Available Assays

Acceptable assays for plasma homocyst(e)ine include HPLC and immunoassay.28 Each laboratory should determine its own gender- and local population-specific reference ranges. The basal plasma homocysteine level should be determined first, and if elevated, further investigation regarding the potential cause as well as therapeutic intervention should be considered. It is unclear whether plasma homocysteine levels should be tested after an overnight fast. Because plasma homocysteine levels can be elevated for several months after myocardial infarction or stroke, testing should be delayed accordingly. In addition to vitamin deficiency, impaired renal function and hypothyroidism are other common causes of hyperhomo-cyst(e)inemia. Vitamin B12 deficiency should be excluded prior to beginning therapy since high-dose folic-acid therapy can precipitate acute B12 neuropathy. If the basal homocysteine level is normal,methionine loading (0.1 g/kg body weight or 3.8gm/m2 body surface area with measurement of plasma homocysteine 4 to 6 hours after the load) should be considered since 25% to 40% of symptomatic patients develop hyperhomocyst(e)inemia only after methionine loading. Therapy includes folic acid (0.5 to 1.0mg/day), vitamin B12 (400 to 1000 pg/day), and/or vitamin B6 (20 to 50mg/day).30


Funded, in part, by grants from the National Institutes of Health (HL66216), the Centers for Disease Control and Prevention (TS306), U.S. Public Health Service; the Doris Duke Charitable Foundation Innovation in Clinical Research; and Mayo Foundation.


1. Soucie JM, et al. The Hemophilia Surveillance System Project Investigators. Am J Hematol. 1998;59:288.

2. Antonatakis SE, et al. Factor VIII gene inversions in severe hemophilia A: results of an International Consortium Study. Blood. 1995;86:2206.

3. Bagnall RD, et al. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002;99:168.

4. Gilles JGG, et al. Factor VIII inhibitors. Thromb Haemost. 1997;78: 641.

5. ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III. Hum Reprod. 2002;17:233.

6. GeneTests: Medical Genetics Information Resource [database online]. Seattle, WA: University of Washington and Children's Health System, 1993-2003. Updated weekly. Available at: http://www.genetests.org.

7. Liu Q, et al. Single tube polymerase chain reaction for rapid diagnosis of the inversion hotspot mutation in hemophilia A. Blood. 1998;92:1458.

8. Higuchi M, Kazazian HH Jr, Kasch L, et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991;88:7405.

9. Naylor JA, et al. Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene. Lancet. 1991;337:635.

10. Buzin CH, et al. Scanning by DOVAM-S detects all unique sequence changes in blinded analyses: evidence that the scanning conditions are generic. Biotechniques. 2000;28:746-50.

11. Nichols WC, et al. Mutations in an endoplasmic-Golgi intermediate compartment protein cause combined deficiency of coagulation factor V and VIII. Cell. 1998;93:61.

12. Warrier I, et al. Factor IX inhibitors and anaphylaxis in haemophilia B. J Pediatr Hematol Oncol. 1997;19:23.

13. Ketterling RP, Bottema CD, Phillips JA 3rd, Sommer SS. Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics. 1991;10:1093.

14. Sadler JE. Von Willebrand disease. In: Scriver CR, Beaudet AL, Valle D, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.

15. Mohlke KL, Purkayastha AA, Westrick RJ, et al. MVWF, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell. 1999;96: 111.

16. Mazurier C, Meyer D. Factor VIII binding assay of von Willebrand factor and the diagnosis of type 2N von Willebrand disease-results of an international survey. On behalf of the Subcommittee on Von Willebrand Factor of the Scientific and Standardization Committee of the ISTH. Thromb Haemost. 1996;76:270.

17. Dahlb├Ąck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004-1008.

18. Sun X, Evatt B, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous throm-bophilia. Blood. 1994;83:3120-3125.

19. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64-67.

20. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community: state of the art. Thromb Haemost. 2001;86:452-463.

21. Heit JA, O'Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162:1245-1248.

22. Press RD, Bauer KA, Kujovich JL, Heit JA. Clinical utility of Factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002;126:1304-1318.

23. Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous throm-boembolism. Ann Intern Med. 1999;130:643-650.

24. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-1457.

25. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 19;88:3698-3703.

26. Gehring NH, Frede U, Neu-Yilik G, et al. Increased efficiency of mRNA 3' end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet. 2001;28:389-392.

27. Soria JM, Almasy L, Souto J, et al. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood. 2000;95:2780-2785.

28. McGlennen RC, Key NS. Clinical and laboratory management of the prothrombin G20210A mutation. Arch Pathol Lab Med. 2002;126: 1319-1325.

29. Key NS, McGlennen RC. Hyperhomocyst(e)inemia and thrombophilia. Arch Pathol Lab Med. 2002;126:1367-1375.

30. Mudd SH, Skoyby F, Levy HL, et al. The natural history of homo-cystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1-31.

Section II

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