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

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Presentazione sul tema: "U.O.D Ematologia Prof.ssa L. Annino IL RISCHIO TROMBOEMBOLICO IN LAPAROSCOPIA."— Transcript della presentazione:

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

2 NUOVA TEORIA DELLA COAGULAZIONE IX IXa TISSUE FACTOR (Tromboplastina) VII/VIIa Ca VIIIa PL CA protrombinatrombina X Xa Va PL CA VIA INTRINSECA

3 TF ATTIVAZIONE DELLA TROMBINA X+V IX+VIIITF+VIIa TROMBINA TF

4 PAR TM PCPCa MONONUCLEATO PAR IIa TF PAR FIBRINOGENOFIBRINA V IXa VIII Xa PIASTRINA CELL. ENDOTELIALE V IXIXa VIIa V VIII IX IXa VIIa Xa ATTIVAZIONE DELLA TROMBINA

5 PAR 2 PAR 1PAR 3PAR 4 TF VIIa TF VIIa Xa ANGIOGENESI VEGF PROTEINASI VEGF PGF HIF-1 AGGREGAZIONE PIASTRINICA EMOSTASI PROTROMBINATROMBINA EMOSTASI ATTIVAZIONE DELLA TROMBINA

6 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 Myeloproliferative disease Hyperhomocystei- naemia Hyperhomocystei- naemia

7 Classification of level of VTE risk in surgical patients (6th ACCP Consensus Conference on Antithrombotic Therapy) Low riskModerate risk High risk Highest risk Minor surgeryMajor surgery Major surgery Major surgery in patients in patients in patients in patients >40 years plus: 40 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 patientsMajor trauma >60 years, Hypercoagulable state Non-majoror with surgery additional in patients risk factors aged years Geerts et al. Chest 2001

8 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

9 Definition of thromboembolic risk categories CategoryCalf-vein ProximalFatal PE (%) thrombosis (%) vein thrombosis (%) High risk > 1 Moderate risk 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

10 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 RiskRisk associated with surgerylevelwith patient Less than 45 min, 1No risk factors no dissection Moderate dissection, 2Age >40 years less than 45 minconfined to bed >4 days Complicated appendectomy Varicose veins, obesity Inflammatory GI disease Neoplastic surgery3Actual/developing cancer Previous thromboembolism Thrombophilia

11 Paris public assistance hospitals recommendations for general surgery Chapuis et al. Sang Thromb Vaiss 1995 Low High Moderate Surgical risk +Patient risk=Thromboembolic Recommended factors factors risk therapeutic regimen No treatment LMWH, UFH or graduated compression stockings (GCS) LMWH + GCS or UFH + GCS

12 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

13 Laparoscopic surgery and 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

14 Laparoscopic surgery and thrombosis Catheline JM, Int. Surg. Investig. 2000; 2(1):41-47 Thromboembolism prophylaxis and incidence of thromboembolic complications of laparoscopic surgery 8 DVT 6 Trendelenburg > 1h Trendelenburg > 3h 2

15 Laparoscopic surgery and thrombosis Catheline JM, Int. Surg. Investig. 2000; 2(1):41-47 Thromboembolism prophylaxis and incidence of thromboembolic complications of laparoscopic surgery In 6/8 cases the DVT occurs : after cessation of LWMH delivery after discharge at home before post-operative day 10

16 Cellula tumorale Tissue Factor Procoagulant protein Attività fibrinolitica T-PA,u-PA,,u-Par Tf, PAI-1, PAI-2 Molecole di adesione Effetto diretto IL 1, TNF, VEGF Effetto indiretto

17 TF PAR TM PCPCa MONONUCLEATO PAR IIa TF FIBRINOGENOFIBRINA PAR V IXa VIII Xa PIASTRINA CELL. ENDOTELIALE V IXIXa VIIa V VIII IX IXa VIIa Xa TF PC VIIa IFN IL 1 CELL. NEOPLASTICA

18 Complex Relation Between Cancer and VTE VTEoccult cancer Cancerincreased risk of VTE - peri-operatively - in non-surgical patients Cancerresistance to prophylaxis and treatment Cancer central catheter thrombosis

19 Thrombopathogenetic Factors in Cancer Patients HypercoagulabilityTF expression Endothelial damagetumour invasion, chemotherapy, radiation, catheters, host response Platelet dysfunctionactivation, thrombocytosis Venous stasisvenous obstruction, immobility, increased blood viscosity TF, tissue factor

20 Embolia Polmonare e Mortalità 2 a 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 OvaioEncefaloPancreasLinfomaLeucemiaColonPolmone Tasso di tromboembolismo in base alla localizzazione del tumore Tasso/ pazienti

22 Cancer and Post-operative VTE More extensive surgery Venous trauma Prothrombotic haemostasis Chemotherapy Radiation Indwelling vascular lines Prolonged immobilization

23 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 factorOR PPrevalence (%) Malignant disease1.7 < Duration of surgery >150 min1.4 < Pre-op hospital stay 6 days1.6 < Previous major orthopaedic event1.7 < Pre-op transfusion >1 unit2.0 < Previous thromboembolism1.7 < Leg ulcer4.2 <

24 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

25 Br J Surg 1997;84:1099–103. ENOXACAN Study Prophylaxis of VTE in Abdominal and Pelvic Cancer Surgery 631 evaluable patients UFHEnoxaparin (n=319)(n=312) Overall58 (18.2%)46 (14.7%) DVT only5645 PE + DVT2 0 Death0 1

26 ENOXACAN Study Blood Loss and Haemorrhagic Complications 1,115 patients UFHEnoxaparin (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.

27 Duration of Thromboprophylaxis 1 week or 1 month or ?

28 Risk of VTE SurgeryDischarge Time ? Risk of VTE over Time

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 2002;346(13):975–80.

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 2002;346(13):975–80.

32 Primary Endpoint Venographically confirmed DVT at Day 28±3 All objectively verified VTE before Day 28±3 Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

33 Risk Factors at Baseline Intent-to-treat for efficacy population, n (%) Placebo Enoxaparin (n=167) (n=165) History of VTE4 (2.4)5(3.0) Varicose veins24 (14.4)17(10.3) Obesity23 (13.8)22(13.3) Chronic heart failure6 (3.6)7(4.2) Chronic lung disease4 (2.4)10(6.1) Hormone replacement4 (2.4)4(2.4 ) Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

34 Characteristics of Surgical Procedures Intent-to-treat for efficacy population, n (%) Placebo Enoxaparin (n=167) (n=165) Location of surgery Gastrointestinal137 (82)141 (86) Gynaecological11 (7) 17 (10) Urological 17 (10)11 (7) Others 3 (2) 2 (1) 2 sites11 (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 Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

35 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 DVT20(12.0)8(4.8)60(10–82) 0.02 Proximal DVT3(1.8)1(0.6) Distal DVT17(10.2)7(4.2) PE10 At 3 months All DVT23(13.8)9(5.5)60(17–81)0.02 Proximal DVT4(2.4)2(1.2) Distal DVT17(10.2)7(4.2) PE 2* 0 *One fatal

36 Incidence of Haemorrhage Placebo Enoxaparin (n=248) (n=253) n (%) In double-blind period Minor9(3.6)12(4.7) Major01(0.4) Total9(3.6)13(5.1) At 3 months Major1(0.4) 2(0.8) Cumulative incidence at 3 months Major1(0.4)3(1.2) Total11(4.4)18(7.1)* *P=0.2 Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

37 Mortality Placebo Enoxaparin (n=167)(n=165) In double-blind period00 At follow-up6 (3.6%)3 (1.8%) Bergqvist D et al. N Engl J Med 2002;346(13):975–80.

38 EPARINA NON FRAZIONATA AT III PROTEINE PLASMATICHE EPARINA SOLO UN TERZO SI LEGA ALLAT III EFFETTO ANTICOAGULANTE NON PREVEDIBILE TERAPIA CON DOSI PERSONALIZZATE NECESSARI FREQUENTI ESAMI DI LABORATORIO PESO MOLECOLARE MEDIO: d

39 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: d

40 PROFILASSI TVP E/O EP 5000 U/ s.c. X 2 o 3 volte/die EPARINA CALCICA EPARINE A BASSO PESO MOLECOLARE ENOXAPARINA U s.c./die DALTEPARINA 2500 U s.c./die NADROPARINA 3000 U s.c./die

41 CHIR. NEOPLASTICA CHIR. ADDOMINALE CHIR. ORTOPEDICA SPLENECTOMIA APPENDIC. COMPLICATA CHIR. MALATTIE INFIAMM. COLON /TENUE APPENDICECTOMIA ERNIA INGUINALE COLECISTECTOMIA ETA < 40aa ETA> 40aa ALLETTATO OBESITA POST – PARTUM CANCRO PRECEDENTE TVP TROMBOFILIA PROFILASSI CON: EPARINA NON FRAZIONATA EPARINE A BASSO PESO MOLECOLARE PROFILASSI PAZIENTI CHIRURGICI

42 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 TVP FAMILIARE OBESITA PILLOLA >65 aa GRAVIDANZA S. NEFROSICA TROMBOFILIA TVP PRECED. CANCRO PROFILASSI CON: EPARINA NON FRAZIONATA EPARINE A BASSO PESO MOLECOLARE

43 TERAPIA CON EPARINA SODICA e.v. TERAPIA TVP TERAPIA EP TERAPIA DELLIMA VANTAGGI: PER e.v. EFFETTO ANTICOAGULANTE IMMEDIATO POSSIBILITA DI MONITORARE LEFFETTO ANTICOAGULANTE BREVE EMIVITA ESISTENZA DELLANTIDOTO

44 TERAPIA CON EPARINA NON FRAZIONATA MONITORAGGIO DELLEFFETTO ANTICOAGULANTE PTT RANGE TERAPEUTICO: PTT in secondi paziente PTT in secondi pool normale =

45 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 < /mm3 TERAPIA CON EPARINA NON FRAZIONATA

46 PTTBOLO EPARINA SOSPENSIONEVARIAZIONE DOSE EPARINA <1.280 U/Kg+ 4 U/kg/h U/Kg+ 2 U/kg/h U/kg/h >3- 3 U/kg/h 1 ora CONTROLLO DEL PTT OGNI 6 ORE

47 EPARINA A BASSO PESO MOLECOLARE (LWMH) INDICAZIONI TERAPEUTICHE NADROPARINADALTEPARINAENOXAPARINA TRATTAMENTO DELLA TVP ACUTA PROFILASSI DELLA COAGULAZIONE IN EMODIALISI TRATTAMENTO DELLANGINA INSTABILE E DELLIMA NON Q PROFILASSI DELLA TVP IN CHIRURGIA GENERALE E IN CHIRURGIA ORTOPEDICA PROFILASSI DELLA TVP IN PAZIENTI NON CHIRURGICI

48 EPARINA A BASSO PESO MOLECOLARE (LWMH) NADROPARINA ENOXAPARINA DALTEPARINA ARDEPARINA TINZAPARINA REVIPARINA DOSI TERAPEUTICHE NELLA TVP/EP 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) Confronto LWMH /EPARINA STANDARD 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%

50 INATTIVA: 100% EPARINA NON FRAZIONATA (1 mg per 100 U di Eparina) 30% ENOXAPARINA 40% DALTEPARINA 60% TINZAPARINA TRATTAMENTO DELLIPERDOSAGGIO DA EPARINA SOLFATO DI PROTAMINA

51 PROFILASSI TVP IN PAZIENTI CHIRURGICI emocromo LWMH giorni INTERVENTODIMISSIONE ENOXAPARINA 4000 U s.c./die DALTEPARINA 2500 U s.c./die NADROPARINA 3000 U s.c./die emocromo LWMH ?? 1 mese ?

52 emocromo a 6 mesi giorni TERAPIA ANTICOAGULANTE DELLA TVP emocromo eparina Anticoagulante orale INR > 2

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 Neoplastici10.6% Non neoplastici5.3% Prandoni 1996 Neoplastici8.6% (3.4% mag) Non neoplastici5.3% (3.0% mag) Palareti 2000 Neoplastici21.6% Non neoplastici4.5%

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 Catheline JM, Int. Surg. Investig. 2000; 2(1):41-47 … all patients will undergo laparoscopy surgery must be prophylaxed with LWMH… ….continued prophylaxis after discharge should be considered in individual patients….

58 Laparoscopic surgery and thrombosis 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

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


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