Molecular Basis of Disorders of Hemostasis and Thrombosis

  • Alice Ma
Part of the Molecular Pathology Library book series (MPLB, volume 4)


A comprehensive recital of the molecular basis of all of the defects leading to disorders of hemostasis and thrombosis is well beyond the scope of this book. This chapter instead presents broad themes, focusing on defects in the soluble coagulation factors, defects in platelet number and function, other defects leading to hemorrhage, and defects predisposing to thrombosis.


Hemolytic Uremic Syndrome Thrombotic Thrombocytopenic Purpura Thrombin Activatable Fibrinolysis Inhibitor High Molecular Weight Kininogen Bernard Soulier Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964;145:1310–1312.PubMedCrossRefGoogle Scholar
  2. 2.
    Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature. 1964;202:498–499.PubMedCrossRefGoogle Scholar
  3. 3.
    Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol. 2001;114(2):249–257.PubMedCrossRefGoogle Scholar
  4. 4.
    Anwar M, Iqbal H, Gul M, Saeed N, Ayyub M. Congenital afibrinogenemia: report of three cases. J Thromb Haemost. 2005;3(2):407–409.PubMedCrossRefGoogle Scholar
  5. 5.
    De Vries A, Rosenberg T, Kochwa S, Boss JH. Precipitating antifibrinogen antibody appearing after fibrinogen infusions in a patient with congenital afibrinogenemia. Am J Med. 1961;30:486–494.CrossRefGoogle Scholar
  6. 6.
    Menache D. fibrinogens. A review. Thromb Diath Haemorrh. 1973;29(3):525–535.PubMedGoogle Scholar
  7. 7.
    Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002;126(4):499–505.PubMedGoogle Scholar
  8. 8.
    Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003;21(6):577–581.PubMedCrossRefGoogle Scholar
  9. 9.
    Chesney CM, Pifer D, Colman RW. Subcellular localization and secretion of factor V from human platelets. Proc Natl Acad Sci USA. 1981;78(8):5180–5184.PubMedCrossRefGoogle Scholar
  10. 10.
    Mariani G, Herrmann FH, Dolce A, et al. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. Thromb Haemost. 2005;93(3):481–487.PubMedGoogle Scholar
  11. 11.
    McVey JH, Boswell E, Mumford AD, Kemball-Cook G, Tuddenham EG. Factor VII deficiency and the FVII mutation database. Hum Mutat. 2001;17(1):3–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Kemball-Cook G. The haemophilia A mutation, structure, test and resource site. [Website] 2003 [cited; Available at:].Google Scholar
  13. 13.
    Oldenburg J, Ananyeva NM, Saenko EL. Molecular basis of haemophilia A. Haemophilia. 2004;10(Suppl 4):133–139.PubMedCrossRefGoogle Scholar
  14. 14.
    Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol. 1999;19(1):170–177.PubMedGoogle Scholar
  15. 15.
    Ariens RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood. 2002;100(3):743–754.PubMedCrossRefGoogle Scholar
  16. 16.
    McMillan C, Roberts H. Congenital combined deficiency of coagulation factors II, VII, IX and X. N Engl J Med. 1966;274:1313–1315.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang B, Ginsburg D. Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders. J Thromb Haemost. 2004;2(9):1564–1572.PubMedCrossRefGoogle Scholar
  18. 18.
    Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427(6974):541–544.PubMedCrossRefGoogle Scholar
  19. 19.
    Kessler CM. Diagnosis and treatment of von Willebrand disease: new perspectives and nuances. Haemophilia. 2007;13(Suppl 5):3–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171–232.PubMedCrossRefGoogle Scholar
  21. 21.
    Favaloro EJ. Appropriate laboratory assessment as a critical facet in the proper diagnosis and classification of von Willebrand disorder. Best Pract Res Clin Haematol. 2001;14(2):299–319.PubMedCrossRefGoogle Scholar
  22. 22.
    Knobl P, Lechner K. Acquired factor V inhibitors. Baillieres Clin Haematol. 1998;11(2):305–318.PubMedCrossRefGoogle Scholar
  23. 23.
    Uprichard J, Perry DJ. Factor X deficiency. Blood Rev. 2002;16(2):97–110.PubMedCrossRefGoogle Scholar
  24. 24.
    Jakway JL. Acquired von Willebrand’s disease. Hematol Oncol Clin North Am. 1992;6(6):1409–1419.PubMedGoogle Scholar
  25. 25.
    Mannucci PM, Lombardi R, Bader R, et al. Studies of the pathophysiology of acquired von Willebrand’s disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood. 1984;64(3):614–621.PubMedGoogle Scholar
  26. 26.
    Takahashi H, Yamada M, Shibata A. Acquired von Willebrand’s disease in hypothyroidism. Thromb Haemost. 1987;58(4):1095.PubMedGoogle Scholar
  27. 27.
    Budde U, Schaefer G, Mueller N, et al. Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood. 1984;64(5):981–985.PubMedGoogle Scholar
  28. 28.
    Han P, Lou J, Wong HB. Wilms’ tumour with acquired von Willebrand’s disease. Aust Paediatr J. 1987;23(4):253–255.PubMedGoogle Scholar
  29. 29.
    Scott JP, Montgomery RR, Tubergen DG, Hays T. Acquired von Willebrand’s disease in association with Wilm’s tumor: regression following treatment. Blood. 1981;58(4):665–669.PubMedGoogle Scholar
  30. 30.
    Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood. 1997;90(1):204–208.PubMedGoogle Scholar
  31. 31.
    Favier R, Aoki N, de Moerloose P. Congenital alpha(2)-plasmin inhibitor deficiencies: a review. Br J Haematol. 2001;114(1):4–10.PubMedCrossRefGoogle Scholar
  32. 32.
    Morimoto Y, Yoshioka A, Imai Y, Takahashi Y, Minowa H, Kirita T. Haemostatic management of intraoral bleeding in patients with congenital deficiency of alpha–plasmin inhibitor or plasminogen activator inhibitor-1. Haemophilia. 2004;10(5):669–674.PubMedCrossRefGoogle Scholar
  33. 33.
    Seri M, Pecci A, Di Bari F, et al. MYH9–related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003;82(3):203–215.CrossRefGoogle Scholar
  34. 34.
    Toren A, Amariglio N, Rozenfeld-Granot G, et al. Genetic linkage of autosomal-dominant Alport syndrome with leukocyte inclusions and macrothrombocytopenia (Fechtner syndrome) to chromosome 22q11–13. Am J Hum Genet. 1999;65(6):1711–1717.PubMedCrossRefGoogle Scholar
  35. 35.
    Epstein CJ, Sahud MA, Piel CF, et al. Hereditary macrothrombocytopathia, nephritis and deafness. Am J Med. 1972;52(3):299–310.PubMedCrossRefGoogle Scholar
  36. 36.
    Pujol-Moix N, Kelley MJ, Hernandez A, Muniz-Diaz E, Espanol I. Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9–related disorders. Haematologica. 2004;89(3):330–337.PubMedGoogle Scholar
  37. 37.
    Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397–398.PubMedCrossRefGoogle Scholar
  38. 38.
    Favier R, Jondeau K, Boutard P, et al. Paris-Trousseau syndrome: clinical, hematological, molecular data of ten new cases. Thromb Haemost. 2003;90(5):893–897.PubMedGoogle Scholar
  39. 39.
    White JG. Platelet storage pool deficiency in Jacobsen syndrome. Platelets. 2007;18(7):52–527.PubMedCrossRefGoogle Scholar
  40. 40.
    Cantor AB. GATA transcription factors in hematologic disease. Int J Hematol. 2005;81(5):378–384.PubMedCrossRefGoogle Scholar
  41. 41.
    Freson K, Matthijs G, Thys C, et al. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet. 2002;11(2):147–152.PubMedCrossRefGoogle Scholar
  42. 42.
    Balduini CL, Pecci A, Loffredo G, et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost. 2004;91(1):129–140.PubMedGoogle Scholar
  43. 43.
    Michaud J, Wu F, Osato M, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99(4):1364–1372.PubMedCrossRefGoogle Scholar
  44. 44.
    Rose MJ, Nicol KK, Skeens MA, Gross TG, Kerlin BA. Congenital amegakaryocytic thrombocytopenia: the diagnostic importance of combining pathology with molecular genetics. Pediatr Blood Cancer. 2008;50(6):1263–1265.PubMedCrossRefGoogle Scholar
  45. 45.
    Geddis AE. Inherited thrombocytopenia: congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Semin Hematol. 2006;43(3):196–203.PubMedCrossRefGoogle Scholar
  46. 46.
    Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. 2008;15(1):30–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. 2002;76(4):319–327.PubMedCrossRefGoogle Scholar
  48. 48.
    Lisman T, Moschatsis S, Adelmeijer J, Nieuwenhuis HK, De Groot PG. Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation. Blood. 2003;101(5):1864–1870.PubMedCrossRefGoogle Scholar
  49. 49.
    Tholouli E, Hay CR, O’Gorman P, Makris M. Acquired Glanzmann’s thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder. Br J Haematol. 2004;127(2):209–213.PubMedCrossRefGoogle Scholar
  50. 50.
    Arthur JF, Dunkley S, Andrews RK. Platelet glycoprotein VI-related clinical defects. Br J Haematol. 2007;139(3):363–372.PubMedCrossRefGoogle Scholar
  51. 51.
    Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest. 1996;97(4):949–956.PubMedCrossRefGoogle Scholar
  52. 52.
    Rao AK, Jalagadugula G, Sun L. Inherited defects in platelet signaling mechanisms. Semin Thromb Hemost. 2004;30(5):525–535.PubMedCrossRefGoogle Scholar
  53. 53.
    Nurden AT, Nurden P. The gray platelet syndrome: clinical spectrum of the disease. Blood Rev. 2007;21(1):21–36.PubMedCrossRefGoogle Scholar
  54. 54.
    Diamandis M, Veljkovic DK, Maurer-Spurej E, Rivard GE, Hayward CP. Quebec platelet disorder: features, pathogenesis and treatment. Blood Coagul Fibrinolysis. 2008;19(2):109–119.PubMedCrossRefGoogle Scholar
  55. 55.
    Walker M, Payne J, Wagner B, Vora A. Hermansky-Pudlak syndrome. Br J Haematol. 2007;138(6):671.PubMedCrossRefGoogle Scholar
  56. 56.
    Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008;15(1):2–29.PubMedCrossRefGoogle Scholar
  57. 57.
    Zwaal RF, Comfurius P, Bevers EM. Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta. 2004;1636(–3):119–128.PubMedGoogle Scholar
  58. 58.
    McCrae KR, ed. Thrombocytopenia. 1st ed. New York: Taylor and Francis; 2006.Google Scholar
  59. 59.
    Michelson AD, ed. Platelets. 2nd ed. Amsterdam: Elsevier; 2006.Google Scholar
  60. 60.
    McCrae KR, Herman JH. Posttransfusion purpura: two unusual cases and a literature review. Am J Hematol. 1996;52(3):205–211.PubMedCrossRefGoogle Scholar
  61. 61.
    Moschowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Y Pathol Soc. 1924;24:21–24.Google Scholar
  62. 62.
    Bukowski RM, Hewlett JS, Harris JW, et al. Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura. Semin Hematol. 1976;13(3):219–232.PubMedGoogle Scholar
  63. 63.
    Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med. 1977;297(25):1386–1389.PubMedCrossRefGoogle Scholar
  64. 64.
    Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393–397.PubMedCrossRefGoogle Scholar
  65. 65.
    Moake JL, Rudy CK, Troll JH, et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982;307(23):143–1435.PubMedCrossRefGoogle Scholar
  66. 66.
    Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood. 1996;87(10):4235–4244.PubMedGoogle Scholar
  67. 67.
    Furlan M, Robles R, Lamie B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood. 1996;87(10):4223–4234.PubMedGoogle Scholar
  68. 68.
    Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276(44):41059–41063.PubMedCrossRefGoogle Scholar
  69. 69.
    Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood. 2001;98(6):166–1666.PubMedCrossRefGoogle Scholar
  70. 70.
    Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488–494.PubMedCrossRefGoogle Scholar
  71. 71.
    Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339(22):1585–1594.PubMedCrossRefGoogle Scholar
  72. 72.
    Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339(22):1578–1584.PubMedCrossRefGoogle Scholar
  73. 73.
    Amirlak I, Amirlak B. Haemolytic uraemic syndrome: an overview. Nephrology (Carlton). 2006;11(3):213–218.CrossRefGoogle Scholar
  74. 74.
    Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365(9464):1073–1086.PubMedGoogle Scholar
  75. 75.
    Dragon-Durey MA, Fremeaux-Bacchi V. Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin Immunopathol. 2005;27(3):359–374.PubMedCrossRefGoogle Scholar
  76. 76.
    Fremeaux-Bacchi V, Kemp EJ, Goodship JA, et al. The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts. J Med Genet. 2005;42(11):85–856.PubMedCrossRefGoogle Scholar
  77. 77.
    Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, et al. The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat. 2007;28(3):22–234.PubMedCrossRefGoogle Scholar
  78. 78.
    Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(2):555–563.PubMedCrossRefGoogle Scholar
  79. 79.
    Levy JH, Hursting MJ. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am. 2007;21(1):65–88.PubMedCrossRefGoogle Scholar
  80. 80.
    Rauova L, Poncz M, McKenzie SE, et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood. 2005;105(1):131–138.PubMedCrossRefGoogle Scholar
  81. 81.
    Griffin JH, Fernandez JA, Gale AJ, Mosnier LO. Activated protein C. J Thromb Haemost. 2007;5(Suppl 1):73–80.PubMedCrossRefGoogle Scholar
  82. 82.
    Cheng T, Liu D, Griffin JH, et al. Activated protein C blocks p53–mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9(3):338–342.PubMedCrossRefGoogle Scholar
  83. 83.
    Esmon CT. The endothelial protein C receptor. Curr Opin Hematol. 2006;13(5):38–385.PubMedCrossRefGoogle Scholar
  84. 84.
    Folsom AR, Aleksic N, Wang L, et al. Antithrombin, and venous thromboembolism incidence: a prospective population-based study. Arterioscler Thromb Vasc Biol. 2002;22(6):1018–1022.PubMedCrossRefGoogle Scholar
  85. 85.
    Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998;92(7):2353–2358.PubMedGoogle Scholar
  86. 86.
    Koster T, Rosendaal FR, Briet E, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995;85(10):2756–2761.PubMedGoogle Scholar
  87. 87.
    Reitsma PH, Bernardi F, Doig RG, et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost. 1995;73(5):876–889.PubMedGoogle Scholar
  88. 88.
    Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. 1987;317(16):991–996.PubMedCrossRefGoogle Scholar
  89. 89.
    Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73(1):87–93.PubMedGoogle Scholar
  90. 90.
    Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet. 1993;341(8838):134–138.PubMedCrossRefGoogle Scholar
  91. 91.
    Seligsohn U, Berger A, Abend M, et al. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med. 1984;310(9):559–562.PubMedCrossRefGoogle Scholar
  92. 92.
    Eby CS. Warfarin-induced skin necrosis. Hematol Oncol Clin North Am. 1993;7(6):1291–1300.PubMedGoogle Scholar
  93. 93.
    Rezende SM, Simmonds RE, Lane DA. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood. 2004;103(4):119–1201.PubMedCrossRefGoogle Scholar
  94. 94.
    Gandrille S, Borgel D, Ireland H, et al. Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997;77(6):1201–1214.PubMedGoogle Scholar
  95. 95.
    Faioni EM, Valsecchi C, Palla A, Taioli E, Razzari C, Mannucci PM. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost. 1997;78(5):1343–1346.PubMedGoogle Scholar
  96. 96.
    Simmonds RE, Ireland H, Lane DA, Zoller B, Garcia de Frutos P, Dahlback B. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect. Ann Intern Med. 1998;128(1):8–14.PubMedGoogle Scholar
  97. 97.
    Coller BS, Owen J, Jesty J, et al. Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis. Arteriosclerosis. 1987;7(5):456–462.PubMedGoogle Scholar
  98. 98.
    Allaart CF, Aronson DC, Ruys T, et al. Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb Haemost. 1990;64(2):206–210.PubMedGoogle Scholar
  99. 99.
    Levin M, Eley BS, Louis J, Cohen H, Young L, Heyderman RS. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr. 1995;127(3):355–363.PubMedCrossRefGoogle Scholar
  100. 100.
    Dahlback 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 USA. 1993;90(3):1004–1008.PubMedCrossRefGoogle Scholar
  101. 101.
    Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–67.PubMedCrossRefGoogle Scholar
  102. 102.
    Dahlback B. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene. Haemostasis. 1994;24(2):139–151.PubMedGoogle Scholar
  103. 103.
    Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet. 1994;343(8909):1361–1362.PubMedCrossRefGoogle Scholar
  104. 104.
    Voorberg J, Roelse J, Koopman R, et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet. 1994;343(8912):1535–1536.PubMedCrossRefGoogle Scholar
  105. 105.
    Zivelin A, Griffin JH, Xu X, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood. 1997;89(2):397–402.PubMedGoogle Scholar
  106. 106.
    Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506–factor V. Blood. 1995;85(12):3405–3411.PubMedGoogle Scholar
  107. 107.
    Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med. 1997;126(7):528–531.PubMedGoogle Scholar
  108. 108.
    Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508.PubMedGoogle Scholar
  109. 109.
    Rosendaal FR, Siscovick DS, Schwartz SM, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood. 1997;89(8):2817–2821.PubMedGoogle Scholar
  110. 110.
    Inbal A, Freimark D, Modan B, et al. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood. 1999;93(7):2186–2190.PubMedGoogle Scholar
  111. 111.
    Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998;97(11):1037–1041.PubMedGoogle Scholar
  112. 112.
    Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation. 2003;107(8):1117–1122.CrossRefGoogle Scholar
  113. 113.
    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. 1996;88(10):3698–3703.PubMedGoogle Scholar
  114. 114.
    Kyrle PA, Mannhalter C, Beguin S, et al. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol. 1998;18(8):1287–1291.PubMedGoogle Scholar
  115. 115.
    Colucci M, Binetti BM, Tripodi A, Chantarangkul V, Semeraro N. Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood. 2004;103(6):2157–2161.PubMedCrossRefGoogle Scholar
  116. 116.
    Leroyer C, Mercier B, Oger E, et al. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost. 1998;80(1):49–51.PubMedGoogle Scholar
  117. 117.
    Salomon O, Steinberg DM, Zivelin A, et al. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol. 1999;19(3):511–518.PubMedGoogle Scholar
  118. 118.
    Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G→A20210 gene variant. Ann Intern Med. 1998;129(2):89–93.PubMedGoogle Scholar
  119. 119.
    Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost. 1997;78(3):990–992.PubMedGoogle Scholar
  120. 120.
    Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol. 1997;98(2):353–355.PubMedCrossRefGoogle Scholar
  121. 121.
    Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene. Br J Haematol. 1997;98(4):907–909.PubMedCrossRefGoogle Scholar
  122. 122.
    Zawadzki C, Gaveriaux V, Trillot N, et al. Homozygous G20210A transition in the prothrombin gene associated with severe venous thrombotic disease: two cases in a French family. Thromb Haemost. 1998;80(6):1027–1028.PubMedGoogle Scholar
  123. 123.
    Howard TE, Marusa M, Channell C, Duncan A. A patient homozygous for a mutation in the prothrombin gene 3′-untranslated region associated with massive thrombosis. Blood Coagul Fibrinolysis. 1997;8(5):316–319.PubMedCrossRefGoogle Scholar
  124. 124.
    Lane DA, Bayston T, Olds RJ, et al. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997;77(1):197–211.PubMedGoogle Scholar
  125. 125.
    Sakuragawa N, Takahashi K, Kondo S, Koide T. Antithrombin III Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res. 1983;31(2):305–317.PubMedCrossRefGoogle Scholar
  126. 126.
    Fischer AM, Cornu P, Sternberg C, et al. Antithrombin III Alger: a new homozygous AT III variant. Thromb Haemost. 1986;55(2):218–221.PubMedGoogle Scholar
  127. 127.
    Okajima K, Ueyama H, Hashimoto Y, et al. Homozygous variant of antithrombin III that lacks affinity for heparin, AT III Kumamoto. Thromb Haemost. 1989;61(1):20–24.PubMedGoogle Scholar
  128. 128.
    Boyer C, Wolf M, Vedrenne J, Meyer D, Larrieu MJ. Homozygous variant of antithrombin III: AT III Fontainebleau. Thromb Haemost. 1986;56(1):18–22.PubMedGoogle Scholar
  129. 129.
    van Boven HH, Vandenbroucke JP, Briet E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood. 1999;94(8):2590–2594.PubMedGoogle Scholar
  130. 130.
    Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency. Incidence and clinical features. Am J Med. 1989;87(3B):34S-38S.PubMedCrossRefGoogle Scholar
  131. 131.
    de Boer AC, van Riel LA, den Ottolander GJ. Measurement of antithrombin III, alpha –macroglobulin and alpha 1–antitrypsin in patients with deep venous thrombosis and pulmonary embolism. Thromb Res. 1979;15(1–2):17–25.PubMedCrossRefGoogle Scholar
  132. 132.
    Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin-III. Lancet. 1977;2(8038):581–584.PubMedCrossRefGoogle Scholar
  133. 133.
    Damus PS, Wallace GA. Immunologic measurement of antithrombin III-heparin cofactor and alpha2 macroglobulin in disseminated intravascular coagulation and hepatic failure coagulopathy. Thromb Res. 1975;6(1):27–38.PubMedCrossRefGoogle Scholar
  134. 134.
    Kauffmann RH, Veltkamp JJ, Van Tilburg NH, Van Es LA. Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome. Am J Med. 1978;65(4):607–613.PubMedCrossRefGoogle Scholar
  135. 135.
    Buchanan GR, Holtkamp CA. Reduced antithrombin III levels during L-asparaginase therapy. Med Pediatr Oncol. 1980;8(1):7–14.PubMedCrossRefGoogle Scholar
  136. 136.
    Weenink GH, Treffers PE, Vijn P, Smorenberg-Schoorl ME, Ten Cate JW. Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity. Am J Obstet Gynecol. 1984;148(8):109–1097.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alice Ma
    • 1
  1. 1.Department of Hematology/OncologyUniversity of North CarolinaChapel HillUSA

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