Hematology Grand Rounds

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Hematology Grand Rounds

• March 28, 2003
• Leslie Andritsos, M.D.

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Case Presentation

• 30 year old woman with no past medical history
• Recently diagnosed with a gene mutation
• Was told she was at risk for thrombosis and
  should be anticoagulated during pregnancy
• Looked it up on the internet

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Case Presentation

• Found articles stating this gene mutation caused
  not only thrombosis and recurrent fetal loss, but
  also leukemia
• Pt and her husband have decided not to have any
  more children because of the fear of transmitting
  the mutation

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Case Presentation

• What is this genetic mutation?
• Heterozygous for MTHFR gene mutation

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MTHFR

• 5,10-Methylenetetrahydrofolate reductase
• Plays key role in folate metabolism
• Channels one-carbon units between nucleotide
  synthesis and methylation reactions
• Involved in folate-dependent remethylation of
  homocysteine
• Deficiency leads to hyperhomocysteinemia
• Gene located on 1p36.3
• Prevalence for homozygous mutation is 5-17 of
  population

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MTHFR

• 2 polymorphisms identified which cause functional
  impairment of enzyme
• C677T valine substituted for alanine at residue
  223, causes enzyme to become thermolabile
• A1298C functional consequences not well
  characterized

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Folate and Homocysteine Metabolic Pathways
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Hyperhomocysteinemia

• Homocysteinuria 1st reported in Ireland 1962
• 1st reported as risk factor for cardiovascular dz
  1969
• Cystathione beta synthase deficiency identified,
  pts had premature CAD

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MTHFR and Thrombosis

• Hyperhomocysteinemia implicated in both arterial
  and venous thrombosis
• Why is homocysteine thrombogenic? Theories
• Direct toxicity to endothelial cells
• Inhibits Protein C activation
• Promotes endothelial tissue factor expression
• Surpresses endothelial cell surface heparin
  sulfate

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Possible mechanism for role in atherogenesis,
thrombogenesis
Lancet Vol 354, 1999
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MTHFR and Venous Thrombosis

• Multitude of studies
• Longitudinal Investigation of Thromboembolism
  Etiology (LITE)
• Prospective study
• Pooled 2 study populations
• ARIC study 15,792 pts
• CHS study 5,201 pts
• Am
  J Hem, 72192-200, 2003

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LITE study

• Pts had fasting blood drawn at baseline for
• Homocysteine level
• MTHFR gene mutation
• Factor V Leiden gene mutation
• Factor VIII levels
• Began enrolling pts 1989. Potential cases of VTE
  identified 1998.
• Am J Hem, 72192-200, 2003

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LITE study
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MTHFR and Arterial Thrombosis

• Meta-analysis looked at 57 studies between
  1986-1999
• The prospective studies found a weak but
  significant assn between homocysteine level and
  CAD
• Found strong assn between homocysteine level and
  CVD
• Did not evaluate pts for MTHFR
• Int J Epidemiology, 3159-70, 2002

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MTHFR and Arterial Thrombosis

• Is there evidence for synergy between
  prothrombotic or ApoE4 polymorphisms and other
  risk factors?
• Case control study, 112 men lt age 52 with first
  AMI
• Found no significant difference in coronary
  angiography between pts with or without mutations
• Greatly increased risk when prothrombotic or
  ApoE4 polymorphisms added to risk of smoking or
  metabolic risk factors
• 
  Blood, 937, 1999

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MTHFR and Arterial Thrombosis

• Do prothrombotic states cause disease in patients
  without atherosclerosis?
• Multicenter study looking at pts lt age 45 with
  1st MI
• 1210 pts, 1210 controls (hospital staff)
• STEMI with development of pathologic Q waves
• All pts had coronary angiography
• Mannucci, et al., Circulation,
  1071117-1122, 2003

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Variables Tested
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Controlled for

• Smoking
• DM-2
• HTN
• FH
• BMI
• Hyperlipidemia
• EtOH
• Cocaine use
• Physical activity

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Results

• Angiography
• 11 had normal coronary angiogram
• 10 had non-significant stenosis
• 69 had significant stenosis

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Results

• None of the 9 polymorphisms studied had an effect
  on risk of MI
• Weakness of study you had to survive your MI to
  participate
• Strongly associated risk factors
• Smoking
• FH

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Case Presentation

• 30 year old woman with no past medical history
• Recently diagnosed with a gene mutation
• Was told she was at risk for thrombosis and
  should be anticoagulated during pregnancy
• Looked it up on the internet

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MTHFR and Pregnancy

• Should pts with mutation be anticoagulated during
  pregnancy?
• Should pts defer pregnancy?

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NEJM 34314, 2000, Thrombophilias and Late Fetal
Demise

• Compared 67 pts with h/o late fetal death with
  normal controls
• Pts with h/o venous thrombosis excluded
• Evaluated for FVL, APL, PGM, MTHFR

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NEJM, 3471, 2002, Thrombophilias and
Intrauterine Growth Restriction

• Case control study
• Screened newborns and parents for MTHFR, PGM, and
  FVL

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MTHFR and Neural Tube Defects

• Association between nutritional status and NTD
  1st noted by a midwife in 1722
• Marked increase in cases in Northeastern US,
  peaked between 1929 and 1932
• Peak in the Netherlands in 1944-1945 (Hunger
  Winter)

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MTHFR and NTD

• C677T leads to 2.9-3.7 fold increased risk of
  spina bifida (found in infants and their mothers)
• Risk can be overcome by periconceptional folate,
  B6, B12 intake by mother
• Am J Med
  Genet 84151-157, 1999

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MTHFR and Malignancy

• ALL
• Lymphoma
• Colorectal Cancer
• Thought to arise from DNA hypomethylation of
  tumor suppressor genes or misincorporation of
  uracil into DNA
• Needs more study

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