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Prof. Rosanna Abbate Univ.di Firenze

Prof. Rosanna Abbate Univ.di Firenze. Incidence of VTE: The third most common vascular disease. Annual incidence (US data). Deep vein thrombosis (DVT) only 1,2. Pulmonary embolism (PE) with or without DVT 3. Up to 145/100,000. Up to 69/100,000. 1. Gillum RF. Am Heart J 1987;114:1262–4

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Prof. Rosanna Abbate Univ.di Firenze

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  1. Prof. Rosanna Abbate Univ.di Firenze

  2. Incidence of VTE: The third most common vascular disease Annual incidence (US data) Deep vein thrombosis (DVT) only1,2 Pulmonary embolism (PE) with or without DVT3 Up to145/100,000 Up to69/100,000 1. Gillum RF. Am Heart J 1987;114:1262–4 2. Anderson FA Jr, et al. Arch Intern Med1991;151: 933–8 3. Silverstein MD, et al. Arch Intern Med 1998;158:585–93

  3. Circa l’80% delle TVP è clinicamente silente2,3 Diagnosi Il TEV spesso non viene diagnosticato se non quando è troppo tardi Oltre il 70% delle EP fatali viene scoperto post mortem1,3 1. Stein PD, et al. Chest 1995; 108(4): 978–81 2. Lethen H, et al. Am J Cardiol 1997; 80(8): 1066–9 3. Sandler DA, et al. J R Soc Med 1989; 82(4): 203–5

  4. 80% 17% 25% 2 years 74% 24% 30% 5 years 69% 30% 30% 8 years VTE:Heavy burden of long-term complications Long-term outcomes after a first DVT in symptomatic patients Cumulative incidence Survival rate Recurrent DVT Post-thrombotic syndrome Prandoni P, et al. Haematologica 1997; 82:423–428

  5. PE1 DVT1 MI2 Stroke2 12500 0 2500 5000 7500 10000 Economic Burden of VTE Direct inpatient costsof a VTE event are comparable with MI orstroke1,2 Additional long-term healthcare costs of a DVT: 75% of the initial cost3 $12,795 $9,337 $9,643 $6,367 Average cost per admission in the US ($) 1. Bick RL. Clin Appl Thromb Hemost 1999;5:2–9 2. Medicare & DRG. 1996. [http://www.hcfa.gov] 3. Bergqvist D, et al. Ann Intern Med 1997;126:454–7

  6. Annual incidence of TE disease in the U.S.A. 600 males 500 females 400 300 Incidence (/100 000) 200 100 0 0-9 >80 9-19 20-29 30-39 40-49 50-59 60-69 70-79 Age (years) Worchester study 1991 Clin Med Cardiol FI

  7. Fattori di rischio di TEV: Età • < 40 a. = 1 TEV su 10.000 soggetti/a. • 40-60 a. = 1 TEV su 1000 soggetti/a. • > 75 a. = 1 TEV su 100 soggetti/a.

  8. All hospitalized All major surgery Abdominal surgery Vascular surgery Neurosurgery Urology Cardiac surgery 0 10 20 30 40 50 60 70 80 VTE: A large population at risk Prevalence of VTE risk in a typical hospital population: Percentage of patients with at least three VTE risk factors 19% of hospitalizedpatients have at least three riskfactors This can be up to70% in some wards Patients with at least three risk factors (%) Anderson FA, et al. Arch Intern Med 1992;152:1660–4

  9. Tromboembolia venosa Triade di Virchow dei fattori di rischio (1) Ipercoagulabilità Ereditaria Acquisita Trombosi venosa Stasi Acquisita Lesione vascolare Acquisita Virchow R. In Gesammelte Abhandlugen zur Wissenschaftlichen Medizin, 1856; Frankfurt: Staatsdruckerei Rosendaal FR. Lancet 1999; 353:1167–1173

  10. Risk factors observed in 1231 consecutive patients treated for acute DVT and/or PE Patients Risk Factor (%) Age ≥40 years 88.5 Obesity 37.8 History for venous thromboembolism 26.0 Cancer 22.3 Bed rest ≥5 days 12.0 Major surgery 11.2 Congestive heart failure 8.2 Varicose veins 5.8 Fracture (hip or leg) 3.7 Estrogen treatment 2.0 Stroke 1.8 Multiple trauma 1.1 Childbirth 1.1 Myocardial infarction 0.7 1 or more risks 96.3 2 or more risks 76.0 3 or more risks 39.0 Clin Med Card –FI Anderson and Spencer, Circulation 2003

  11. Risk Factors for VTE Strong risk factors (odds ratio >10) Fracture (hip or leg) Hip or knee replacement Major general surgery Major trauma Spinal cord injury Clin Med Card –FI Anderson and Spencer, Circulation 2003

  12. Risk Factors for VTE Moderate risk factors (odds ratio 2-9) Arthroscopic knee surgery Central venous lines Chemotherapy Congestive heart /respiratory failure Hormone replacement therapy Malignancy Oral contraceptive therapy Paralytic stroke Pregnancy/, post-partum Previous venous thromboembolism Thrombophilia Anderson and Spencer, Circulation 2003

  13. Risk Factors for VTE Weak risk factors (odds ratio <2) Bed rest >3 days Immobility due to sitting (e.g. prolonged car or air travel) Increasing age Laparoscopic surgery (e.g. cholecystectomy) Obesity Pregnancy/, ante-partum Varicose veins Anderson and Spencer, Circulation 2003

  14. The incidence of newly diagnosed malignancies during first year in unselected cohorts of pts with confirmed VTE Gore, 1992 Goldberg, 1987 Griffin, 1987 Monreal, 1988 Nordstrom, 1994 Ahmed, 1996 Hettiarachchi, 1997 Prandoni, 1992 Bastounis, 1996 Monreal, 1991 Ranft, 1991 8.8 % 3.7 % 3.5 % 8.5 % 4.8 % 1.5 % 4.0 % 6.0 % 9.1 % 10.6 % 11.5 % 0 5 10 15 Incidence of newly diagnosed malignancies (%) Clin Med Cardiol FI Prins et al, 1997

  15. Risk factors for DVT: Cancer Cancer RR for VTE: 7 Cancer is responsible for 10-15% of all VTE in general population Goldberg et al, 1987 Clin Med Cardiol FI

  16. Extensive screening for occult malignantdisease in idiopathic TE A prospective randomized clinical trial (stopped prematurely) N=201 Extensive screening US abdomen/pelvis CT scanning abdomen/pelvis Gastroscopy , Flexible sigmoidoscopy CEA, alphaFP,CA 125 Hemoccult Sputum cytology Gynecol exam.+PAP smear Mammography Transabd. US of prostate PSA Piccioli et al J Thromb Haemost 2004

  17. Extensive screening for occult Malignant disease in idiopathic TE-2 yrs f-up A prospective randomized clinical trial (stopped prematurely) N=201 Neoplasia identified in 13.1% pts extensively screened vs 0 in routine clinical examination Sensitivity of extensive screening : 93% Mean delay 1 month vs 11 months Mortality 2% vs 3.9 % Piccioli et al J Thromb Haemost 2004

  18. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy An underestimated phenomenon Annual incidence of VTE: 10.9% Clin Med Card –FI Hans-Martin MB Otten et al., Arch Intern Med 2004

  19. Fattori di rischio di TVP: IMMOBILIZZAZIONE • Rischio relativo = 11 volte (Leiden Thrombophilia Study) • Rischio attribuibile per tutte le TVP = 15%

  20. Odds ratios on the risk of travel and thrombosis for different duration categories of travelling in patients with suspected venous thromboembolism Duration of travelling Patients with Patients without Pooled odds ratio venous venous (95% CI) thromboembolism thromboembolism Number of patients 477 1470 Any travel (%) 32* (7%) 105** (7%) 0.9 (0.6-1.4) Duration 3-5 hours 9 44 0.7 (0.3-1.3) Duration 6-10 hours 10 34 0.9 (0.4-1.8) Duration 11-15 hours 8 10 2.5 (1.0-6.2) Duration >16 hours 3 8 1.3 (0.4-4.3) * for two patients duration of travel is missing ** for nine patients duration of travel is missing Clin Med Card –FI Ten Walde, Thromb Haemostas 2003

  21. Acute MI We recommend that most patients with acute MI receive prophylactic or therapeutic anticoagulant therapy with sc LDUH or iv heparin (GRADE 1A) Ischemic Stroke • For patients with ischemic stroke and impaired mobility, we recommend the routine use of LDUH, LMWH, or the heparinoid, danaparoid (all GRADE A) • If anticoagulant prophylaxis is controindicated we recommend mechanical prophylaxis with ES or IPC (GRADE 1C+) Other Medical Conditions In general medical patients with risk factors for VTE (including cancer, bedrest, heart failure, severe lung disease), we recommend LDUH or LMWH (GRADE 1A) Sixth ACCP Consensus Conference2001 Clin Med Cardio, Fi

  22. Risk factors for VTE-Medical patients Inflammatory bowel disease Renal Transplantation Nephrotic syndrome Sepsis Hyperviscosity syndrome Myeloproliferative disease Paroxysmal nocturnal hemoglobinuria Modified by G.F.Gensini et al, 1997 Seminars in Thrombosis and Hemostasis Clin Med Cardiol FI

  23. APC THROMBOMODULIN Protein s aPL Thrombin Protein C TF PAI PGI2 EC

  24. CRITERI CLINICI • Trombosi vascolari : uno o più episodi di trombosi arteriose, venose o dei piccoli vasi, in qualsiasi organo o tessuto, confermate da tecniche di imaging, doppler o dall’istopatologia • Mortalità in gravidanza: • Una o più morti fetali oltre la 10° settimana; • Uno o più parti prematuri prima della 34° settimana, accompagnati da preeclampsia o severa insufficienza placentare; • Tre o più aborti spontanei in assenza di anomalie ormonali o cromosomiche prima della 10° settimana.

  25. CRITERI PER LA DIAGNOSI DEL LUPUS ANTICOAGULANT PROPOSTI DAI SSC(Brandt J.T.,Thromb.Haemost 1995;74: 1185-90) • Prolungamento di 2 o più test di screening PL dipendenti (aPTT, KCT, dRVVT, dPT o TTI) • Studi di mixing (1:1) per dimostrare la presenza di un inibitore ed escludere eventuali carenze di fattori • Test di conferma per dimostrare che l’inibitore è diretto contro i PL • Esclusione di altre coagulopatie (es. inibitore del fattore VIII o presenza di eparina)

  26. RICERCA DEGLI ANTICORPI ANTIFOSFOLIPIDI NELLA PRATICA CLINICA • Lupus anticoagulant • Anticorpi anticardiolipina • Anticorpi antibeta 2 glicoproteina • NECESSARIO ESCLUDERE CONDIZIONI INFIAMMATORIE E INFETTIVE e • E’ OBBLIGATORIO CONFERMA DOPO 6 SETTIMANE • Interferenza terapia anticoagulante

  27. Long-term AnticoagulationSixth ACCP Consensus Conference on Anti thrombotic Therapy 2001 For patients with recurrent idiopathic VTE or a continuing risk factor such as …….or …………. anticardiolipin antibody syndrome, we recommend treatment for 12 months or longer (grade 1C)

  28. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome Moderate intensity: INR 2.0-3.0 High intensity: INR 3.1-4.0 No differences in recurrencies and bleeding were found between the two INR NEJM 2002

  29. EP di 2° generazione (levonorgestrel) 4.2 EP di 3° generazione (Desogestrel,Gestodene) 9.2 Rischio relativo medio per TEV dell’uso di EP (rispetto al non uso di EP)

  30. Risk factors for DVT: Pregnancy and post-partum Pregnancy: RR 5-10 DVT incidence during pregnancy: 0.5-1/1000 Post-partum:RR 10-15 The risk for DVT is potentiated by additional risk factors: immobilization cesarean delivery instrumental procedures Clin Med Cardiol FI NHI Consensu Conference, 1986

  31. 0 1 2 3 4 5 Hormone Replacement Therapy Risks Venous TE and HRT use Daly et al., Lancet 1996 3.5 Venous TE and HRT use Jick et al., Lancet 1996 3.3 Pulmonary Embolism and HRT use Grodstein et al., Lancet 1996 2.1 RELATIVE RISK Clin Med Card FI

  32. TVP: fattori di rischio Thromb Haemost 2001 86: 452-63

  33. Relative risk of non-fatal venous Thromboembolism in subjects of the VITA project( cross-sectional study,n= 15055) Odds ratio Corrected odds ratio (95% CI) (95% CI) Previous SVT4.9 (3.0-7.8) 6.8 (3.9-12.0) Oral contraceptives use* 3.9 (1.9-8.0) 4.7 (2.0-10.8) Positive family history 3.5 (2.0-6.1) 4.5 (2.4-8.5) Smoking 1.6 (1.1-2.3) 1.7 (1.0-2.7) Body mass index** Lower-tertile 0.7 (0.4-1.2) 0.5 (0.3-0.9) Upper-tertile 1.7 (1.1-2.6) 2.9 (1.4-6.2) SVT, superficial vein thrombophlebitis; VTE, venous thromboembolism *Use of oral contraceptives at time of VTE or at time of investigation; percentages are referred to the femal population **The mid-tertile was taken as the baseline for risk estimation Clin Med Card –FI Tosetto et al., J Thromb Haemostas 2003

  34. Thrombosis can be caused by interacting genetic and acquired risk factors Risk Factors Risk Factors Genetic+Genetic Genetic+Acquired Thromboembolism Lane, 1996 Clin Med Cardio, Fi

  35. Frequency (%) of inherited thrombophilic Syndromes in the general population and In patients with venous thrombosis General Unselected patients selected patients Population with venous thrombosis with venous thrombosis* Syndrome AT deficiency 0.02-0.17 1.1 0.5-4.9 PC deficiency 0.14-0.5 3.2 1.4-8.6 PS deficiency - 2.2 1.4-7.5 APC resistance 3.6-6.0 21.0 10-64 Prothrombin 1.7-3.06.2 18 G20210A * Age 45 years and/or recurrent thrombosis. Adapted from De Stefano V, Finazzi G, Mannucci PM Clin Med Card –FI Anderson and Spencer, Circulation 2003

  36. Via intrinseca Via estrinseca Superficie di contatto XII lesione XIIa XI IX XIa TF + VIIa IXa Membrana delle piastrine + VIII X APCR Membrana delle piastrine Complesso protrombinasico Xa + PS + PS Va Leiden Proteina C Attivata Va Trombina Protrombina

  37. Estimated population incidence of first DVT in women aged 15-49, according to presence of Factor V Leiden mutation and use of OC Factor V Leiden neg Non OC use Current OC use Factor V Leiden pos Non OC use Current OC use Patients 36 84 10 25 Person- yrs 437870 275858 17515 8757 Incidence/ 10000/yrs 0.8 3.0 5.7 28.5 OR 1 3.75 7.12 36.62 Vandenbroucke et al, 1994 Clin Med Cardiol FI

  38. Risk of DVT in long-haul flights (>8h) in economic class passengers No stockings passengers, n=116 30% RR=3.96 20% F II mutation 10% No F II mutation 0% FV Leiden No FV Leiden The Lancet 2001

  39. Haemostasis-related risk factors in 958patients with DVT referred to Thrombosis Center, Florence (1999-2000) APCR 32.9% Factor V Leiden 30.3% Prothrombin polymorphism 12.6% Inhibitors’ deficiences 3.2% Centro Trombosi , FI Clin Med Gen e Cardiol, FI

  40. Percentuale di TV spiegate dalle alterazioni trombofiliche ereditarie note 1978 2% 1982 10% 1984 15% 1994 55% 1996 73% Clin Med Cardio, Fi

  41. Fasting Homocysteine levels in case-control studies on VENOUS thrombosis Brattstrom den Heijer Amundsen Fermo den Heijer Cattaneo Simioni Ridker ALL 1 10 90 From Cattaneo M, Thromb Haemost 2000

  42. HOMOCYSTEINE METABOLISM Diet Methionine Tetrahydrofolate dimethylglycine SAM Methionine Synthase Vit.B12 5,10 CH3 Tetrahydrofolate Betaine SAH MTHFR HOMOCYSTEINE 5 CH3 Tetrahydrofolate Transulfuration CBS Vit.B6 Remethylation Cysteine

  43. Fasting Homocysteine levels in case-control studies on VENOUS thrombosis Brattstrom den Heijer Amundsen Fermo den Heijer Cattaneo Simioni Ridker ALL 1 10 90 From Cattaneo M, Thromb Haemost 2000

  44. Prevalence of MTHFR in the different populations Abbate R et al, Thromb Haemost 1998

  45. tHcy for Genotypes of C677T MTHFR Mutation Folate > 11.5 nmol/l Folate < 11.5 nmol/l 25 Fasting tHcy (µmol/L) 20 15 10 CC CT TT MTHFR Genotypes Girelli et al., Blood 1998

  46. C677T mutation in the MTHFR gene and risk of venous thrombosis: the VITA project 20 13.1% 15 12.3% % 10 5 0 Controls DVT patients Tosetto et al, BJH 1997

  47. Hyperhomocysteinaemia and thrombophilic genotypes in DVT Patients (n=111) OR (95% CI) Hyperhomocysteinemia 3.7 (1.4-9.6) Hyperhomocysteinemia + Factor V Leiden 29.9 (2-419) Hyperhomocysteinemia + Prothrombin mutation 49.8 (1.7-1471) De Stefano V et al, BJH 1999

  48. Haemostasis-related risk factors in 958patients with DVT referred to Thrombosis Center, Florence (1999-2000) Hyperhomocysteinemia 36.3% APCR 32.9% Factor V Leiden 30.3% Prothrombin polymorphism 12.6% Inhibitors’ deficiences 3.2% Centro Trombosi , FI Clin Med Gen e Cardiol, FI

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