1. Thrombophilia For the Clinician
Dr Cleona Duggan

2. 24-year-old healthy woman on birth control pills
Case Study
24-year-old healthy woman on birth control pills
L > R
by 4 cm
by 2.5 cm
The patient shown in this slide, a healthy 24-year-old woman on birth control pills, has a swollen left foot up to the groin; the patient avoids putting weight on the left foot.
Reprinted with permission from Moll S. Arterioscler Thromb Vasc Biol. 2008;28:
Moll S. A clinical perspective of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2008;28:

3. Natural Anticoagulant System
506
act. protein C
Normal Factor V Va
XII
VII X
Protein S Va
act. protein C
Factor V Leiden
506
act. protein C Va
Thrombin
Antithrombin
Activated protein C (APC) is a potent inhibitor of the coagulation system, cleaving the activated forms of factors V and VIII (FVa and FVIIIa). The factor V Leiden mutation is a point mutation in the factor V gene, leading to a factor V molecule with an arginine-to-glutamine substitution at position 506. This abolishes a cleavage site of APC and makes FVa less susceptible to inactivation, referred to as “APC resistance.” Factor V Leiden accounts for more than 90% of APC resistance.
Clot
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:
Foy P, Moll S. Thrombophilia: 2009 Update. Curr Treat Options Cardiovasc Med. 2009;11:

4. Factor V Leiden/Prothrombin 20210
Discovered
Prevalence
Caucasians
African Americans
Factor V Leiden1
1994 5%
1.2%
Prothrombin mutation2
1996 2%
0.5%
Data from a study by Ridker et al indicate that the prevalence of factor V Leiden is greater among Caucasians than minority Americans. The results have implications for screening for factor V Leiden in high-risk groups such as those with prior VTE or coexisting defects of anticoagulation and women at risk for postpartum thrombosis or seeking oral contraceptives.1
Heterozygous prothrombin mutations are found in about 2% of the US population. The mutation is uncommon in African Americans and is rare in Asians, Africans, and Native Americans.2
1. Ridker PM, et al. JAMA. 1997;277:
2. Varga EA, Moll S. Circulation. 2004;110:e15-e18.
Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leidin in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277:
Varga EA, Moll S. Prothrombin mutation (factor II mutation). Circulation. 2004;110:e15-e18.

5. Factor V Leiden/Prothrombin 20210
Prothrombin = II20210 = G20210A: mutation in promoter region, leading to increased factor II levels
Moderate/mild risk factor for DVT/PE
Only very mild risk factor for recurrent VTE (FVL OR, 1.41; prothrombin OR, 1.72)
Only marginal risk factor for arterial clots
Mild risk factor for pregnancy loss
The two most common genetic polymorphisms that predispose to a first episode of VTE are factor V Leiden and prothrombin Ho and colleagues performed a meta-analysis to estimate the relative risk of recurrent VTE associated with these traits. Pooled results from 10 studies involving 3104 patients with first-ever VTE found that factor V Leiden was present in 21.4% of patients and associated with an increased odds of recurrent VTE of Pooled results from 9 studies involving 2903 patients with first-ever VTE found prothrombin in 9.7% of patients and associated with an increased odds of recurrent VTE of
These data call into question the cost effectiveness of routine testing for these common inherited traits among patients with a first episode of VTE. For practical purposes, there is no clinically meaningful association between factor V Leiden or prothrombin and arterial thromboembolic events.2
Ho WK, et al. Arch Intern Med. 2006;166:
Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166:
Foy P, Moll S. Thrombophilia: 2009 Update. Curr Treat Options Cardiovasc Med. 2009;11:

6. Protein C, S, and Antithrombin Deficiency
Prevalence:
1:500 (C and S) to 1:5,000 (AT)
How do you test?
Activity
>100 mutations account for each deficiency; thus: genetic testing not done in routine practice
Acquired deficiency:
Liver disease (C, S, AT)
Warfarin therapy (C, S)
Estrogens, pregnancy (S)
Inflammatory diseases (S)
Heparin therapy (AT)
Acute thrombosis (S, AT)
Practical point:
Always question the diagnosis!
How do you treat?
Consider AT concentrate
Severe neonatal C deficiency: protein C concentrate
Protein, C, S, and antithrombin deficiency are tested by activity and antigen levels. There are more than 100 mutations accounting for each deficiency, so genetic testing is not useful in most cases.
Acquired deficiencies can be due to liver disease, inflammatory disease, acute thrombosis, warfarin therapy, estrogens, pregnancy, and heparin therapy.
Because of these influences of clinical scenarios and therapies on clotting factor levels, a physician should always question the diagnosis of inherited protein C, protein S, or antithrombin deficiency.
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21:7-15.

7. Other Thrombophilias Elevation of factor VIII
Elevations of fibrinogen, factors II, IX, XI
Fibrinolysis abnormalities:
Plasminogen deficiency
Decreased tPA levels and polymorphisms
Elevated PAI-1 level and polymorphisms
Elevated TAFI levels
Myeloproliferative disorders (JAK-2 mutation)
Paroxysmal nocturnal hemoglobinuria (PNH)
While elevated factor VIII levels are a risk factor for first episode of VTE, data about its role as a risk factor for recurrent VTE have been less consistent. Results of studies looking for associations of fibrinolysis abnormalities, include plasminogen deficiency and polymorphisms and decreases in tPA, PAI-1, and TAFI, with venous and arterial thromboembolism have often been inconsistent.
tPA=tissue plasminogen activator; PAI-1=plasminogen activator inhibitor 1; TAFI=thrombin activatable fibrinolysis inhibitor.
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:
Foy P, Moll S. Thrombophilia: 2009 Update. Curr Treat Options Cardiovasc Med. 2009;11:

8. Obesity and Thrombophilia
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Obesity is a risk factor for VTE
Conclusion: lose weight
Odds ratio
The presence of obesity greatly increases the risk associated with other factors (oral contraceptives, factor V Leiden, and prothrombin 20210) for thrombophilia. For example, oral contraceptive use and obesity increases the risk more than 20-fold.
Conclusion: Lose weight.
<20
≥20 and <22.5
≥22.5 and <25
≥25 and <27.5
≥27.5 and <30
≥30 and <32.5
≥32.5 and <35
≥35
BMI np nc
Reprinted with permission from Pomp ER, et al. Br J Haematol. 2007;139:
Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007;139:

9. Obesity and Thrombophilia OR for Venous Thrombosis
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous Thrombosis
95% CI
OC use
< 25 No 1
≥ 30
3.04
Yes
23.78
This slide presents further analysis of data from the study by Pomp et al.
Pomp ER, et al. Br J Haematol. 2007;139:
Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007;139:

10. Obesity and Thrombophilia OR for Venous Thrombosis
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous Thrombosis
95% CI
OC use
< 25 No 1
≥ 30
3.04
Yes
23.78
FVL
< 25 No 1
≥ 30
2.48
Yes
7.86
This slide presents further analysis of data from the study by Pomp et al.
Pomp ER, et al. Br J Haematol. 2007;139:
Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007;139:

11. Obesity and Thrombophilia OR for Venous Thrombosis
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous Thrombosis
95% CI
OC use
< 25 No 1
≥ 30
3.04
Yes
23.78
FVL
< 25 No 1
≥ 30
2.48
Yes
7.86
Prothrombin 20210
2.45
6.58
This slide presents further analysis of data from the study by Pomp et al.
Pomp ER, et al. Br J Haematol. 2007;139:
Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007;139:

12. Smoking and Thrombophilia OR for Venous Thrombosis
Combined effect of smoking and genetic risk factors for VTE
Conclusion: stop smoking
Smoking
Risk Factor
OR for Venous Thrombosis
95% CI
Factor V Leiden No 1
Current
1.43
Yes
5.05
Smoking also greatly enhances the risk associated with other factors (factor V Leiden, and prothrombin 20210) for thrombophilia. For example, factor V Leiden and smokers are at 6-fold increased risk of venous thrombosis.
Prothrombin 20210 No 1
Current
1.41
Yes
6.06
Pomp ER, et al. Am J Hematol. 2008;83:
Pomp ER, Rosendaal FR, Doggen CJM. Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Hematol. 2008;83:

13. Contraceptives and Thrombosis1,2
Risk  compared to women who do not take OCP
Absolute risk/year
All women of reproductive age 1
1 : 12,500
OCP
2-6x ’d
1 : 3,000
Hetero FVL
4x ’d
Hetero FVL + OCP
20-30x ’d
1 : 500
BMI >30 + OCP
24x ’d
Homozygous FVL + OCP
50-100x ’d
1 : 150
BMI >30 + smoking + OCP
???
Homozygous FVL + BMI >30 + smoking + OCP
Risk of thrombosis with contraceptive use increases from 2- to 6-fold with contraceptive use alone to more than 50-fold when homozygous factor V Leiden is present. The risk is increased further when obesity and smoking are also present.1,2 Knowing the absolute risk data helps the clinician discuss thrombotic risk with a patient in a more meaningful way than talking about relative risks.
OCP=oral contraceptive; BMI=body mass index.
Varga E. J Genet Couns. 2007;16:
Pomp ER, et al. Br J Haematol. 2007;139:
Varga E. Inherited thrombophilia: key points for genetic counseling. J Genet Couns. 2007;16:
Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007;139:

14. Thrombophilia Testing

15. Pros and Cons of Thrombophilia Testing
“Power to prevent clots”
surgery (red flag)
birth control pill, pregnancy
Explanations
Influence on medical treatment
choice of drug (antiplatelet vs anticoagulation)
length of warfarin therapy
intensity of warfarin therapy
Cons
Cost
Worry
Bad medical advice
Insurance implications
Controversy exists with respect to which individuals to test for thrombophilia and what tests to administer. If testing is pursued, then appropriate testing and correct interpretation of test results is essential, as well as education of the patient about the relevance of the detected thrombophilia.
Physicians may want to test for the presence of thrombophilias because test results may influence the decision to initiate prophylactic anticoagulant treatment, the choice of drug or the length of treatment after a thrombosis. Testing can also help explain why a patient developed a thrombosis, help counsel about future risk, and help in advising asymptomatic family members to get tested.
Reasons against testing include the lack of therapeutic consequences even if a thrombophilia is detected, the risk of misinterpretation of a test result and of incorrect medical advice, the risk of having to pay higher health or life insurance premiums or being denied insurance, and costs, among other issues.
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21:7-15.

16. Who Should Be Tested?1-4 Ultra-liberal Arch-conservative
Any patient with VTE
Any patient with spontaneous VTE
General population
Younger patient with VTE
Younger patient with VTE + family history
Nobody
There is no general consensus as to which patients and family members should be tested for thrombophilias. Current guidelines vary markedly in their recommendations as to who should and should not be tested, with some suggesting very limited testing, very liberal testing, or an intermediate level.1-4
Ultra-liberal
Arch-conservative
Grody WW, et al. Genet Med. 2001;3:
Walker ID, et al. Br J Haematol. 2001;114:
Nicolaides AN, et al. Int Angiol. 2005;24:1-26.
Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:
Baglin T, et al. Br J Haematol. 2010;149:
Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on Factor V Leiden mutation testing. Genet Med. 2001;3:
Walker ID, Preston EE, Baglin T, et al. Guideline. Investigation and management of heritable thrombophilia. Br J Haematol. 2001;114:
Nicolaides AN, Breddin HK, Carpenter P, et al. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence. Int Angiol. 2005;24:1-26.
Van Cott EM, Laposata M, Prins MH. Laboratory evaluation of hypercoagulability with venous or arterial thrombosis. Arch Pathol Lab Med. 2002;126:

17. Which Patient to Test for Thrombophilia?
Europ Genetics Foundation, Mediterranean League on Thromboembolism, Internat. Union of Angiology, etc, 20051
CAP, 20022
Thrombosis Interest Group of Canada, 20063
Am Coll Med Geneticists, 20014
Br Committee for Standards in Haematol, 20105
Currently available guidelines are listed in this slide.1-4
Ultra-liberal
Arch-conservative
Nicolaides AN, et al. Int Angiol. 2005;24:1-26.
Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:
The Thrombosis Interest Group of Canada. Available at:
Grody WW, et al. Genet Med. 2001;3:
Baglin T, et al. Br J Haematol. 2010;149:
Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on Factor V Leiden mutation testing. Genet Med. 2001;3:
Walker ID, Preston EE, Baglin T, et al. Guideline. Investigation and management of heritable thrombophilia. Br J Haematol. 2001;114:
Nicolaides AN, Breddin HK, Carpenter P, et al. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence. Int Angiol. 2005;24:1-26.
Van Cott EM, Laposata M, Prins MH. Laboratory evaluation of hypercoagulability with venous or arterial thrombosis. Arch Pathol Lab Med. 2002;126:

18. When to Consider Thrombophilia Testing
VTE occurring at a younger age (ie, <50 years)
Unprovoked VTE
Recurrent VTE
Thrombosis at an unusual site (splanchnic, sinus/cerebral, or renal veins)
Unusually extensive spontaneous VTE
Family history of VTE
Asymptomatic individual with family history of strong thrombophilia
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Homozygous factor V Leiden
Homozygous prothrombin mutation
Compound thrombophilias
This table lists the type of patients for whom thrombophilia testing can be considered. However, individual decisions, often in discussion with the patient, must be made when deciding whom and how extensively to test.
Recurrent VTE while adequately anticoagulated
Unexplained arterial thromboembolism in a young person (ie, no arteriosclerosis risk factors, no cardio-embolic source)
≥3 unexplained pregnancy losses before week 10, or ≥1 loss after week 10
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:
Foy P, Moll S. Thrombophilia: 2009 Update. Curr Treat Options Cardiovasc Med. 2009;11:

19. Family Implications of Thrombophilia

20. Why to Test an Asymptomatic Family Member
To put the person on anticoagulants
To manage the individual differently:
Lifestyle changes (obesity, smoking)
Advice on oral contraceptives, hormone therapy
Airline travel
Pregnancy
Surgery
Controversy currently exists regarding which patients and asymptomatic family members to test and also the extent of laboratory thrombophilia work-up in individual patients with venous or arterial thromboembolism.
A variety of reasons for and against testing can be cited, and weighted differently based on individual opinions. Asymptomatic family members might be appropriate to test if they have one or more additional risk factors for thrombophilia.
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21:7-15.

21. Key Points About Positive Family History
Positive family history (1st degree relative) is VTE risk factor ( fold increased risk)2
Risk is independent of presence of known genetic thrombophilias
Risk is due to unknown risk factor
A family history should be considered when estimating an individual’s risk for VTE. A family history of VTE is associated with VTE occurrence, irrespective of the presence of factor V Leiden mutation, G20210A prothrombin gene mutation, and acquired risk factors.1
Family history corresponds poorly with known genetic risk factors.2
Noboa S, et al. Thromb Res. 2008;122:
Bezemer ID, et al. Arch Intern Med. 2009;169:
Noboa S, Le Gal G, Lacut K, et al. Family history as a risk factor for venous thromboembolism. Thromb Res. 2008;122:
Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med. 2009;169:

22. Strategy for Familial Testing
Proband’s thrombophilia
Male Family Member
Sons
Brothers
Hetero FVL or hetero prothrombin 20210 no
Homo FVL or homo prothrombin 20210
reasonable
Double hetero
C, S, AT
Female Family Member
Daughters
Sisters no
yes
This slide presents one approach to familial testing for various thrombophilias.
“Reasonable,” because: consider LMWH with airline travel, cast, non-major surgery; prolonged after major surgeries.
“Yes,” because: advise against oral contraceptives/hormone therapy; give ante- and postpartum anticoagulation.
Slide courtesy of Moll S.

23. Lifestyle Changes Lose weight Stop smoking
Know the symptoms of DVT and PE
Know the risk factors for DVT and PE
Know your family history
Appropriate lifestyle changes for decreasing venous thrombosis risk include having a patient lose weight and stop smoking, and ensuring that they know the symptoms and risk factors for DVT and PE and their family medical history.