quale profilassi e quale terapia nei soggetti portatori di...

Quale profilassi e quale terapia

nei soggetti portatori di trombofilia

Bari, 9 aprile 2016

Maurizio Margaglione

Genetica Medica

Università di Foggia

• Emostasi

• Trombosi

• Trombofilia

• Test (genetici)

• Consulenza (genetica)

Profilassi, terapia e trombofilia

Trombofilia: semantica

• Presenza di una tendenza familiare ad alta

penetranza al tromboembolismo

Tendenza al tromboembolismo geneticamente determinato. (Lane DA et al, Thromb Haemost 1996;76:651-662.)

Trombofilia ereditaria

• Presenza di un difetto protrombotico

• Entrambi i casi

• Emostasi

• Trombosi

• Trombofilia

• Test (genetici)



Materiali Test

- Diagnostici

-Test del

portatore

Test genetici

- Presintomatici/ predittivi

- Predittivi di suscettibilità

- Test prognostici

- Farmacogenetici

- Indagini medico-legali

Cromosomi

(citogenetica)

DNA - RNA

(genetica

molecolare)

Altri (proteine,

metaboliti, ecc)

TEST DI SUSCETTIBILITA’

Who has a genetic risk?

TROMBOSI

EMORRAGIA

LABORATORY SCREENING Italian Working Group on Thrombophilia

October 2004

• AT heparin cofactor

• PC (functional assay)

• PS (immunologic assay)

• APC-resistance (and/or FV Leiden)

• PT 20210A

• Fasting homocysteine

• LAC and aPL (aCL e aGPI)

Routinary search for other polymorphisms in factor V,

factor II, and MTHFR (as well as in other genes) is

discouraged .

Altri polimorfismi NON UTILI per uno

screening trombofilico

• Factor V H1299R

• Factor VII

• Factor XIII V34L

• Beta Fbg -455GA

• Plt Ag HPA1 a/b

• MTHFR C677T

• MTHFR A1298C

• ApoLp B-100 R3500Q

• ApoE (e2, e3, e4)

• Beta-thromboglobulin

• PAI 4G/5G

• …….

• Emostasi

• Trombosi

• Trombofilia

• Test (genetici)



Monogenic vs. multifactorial model

Obesity

Contraceptives

Immobility

Trauma or

Surgery

VTE Risk Factors

Genetic

Predisposition

Genetic VTE Risk Factors

Coagulation

Factor V Leiden

Factor II 20210A

Antithrombin

Protein C

Protein S

Gain of

Function

Loss of

Function

~35% of patients with thrombosis have one of these risk factors

Obesity and Thrombophilia

BMI Risk Factor OR for Venous

Thrombosis 95% CI

OC use

< 25 No 1

≥ 30 No 3.04 1.66-5.57

≥ 30 Yes 23.78 13.35-42.34

Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE

FVL

< 25 No 1

≥ 30 No 2.48 2.13-2.88

≥ 30 Yes 7.86 4.70-13.15

Pomp, et al. Br J Haematol. 2007.


Obesity and Thrombophilia

BMI Risk Factor OR for Venous

Thrombosis 95% CI

OC use

< 25 No 1

≥ 30 No 3.04 1.66-5.57

≥ 30 Yes 23.78 13.35-42.34

Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE

Prothrombin 20210

< 25 No 1

≥ 30 No 2.45 2.12-2.82

≥ 30 Yes 6.58 2.31-18.69

FVL

< 25 No 1

≥ 30 No 2.48 2.13-2.88

≥ 30 Yes 7.86 4.70-13.15

Smoking and Thrombophilia

Smoking Risk Factor OR for Venous

Thrombosis 95% CI

Factor V Leiden

No No 1

Current No 1.43 1.26-1.63

Current Yes 5.05 3.46-7.38

Combined effect of smoking and genetic risk factors for VTE

Prothrombin 20210

No No 1

Current No 1.41 1.25-1.60

Current Yes 6.06 2.67-13.76


FV LEIDEN + FII A20210

RELATIVE RISK OF RECURRENT THROMBOEMBOLISM

Study FV Leiden FII A20210 Both

RR (95% CI) RR (95% CI) RR (95% CI)

De Stefano, 1999 1.1 (0.7-1.6) not evaluated 2.7 (1.4-5.0)

Margaglione, 1999 1.4 (0.7-2.6) 1.8 (0.9-3.8) 4.8 (1.9-12.2)

Study FV Leiden FII A20210 Both

HR (95% CI) HR (95% CI) HR (95% CI)

Lijfering, 2008 1.1 (0.8–1.6) 0.7 (0.4–1.2) 1.0 (0.5–1.8)

Any patient

with

spontaneous

VTE

Younger

patient with

VTE + family

history

Any

patient

with

VTE

General

population

Younger

patient

with

VTE

Arch-conservative Ultra-liberal

Nobody

Who Should Be Tested?

1. Nicolaides AN, et al. Int Angiol. 2005;24:1-26.

2. Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:1281-1295.

3. The Thrombosis Interest Group of Canada. Available at: http://www.tigc.org/

eguidelines/hypercoagstates.htm. 1. Grody WW, et al. Genet Med. 2001;3:139-148.

2. Baglin T, et al. Br J Haematol. 2010;149:209-220.

Am Coll Med

Geneticists, 20014 Br Committee for

Standards in

Haematol, 20105

Europ Genetics

Foundation,

Mediterranean League on

Thromboembolism,

Internat. Union of

Angiology, etc, 20051

Which Patient to Test for Thrombophilia?

CAP, 20022

Arch-conservative Ultra-liberal

Thrombosis Interest

Group of Canada, 20063

http://www.tigc.org/

“ In this real-world setting, testing for

inherited thrombophilia is frequently at

odds with the recommendations of the

CAP consensus conference. There is a

need for wider dissemination of concise

thrombophilia testing guidelines.”

Jackson et al. BMC Clinical Pathology 2008;8:3

Testing for hereditary thrombophilia: a retrospective

analysis of testing referred to a national laboratory

Consulenza genetica e test genetici

Eventuali problematiche

Sorensen et al. JTH 2011 Zoller et al. JTH 2011

Family history as a risk factor for VTE

Bezemer et al. Arch Intern Med. 2009

The Value of Family History as a Risk Indicator for Venous Thrombosis

Key Points About Positive Family History

• Positive family history (1st degree relative) is VTE

risk factor (2.5-4.2 fold increased risk)

• Risk is inversely related to age when VTE occurred

• Risk is independent of presence of known genetic

thrombophilias

• Risk is due to unknown/additional risk factor

Other Inherited Risk Factors

Hyperhomocysteinemia (?)

Factor VIII (mixed)

Dysfibrinogenemias

Factor V mutations Very rare

Factor II mutations

Unique mutations

ABO

Hemoglobinopathies

Chi va studiato?

Come interpretare un test positivo/negativo?

• Asintomatico

• Asintomatico a rischio

- Tr. arteriosa

- TVP

- Gravidanza

- EP/Ter Sost

• Sintomatico

- Tr. arteriosa

- TVP

- Gravidanza

• Asintomatico

• Adulto

• Minore

• Asintomatico a rischio

- Tr. arteriosa

- TVP

- Gravidanza

- EP/Ter Sost

• Sintomatico

- Tr. arteriosa

- TVP

- Gravidanza

Quali test eseguire?

Guidelines for testing for inherited thrombophilia

De Stefano, Rossi. Thromb Haemost 2013

Individuo sano/Asintomatico

• Indiscriminate testing for heritable

thrombophilia in unselected patients presenting

with a first episode of venous thrombosis is not

indicated.

• Testing for heritable defects and, in particular,

genetic testing should be avoided in children

unless there is a strong clinical indication for it.

British Society for Haematology

Br. J. Haematol. 2001;114:512-28

Br. J. Haematol. 2010;149:209-20

Arterial Thrombosis

Factors

Contributing

to

Thrombosis

Vessel Wall

Damage Altered Blood

Flow (Stasis)

Hypercoagulability

NO SCREENING FOR INHERITED THROMBOPHILIA

Testing for thrombophilia is unlikely

to be informative in an elderly

subject with a first venous

thromboembolism in whom the

family history is negative.

Paziente sintomatico

British Society for Haematology

Br. J. Haematol. 2001;114:512-28

• Testing is NOT recommended in unselected patients with UPPER LIMB

venous thrombosis (1B).

• Testing is NOT recommended in patients with CENTRAL VENOUS

CATHETER (CVC)-related thrombosis (1C).

• Testing for heritable thrombophilia after a first episode of cerebral vein

thrombosis (CVT) has uncertain predictive value for recurrence (C).

Decisions regarding DURATION OF ANTICOAGULANT THERAPY in

relation to the results of testing are NOT EVIDENCE-BASED.

• Testing is NOT indicated in patients with RETINAL VEIN occlusion (1B).

• Testing for heritable thrombophilia after a first episode of intra-abdominal

vein thrombosis has uncertain predictive value for recurrence (C). Br. J. Haematol. 2010;149:209-20



● a history of recurrent VTE;

● VTE before the age of 50 years;

● unprovoked VTE at any age; however, testing for protein C,

protein S, and antithrombin deficiency may be of lower

diagnostic yield in patients with a first lifetime VTE after age

50 years;

● VTE at unusual sites (eg, cerebral, mesenteric, portal,

hepatic);

● VTE patients with a positive family history of VTE; and

● VTE secondary to pregnancy, oral contraceptives, or hormone

replacement therapy.

Arch Pathol Lab Med 2002;126:1281-95

College of American Pathologists

Lo screening per trombofilia è indicato in caso di:

• Aborti ricorrenti (n=3) apparentemente inspiegati

• Morti endouterine ( n=1 >20 settimane di

gestazione)

• Preeclampsia, FGR non altrimenti spiegato

Prevenzione Del Tromboembolismo Venoso Associato Alla Gravidanza Statement condiviso tra le Società Italiana per lo Studio dell’Emostasi e

della Trombosi (SISET) e la Società Italiana di Ginecologia e Ostetricia (SIGO)

estensori del documento: E. Grandone, R. Abbate, V. De Stefano, E.M. Faioni, I. Martinelli,

G.Palareti, D. Tormene, F. Sirimarco, P. Martinelli. 2008

Trombofilia nella donna

Lijfering WM, et al. Blood 2009 113: 5314-5322

First venous thrombosis in relatives with thrombophilic defects

Low-risk

LR

High-risk

HR



Recurrent venous thrombosis

LR

HR

Cafolla et al. Eur J Haematol 2012;88:336-339

38 - 45

50 - 61 53 - 61 54 - 57 27 - 53 12 - 15 14 - 16

39 32 21

INTERACTION BETWEEN INHERITED AND AQUIRED FACTORS (a large family)

http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2011.01742.x/full#f1

1.6.1 Do not offer thrombophilia testing to patients who are

continuing anticoagulation treatment.

1.6.2 CONSIDER TESTING FOR ANTIPHOSPHOLIPID ANTIBODIES

IN PATIENTS WHO HAVE HAD UNPROVOKED DVT OR PE if it is

planned to stop anticoagulation treatment.

1.6.3 CONSIDER TESTING FOR HEREDITARY THROMBOPHILIA IN

PATIENTS WHO HAVE HAD UNPROVOKED DVT OR PE AND WHO

HAVE A FIRST-DEGREE RELATIVE WHO HAS HAD DVT OR PE if it

is planned to stop anticoagulation treatment.

1.6.4 Do not offer thrombophilia testing to patients who have had

provoked DVT or PE.

1.6.5 Do not routinely offer thrombophilia testing to first-degree

relatives of people with a history of DVT or PE and thrombophilia.

NICE 2012.

1.6 Thrombophilia testing

Value of Genetic Thrombophilia Testing

• Testing not useful for arterial thrombosis

• Testing does not affect management of acute events

• Test results may influence decisions

– Prophylaxis during high-risk procedures

– Need to evaluate family members

– Estimate future risk for venous thrombosis (i.e.,

pregnancy complications, risk associated with oral

contraceptives, etc.)

– How long & how intensively to treat (?)

• Prevention of recurrence

VTE

Threshold Number

of risk

factors

for VT

Venous thrombosis is a multifactorial disease

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