 60 TINZAPARINA

51
PROFILASSI TVP IN PAZIENTI CHIRURGICI
1 mese ?
giorni
52
TERAPIA ANTICOAGULANTE DELLA TVP
emocromo
eparina
1 2 3 4 5 6 3 a 6 mesi
giorni
53
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

54
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

55
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

56
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 dazione
• più maneggevoli per le interruzioni/ripristino
  della terapia anticoagulante (piastrinopenia,
  manovre invasive)

57
Laparoscopic surgery and thrombosis
all patients will undergo laparoscopy
surgery must be prophylaxed with
LWMH .continued prophylaxis after discharge
should be considered in individual patients.
Catheline JM, Int. Surg. Investig. 2000
2(1)41-47
58
Laparoscopic surgery and thrombosis
RECOMMENDATIONS

• 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

Meshinkhes 2003
59
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