friday talk #1 moll - thromophilia - gasco talk 1 moll...9/13/2017 1 stephan moll, md medicine,...
TRANSCRIPT
9/13/2017
1
Stephan Moll, MD
Medicine, Heme-Coag
UNC Chapel Hill, NC
GASCO
Atlanta
Sept 8th , 2017
Thrombophilia
12
3
4 5APLA
ACALA
Anti-ß2-GP I
Disclosures
Off-label product use discussion: NONE
Conflicts of interest: NONE
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Topics
Introduction
Whom to Test
When to Test
My Choosing Wisely® Suggestions
What to Test
Introduction
2 3 41 5 6 7
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VTE due to major transient risk factor
Woman with unprovoked VTE
Woman with VTE on hormones
Long-term
3 months
Recurrence Triangle
• PE• DVT
Man with unprovoked VTE
Non-major transient risk factor
• PE• DVT
Stro
ng
T
hro
mb
op
hilia
D-d
imer
+
-
[Choosing Wisely®; Hicks LK, et al. Hematology Am SocHematol Educ Program. 2014;2014: 599-603]
ACCP, AHA, ISTH, BJH
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1. APLA syndrome
2. Antithrombin deficiency
3. Protein C deficiency
4. Protein S deficiency
5. Homozygous factor V Leiden
6. Homozygous II20210 mutation
7. Heterozygous FVL plus heterozygous II20210
“Strong” Thrombophilias
Yes
yes / no
unknown
yes / no
[Segal J et al. JAMA 2009; 301:2472-85][Lijfering WM et al. Circulation 2010;121:1706-12]
[Garcia D et al. Blood 2013;122:817-824]
VTE due to major transient risk factor
Woman with unprovoked VTE
Woman with VTE on hormones
Long-term
3 months
• PE• DVT
Man with unprovoked VTE
Non-major transient risk factor
• PE• DVT
Recurrence Triangle
1 year
1 % 3 %
5 % 15 %
10 % 30 %
5 years
Cumulative VTE Recurrence Rate
[Kearon C et al. Blood 2014;123:1794-1801]
6 % *
*[Douketis J et al. BMJ 2011;342:d813]
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Downsides of Thrombophilia Testing
1. Don’t over-focus on the thrombophilia
Take-home point
Clinic Patient
39 year old woman…
• Proximal arm DVT and PE 4/2016
• VTE risk factors: (a) hetero FV Leiden, (b) hetero II20210 mutation.
• FH: Parents with VTE. “Neither one of them has factor V or factor II”.
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Clinic Patient
Father
100051316642
Mother
Downsides of Thrombophilia Testing
1. Don’t over-focus on the thrombophilia
2. Caveat: Wrong test ordered
3. Caveat: Misinterpretation of tests
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Decision Making Based on Thrombophilia
62 year old…
• proximal leg DVT 3 weeks after hip replacement surgery
• APLA testing positive = life-long anticoagulation
Downsides of Thrombophilia Testing
1. Don’t over-focus on the thrombophilia
2. Caveat: Wrong test is ordered
3. Caveat: Misinterpretation of tests
4. Caveat: Wrong/questionable decision making based on test result
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Cost
$ 632.00
$ 398.00
$ 772.00
$ 356.00
$ 226.00
$ 2,681.00
$ 221.00
Cost
$ 772.00
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Downsides of Thrombophilia Testing
1. Don’t over-focus on the thrombophilia
2. Caveat: Wrong test is ordered
3. Caveat: Misinterpretation of tests
4. Caveat: Wrong decision making based on test result
5. Be aware of cost of testing
What to Test?
Whom to Test?
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• Factor V Leiden
• Prothrombin 20210
• Protein C deficiency
• Protein S deficiency
• Antithrombin deficiency
• Antiphospholipid antibodies(ACA, LA, anti-β2-GPI)
• ↑ Homocysteine, MTHFR
• ↑ Fibrinogen, factor VIII, IX, XI
• PAI-1, tPA levels and polymorphisms
• CBC, CD55/59, JAK-2 + CALR
Acquired
Most common
Classics
Others
Inherited and Acquired Thrombophilias
Whom to Test
• Controversial
• Guideline in development: ASH 2015, ongoing
• Terminology used:
• “testing can be considered”
• “benefit of testing unclear”
• “lack of evidence that testing impacts clinical outcomes”
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Any pt with
spontan. VTE
Young pt
with FHx
Any pt
with VTE
Everybody Young pt Nobody
Whom to Test for Thrombophilia?
NihilistUltra-liberal
1
2
3
4
5
DVT/PE, intermediate risk recurrence
VTE in unusual locations, unprovoked
Arterial thrombosis, unexplained
VTE: Patient requests testing
Family members (if “strong thrombophilia” in index pt)
In Whom I Consider Testing
Pregnancy loss(es), unexplainedNo
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VTE due to major transient risk factor
Woman with unprovoked VTE
Woman with VTE on hormones
Long-term
3 months
Recurrence Triangle
• PE• DVT
Man with unprovoked VTE
Non-major transient risk factor
• PE• DVT
Stro
ng
T
hro
mb
op
hilia
D-d
imer
+
-
[Choosing Wisely®; Hicks LK, et al. Hematology Am Soc Hematol Educ Program. 2014;2014: 599-603]
ACCP, AHA, ISTH, BJH
Recurrence Triangle
In VTE patients: In intermediate risk-of-recurrence patients I consider testing
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Risk of 1st VTE with thrombophilias
[Mo
ll S
. J T
hro
mb
Th
rom
bol
ys 2
01
5; ;
39
(3):
367
-78]
Relative risk increase for first VTE
No thrombophilia Reference group
II20210, hetero 3.8 (95% CI 3.0-4.9)
FVL, heterozygous 4.9 (95% CI 4.1-5.9)
II20210, homozygous Insufficient data
FVL, homozygous 18 (95% CI 4.1-41)
Hetero II20210 PLUS hetero FVL
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)
Risk of Recurrent VTE with Thrombophilias
(95% CI 0.96-2.21)II20210, hetero: 1.45
(95% CI 1.14-2.12)FVL, hetero: 1.561
[Segal J et al. JAMA 2009; 301:2472-85]
(95 % CI 1.18-5.97)FVL, homo: 2.65
[Segal J et al. JAMA 2009; 301:2472-85; meta-analysis]
FVL, homo: 1.2 (95 % CI 0.5-2.6)
[Lijfering WM et al. Circulation 2010;121:1706-12]
2
(95 % CI 0.50-46.3)FVL + II2010: 4.81
[Segal J et al. JAMA 2009; 301:2472-85; meta-analysis]
FVL + II2010: 1.0 (95 % CI 0.6-1.9)
[Lijfering WM et al. Circulation 2010;121:1706-12]
3
II20210, homo: insufficient data4
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Protein C
Protein S
Antithrombin
2.8 (95 % CI 2.0 – 4.0)
[Lijfering WM et al. Circulation 2010;121:1706-12]
5
[Garcia D et al. Blood 2013;122:817-824]
(95 % CI 0.99-2.00)
(95 % CI 0.76-3.11)
(95 % CI 0.83-9.64)
APLA: 1.41
ACA: 1.53
LA: 2.83
APLA syndrome:[Kearon C et al; Chest 2012;141:e419S-494S]
2.0
6
Risk of Recurrent VTE with Thrombophilias
Acquired deficiency:
• Liver disease (C, S, AT)
• Warfarin therapy (C, S)
• Estrogens, pregnancy (S)
• Inflammatory diseases (S)
• Heparin therapy (AT)
• Acute thrombosis (S, AT)
Protein C, S and Antithrombin Deficiency
How do you test?
• C, S, AT activity
• free S antigen
• >100 mutationsHow do you treat?
• Consider AT concentrate
• Severe neonatal C deficiency: protein C concentrate
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APLA
ACALA
Anti-ß2-GP I
I) Antibody test (ELISA)
• anticardiolipin
• anti-ß2-glycoprotein I
• antiphosphatidylserine
• antiphosphatidylcholine
• antiphosphatidylethanolamine
II) Functional test
• lupus anticoagulant (inhibitor)
[Sapporo criteria: Miyakis S. J Thromb Haemost. 2006;4:295-306]
Antiphospholipid Antibodies
[Miyakis S, et al. J Thromb Haemost. 2006;4:295-306]
Updated Sapporo Criteria for APS (2006):
Clinical criteria:
– Vascular thrombosis
– Pregnancy morbidity
Laboratory criteria*:
– Anticardiolipin antibodies (IgG or IgM)(medium or high titer: >40 GPL/MPL or >99th percentile)
– Anti-β2-glycoprotein I antibodies (IgG or IgM) (>99th percentile)
– LA
*2 or more occasions, >12 wks apart.
APLA: Sapporo/Sydney Criteria
[J Thromb Haemost. 2014 May;12(5):792-5]
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[Galli M, et al. Blood. 2003;101:1827-1832; Ruffatti A, et al. Thromb Haemost. 2006;96:337-341]
Conclusions:
1. LA stronger and more definitive risk factor for
thrombosis than ACA.
2. Risk for thrombosis is highest if positive APLA
by multiple assays.
APLA: Risk for 1st Thrombosis
Are APLA a Risk Factor for Recurrent VTE?
[Garcia D et al. Blood 2013;122:817-824]
• 8 eligible studies
• All had important methodologic limitations.
• “We judged the overall quality of the evidence as very low”.
Systematic Review
• Although it appears that pos. APLA predict ↑’d risk of VTE
recurrence, the strength of this association is uncertain.
Conclusion
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Risk for Recurrent VTE
[Garcia D et al. Blood 2013;122:817-824]
1. Are APLA a risk factor for recurrent VTE? “They appear to be!”
Risk for Recurrent VTE
2. Which of the APLA best predicts recurrent VTE?
LA
ACA
[Garcia D et al. Blood 2013;122:817-824]
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• “APLA syndrome”: question the diagnosis
• moderately high titers of ACA (40 U/mL)
• Include anti-β2-GP-I antibody testing
• Test outside the acute event
• Repeat APLA testing (3 months apart)
• Know the LA tests and their interpretation
APLA: Practical Points
• Role of IgA antibodies unclear
Practical point:
Don’t Test for MTHFR.
Practical point:
Test for homocysteine?– no good indication.
• MTHFR C677T, homozygous TT, or A1298C
• May have higher homocysteine levels
• Not a risk factor for thrombosis or pregnancy complications
Homocysteine, MTHFR
MTHFR=methylenetetrahydrofolate reductase
[den Heijer MJ. Thromb Haemost. 2005;3:292-299][Klerk M. JAMA. 2002;288:2023-2031]
[Rey E. Lancet. 2003;361:901-908[ACOG Bulletin #124, 2011]
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Factor VIII
Factor VIII NOT a useful clinical tool to predict recurrent VTE
1 2 3 4 5
Arterial thromboembolism
6 7
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Unexplained Arterial Thrombosis
1. Arteriosclerosis documented or risk factors present?
2. Cardioembolic source?
3. Other causes (hormones, cocaine, vasculitis, etc?)
4. Thrombophilia?
[Moll S. J Thromb Thrombolys 2015; ;39(3):367-78]
Arterial Thrombosis
FVL: OR 1.21 (95% CI, 0.99-1.49)
II20210: OR 1.32 (95% CI, OR 1.03-1.69)
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)
Antithrombin deficiency
• “Not a risk factor”Mahmoodi BK, et al. Circulation. 2008;118:1659-1667]
[Kim RJ et al. Am Heart J 2003;146:948-957]
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Unexplained Arterial Thrombosis
How to best treat (secondary prevention)?
1. Anti-platelet therapy?
2. Anticoagulant?
3. Both together?
1 2 43 5
When to Test?
6 7
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Influence of Anticoagulants on Thrombophilia Tests
[Moll S. J Thromb Thrombolys 2015;39:367-378]
When To Test
$ 632.00
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Which Family Members to Test for Thrombophilia
1 2 53 4 6 7
Multi-factorial Nature of VTE
• Fam H/o VTE
• Thrombophilia (mild, “strong”)
• Hormones
• Body mass index
• Smoking
• Previous surgeries, fractures, pregnancies, hormone use WITHOUT VTE
• What is this ASYMPTOMATIC family member’s ABSOLUTE risk for VTE?
[Noboa S, et al. Thromb Res. 2008;122:624-629]1. [Bezemer ID, et al. Arch Intern Med. 2009;169:610-615]
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Which Family Members to Consider for Thrombophilia Screening?
Proband’s thrombophilia
Male Family Member
Sons Brothers
Hetero FVL or hetero prothrombin 20210
no no
Homo FVL or homo prothrombin 20210
no reasonable
Double hetero reasonable reasonable
C, S, ATreasonable reasonable
Female Family Member
Daughters Sisters
no no
no yes
yes yes
yes yes
“Reasonable” because: consider LMWH with airline travel, cast, non-major surgery; prolonged after major surgeries.“reasonable”
“Yes” because: advise against estrogen contraceptives/hormone therapy; give ante-and postpartum anticoagulation.“yes”
Pregnancy Loss and
Other Poor Pregnancy Outcomes
1 2 3 5 64 7
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Pregnancy Loss / Complications
[Skeith L et al. Blood 2016;127:1650-5]
Pregnancy Loss / Complications
[Skeith L et al. Blood 2016;127:1650-5]
All trials
Multicenter trials only
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Pregnancy loss + thrombophilia (other than APLA): LMWH treatment
NOT indicated.
1
Pregnancy loss: thrombophilia testing NOT indicated (other than
APLA)2
ACOG
[Obstet Gynecol 2013 Sep;122(3):706-17]
Testing NOT recommended for recurrent pregnancy loss,
placental abruption, IUGR or preeclampsia
Inherited thrombophilias
APLA
Testing may be appropriate for women with fetal loss
1
2
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My Choosing Wisely® Suggestions
1 2 3 4 75 6
My Choosing Wisely® Suggestions
My 15 Choosing Wisely® Suggestions
a) For health care professionals
b) For clinical laboratories
c) For hospital systems
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My Choosing Wisely® Suggestions
Thrombophilia Testing
4. … if not able to interpret the test or don’t know what to do with the results.
3. … while patient is on an anticoagulant.
1. … during an acute thrombotic episode.
2. … a hospitalized patient.
Do NOT test ….
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Summary
1 Often little/no evidence of benefit of testing
3 When to test: NOT acutely, NOT inpatient, NOT on anticoagulation.
2 Whom to test?
1. ..
2. Unexplained unusual venous thrombosis
3. Unexplained arterial clot in the young
• Factor V Leiden
• Prothrombin 20210
• Protein C deficiency
• Protein S deficiency
• Antithrombin deficiency
• Antiphospholipid antibodies(ACA, LA, anti-β2-GPI)
• ↑ Homocysteine, MTHFR
• ↑ Fibrinogen, factor VIII, IX, XI
• PAI-1, tPA levels and polymorphisms
• CBC, CD55/59, JAK-2 (exon 12, CALR)
Acquired
Most common
Classics
Others
Summary
Inherited and Acquired Thrombophilias
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