Thrombophilia screening

Gualtiero PalaretiDept. Angiology & Blood Coagulation

“Marino Golinelli”University Hospital S. Orsola-Malpighi

Bologna, Italy

Ascertained thrombophilic alterations

Inherited

• Antithrombin deficiency Reduced anticoagulation

• Protein C deficiency “ “

• Protein S deficiency “ “

• Mut. R506Q (FV Leiden) Activated PC resistance

• Mut. G20210A (Prothrombin) Increased prothrombin levels

Mixed

• Increased F. VIII levels

Acquired

• Lupus Anticoagulant (LAC) Anti phospholipid Ab

Prevalence of thrombophilic alterations in the general population

Year Prevalence

Antithrombin 1965 0.05-0.2%

Protein C 1981 0.2-0.3%

Protein S 1984 ?

Mut. R506Q (FV Leiden) 1993-94 3-7%

Mut. G20210A (Prothrombin) 1996 1-3%

LAC ---- 3-5%

Increased F. VIII levels ---- 10%

Prevalence of thrombophilic alterations in subjects with VTE events

Prevalence RR

Antithrombin 1% 5-50

Protein C 3% 7-10

Protein S 1-2% 6-10

Mut. R506Q (FV Leiden) 15-20% 7-10

Mut. G20210A (Prothrombin) 6% 2-3

Increased F. VIII levels 25% 4

LAC 5% 9

May Thrombophilia Screening affect the initial treatment of DVT?

NO!!

May Thrombophilia Screening affect the choice of the initial anticoagulant

drug?

Not now

In future, an immediately active anticoagulant that does not need

antithrombin (AT) may be preferred when AT is reduced

May results of Thrombophilia Screening be useful to assess the risk

of recurrence?

From Baglin et al.Lancet 2003

(from Christiansen et al, JAMA 2005)

Ho et al, Arch Intern Med 2006

Risk of recurrence incommon thrombophilia

Recurrence in subjects with/without thrombophilia(Palareti et al. Circulation 2003)

D-d carried out 1 month after OAT interruption and recurrences (Palareti et al., Circulation 2003)

0 250 500 750 10000.0

0.1

0.2

0.3

0.4

Thrombophilic alterationsand altered D-Dimer

Thrombophilic alterationsand normal D-Dimer

Hazard ratio = 8.34(95%CI: 2.72-17.43)

Days

Cum

ula

tive p

robabili

ty o

fre

curr

ence

Cumulative probability of VTE recurrence according to the plasma levels of Factor VIII in patients with a first

unprovoked VTE.

0 250 500 7500.0

0.1

0.2

0.3

0.4

Chromogenic Factor VIII > 90th percentile

Chromogenic Factor VIII 90th percentile

Hazard ratio= 2.80 (95% CI: 1.47-16.8) p=0.0097

Days

Cu

mu

lati

ve

pro

ba

bil

ity

of

rec

urr

en

ce

Legnani et al, Br J Haematol 2004

Not all the thrombophilic defects carry the same risk

Risk of recurrent venous thromboembolism in patients with hereditary deficiency of either protein S, protein Cor antithrombin (Brouwer et al. Thromb Haemost 2009)

Conclusions: These patients have a high absolute risk of recurrence. The risk is increased after a first spontaneous event, and by concomitance of other thrombophilic defects.

What are annualised recurrence rates for unselected patients with

AT, PC, PS deficiency and

homozygotes and compound heterozygotes of FVL/F2G20210A ?

Trevor Baglin, Joseph Emmerich, Clive Kearon, Gualtiero Palareti, Paolo Prandoni, Sam Schulman

AT, PC, PS deficiency, all patients n = 223

recurrence by deficiency

p = ns

AT

PC

PS Annualised recurrence rates

recurr follow up

AT 16/46 (35%) 150 pt-yrs

10.7% (6.2 – 16.7)

PC 21/75 (28%) 321 pt-yrs

6.6% (4.1 – 9.9)

PS 25/102 (25%) 286 pt-yrs

8.7% (5.7 – 12.6)

recurrence by defect

p = ns

FVL hom

FVLF2 comp

F2 hom

Annualised recurrence rates

recurr follow up

FVL/ 10/23 (43%) 90 pt-yrs

FVL 11.1% (5.5 – 19.5)

FVL/ 12/45 (27%) 176 pt-yrs

F2 6.8% (3.6 – 11.6)

F2/ 3/12 (25%) 55 pt-yrs

F2 5.5% (1.1 – 15.1)

FVL & F2G20210A, all patients n = 80

May results of Thrombophilia Screening influence the duration of

anticoagulation?

An indefinite anticoagulation can be suggested in carriers of AT, PC, PS

deficiency or combined defects whose 1st event was idiopathic

May Thrombophilia Screening be useful in particular groups of patients?

Examples:

•Women with 1st VTE during pregnancy

•Children with 1st VTE

Does thrombophilia screeninghelp us manage patients

with a history of VTE during pregnancy?

American College of Obstetricians and Gynecologists

Int J Gynaecol Obstet 2001;75:203-12.

Pregnant subjects with previous VTE(ACOG 2001)

Pregnant patients with a history of thrombosis found to be antithrombin III deficient, homozygous for the factor V Leiden mutation or prothrombin G20210A mutation, or heterozygous for both mutations should be given therapeutic anticoagulation for the duration of their pregnancy and in the postpartum period.

All other patients are candidates for prophylactic anticoagulation in the antepartum and postpartum period.

..compared with children with the FV mutationor no thrombophilia, children with the FII variant are atincreased risk for recurrent VTE. This may have significant implications on outcome and possibly treatment modalities.

May results of Thrombophilia Screening of a pt with DVT be useful

for relatives?

Yes, for asymptomatic carriers

•To reduce exposition to other risk factors

•To offer appropriate prophylaxis in high-risk situations

Synergic effect of some risk factors

Risk

• Gene-gene interaction Mut. R506Q (FV Leiden) heteroz. Mut. R506Q (FV Leiden) homoz.

7-1070-90

• Gene-environment interaction Pill Mut. R506Q (FV Leiden) Pill + Mut. R506Q (FV Leiden)

3-47-10

35-40

Hypothesis:Positive results may influence patient management such as: - prolonged anticoagulant treatment or - intensified prophylaxis in high-risk situations.

Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis

Coppens et al., J Thromb Haemost 2008; 6: 1474–7

Results:The OR for recurrence was 1.2 [95% CI 0.9-1.8] for tested vs. non-tested patients.

Anxiety significantly (p≤0.05) decreased in the altered group and a non-significant improvement in perceived health status after TS result communication was recorded in both altered and normal result subjects

(from Mazzolai, EJVES 2007)

Final comments: Thrombophilia screening in pts with DVT

- No influence on initial treatment

- Risk of recurrence

- Prolonged duration of anticoagulation in very high-risk subjects

- Possible information on selected groups (women/pregnancy; children)

- Useful for relatives, but only if associated with appropriate counseling