Thrombophilia screening Gualtiero Palareti Dept. Angiology & Blood Coagulation “Marino Golinelli” University Hospital S. Orsola-Malpighi Bologna, Italy
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