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  • Factor V Leiden
  • Antiphospholipid Syndrome
  • General Clotting Information
  • Prothrombin Gene Mutation
  • Hyperhomocysteinemia
  • Diseases from abnormal clotting
  • Antithrombin III deficiency
  • References
  • Protein C deficiency
  • Protein S deficiency

    Homocystinuria (homocystine excreted in the urine) was first reported in 1962. Homocystinuria is associated with a syndrome of mental retardation, skeletal and visual problems and arterial as well as venous thrombosis. There are two primary enzymes that, when a defect is present, can result in either homocystinuria or hyperhomocysteinemia (hyper=high) as discussed below.

    Mechanism of Hyperhomocysteinemia:
    Homocysteine is a naturally occurring molecule in the body and it is required in several reactions that occur within the cells that comprise the human body. The reactions are detailed in the figure above; they result in the formation of cysteine and methionine, which can be further used by the body. If the pathways to either cysteine or methionine are blocked, then homocysteine levels may rise.

    Three enzymes in the above diagram will be focused on, as they are associated with elevated levels of homocysteine. These enzymes are methylenetetrahydrofolate reductase (MTHFR), cystathionine beta-synthase (CBS) and methionine synthase (MS).

    MS requires vitamin B12 (methylcobalamin) in order to carry out its reaction. If a patient does not have an adequate supply of vitamin B12, then homocysteine is not converted to methionine and the net result is an increase in homocysteine.

    MTHFR is required to form 5-methyl tetrahydrofolate (as depicted above). This is required in order to convert homocysteine to methionine. If this can not be formed, then homocysteine levels will increase.

    The final enzyme associated with elevated homocysteine levels in CBS; this is required in order to convert homocysteine to cysteine. If this enzyme is not present, then homocysteine levels will increase.

    A person who is heterozygous (see *below) for a mutation in CBS or in MTHFR will generally have mild increases in homocysteine levels. There is another type of mutation that can occur with MTHFR. This mutation results in a thermolabile variant (that means that the protein becomes inactivated with heat). A patient who is heterozygous for this mutation has no evidence of hyperhomocysteinemia or increased risk of thrombotic disorders. Patients who are homozygous (see * below) for the defect can develop hyperhomocysteinemia. In addition to the above causes, deficiencies in Vitamin B6 and folate can lead to increased levels of homocysteine. Other causes include certain medications and kidney disease.

    Epidemiology of Hyperhomocysteinemia:
    The prevalence of hyperhomocysteinemia in the general population is not known. Studies looking at the prevalence of homozygosity (both (2) copies of the gene are mutated) for the thermolabile variant mutation in MTHFR have shown a prevalence near 15% in European, Middle Eastern and Japanese populations, compared with a range at or below 1.4% in African Americans. Patients who are heterozygous (1 copy of the mutated gene) are seen in 30-40% of the population.

    Heterozygosity for the CBS mutation is thought to occur in .4% to 1.4% of the population. Homozygosity for the CBS mutation is quite rare.

    Risks of Hyperhomocysteinemia:
    In patients with profound hyperhomocysteinemia leading to homocystinuria, patients generally have skeletal and ocular (eye) problems as well as mental retardation/developmental delay and thrombotic complications. These problems are seen in patients who are homozygous for either CBS deficiency or MTHFR deficiency (not to be confused with the thermolabile variant).

    The idea that elevations of homocysteine are associated with arterial thrombotic disease was first put forth in 1969 in relation to patients with homocystinuria. While establishing this relationship, physicians looked to see if milder elevations (such as those seen from vitamin deficiencies, heterozygosity for CBS or MTHFR deficiency or homozygosity for the thermolabile variant of MTHFR) increase risk. Numerous studies have looked at the risk for heart disease, strokes and peripheral vascular disease (arterial disease). Many of these studies, but not all, have shown an increase risk for arterial disease as a result of elevated homocysteine levels. At this time, studies have not separated the various causes of hyperhomocysteinemia and the associated risk.

    In the studies where an increased risk was shown, it was generally in the range of the other modifiable risk factors for arterial disease: smoking, hypertension (high blood pressure), hyperlipidemia (high cholesterol), obesity, sedentary lifestyle (inadequate regular exercise). As a result, modification of the above risk factors in addition to control of hyperhomocysteinemia will have a more significant impact on lowering one's risk of arterial disease than controlling the hyperhomocysteinemia alone.

    The risk of venous thrombotic disease in patients with hyperhomocysteinemia was first addressed in 1991. As with arterial disease, many studies have shown an increased risk of venous thrombotic disease in the range of 2-4 times the normal person's risk. However, there are studies that do not support this observation.

    Treatment of Hyperhomocysteinemia:
    Unlike many other thrombophilic disorders, hyperhomocysteinemia can be treated directly with vitamin supplementation. The primary vitamin used to lower homocysteine levels is folate and studies have clearly shown a decrease in homocysteine levels with folate. Taking folate and vitamin B12 can lead to an additional decrease in homocysteine levels above that seen with folate alone. A study looking at the use of vitamin B6 did not show any increased benefit in using folate and vitamin B6 over just folate alone. Although vitamin supplementation has been shown to lower homocysteine levels, there is no data at this time that addresses what impact this has on a person's risk of venous or arterial thrombotic problems.

    As a side note, in the USA, the Food and Drugs Administration has implemented folate supplementation in grains. This was done because low levels of folate are associated with birth defects (specifically neural tube defects). Although the supplementation present has been shown to lower homocysteine levels as well as raise the level of folate, it has been suggested that this, alone, is not enough to normalize homocysteine levels in patients with hyperhomocysteinemia.

    When one has a venous clot, regardless of what thrombophilic state(s) one may have, that person will receive anticoagulation. This is accomplished by several different medications: 1) heparin, 2) warfarin and 3) low-molecular-weight heparins. These medications are generally used for 3-6 months. Further continuation is generally not indicated in hyperhomocysteinemia after a single thromboembolic episode given the risk of bleeding associated with anticoagulation. Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (for example, multiple thrombophilic states) are likely started on long-term anticoagulation.

    Long-term anticoagulation has risks associated with it (approximately a 3% chance per year of having a major hemorrhage, of which approximately 1/5 are fatal). Beginning long-term anticoagulation is influenced by the patient's overall risk of recurrent thrombosis balanced against the risks associated with long-term anticoagulation on an individual basis.

    Further Information:
    For further information on the other thrombophilic states, please refer to their respective pages. Brief information on the various medications that are discussed above and are regularly used to treat clotting disorders is discussed on the medication pages. A selection of the references used to compile this information is listed on the references page.

    Thrombophilic Status
    Relative Risk of Venous Thrombosis
    Normal 1
    Oral contraceptive (OCP) use 4
    Factor V Leiden, heterozygous 5 to 7
    Factor V Leiden, heterozygous + OCP 30 to 35
    Factor V Leiden, homozygous 80
    Factor V Leiden, homozygous + OCP ??? >100
    Prothrombin Gene Mutation, heterozygous 3
    Prothrombin Gene Mutation, homozygous ??? Also possible risk of arterial thrombosis
    Prothrombin Gene Mutation, heterozygous + OCP 16
    Protein C deficiency, heterozygous 7
    Protein C deficiency, homozygous Severe thrombosis at birth
    Protein S deficiency, heterozygous 6
    Protein S deficiency, homozygous Severe thrombosis at birth
    Antithrombin deficiency, heterozygous 5
    Antithrombin deficiency, homozygous Thought to be lethal prior to birth
    Hyperhomocysteinemia 2 to 4
    Hyperhomocysteinemia combined with Factor V Leiden, heterozygous 20
    *The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.