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Semin Thromb Hemost 2001; 27(4): 313-324
DOI: 10.1055/s-2001-16885
DOI: 10.1055/s-2001-16885
Molecular Biology of Blood Coagulation
Further Information
Publication History
Publication Date:
31 August 2001 (online)
ABSTRACT
A complex network of hemostasis proteins maintains the blood flow and integrity of the vascular system. Molecular biology techniques have led to identification and cloning of the corresponding genes, thereby providing the basis for development of various recombinant clotting factor concentrates. Further analysis of these genes allowed for phenotype and genotype correlations in patients with hemorrhagic or thromboembolic disorders and analysis of structure and function relationships of the involved proteins. All these efforts result in a greatly advanced understanding of the hemostatic network. The aim of this article is to illustrate this progress by reporting on the recent results in representative hereditary hemorrhagic and such thromboembolic conditions as hemophilia, von Willebrand disease, and thrombotic disorders.
KEYWORD
Blood coagulation factors - factor VIII - hemophilia A - genotype-phenotype correlation - structure-function relationships
REFERENCES
- 1 Lane D A, Grant P J. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood . 2000; 95 1517-1532
- 2 Bertina R M, Koeleman B P, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature . 1994; 369 64-67
- 3 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. 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 3698-3703
- 4 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden/activated protein C resistance. Blood . 1995; 85 1504-1508
- 5 Toole J J, Knopf J L, Wozney J M. Molecular cloning of a cDNA encoding human antihaemophiliac factor. Nature . 1984; 312 342
- 6 Vehar G A, Keyt B, Eaton D. Structure of human factor VIII. Nature . 1984; 312 337-342
- 7 Pittman D D, Alderman E M, Tomkinson K N. Biochemical, immunological, and in vivo functional characterization of the B-domain deleted factor VIII. Blood . 1993; 81 2925-2935
- 8 Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J. A transcribed gene in an intron of the human factor VIII gene. Genomics . 1990; 7 1-11
- 9 Levinson B, Kenwrick S, Gamel P, Fisher K, Gitschier J. Evidence for a third transcript from the human factor VIII gene. Genomics . 1992; 14 585-589
- 10 Naylor J A, Green P M, Pizza C R, Gianelli F. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet . 1993; 2 11-17
- 11 Lakich D, Kazazian Jr H H, Antonarakis S E, Gitschier J. Inversions disrupting the factor VIII gene as a common cause of severe hemophilia A. Nat Genet . 1993; 5 236-241
- 12 Oldenburg J. Mutation profiling in haemophilia A. Thromb Haemost 2001 (in press).
- 13 Vidal F, Farssac E, Altisent C, Puig L, Gallardo D. Rapid haemophilia A molecular diagnosis by a simple DNA sequencing procedure: Identification of 144 novel mutations. Thromb Haemost 2001 (in press).
- 14 Pattinson J K, Millar D S, McVey J H. The molecular genetic analysis of hemophilia A: A direct search strategy for the detection of point mutations in the factor VIII gene. Blood . 1990; 76 2242-2248
- 15 Kemball-Cook G, Tuddenham E GD, Wacey A I. The factor VIII structure and mutation resource site: HAMSTeRS version 4. Nucleic Acids Res . 1998; 26 216-219
- 16 Becker J, Schwaab R, Möller-Taube A. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type dependent sex ratio of mutation frequencies. Am J Hum Genet . 1996; 58 657-670
- 17 Schwaab R, Oldenburg J, Schwaab U. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol . 1995; 91 458-464
- 18 Schwaab R, Brackmann H H, Meyer C. Haemophilia A. Mutation type determines risk of inhibitor formation. Thromb Haemost . 1995; 74 1402-1406
- 19 Oldenburg J, Brackmann H H, Schwaab R. Risk factors for inhibitor development in hemophilia A. Haematologica . 2000; 85(Suppl) 7-14
- 20 Young M, Inaba H, Hoyer L W. Partial correction of a severe molecular defect in haemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet . 1997; 60 565-573
- 21 Oldenburg J, Schröder J, Schmitt C, Brackmann H H, Schwaab R. Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the severe haemophilia A genotype. Thromb Haemost . 1998; 79 452-453
- 22 Nichols W C, Amano K, Cacheris P M. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood . 1996; 88 1183-1187
- 23 Lee D H, Walker I R, Teitel J. Effect of the factor V Leiden mutation on the clinical expression of severe haemophilia A. Thromb Haemost . 2000; 83 387-391
- 24 Mazurier C, Dieval J, Jorieux S, Delobel J, Goudemand M. A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction. Blood . 1990; 75 20-26
- 25 Gaucher C, Jorieux S, Mercier B, Oufkir D, Mazurier C. The ``Normandy'' variant of the von Willebrand disease: Characterization of a point mutation in the von Willebrand factor gene. Blood . 1991; 77 1937-1941
- 26 Nichols W C, Seligsohn U, Zivelin A. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell . 1998; 93 61-70
- 27 Pemberton S, Lindley P, Zaitsev V. A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin. Blood . 1997; 89 2413-2421
- 28 Gale A J, Pellequer J-L, Getzoff E D, Griffin J H. Structural basis for hemophilia A caused by mutations in the C domains of blood coagulation factor VIII. Thromb Haemost . 2000; 83 78-85
- 29 Pratt K P, Shen B W, Takeshima K. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature . 1999; 402 439-441
- 30 Stoylova S S, Lenting P J, Kemball-Cook G, Holzenburg A. Electron crystallography of human blood coagulation factor VIII bound to phospholipid monolayers. J Biol Chem . 1999; 51 36573-36578
- 31 Oldenburg J, Brackmann H H, Schwaab R. Molecular genetics in haemophilia A. Vox Sang . 2000; 2(Suppl) 33-38
- 32 Jacquemin M, Laved'homme R, Benhida A. A novel cause of mild/moderate haemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood . 2000; 96 958-965
- 33 Liu M L, Shen B W, Nakaya S. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-Angstrom human C2-domain crystal structure. Blood . 2000; 96 979-987
- 34 Hay C R, Ludlam C A, Colvin B T. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb Haemost . 1998; 79 762-766
- 35 Saenko E L, Yakhyaev A V, Mikhailenko I, Strickland D K, Sarafanov A G. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem . 1999; 274 37685-37692
- 36 Schwarz H P, Lenting P J, Binder B. Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. Blood . 2000; 95 1703-1708
- 37 Lenting P J, Neels J G, van den Berg M B. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor related protein. J Biol Chem . 1999; 274 23734-23739
- 38 Anson D S, Choo K H, Rees D HJ. The gene structure of human antihemophilic factor IX. Embo J . 1984; 3 1053-1060
- 39 Giannelli F, Green P M, Sommer S S. Haemophilia B: database of point mutations and short additions and deletions-eighth edition. Nucleic Acids Res . 1998; 6 265-268
- 40 Giannelli F, Choo K H, Rees D JG. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature . 1983; 303 181-182
- 41 Thorland E C, Drost J B, Lusher J M. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia . 1999; 5 101-105
- 42 Jadhav M, Warrier I. Anaphylaxis in patients with hemophilia. Semin Thromb Hemost . 2000; 26 205-208
- 43 Kurachi S, Furukawa M, Salier J P. Regulatory mechanism of human factor IX gene: protein binding at the Leyden specific region. Biochemistry . 1994; 33 1580-1591
- 44 Morgan G E, Rowley G, Green P M. Further evidence for the importance of an androgen response element in the factor IX promotor. Br J Haematol . 1997; 98 79-85
- 45 Chu K, Wu S M, Stanley T, Stafford D W, High K A. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest . 1996; 98 1619-1625
- 46 Oldenburg J, Quenzel E M, Harbrecht U. Missense mutation at Ala-10 in the factor IX-propeptide: an insignificant variant in normal life but a decisive cause for bleeding during oral anticoagulant therapy. Br J Haematol . 1997; 98 240-244
- 47 Stanley T B, Humphries J, High K A, Stafford D W. Amino acids responsible for reduced affinities of vitamin K-dependent propeptides of the carboxylase. Biochemistry . 1999; 38 15681-15687
- 48 Oldenburg J, Kriz K, Wuillemin W A. Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10). Thromb Haemost . 2001; 85 454-457
- 49 Bajaj S P. Region of factor IXa protease domain that interacts with factor VIIIa: analysis of select hemophilia B mutants. Thromb Haemost . 1999; 82(Suppl) 218-225
- 50 Mertens K, Celie P HN, Kolkman J A, Lenting P J. Factor VIII-factor IX interactions: molecular sites involved in enzyme-cofactor complex assembly. Thromb Haemost . 1999; 82(Suppl) 209-217
- 51 Werner E J, Broxson E H, Tucker E L. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr . 1993; 123 893-898
- 52 Federici A B. Diagnosis of von Willebrand factor. Haemophilia . 1998; 4 654-660
- 53 Mancuso D J, Tuley E A, Westfield L A. Structure of the gene for human vWF. J Biol Chem . 1989; 264 19514-19527
- 54 Mancuso D J, Tuley E A, Westfield L A. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry . 1991; 30 253-269
- 55 Sadler J E. A revised classification of von Willebrand disease. Thromb Haemost . 1994; 71 520-525
- 56 Meyer D, Fressinaud E, Gaucher C. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from patient to the gene. Thromb Haemost . 1997; 78 451-456
- 57 Schneppenheim R, Budde U, Obser T. Expression and characterization of von Willebrand dimerization defects in different types of von Willebrand disease. Blood . 2001; 97 2059-2066
- 58 Ruggeri Z M. Structure function of von Willebrand factor. Thromb Haemost . 1999; 82 576-584
- 59 Nishino M, Girma J-P, Rothschild C, Fressinaud E, Meyer D. New variant of von Willebrand disease with defective binding to factor VIII. Blood . 1989; 74 1591-1599
- 60 Gill J C, Endres-Brooks J, Bauer P J, Marks Jr J W, Montgomery R R. The effect of AB0 blood group on the diagnosis of von Willebrand disease. Blood . 1987; 69 1691-1695
- 61 Mohlke K L, Purkayastha A A, Westrick R J. Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell . 1998; 96 111-120
- 62 Furan M, Lämmle B. Von Willebrand factor in thrombotic thrombocytopenic purpura. Thromb Haemost . 1999; 82 592-600
- 63 Huizinga E G, van der Plas M R, Kroon J, Sixma J J, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure . 1997; 5 1147-1156
- 64 Emsley J, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem . 1998; 273 10396-10401
- 65 Al-Mondhiry H, Ehmann W C. Congental afibrinogenemia. Am J Hematol . 1994; 46 343-347
- 66 Cooper D N, Millar D S, Wacey A, Pemberton S, Tuddenham E GD. Inherited factor X deficiency: molecular genetics and pathophysiology. Thromb Haemost . 1997; 78 161-172
- 67 Oldenburg J, von Brederlow B, Fregin A. Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost . 2000; 84 937-941
- 68 Salooja N, Martin P, Khair K, Liesner R, Hann I. Severe factor V deficiency and neonatal intracranial hemorrhage: a case report. Haemophilia . 2000; 6 44-46
- 69 Guasch J F, Leusen R P, Bertina R M. Molecular characterization of a type I quantitative factor V deficiency in a thrombosis patient that is ``pseudohomozygous'' for activated protein C resistance. Thromb Haemost . 1997; 77 232-237
- 70 Seligsohn U. Factor XI deficiency. Thromb Haemost . 1993; 70 68-71
- 71 Bolton-Maggs P HB. The management of factor XI deficiency. Haemophilia . 1998; 4 683-688
- 72 Abbondanzo S L, Gootenberg J E, Lofts R S, McPherson R A. Intracranial hemorrhage in congenital deficiency of factor XIII. Am J Pediatr Hematol Oncol . 1988; 10 65-68
- 73 Nordstrom M, Lindblad B, Bergquist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Int Med . 1992; 232 155-160
- 74 Brown R D, Whisnant J P, Sicks J D, O'Fallon W M, Wiebers D O. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke . 1996; 27 373-380
- 75 Pabinger I, Bruckner S, Kyrle P A. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis . 1992; 3 547-553
- 76 Bayston T A, Lane D A. Antithrombin: molecular basis of deficiency. Thromb Haemost . 1997; 78 339-343
- 77 Tait R C, Walker I D, Reitsma P H. Prevalence of protein C deficiency in the healthy population. Thromb Haemost . 1995; 73 87-93
- 78 Reitsma P H. Protein C deficiency: from gene defects to disease. Thromb Haemost . 1997; 78 344-350
- 79 Borgel D, Gandrille S, Aiach M. Protein S deficiency. Thromb Haemost . 1997; 78 351-356
- 80 Dahlbäck B, Catlsson M, Svensson P J. Familial thrombophilia due to 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 1004-1108
- 81 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem . 1994; 269 18735-18738
- 82 Zivelin A, Griffin J H, Xu X. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood . 1997; 89 397-401
- 83 Zivelin A, Rosenberg N, Faier S. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood . 1998; 92 1119-1124