friday talk #1 moll - thromophilia - gasco talk 1 moll...9/13/2017 1 stephan moll, md medicine,...

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

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e-mail

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]




Long-term

3 months

• PE• DVT



• 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



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



2. Caveat: Wrong test is ordered


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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2. Caveat: Wrong test is ordered


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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Long-term

3 months

Recurrence Triangle

• PE• DVT



• 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)


3

II20210, homo: insufficient data4

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Protein C

Protein S

Antithrombin

2.8 (95 % CI 2.0 – 4.0)


5


(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?


• 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


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


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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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1 2 3 4 75 6


My 15 Choosing Wisely® Suggestions

a) For health care professionals

b) For clinical laboratories

c) For hospital systems

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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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friday talk #1 moll - thromophilia - gasco talk 1 moll...9/13/2017 1 stephan moll, md medicine,...

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