Haemophilia A and haemophilia B: molecular insights

This review focuses on selected areas that should interest both the scientist and the clinician alike: polymorphisms within the factor VIII and factor IX genes, their linkage, and their ethnic variation; a general assessment of mutations within both genes and a detailed inspection of the molecular pathology of certain mutations to illustrate the diverse cause–effect relations that exist; a summary of current knowledge on molecular aspects of inhibitor production; and an introduction to the new areas of factor VIII and factor IX catabolism. An appendix defining various terms encountered in the molecular genetics of the haemophilias is included, together with an appendix providing accession numbers and locus identification links for accessing gene and sequence information in the international nucleic acid databases.

[1]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[2]  J. Jesty,et al.  The activation of Factor IX by tissue factor-Factor VII in a bovine plasma system lacking Factor X. , 1983, Thrombosis research.

[3]  D. Bentley,et al.  The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots. , 1990, Nucleic acids research.

[4]  M. Griffith,et al.  Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Lichter,et al.  DNA chip technology ante portas , 1999, Journal of Molecular Medicine.

[6]  K. Kurachi,et al.  Activation of human factor IX (Christmas factor). , 1978, The Journal of clinical investigation.

[7]  P. Lenting,et al.  The life cycle of coagulation factor VIII in view of its structure and function. , 1998, Blood.

[8]  J. Gitschier,et al.  Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene , 1985, Nature.

[9]  J. Oldenburg,et al.  Missense mutations at ALA‐10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy , 1997, British journal of haematology.

[10]  P. Fay.  Factor VIII Structure and Function , 1993, Thrombosis and Haemostasis.

[11]  C. Kessler,et al.  The genetic basis of inhibitor development in haemophilia A , 1998, Haemophilia : the official journal of the World Federation of Hemophilia.

[12]  K. High,et al.  A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. , 1996, The Journal of clinical investigation.

[13]  M. Vidaud,et al.  Fast and Efficient Mutation Detection Method Using Multiplex PCR and Cycle Sequencing , 2000, Thrombosis and Haemostasis.

[14]  Swee Lay Thein,et al.  Hypervariable ‘minisatellite’ regions in human DNA , 1985, Nature.

[15]  R. Ljung,et al.  Haplotype Analysis of Identical Factor IX Mutants Using PCR , 1992, Thrombosis and Haemostasis.

[16]  S. Antonarakis,et al.  Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. , 1988, American journal of human genetics.

[17]  S. W. Lin,et al.  MAPPING OF 6 MONOCLONAL ANTIBODIES TO HUMAN FACTOR IX , 1987, Thrombosis and Haemostasis.

[18]  A. Jeffreys,et al.  Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA , 1988, Nature.

[19]  S. P. Fodor,et al.  Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays , 1999, Nature Genetics.

[20]  D. Sinha,et al.  Kinetics of the Factor XIa catalyzed activation of human blood coagulation Factor IX. , 1984, The Journal of clinical investigation.

[21]  S. Bajaj,et al.  Region of Factor IXa Protease Domain that Interacts with Factor VIIIa: Analysis of Select Hemophilia B Mutants , 1999, Thrombosis and Haemostasis.

[22]  C. Noyes,et al.  Evidence for a prevalent dimorphism in the activation peptide of human coagulation factor IX. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Oldenburg,et al.  Intron 22‐specific long PCR for the Xba I polymorphism in the factor VIII gene , 1999, British journal of haematology.

[24]  Kenneth J. Smith,et al.  Interaction of Factor IXa with Factor VIIIa , 1997, The Journal of Biological Chemistry.

[25]  B. Furie,et al.  Effect of propeptide mutations on post-translational processing of factor IX. Evidence that beta-hydroxylation and gamma-carboxylation are independent events. , 1987, The Journal of biological chemistry.

[26]  W. Ollier,et al.  HLA Class II Profile: A Weak Determinant of Factor VIII Inhibitor Development in Severe Haemophilia A , 1997, Thrombosis and Haemostasis.

[27]  P. Lenting,et al.  Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein. , 2000, Blood.

[28]  M. Crossley,et al.  Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia B , 1990, Nature.

[29]  D. Bentley,et al.  Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. , 1995, Human molecular genetics.

[30]  David Valle,et al.  The skipping of constitutive exons in vivo induced by nonsense mutations , 1993, Science.

[31]  P. Green,et al.  Ultrarapid mutation detection by multiplex, solid-phase chemical cleavage. , 1995, Genomics.

[32]  Stylianos E. Antonarakis,et al.  Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A , 1993, Nature Genetics.

[33]  B. Keyt,et al.  Structure of human factor VIII , 1984, Nature.

[34]  G. Bray,et al.  Relationship between Factor VIII Mutation Type and Inhibitor Development in a Cohort of Previously Untreated Patients Treated with Recombinant Factor VIII (Recombinate™) , 2000, Thrombosis and Haemostasis.

[35]  J. Gitschier,et al.  Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Girolami,et al.  Prevalence of anti‐FVIII antibodies in severe haemophilia A patients with inversion of intron 22 , 1997, British journal of haematology.

[37]  S. Antonarakis,et al.  Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots , 1986, Nature.

[38]  E. Diamandis.  Sequencing with microarray technology--a powerful new tool for molecular diagnostics. , 2000, Clinical chemistry.

[39]  P. Collins,et al.  Specific analysis of the intron 22 XbaI polymorphism of the human factor VIII gene using long‐distance PCR , 1999, British journal of haematology.

[40]  H. Saito,et al.  Carrier detection in Japanese hemophilia A by use of three intragenic and two extragenic factor VIII DNA probes: a study of 24 kindreds. , 1988, The Journal of laboratory and clinical medicine.

[41]  J. Sixma,et al.  Factor VIII binds to von Willebrand factor via its Mr-80,000 light chain. , 1987, European journal of biochemistry.

[42]  G. Vehar,et al.  Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity. , 1986, Biochemistry.

[43]  R. Lawn,et al.  A new polymorphism in the factor VIII gene for prenatal diagnosis of hemophilia A. , 1986, Nucleic acids research.

[44]  G. Camerino,et al.  A new MspI restriction fragment length polymorphism in the hemophilia B locus , 2004, Human Genetics.

[45]  J. H. Wang,et al.  Identification and functional importance of tyrosine sulfate residues within recombinant factor VIII. , 1992, Biochemistry.

[46]  F. Giannelli.  3 Factor IX , 1989 .

[47]  F. Zintl,et al.  Female Twins with Severe Christmas Disease (Hemophilia B) , 1993, Thrombosis and Haemostasis.

[48]  P. Winship,et al.  A −793 G to A transition in the factor IX gene promoter is polymorphic in the caucasian population , 1996, British journal of haematology.

[49]  B. Osterud,et al.  Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Oldenburg,et al.  Haemophilia A: Mutation Type Determines Risk of Inhibitor Formation , 1995, Thrombosis and Haemostasis.

[51]  S. Antonarakis,et al.  CARRIER TESTING STRATEGY IN HAEMOPHILIA A , 1986, The Lancet.

[52]  I. Mikhailenko,et al.  Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism* , 1999, The Journal of Biological Chemistry.

[53]  M. Shima,et al.  Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. , 1999, Trends in cardiovascular medicine.

[54]  M. Zago,et al.  Factor IX gene haplotypes in Brazilian Blacks and characterization of unusual Ddel alleles , 1994, British journal of haematology.

[55]  P. Fernlund,et al.  Vitamin K dependent modifications of glutamic acid residues in prothrombin. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[56]  A. Cantor,et al.  Recognition site directing vitamin K-dependent γ-carboxylation resides on the propeptide of factor IX , 1987, Cell.

[57]  J. Voorberg,et al.  Intracellular accumulation of factor VIII induced by missense mutations Arg593→Cys and Asn618→Ser explains cross‐reacting material‐reduced haemophilia A , 2000, British journal of haematology.

[58]  E. Tuddenham.  Molecular Biological Aspects of Inhibitor Development , 1999, Vox Sanguinis.

[59]  B. Trask,et al.  Physical mapping studies on the human X chromosome in the region Xq27-Xqter. , 1987, Genomics.

[60]  D. Wolberg.  Human Evolution , 1927, Nature.

[61]  B. Binder,et al.  Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. , 2000, Blood.

[62]  M. Schwartz,et al.  A new Hind III restriction fragment length polymorphism in the hemophilia A locus , 1987, Human Genetics.

[63]  S. Sommer,et al.  Recurrent nonsense mutations at arginine residues cause severe hemophilia B in unrelated hemophiliacs , 1990, Human Genetics.

[64]  J. Oldenburg,et al.  Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain. , 1991, Thrombosis research.

[65]  E. Tuddenham.  Factor VIII and haemophilia A. , 1989, Bailliere's clinical haematology.

[66]  M. Schwartz,et al.  Female haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X‐chromosome inactivation? , 1989, Clinical genetics.

[67]  M. Schwartz,et al.  Absence of Correlation between X Chromosome Inactivation Pattern and Plasma Concentration of Factor VIII and Factor IX in Carriers of Haemophilia A and B , 2000, Thrombosis and Haemostasis.

[68]  P. Green,et al.  Further evidence for the importance of an androgen response element in the factor IX promoter , 1997, British journal of haematology.

[69]  P. Green,et al.  Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. , 1993, Human molecular genetics.

[70]  J. Vermylen,et al.  A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. , 2000, Blood.

[71]  K. Kurachi,et al.  Possible absence of common polymorphisms in coagulation factor IX gene in Japanese subjects. , 1987, Blood.

[72]  A. Thompson,et al.  The factor IX BamHI polymorphism: T-to-G transversion at the nucleotide sequence-561 , 1989, Human Genetics.

[73]  R. Ljung,et al.  Determination of factor IX allotypes for carrier identification in haemophilia B , 1987, British journal of haematology.

[74]  R. Foley.  The context of human genetic evolution. , 1998, Genome research.

[75]  C. Rothschild,et al.  New variant of von Willebrand disease with defective binding to factor VIII. , 1989, Blood.

[76]  K. Kurachi,et al.  Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). , 1985, Biochemistry.

[77]  F. Giannelli,et al.  Start of UK Confidential Haemophilia A Database: Analysis of 142 Patients by Solid Phase Fluorescent Chemical Cleavage of Mismatch , 1999, Thrombosis and Haemostasis.

[78]  S. Antonarakis,et al.  MspI polymorphism in the 3' flanking region of the human factor VIII gene. , 1987, Nucleic Acids Research.

[79]  A. Wong,et al.  Restriction fragment length polymorphisms associated with factor VIII: C gene in Chinese , 1988, Human Genetics.

[80]  H. Pollmann,et al.  Molecular diagnostics of 15 hemophilia A patients: Characterization of eight novel mutations in the factor VIII gene, two of which result in exon skipping , 1998, Human mutation.

[81]  S. Lord,et al.  The utility of a HindIII polymorphism of factor VIII examined by rapid DNA analysis , 1990, British journal of haematology.

[82]  J. V. van Mourik,et al.  The Light Chain of Factor VIII Comprises a Binding Site for Low Density Lipoprotein Receptor-related Protein* , 1999, The Journal of Biological Chemistry.

[83]  A. Thompson,et al.  Use of a BamHI polymorphism in the factor IX gene for the determination of hemophilia B carrier status. , 1986, Blood.

[84]  H Brandstetter,et al.  X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[85]  J. Vermylen,et al.  Some Factor VIII (FVIII) Inhibitors Recognise a FVIII Epitope(s) that Is Present only on FVIII-vWF Complexes , 1999, Thrombosis and Haemostasis.

[86]  Howarth,et al.  Linkage analysis in haemophilia A: simultaneous genotyping of two polymorphisms of the human factor VIII gene using induced heteroduplex formation , 1998, Haemophilia : the official journal of the World Federation of Hemophilia.

[87]  A. Hanauer,et al.  Common intragenic and extragenic polymorphisms of blood coagulation factors VIII and IX are different in Chinese and Caucasian populations , 1990, Clinical genetics.

[88]  B. Levinson,et al.  Mutations of factor VIII cleavage sites in hemophilia A. , 1988, Blood.

[89]  S. Antonarakis,et al.  Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. , 1997, American journal of human genetics.

[90]  R. Bertina,et al.  Hemophilia B Leyden: a sex-linked hereditary disorder that improves after puberty. , 1982, The New England journal of medicine.

[91]  D. Bentley,et al.  Haemophilia B mutations in a complete Swedish population sample: a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity , 1991, British journal of haematology.

[92]  G. Card,et al.  A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin. , 1997, Blood.

[93]  David J. Werrett,et al.  Forensic application of DNA ‘fingerprints’ , 1985, Nature.

[94]  E. Saenko,et al.  The Acidic Region of the Factor VIII Light Chain and the C2 Domain Together Form the High Affinity Binding Site for von Willebrand Factor* , 1997, The Journal of Biological Chemistry.

[95]  S. Antonarakis,et al.  Characterization of mutations in the factor VIII gene by direct sequencing of amplified genomic DNA. , 1990, Genomics.

[96]  P. Green,et al.  The molecular basis of haemophilia A and B. , 1996, Bailliere's clinical haematology.

[97]  G. Brownlee,et al.  Carrier detection in haemophilia B using two further intragenic restriction fragment length polymorphisms. , 1984, Nucleic acids research.

[98]  F E Preston,et al.  Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. , 1995, Blood.

[99]  E. Tuddenham,et al.  Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in human haemophilia A and von Willebrand's disease , 1982, British journal of haematology.

[100]  S. Thibodeau,et al.  Carrier testing in hemophilia B with an immunoassay that distinguishes a prevalent factor IX dimorphism. , 1987, Blood.

[101]  B. Keyt,et al.  Expression of active human factor VIII from recombinant DNA clones , 1984, Nature.

[102]  J. Sixma,et al.  The effect of thrombin on the complex between factor VIII and von Willebrand factor. , 1987, European journal of biochemistry.

[103]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[104]  C. Mazurier.  von Willebrand Disease Masquerading as Haemophilia A , 1992, Thrombosis and Haemostasis.

[105]  S. Kenwrick,et al.  Evidence for a third transcript from the human factor VIII gene. , 1992, Genomics.

[106]  D. Bentley,et al.  Molecular pathology of haemophilia B. , 1989, The EMBO journal.

[107]  K. Nicolaides,et al.  Report of a joint WHO/WFH meeting on the control of haemophilia: carrier detection and prenatal diagnosis. , 1993, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[108]  D. G. Rees,et al.  DETECTION OF POLYMORPHISMS AT CYTOSINE PHOSPHOGUANADINE DINUCLEOTIDES AND DIAGNOSIS OF HAEMOPHILIA B CARRIERS , 1989, The Lancet.

[109]  C. Altisent,et al.  Rapid Hemophilia A Molecular Diagnosis by a Simple DNA Sequencing Procedure: Identification of 14 Novel Mutations , 2001, Thrombosis and Haemostasis.

[110]  G. Brownlee,et al.  CHARACTERISATION AND USE OF AN INTRAGENIC POLYMORPHIC MARKER FOR DETECTION OF CARRIERS OF HAEMOPHILIA B (FACTOR IX DEFICIENCY) , 1984, The Lancet.

[111]  H. Saito,et al.  Three Distinct Point Mutations in the Factor IX Gene of Three Japanese CRM+ Hemophilia B Patients (Factor IX BMNagoya 2, Factor IX Nagoya 3 and 4) , 1991, Thrombosis and Haemostasis.

[112]  P. Green,et al.  Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene , 1991, The Lancet.

[113]  A. Goodeve.  Laboratory methods for the genetic diagnosis of bleeding disorders. , 1998, Clinical and laboratory haematology.

[114]  C. Ross,et al.  Microsatellite evolution — evidence for directionality and variation in rate between species , 1995, Nature Genetics.

[115]  S. Antonarakis,et al.  Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. , 1985, The New England journal of medicine.

[116]  S. Hassock,et al.  A novel DNA inversion causing severe hemophilia A. , 1996, Blood.

[117]  M. Shima,et al.  A Factor VIII Neutralizing Monoclonal Antibody and a Human Inhibitor Alloantibody Recognizing Epitopes in the C2 Domain Inhibit Factor VIII Binding to von Willebrand Factor and to Phosphatidylserine , 1993, Thrombosis and Haemostasis.

[118]  D. Bentley,et al.  Direct detection of point mutations by mismatch analysis: application to haemophilia B. , 1989, Nucleic acids research.

[119]  K. Berkner,et al.  Isolation of the human gamma-carboxylase and a gamma-carboxylase-associated protein from factor IX-expressing mammalian cells. , 1996, Biochemistry.

[120]  C. Nichols,et al.  An MseI RFLP in the 5’flanking region of the factor IX gene: its use for haemophilia B carrier detection in Caucasian and Thai populations , 1993, British journal of haematology.

[121]  E. Tuddenham,et al.  Haemophilia A diagnosis by analysis of a hypervariable dinucleotide repeat within the factor VIII gene , 1991, The Lancet.

[122]  C. Niehrs,et al.  Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. , 1991, The Journal of biological chemistry.

[123]  J. T. Matschiner,et al.  Changes in phylloquinone epoxidase activity related to prothrombin synthesis and microsomal clotting activity in the rat. , 1974, The Biochemical journal.

[124]  S. Lord,et al.  The Malmö polymorphism of factor IX: establishing the genotypes by rapid analysis of DNA. , 1989, Blood.

[125]  S. Antonarakis,et al.  Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[126]  J. Oldenburg,et al.  HLA Genotype of Patients with Severe Haemophilia A due to Intron 22 Inversion with and without Inhibitors of Factor VIII , 1997, Thrombosis and Haemostasis.

[127]  R. White,et al.  The genetic linkage map of the human X chromosome. , 1985, Science.

[128]  V. Chan,et al.  Multiple Xbal polymorphisms for carrier detection and prenatal diagnosis of haemophilia A , 1989, British journal of haematology.

[129]  M. Vidaud,et al.  The molecular genetic analysis of hemophilia A: a directed search strategy for the detection of point mutations in the human factor VIII gene. , 1990, Blood.

[130]  I. Sussman,et al.  Stabilization of factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease. , 1977, The Journal of clinical investigation.

[131]  S. Sommer,et al.  Single-tube polymerase chain reaction for rapid diagnosis of the inversion hotspot of mutation in hemophilia A. , 1998, Blood.

[132]  M. Crossley,et al.  Recovery from hemophilia B Leyden: an androgen-responsive element in the factor IX promoter. , 1992, Science.

[133]  A I Wacey,et al.  Mutation databases on the Web. , 1998, Journal of medical genetics.

[134]  Jeffrey H. Miller,et al.  Mutagenic deamination of cytosine residues in DNA , 1980, Nature.

[135]  D. Lakich,et al.  A transcribed gene in an intron of the human factor VIII gene. , 1990, Genomics.

[136]  D. Rees,et al.  The gene structure of human anti‐haemophilic factor IX. , 1984, The EMBO journal.

[137]  S. Antonarakis.  Molecular Genetics of Coagulation Factor VIII Gene and Hemophilia A , 1995, Thrombosis and Haemostasis.

[138]  S. Bajaj,et al.  "Founder" effect in different families with haemophilia B mutation , 1990, The Lancet.

[139]  S. Lord,et al.  The varying frequencies of five DNA polymorphisms of X-linked coagulant factor IX in eight ethnic groups. , 1991, American journal of human genetics.

[140]  J. Oldenburg,et al.  Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the severe haemophilia A phenotype. , 1998, Thrombosis and haemostasis.

[141]  P. Reitsma,et al.  Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX. , 1990, The Journal of biological chemistry.

[142]  E. Chen,et al.  Characterization of the human factor VIII gene , 1984, Nature.

[143]  K. Smith,et al.  The role of amino-terminal residues of the heavy chain of factor IXa in the binding of its cofactor, factor VIIIa. , 1994, Blood.

[144]  P. Green,et al.  First Report on UK Database of Haemophilia B Mutations and Pedigrees , 1994, Thrombosis and Haemostasis.

[145]  S. Antonarakis,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. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[146]  V. Chapman,et al.  Sequence of the human factor VIII-associated gene is conserved in mouse. , 1992, Genomics.

[147]  P. Lenting,et al.  Factor VIII-Factor IX Interactions: Molecular Sites Involved in Enzyme-Cofactor Complex Assembly , 1999, Thrombosis and Haemostasis.

[148]  H. Saito,et al.  Diagnosis of Hemophilia B Carriers Using Two Novel Dinucleotide Polymorphisms and Hha I RFLP of the Factor IX Gene in Japanese Subjects , 1995, Thrombosis and Haemostasis.

[149]  P. Collins,et al.  A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences , 2000, British journal of haematology.

[150]  G. Sarkar,et al.  Segments containing alternating purine and pyrimidine dinucleotides: patterns of polymorphism in humans and prevalence throughout phylogeny. , 1991, Nucleic acids research.

[151]  D. Bowen.  An Effective Route for the Isolation of Human Genetic Loci Exemplified Using the BglI Restriction Fragment Length Polymorphism of the Factor VIII Gene , 2000, Thrombosis and Haemostasis.