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Coagulation Disorders

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Molecular Pathology in Clinical Practice

Abstract

The vascular system is a series of interconnected biologic conduits filled with fluid moving under pressure. This system is subject to injury, with exsanguination avoided by the functions of the hemostatic system. Normal hemostasis is a reparative process and consists of three major mechanisms: (1) vasospasm, (2) platelet plug formation, and (3) the procoagulant system. While inherited or acquired disorders of all three mechanisms can cause clinically abnormal bleeding, this chapter reviews the molecular basis of the more commonly inherited disorders of the procoagulant system (e.g., hemophilia A and B, and von Willebrand disease) associated with abnormal bleeding.

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References

  1. Soucie JM, et al. Occurrence of hemophilia in the United States. The Hemophilia Surveillance System Project Investigators. Am J Hematol. 1998;59:288–94.

    Article  CAS  PubMed  Google Scholar 

  2. Antonarakis SE, et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 1995;86:2206–12.

    CAS  PubMed  Google Scholar 

  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;99:168–74.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Gouw SC, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012;119:2922–34.

    Article  CAS  PubMed  Google Scholar 

  6. ESHRE. ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001). Hum Reprod. 2002;17:233–46.

    Article  Google Scholar 

  7. Liu Q, et al. Single-tube polymerase chain reaction for rapid diagnosis of the inversion hotspot of mutation in hemophilia A. Blood. 1998;92:1458–9.

    CAS  PubMed  Google Scholar 

  8. Rossetti LC, et al. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int22h and int1h hotspots in the factor VIII gene. J Thromb Haemost. 2008;6:830–6.

    Article  CAS  PubMed  Google Scholar 

  9. Payne AB, et al. Utility of multiplex ligation-dependent probe amplification (MLPA) for hemophilia mutation screening. J Thromb Haemost. 2012;10:1951–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Higuchi M, 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 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;337:635–9.

    Article  CAS  PubMed  Google Scholar 

  12. 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. 752–3.

    CAS  PubMed  Google Scholar 

  13. Nichols WC, et al. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell. 1998;93:61–70.

    Article  CAS  PubMed  Google Scholar 

  14. Yoshitake S, et al. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985;24:3736–50.

    Article  CAS  PubMed  Google Scholar 

  15. Simioni P, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361:1671–5.

    Article  CAS  PubMed  Google Scholar 

  16. de la Salle C, et al. Common intragenic and extragenic polymorphisms of blood coagulation factors VIII and IX are different in Chinese and Caucasian populations. Clin Genet. 1990;38:434–40.

    Article  PubMed  Google Scholar 

  17. Warrier I, et al. Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol. 1997;19:23–7.

    Article  CAS  PubMed  Google Scholar 

  18. Ketterling RP, et al. Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics. 1991;10:1093–6.

    Article  CAS  PubMed  Google Scholar 

  19. Sadler JE. Von Willebrand disease. In: Scriver CR, Beaudet al, Valle D, et al., editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001.

    Google Scholar 

  20. Mohlke KL, et al. Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell. 1999;96:111–20.

    Article  CAS  PubMed  Google Scholar 

  21. Bellissimo DB, et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012;119:2135–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 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;76:270–4.

    CAS  PubMed  Google Scholar 

  23. Bertina RM, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–7.

    Article  CAS  PubMed  Google Scholar 

  24. Lockwood C, Wendel G. Practice bulletin no. 124: inherited thrombophilias in pregnancy. Obstet Gynecol. 2011;118:730–40.

    Article  PubMed  Google Scholar 

  25. Middeldorp S, et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med. 1998;128:15–20.

    Article  CAS  PubMed  Google Scholar 

  26. Press RD, et al. Clinical utility of factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002;126:1304–18.

    PubMed  Google Scholar 

  27. Wu O, et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess. 2006;10:1–110.

    Article  CAS  PubMed  Google Scholar 

  28. Heit JA, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001;86:452–63.

    CAS  PubMed  Google Scholar 

  29. Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med. 1999;130:643–50.

    Article  CAS  PubMed  Google Scholar 

  30. Heit JA, et al. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Thromb Haemost. 2005;3:305–11.

    Article  CAS  PubMed  Google Scholar 

  31. Vandenbroucke JP, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453–7.

    Article  CAS  PubMed  Google Scholar 

  32. van Vlijmen EF, et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood. 2011;118:2055–61. quiz 2375.

    Article  PubMed  Google Scholar 

  33. Falck-Ytter Y, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S–325.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Gould MK, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e227S–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Kahn SR, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e195S–226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Kearon C, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Poort SR, et al. 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. 1996;88:3698–703.

    CAS  PubMed  Google Scholar 

  38. Gehring NH, et al. Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet. 2001;28:389–92.

    Article  CAS  PubMed  Google Scholar 

  39. Soria JM, et al. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood. 2000;95:2780–5.

    CAS  PubMed  Google Scholar 

  40. McGlennen RC, Key NS. Clinical and laboratory management of the prothrombin G20210A mutation. Arch Pathol Lab Med. 2002;126:1319–25.

    CAS  PubMed  Google Scholar 

  41. Brouwer JL, et al. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101:93–9.

    CAS  PubMed  Google Scholar 

  42. Key NS, McGlennen RC. Hyperhomocyst(e)inemia and thrombophilia. Arch Pathol Lab Med. 2002;126:1367–75.

    CAS  PubMed  Google Scholar 

  43. 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Hickey SE, et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15:153–6.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    Rajiv K. Pruthi M.B.B.S. & Aneel A. Ashrani M.D., M.S.

  2. Department of Laboratory Medicine and Pathology, Division of Hematopathology and Laboratory Genetics, Mayo Clinic College of Medicine, Rochester, 200 First Street, SW, Rochester, MN, 55905, USA

    Michelle L. Kluge M.S., C.G.C. & Aneel A. Ashrani M.D., M.S.

  3. Mayo Comprehensive Hemophilia Center, Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA

    Michelle L. Kluge M.S., C.G.C.

  4. Special Coagulation Laboratory, Mayo Comprehensive Hemophilia Center, Rochester, MN, USA

    Aneel A. Ashrani M.D., M.S.

Authors
  1. Rajiv K. Pruthi M.B.B.S.
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  2. Michelle L. Kluge M.S., C.G.C.
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  3. Aneel A. Ashrani M.D., M.S.
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Corresponding author

Correspondence to Rajiv K. Pruthi M.B.B.S. .

Editor information

Editors and Affiliations

  1. Pathology and Laboratory Medicine, University of Vermont College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA

    Debra G.B. Leonard

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© 2016 Springer International Publishing Switzerland

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Pruthi, R.K., Kluge, M.L., Ashrani, A.A. (2016). Coagulation Disorders. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_15

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  • DOI: https://doi.org/10.1007/978-3-319-19674-9_15

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-19673-2

  • Online ISBN: 978-3-319-19674-9

  • eBook Packages: MedicineMedicine (R0)

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