Factor V Leiden: An Inherited Risk Factor for Venous Thromboembolism

1
Factor V LeidenAn Inherited Risk Factor for
Venous Thromboembolism

• Mary Ann Knovich, M.D.
• Internal Medicine Grand Rounds
• November 18, 1998

2
Case Presentation

• RD - 32 WM with no medical problems
• 2 week h/o chest pressure and shortness of
  breath, some pleuritic chest pain worse with
  exertion.
• EKG - TWI in anterior leads.
• Pt started on heparin drip, and transferred to
  CCU at NCBH.

3
Past Medical History

• PMH/PSH None
• MEDS None
• Allergies NKDA
• Cardiac Risk Factors Tob, FH

4
History

• SH Tobacco ½ pack per day x 14 yrs, No
  EtOH or drug use. Married 1 month ago. Works in
  management at a tractor supply store.
• FH Father - MI age 50. DVT age 20 with trauma.
  Sister with multiple miscarriages

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Physical Exam

• Gen WD, WN WM, mildly anxious in NAD
• VS HR120, BP 110/70, R 22, afeb, O2 sat 98 on
  2l nc
• Neck no JVD or carotid bruits
• Lungs CTA
• Heart Tachy S1, S2, no S3, S4, or m
• Extremities No edema, cyanosis, or calf
  tenderness

6
Studies

• Labs Creatinine kinase, electrolytes, renal
  function, CBC, PT nl, PTT 60 sec.
• EKG- TWI leads V1-V4.
• CXR NACPD

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Hospital Course

• emergent cardiac catheterization - showed normal
  cors, normal LV systolic function.
• became hemodynamically unstable
• pulmonary angiography - large b/l pulmonary
  emboli
• severe pulmonary HTN - PA systolic pressure 80mm
  Hg.

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Hospital Course (cont)

• Pigtail catheter placed in PA-continuous
  urokinase infusion. Heparin was continued.
• Remained hemodynamically stable
• 2 follow-up PA grams showed continued resolution
  of thrombi.
• Started on Coumadin for a goal INR 3
• Discharged to home in stable condition after a
  10-day hospitalization

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Further Studies

• Lower venous duplex negative for DVT b/l.
• CT chest, abdomen, and pelvis -no evidence of
  malignancy.
• Thrombophilia screen - normal activity of
  HepCofactor, Protein C, Protein S, plasminogen,
  ATIII. Anti-Cardiolipin antibodies were normal.
  No detectable lupus inhibitor.
• Factor V Leiden - heterozygous by PCR

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Questions

• What is Factor V Leiden?
• How prevalent is this mutation?
• What is the associated risk for thromboembolic
  disease?
• What are the recommendations for anticoagulation
  in patients with Factor V Leiden?

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Importance of Factor V Leiden in Internal Medicine

• Venous thromboembolism - 250,000 hospital
  admissions annually in US
• PE - cause of death in 50,000 to 100,000 persons
  per year
• 21 of older patients hospitalized for PE die
  during that admission
• Factor V Leiden is the most common inherited risk
  factor thus far described for VTE

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The Coagulation Cascade
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The Protein C Anticoagulant system

• Protein C is a key regulatory protein of the
  hemostatic system
• Vitamin K-dependent zymogen
• synthesized in liver
• circulates in plasma
• Inactivates activated forms of Factor V and
  Factor VIII

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Model of anticoagulant Protein C system
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Native Factor V

• Large single-chain glycoprotein
• activated to Factor Va by thrombin
• Activated Protein C cleaves factor Va at 3
  amino acid positions

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Activation and Inactivation of Normal Factor V
and Factor V Leiden
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The Coagulation Cascade
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Factor V Leiden

• mutation in Factor V gene
• Substitution of adenine for guanine at nucleotide
  position 1691
• Results in replacement of arginine by glutamine
  at amino acid position 506

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Mutated Factor V

• Activated by thrombin in a normal way
• Impaired inactivation by Activated Protein C
• not cleaved at amino acid position 506
• Maintains full cofactor activity until it is
  inactivated by the secondary cleavages at amino
  acid positions 306 and 679
• Results in life-long hypercoagulability

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Activation and Inactivation of Normal Factor V
and Factor V Leiden
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The Coagulation Cascade
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Prevalence of Factor V Leiden Mutation

• Varies widely from one population to another
• Nearly 14 prevalence of the allele among healthy
  controls in Sweden and Greece
• Low prevalence (Africa, and Asia

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Prevalence of Factor V Leiden Mutation

• Large cross-sectional study in US ( Ridker et al,
  JAMA, 1997)
• Prevalence of Factor V Leiden mutation was
  determined in a cohort of 4047 men and women
• Caucasians - 5.27
• Hispanic Americans - 2.21
• African Americans - 1.23
• Asian Americans - 0.45
• Native Americans - 1.25
• Overall carrier frequency of mutation was 3.71
• Allele frequency was 1.89

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How did the mutation arise?

• Confined geographical spread and genetic analysis
  support hypothesis that the mutation arose from a
  single individual

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Evolutionary advantages of Factor V Leiden

• advantages in fertility
• hypercoagulability reduces blood loss with
• menstruation
• postpartum hemorrhage
• trauma

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What is the Risk for Arterial and Venous
Thrombosis in Patients with the Factor V Leiden
Mutation?
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The Leiden Thrombophilia Study (Koster et al,
1993)

• Large, population-based, patient-control study
• 301 patients with 1st episode of objectively
  confirmed DVT
• selected from the files of thrombosis centers in
  Leiden, Rotterdam, and Amsterdam in the
  Netherlands
• age
• DVT not related to malignancy
• 301 age and sex matched healthy controls
• patients asked to provide controls

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The Leiden Thrombophilia Study

• 21 of patients vs. 5 of healthy controls had
  resistance to APC in clotting assays
• Estimated 7-fold increase (matched odds ratio of
  6.6) in risk for DVT in persons with APC
  resistance
• Provided evidence for the association of APC
  resistance with an increased risk for thrombosis

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The Leiden Thrombophilia Study

• Rosendaal et al, Blood, 1995
• Risk for VTE among patients homozygous for Factor
  V Leiden mutation was increased 80-fold
• Homozygous patients presented with initial VTE at
  a younger age (median age 31 yrs) vs.
  heterozygotes (median age 46 yrs)

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Relationship between Genotype to Severity of
Thrombotic Events in 50 Families

• Zoller et al, J. Clin Invest, 1994
• Investigated 308 family members from 50 families
  with APC resistance
• 146 normals
• 144 heterozygotes
• 18 homozygotes

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Thrombotic risk related to genotype in 50
families with inherited APC resistance
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Physicians Health Study

• large-scale epidemiologic assessment of the
  Factor V mutation in a healthy population of
  predominantly white men
• followed prospectively for the occurrence of CV
  disease, in particular arterial and venous
  thrombosis
• confirmed the association between Factor V Leiden
  mutation and the risk for VTE

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Physicians Health Study (Ridker et al, NEJM,
1995)

• Random, Double-blinded, Placebo-controlled study
• 22,071 predominantly white male physicians
  randomly assigned to receive ASA, beta-carotene,
  both, or neither
• 14,916 (68) returned base-line blood samples
• Occurrence of DVT, PE, MI, or stroke during
  follow-up period of 8.6 years

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Strengths of the Physicians Health Study

• nested case control design allowed for detection
  of the Factor V Leiden mutation within the scope
  of a much broader RCT
• performed in a large cohort of apparently healthy
  men (n14,916)

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Strengths of the Physicians Health Study

• not limited to thrombophilic patients or
  families
• Previous studies done in
• families with hypercoagulable defects
• pts with recurrent TE events
• pts referred for tx of DVTs
• subject to bias of case reports, case series, and
  retrospective studies of selected referral
  populations

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Strengths of the Physicians Health Study

• use of PCR, restriction-enzyme digest to detect
  Factor V Leiden mutation
• physicians as accurate reporters of their TE
  events, PMH, risk factors, family history
• not limited to younger patients
• age of physicians ranged from 40-84, with a mean
  age of 60.3 years

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Physicians Health Study (cont.)

• Of the 14,916 who returned base-line blood
  samples, 704 suffered a DVT, PE, MI, or stroke
• Each patient was matched to a control based on
• age
• smoking habits
• time since randomization

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Physicians Health Study (cont.)

• 704 thrombotic events
• 704 controls free of cardiovascular disease
• Blood samples thawed
• DNA analyzed by PCR for Factor V Leiden Mutation

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Prevalence of Mutation in 704 Controls Free of
Cardiovascular Disease

• 94 homozygous for gene coding for Native Factor
  V
• 6 were heterozygous for genes coding for Native
  and Mutated Factor V
• None were homozygous for Factor V Leiden mutation

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Prevalence of Factor V Mutation in 1408
Apparently Healthy Men in the Physicians Health
Study
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Physicians Health Study (cont.)

• Relative risk of MI, Stroke, and DVT or PE in
  subjects with the mutation was determined
• Analysis then adjusted for
• smoking status
• h/o HTN
• hypercholesterolemia
• body-mass index
• diabetes
• family history of CAD

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Relative Risk of MI, Stroke, and Venous
Thrombosis Associated with the Presence of the
Factor V Mutation
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Physicians Health Study (cont.)

• Subjects grouped according to age
• In men age 60 with a 1o DVT, prevalence of
  mutation was 25.8, with a RR of 5.3

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Men 60 years of age

• Relative risk adjusted forsmoking, h/o HTN,
  hypercholesterolemia, Body Mass Index, DM, family
  h/o CAD
• Adjusted relative risk of any DVT was 4.0
• Adjusted relative risk for primary DVT was 7.0
  (p

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Adjusted Relative Risks for Future Venous
Thromboembolism among Apparently Healthy Men with
Factor V Leiden Mutation
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Long-Term Management Issues

• After a defined period of anticoagulation
  treatment for an acute thrombotic event, how
  should patients with this mutation be managed?
• Most information comes from anecdotal reports,
  cross-sectional studies, and uncontrolled
  clinical observations.

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Long-Term Management Issues

• Little reliable data regarding
• magnitude of thrombotic risk
• optimal intensity of anticoagulation
• duration of anticoagulant treatment
• No data from RCTs to show that long-term
  prophylaxis will prevent recurrent thromboses in
  patients with the factor V Leiden mutation

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Long-Term Management Issues

• Must assess relative benefit of long-term
  anticoagulation to prevent thromboembolic
  complications
• vs.
• Potential side-effects, bleeding risk, cost, and
  inconvenience for patients

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Long-Term Management Issues

• Clinical trials designed to evaluate the
  benefit-to-risk ratio of screening for Factor V
  Leiden and subsequent long-term anticoagulation
  are needed
• Such studies will need to consider
• different rates of mutation in various patient
  groups
• thrombosis with Factor V Leiden is not limited to
  young patients

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Management Guidelines

• High-Risk Classification
• 2 or more spontaneous thromboses
• 1 spontaneous life-threatening thrombosis
• 1 spontaneous thrombosis at an unusual
  site
• (mesenteric or cerebral veins)
• 1 spontaneous thrombosis in the presence
  of
• more than a single genetic defect

• Management
• indefinite anticoagulation

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Management Guidelines

• Moderate Risk Classification
• 1 thrombosis with a prothrombotic stimulus
• Asymptomatic patients

• Management
• Vigorous prophylaxis during high-risk situations

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Conclusions

• Factor V Leiden is the most commonly inherited
  risk factor for thromboembolic disease.
• It is a mutation in a single nucleotide in the
  gene coding for Factor V.
• The mutated Factor V is resistant to degradation
  by Activated Protein C , and results in life-long
  increased risk of hypercoagulability.

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Conclusions

• Heterozygosity for Factor V Leiden predisposes
  patients to DVTs and PEs, but not to MI or
  stroke.
• The mutation is found in about 5 of the US
  population.
• RCTs to include women and minority groups are
  needed to assess the risks and benefits of
  long-term anticoagulation to prevent VTE in
  Factor V Leiden patients.

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Special Thanks to

• Brad Sherrill, MD
• Amanda Ebright, MD
• Brian Bartholmai, MD