4 5 - AC Forum

4/10/15
APLA
1
2
3
Disclosures
4 5
ACA
LA
Anti-ß2-GP I
1.  Consultant for: rEVO Biologics (antithrombin)
Thrombophilia Testing
2. Speaker bureau: NONE
3. Off-label product use discussion: NONE
Stephan Moll, MD
Medicine, Heme-Coag
UNC Chapel Hill, NC
ACF, Washington, DC
2015
Testing: 6 Types of Patients
1
DVT or PE, selected patients
2
VTE in unusual locations
3
Arterial thrombosis, unexplained
4
Pregnancy loss
5
Patient requests testing
6
Family members of probands with strong thrombophilia
1 2 3 4 5 6
DVT/PE
Recurrence Triangle
Recurrence Triangle
VTE Recurrence Rate
1 year
VTE due to major transient risk factor
VTE due to major transient risk factor
+
Man with unprovoked VTE
•  DVT
•  PE
Other considerations: Bleeding risk; patient preference (“Warfarin Hate Factor”)
Woman with VTE on hormones
-
Non-major transient risk factor
D-dimer
Long-term
•  DVT
•  PE
D-dimer
Woman with unprovoked VTE
-
3 months
Woman with unprovoked VTE
Long-term
•  DVT
•  PE
Man with unprovoked VTE
•  DVT
•  PE
+
Strong
Thrombophilia
Woman with VTE on hormones
Non-major transient risk factor
Strong
Thrombophilia
3 months
5 years
1%
3%
5%
15 %
10 %
30 %
Men > women:
1.5 - 2.0x
D-Dimer pos > neg
1.5 - 2.5x
Hered. thrombophilia
̴ 1.5x
APLA
̴ 2.0x
[Kearon C et al. Blood 2014;123:1794-1801]
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4/10/15
“Strong Thrombophilias”
“Strong Thrombophilias”
1.  APLA syndrome
1.  APLA syndrome
2.  Antithrombin deficiency
2.  Antithrombin deficiency
3.  Protein C deficiency
3.  Protein C deficiency
4.  Protein S deficiency
4.  Protein S deficiency
5.  Homozygous factor V Leiden
5.  Homozygous factor V Leiden
yes / no
6.  Homozygous II20210 mutation
6.  Homozygous II20210 mutation
unknown
7.  Heterozygous FVL plus heterozygous II20210
7.  Heterozygous FVL plus heterozygous II20210
yes / no
Thrombophilia and Recurrent VTE
II20210, hetero: 1.45
(95% CI 0.96-2.21)
FVL, hetero: 1.56
(95% CI 1.14-2.12)
Thrombophilia and Recurrent VTE
[Segal J et al. JAMA 2009; 301:2472-85]
1
FVL, homo: 2.65
(95 % CI 1.18-5.97)
FVL, homo: 1.2
(95 % CI 0.5-2.6)
4
Protein C
5
Protein S
6
Antithrombin
2.8
(95 % CI 2.0 – 4.0)
[Lijfering WM et al. Circulation 2010;121:1706-12]
[Segal J et al. JAMA 2009; 301:2472-85]
[Lijfering WM et al. Circulation 2010;121:1706-12]
2
Yes
7
APLA: 1.41
(95 % CI 0.99-2.00)
FVL + II2010: 4.81
(95 % CI 0.50-46.3)
ACA: 1.53
(95 % CI 0.76-3.11)
FVL + II2010: 1.0
(95 % CI 0.6-1.9)
LA: 2.83
(95 % CI 0.83-9.64)
[Garcia D et al. Blood 2013;122:817-824]
[Segal J et al. JAMA 2009; 301:2472-85]
[Lijfering WM et al. Circulation 2010;121:1706-12]
APLA syndrome: ̴ 2.0
3
[Kearon C et al; Chest 2012;141:e419S-494S]
II20210, homo: insufficient data
#1
Recurrence Triangle
VTE due to major transient risk factor
3 months
Woman with VTE on hormones
Non-major transient risk factor
✔ Key Points
[Choosing Wisely®;
Hicks LK, et al. Hematology Am Soc
Hematol Educ Program. 2014;2014:
599-603]
[Choosing Wisely®;
Hicks LK, et al. Blood 2013;122:3879-83]
DVT/PE
Risk of recurrence triangle
Woman with unprovoked VTE
Long-term
•  DVT
•  PE
Man with unprovoked VTE
•  DVT
•  PE
I consider thrombophilia testing in intermediate risk of recurrence pts.
D-dimer is also helpful in these patients - and may be more important for
decision making than thrombophilia w/u.
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Example
1 2 3 4 5 6
•  38 yr old woman
•  Proximal leg DVT + segmental PE
•  VTE risk factors: (a) OCP x 4 months, (b) BMI 32.1
VTE in Unusual Locations
•  Testing: Homozygous FVLeiden; D-dimer (on anticoag) neg
Cont. anticoag; f/u in 1 year
Unusual Thromboses
Unusual Thromboses
Example: Cerebral and Sinus Vein Thrombosis
Length of treatment
•  General lack of data on VTE recurrence
•  Transient risk factor:
3-6 months
•  Difficult to know/decide how long to treat
•  Unprovoked clot:
6-12 months
•  Whatever one does is based on little good evidence.
•  Strong thrombophilia: Long-term
[Am Heart and Am Stroke Association: Saposnik G et al. Stroke 2011; 42:1158-1192]
1. Clot risk
2. Bleed risk
3. Patient preference
#2
✔
Key Point
1 2 3 4 5 6
Arterial Thrombosis
Unprovoked unusual thromboses
Thrombophilia testing: Yes
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Unexplained Arterial Thrombosis
Unexplained Arterial Thrombosis
1.  Arteriosclerosis documented or risk factors present?
2.  Cardioembolic source?
3.  Other causes (hormones, cocaine, vasculitis, etc?)
4.  Thrombophilia?
http://professionalsblog.clotconnect.org/2011/01/31/unexplained-arterialthrombosis-causes-thrombophilia-testing
[Moll S. J Thromb Thrombolys 2015; ;39(3):367-78]
Arterial Thrombosis
Arterial Thrombosis
FVL: OR 1.21 (95% CI, 0.99-1.49)
II20210: OR 1.32 (95% CI, OR 1.03-1.69)
How to best treat (secondary prevention?
[Kim RJ et al. Am Heart J 2003;146:948-957]
1.  Anti-platelet therapy?
Protein C and S deficiency
•  <55 yrs: 4.7-fold (95 % CI 1.5-4.2)
•  >55 yrs: 1.1-fold (95 % CI 1.1-18.3)
2.  Anticoagulant?
3.  Both together?
Antithrombin deficiency
•  “Not a risk factor”
Mahmoodi BK, et al. Circulation. 2008;118:1659-1667]
#3
✔
Key Point
Unexplained arterial thromboses
1 2 3 4 5 6
Which Family Members to Test
Thrombophilia testing: Yes - The more information, the better – even
though we don’t have all the answers.
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Which Family Members to Screen for Thrombophilia?
Risk of 1st VTE with thrombophilias
Relative risk increase
for first VTE
member’s risk for VTE.
Reference group
II20210, hetero
3.8 (95% CI 3.0-4.9)
FVL, heterozygous
4.9 (95% CI 4.1-5.9)
II20210, homozygous
•  Increased risk is irrespective of presence of FVL or II20210:
•  Positive FHx, but no FVL or II20210: OR 2.6 (95% CI, 1.7-3.8)
FVL, homozygous
•  Positive FHx plus FVL or II20210: OR 3.6 (95% CI, 1.2-4.0)
Hetero II20210 PLUS
hetero FVL
[Noboa S, et al. Thromb Res. 2008;122:624-629]
Insufficient data
18 (95% CI 4.1-41)
20 (95% CI 11.1-36.1)
Protein S deficiency
30.6 (95% CI 26.9-55.3)
Protein C deficiency
24.1 (95% CI 13.7-42.4)
Antithrombin deficiency
28.2 (95% CI 13.5-58.6)
1.  [Bezemer ID, et al. Arch Intern Med. 2009;169:610-615]
Which Family Members to Consider for Thrombophilia Screening?
Proband’s
thrombophilia
Male Family Member
Female Family Member
Contraceptive Options in Thrombosis / Thrombophilia
Estrogen combination pill
•  3rd generation
Sons
Brothers
Daughters
Sisters
Hetero FVL or hetero
prothrombin 20210
no
no
no
no
•  2nd generation
Homo FVL or homo
prothrombin 20210
no
reasonable
no
yes
•  Injectable progestins
reasonable
reasonable
yes
yes
reasonable
reasonable
yes
yes
Double hetero
C, S, AT
“reasonable” because: consider LMWH with airline travel, cast, non-major surgery;
“Reasonable”
prolonged after major surgeries.
“yes”
“Yes” because: advise against estrogen contraceptives/hormone therapy; give anteand postpartum anticoagulation.
#4
✔
Key Point
Family Screening
[Moll S. J Thromb Thrombolys 2015; ;39(3):367-78]
No thromobphilia
•  Having a 1st degree relative with VTE, increases a family
Norelgestromin & ethinyl estradiol
Etonogestrel & estradiol ring
Drospirenone & ethinyl estradiol
•  Depot proparation
•  rod
Progestin pill (minipill)
1
Progestin-releasing IUDs
Non-hormonal methods
1. Weiss G. Am J Obstet Gynecol. 1999;180:S295-S301.
2. Rosendaal FR, et al. Thromb Haemost. 2001;6:112-23.
3. Conard J, et al. Contraception. 2004;70:437-441.
4. Bergendal A, et al. Acta Obstet Gynecol Scand. 2009;88:261-266.
5. Barsoum M et al. Thromb Res 2010;126:373-8.
6. Van Hylkama-Vlieg A et al. Arterioscler Thromb Vasc Biol 2010;30:2297-300.
7. Mantha S et al. BMJ 2012;Aug 7;345:34944.
1 2 3 4 5 6
Pregnancy Loss
•  Mild thrombophilias: No
•  Strong thrombophilias: consider; caveat: female/male; siblings/children
Proband’s
thrombophilia
Male Family Member
Sons
Brothers
Female Family Member
Daughters
Sisters
Hetero FVL or hetero
prothrombin 20210
no
no
no
no
Homo FVL or homo
prothrombin 20210
no
reasonable
no
yes
reasonable
reasonable
yes
yes
reasonable
reasonable
yes
yes
Double hetero
C, S, AT
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#5
Pregnancy Loss
✔
Key Point
Anticoagulation in Pregnancy Complications
“Whether anticoagulant therapy prevents recurrent
miscarriage in women with inherited thrombophilia is
controversial – inconsistent results from trials.”
Unexplained pregnancy loss
Middeldorp S. Hematology 2014; ASH Education Program:393-399]
•  Benefit of testing and of LMWH treatment if thrombophilia found is
unclear.
•  Enroll patients into trials; or: non-evidence-based decision.
1 2 3 4 5 6
Patient Requests Testing
Patient Requests Testing
1 2 3 4 5 6 7
Who Should Test? When to Test?
1. Only the MD who is knowledgeable about the 4Ps should test.
•  Patient selection
Caveats
•  Pretest counseling
•  Proper lab test interpretation
•  Provision of education and advice
[Cushman M. Clin Chem 2014;50:134-7]
2. Do not test while patient is on an anticoagulant.
3. Do not test during acute thrombotic episode.
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Inherited and Acquired Thrombophilias
Most
common
•  Factor V Leiden
Summary
1
Whom to test?
•  Prothrombin 20210
•  Protein C deficiency
Classics
•  Protein S deficiency
•  Antithrombin deficiency
Acquired
•  Antiphospholipid antibodies
(ACA, LA, anti-β2-GPI)
2
•  ↑ Homocysteine, MTHFR
3
•  ↑ Fibrinogen, factor VIII, IX, XI
Others
•  PAI-1, tPA levels and polymorphisms
4
What to test?
1
DVT/PE, intermediate risk recurrence
2
VTE in unusual locations, unprovoked
3
Arterial thrombosis, unexplained
4
Pregnancy loss, unexplained
5
VTE: Patient requests testing
6
Family members
When to test?
Who should order tests?
•  CBC, CD55/59, JAK-2
7