Prof rosanna abbate univ di firenze
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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

Prof. Rosanna Abbate

Univ.di Firenze


Incidence of vte the third most common vascular disease

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


Prof rosanna abbate univ di firenze

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


Vte h eavy burden of long term complications

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


Economic b urden of vte

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


Prof rosanna abbate univ di firenze

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


Fattori di rischio di tev et

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.


Vte a large population at risk

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

Risk factors observed in 1231 consecutive

patients treated for acute DVT and/or PE

Patients

Risk Factor(%)

Age ≥40 years88.5

Obesity37.8

History for venous thromboembolism26.0

Cancer22.3

Bed rest ≥5 days12.0

Major surgery11.2

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 risks96.3

2 or more risks76.0

3 or more risks39.0

Clin Med Card –FI Anderson and Spencer, Circulation 2003


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Fattori di rischio di tvp immobilizzazione

Fattori di rischio di TVP: IMMOBILIZZAZIONE

  • Rischio relativo = 11 volte

    (Leiden Thrombophilia Study)

  • Rischio attribuibile per tutte le TVP = 15%


Prof rosanna abbate univ di firenze

Odds ratios on the risk of travel and thrombosis

for different duration categories of travelling

in patients with suspected

venous thromboembolism

Duration of travellingPatients withPatients withoutPooled odds ratio

venousvenous(95% CI)

thromboembolismthromboembolism

Number of patients4771470

Any travel (%)32* (7%)105** (7%)0.9 (0.6-1.4)

Duration 3-5 hours9440.7 (0.3-1.3)

Duration 6-10 hours10340.9 (0.4-1.8)

Duration 11-15 hours8102.5 (1.0-6.2)

Duration >16 hours381.3 (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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

APC

THROMBOMODULIN

Protein s

aPL

Thrombin

Protein C

TF

PAI

PGI2

EC


Criteri clinici

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.


Prof rosanna abbate univ di firenze

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)


Ricerca degli anticorpi antifosfolipidi nella pratica clinica

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


Long term anticoagulation sixth accp consensus conference on anti thrombotic therapy 2001

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)


Moderate intensity inr 2 0 3 0 high intensity inr 3 1 4 0

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


Rischio relativo medio per tev dell uso di ep rispetto al non uso di ep

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)


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

TVP: fattori di rischio

Thromb Haemost 2001 86: 452-63


Prof rosanna abbate univ di firenze

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 history3.5 (2.0-6.1)4.5 (2.4-8.5)

Smoking1.6 (1.1-2.3)1.7 (1.0-2.7)

Body mass index**

Lower-tertile0.7 (0.4-1.2)0.5 (0.3-0.9)

Upper-tertile1.7 (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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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 0.02-0.171.10.5-4.9

PC deficiency 0.14-0.53.21.4-8.6

PS deficiency -2.21.4-7.5

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

Haemostasis-related risk factors in

958patients with DVT referred to Thrombosis Center, Florence (1999-2000)

APCR32.9%

Factor V Leiden30.3%

Prothrombin polymorphism12.6%

Inhibitors’ deficiences 3.2%

Centro Trombosi , FI

Clin Med Gen e Cardiol, FI


Prof rosanna abbate univ di firenze

Percentuale di TV spiegate dalle alterazioni trombofiliche ereditarie note

19782%

198210%

198415%

199455%

199673%

Clin Med Cardio, Fi


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

Prevalence of MTHFR in the different populations

Abbate R et al, Thromb Haemost 1998


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

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


Prof rosanna abbate univ di firenze

Hyperhomocysteinaemia and

thrombophilic genotypes in DVT

Patients (n=111)

OR (95% CI)

Hyperhomocysteinemia3.7 (1.4-9.6)

Hyperhomocysteinemia +

Factor V Leiden29.9 (2-419)

Hyperhomocysteinemia +

Prothrombin mutation49.8 (1.7-1471)

De Stefano V et al, BJH 1999


Prof rosanna abbate univ di firenze

Haemostasis-related risk factors in

958patients with DVT referred to Thrombosis Center, Florence (1999-2000)

Hyperhomocysteinemia36.3%

APCR32.9%

Factor V Leiden30.3%

Prothrombin polymorphism12.6%

Inhibitors’ deficiences 3.2%

Centro Trombosi , FI

Clin Med Gen e Cardiol, FI


Prof rosanna abbate univ di firenze

High levels of FVIII in venous thrombosis

= SINGLE episode of DVT

= RECURRENCE venous thromboembolism

25

20

15

OR

10

5

0

100-150

U/dl

150-175

U/dl

175-200

U/dl

>200

U/dl

Kraaijenhagen, Thromb Haemost 2000


Prof rosanna abbate univ di firenze

Test consigliabili per

uno screening per trombofilia*

Resistenza alla Proteina C attivata (e/o Fattore V Leiden

Mutazione G20210A del gene della Protrombina

Antitrombina

Proteina C

Proteina S (dosaggio immunologico della frazione libera)

Omocisteina e ?

Ricerca fenomeno Lupus Anticoagulant (LAC)

Anticorpi anticardiolipina

Fattore VIII

*è opportuno avere un criterio di funzionalità epatica: eseguire PT


Prof rosanna abbate univ di firenze

Raccomandazioni per lo screening

di laboratorio

Storia documentata di TEV in assenza di circostanze a rischio trombotico elevato (neoplasia o chirurgia ad alto rischio) o

TFS ricorrenti

o patologia gravidica (MEF 20 sett,aborti ?, preeclampsia severa, IUGR) dopo esclusione di altre cause

Storia documentata di trombosi arteriosa (limitatamente al dosaggio omocisteina basale o alla ricerca LAC/ACA)


Prof rosanna abbate univ di firenze

Raccomandazioni per lo screening

di laboratorio

Donne asintomatiche con storia familiare positiva per TEV o TFS ricorrenti prima della prescrizione di estroprogestinici o di trattamento sostitutivo ormonale o prima della programmazione della prima gravidanza (senza la ricerca LAC/ACA) 1

Familiari di primo grado di soggetti diagnosticati portatori di trombofilia ereditaria 2


Prof rosanna abbate univ di firenze

Linee guida per l’esecuzione di

uno screening per trombofilia

  • In linea generale lo screening per trombofilia non va eseguito durante*:

la fase acuta di un evento trombotico sia venoso che arterioso

la terapia anticoagulante (eparina, anticoagulanti orali)

malattie intercorrenti acute che possono influenzare i risultati

trattamento estro-progestinico

la gravidanza

in caso di epatopatie gravi

B) Si consiglia di eseguire lo screening per trombofilia a distanza di almeno tre mesi dall’evento tromboembolico venoso acuto e dopo la sospensione del trattamento anticoagulante da almeno 20-30 gg.

*tali controindicazioni non riguardano i test genetici


Prof rosanna abbate univ di firenze

Raccomandazioni di profilassi

antitrombotica primaria

Profilassi con eparina LMW in tutti i soggetti portatori di trait trombofilico in occasione di chirurgia (anche se a basso rischio), ingessatura, immobilizazione


Prof rosanna abbate univ di firenze

Raccomandazioni di profilassi antitrombotica in gravidanza e puerperio

Profilassi per tutto il puerperio in tutte le donne portatrici di trait trombofilico

Profilassi per tutta la gravidanza e il puerperio nelle donne con storia di TEV o TFS

Profilassi per tutta la gravidanza nelle donne con storia di patologia gravidica e presenza di trait trombofilico

Profilassi per tutta la gravidanza e il puerperio nelle donne con difetto di AT, PC,PS, omozigosi o difetti multipli


Prof rosanna abbate univ di firenze

Raccomandazioni di profilassi

antitrombotica secondaria a tempo indeterminato

Pazienti con un episodio idiopatico di TEV e presenza LAC/ACA ad alto titolo, malattia neoplastica, presenza di traits trombofilici combinati

Pazienti con due o più episodi idiopatici di TEV, indipendentemente dall’esito dello screening laboratoristico


Prof rosanna abbate univ di firenze

Duration of OAT after VTE (ACCP CHEST 2004)

First event with reversible or time-limited risk factor 1A

3 mo

Idiopathic VTE, first event 1A

6-12 mo

to lifetime

First event* with

Cancer until resolved 1C

Anticardiolipin antibody 1C

Combined deficiency 2C

AT,PC,PS FV Leiden FII202210 mutation, hcy, VIII 2C

Recurrent event, idiopathic or with thrombophilia 2A


Prof rosanna abbate univ di firenze

Controindicazioni a trattamento

estroprogestinico

Donne con storia di TEV o TFS o

trombosi arteriosa

Donne asintomatiche con storia familiare positiva per TEV oTFS, e portatrici di trait trombofilico (in particolare difetto di AT, PC, PS, omozigosi o difetti multipli)


Prof rosanna abbate univ di firenze

High levels of FXI in venous thrombosis

2.5

2.0

1.5

OR

1.0

0.5

0

1

2

3

4

Quartile

Meijers JCM, NEJM 2000


Prof rosanna abbate univ di firenze

High levels of FIX in venous thrombosis

*= adjusted for age, sex and OC use

5.0

*

4.0

3.0

*

OR

2.0

*

*

1.0

0

<100

U/dl

100-125

U/dl

125-150

U/dl

>150

U/dl

Van Hylckama Vlieg, Blood 2000


Prof rosanna abbate univ di firenze

Thromboresistant Properties of Endothelium

FXa

Lipo-

protein

TFPI

TFPI

TFPI

Heparin

TF

FVIIa

FXa

HSPG

TFPI

TFPI

EC

Colman et al., 1994

Clin Med Gen Cardiol FI


Prof rosanna abbate univ di firenze

Odds Ratios for DVT, by TFPI levels

DVT n=473,contr n=473

OR (95% CI)

TFPI free antigen

10th percentile 1.7 (1.1 - 2.6)

5 th percentile 2.1 (1.1 - 4.1)

2nd percentile2.2 (0.89- 5.3)

TFPI total antigen

10th percentile 1.5 (0.98 - 2.3)

5 th percentile 2.1 (1.1 - 4.1)

2nd percentile3.0 (1.3 - 7.2)

TFPI activity

10th percentile 1.1 (0.73 - 1.8)

5 th percentile 1.6 (0.87 - 2.8)

2nd percentile2.4 (1.1 - 5.1)

Dahm A. et al. Blood, 2003

Clin Med Card FI


Prof rosanna abbate univ di firenze

TAFI - Mechanism of Action

Thrombin

PLG

aTAFI

TAFI

t-PA

Pro-Carboxypeptidase

- COOH -

Lysine

Modified Fibrin

(unlinked with

Lysine)

PLI

Fibrin

Endothelial Cells

Clin Med Card FI


Prof rosanna abbate univ di firenze

Risk for recurrent VTE according to TAFI level.

(P= .006, Wilcoxon rank sum test; P= .02, log rank test)

30

20

10

0

TAFI ≥75th percentile

Cumulative probability of recurrence (%)

TAFI <75th percentile

0 12 24 36 48 60

Months after discontinuation of anticoagulaton

No. of Patients of Risk

TAFI ≥75th percentile 154 123 100 6541 27

TAFI <75th percentile 446 387 331 261 195 139

Clin Med Card –FI Eichinger S et al., Blood 2004


Prof rosanna abbate univ di firenze

Recurrent VTE after discontinuation of OAT

Factor V Leiden

0.2

NO Factor V Leiden

Cumulative probability

of recurrence

0.1

0.0

12

24

36

Months

Clin Med Card –FI Eichinger et al, Thromb Haemostas 1997


Prof rosanna abbate univ di firenze

Independent* risk factors for idiopathic VTE

2.1 (1.3-3.4)

Lp(a)>300 mg/L

4.0 (1.4-10.2)

aCL

4.1 (1.4-10.2)

Homocysteine

4.5 (2.5-8.0)

Factor V

Leiden

1

2

3

4

5

6

7

8

9

10

*Adjusted for acquired (trauma, surgery, use of oral contraceptives, pregnancy and puerperium, hormone replacement therpay), and thrombophilic risk factors

OR (95% CI)

Am J Med 2003


Prof rosanna abbate univ di firenze

Independent* risk factors for recurrences

Factor V Leiden

+

FII

polymorphisms

3.7 (1.6-8.4)

5.0 (3.0-8.4)

Homocysteine

5.1 (3.1-8.4)

Lp(a)>300 mg/L

1

2

3

4

5

6

7

8

9

10

Am J Med 2003

*Adjusted for acquired (trauma, surgery, use of oral contraceptives, pregnancy and puerperium, hormone replacement therpay), and thrombophilic risk factors

OR (95% CI)


Prof rosanna abbate univ di firenze

An association between atherosclerosis

and venous thrombosis

OR for carotid plaques in patients with

spontaneous vs secondary

Venous thrombosis = 2.495% CI(1.4-4.0)

Paolo Prandoni et al., NEJM 2004


Has dd a predictive role for vte recurrences after oat withdrawal

Has DD a predictive role for VTE recurrences after OAT withdrawal?

  • Normal DD levels at 3 m from OAT withdrawal have a very high NPV (95.6%) for VTE recurrence

Palareti 2001


Prof rosanna abbate univ di firenze

Residual Vein Thrombosis and D-dimer are independent risk factors for recurrence after a first episode of VTECosmi et al, O141

Residual Vein Thrombosis :HR 2.7 1.1-6

High D-Dimer : HR 2.7 1.1-6.3

RVT and high D-Dimer: HR 5.1 2.3-9


Sources of variation in d dimer testing

Sources of variation in D-dimer testing

  • Due to patient characteristics

  • Extent of VTE

  • Duration of symptoms

  • Anticoagulant treatments

  • Age

  • Co-morbid conditions


Possible sources of d dimers

Possible sources of D-dimers

  • Venous clots

  • Arterial clots

  • Extravascular fibrin (ascitic fluid)

  • Surgical lesions

  • Large skin lesions

  • Atherosclerotic lesions

  • Large hematomas


Prof rosanna abbate univ di firenze

Problemi aperti

Trait trombofilico e malattia neoplastica

Trait trombofilico e tamoxifene

Trait trombofilico e fecondazione assistita

Trait trombofilico e viaggio aereo


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