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Semin Thromb Hemost 2014; 40(08): 895-902
DOI: 10.1055/s-0034-1395161
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Historical Review on Genetic Analysis in Hemophilia A[*]

Johannes Oldenburg
1   Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany
,
Behnaz Pezeshkpoor
1   Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany
,
Anna Pavlova
1   Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
06 November 2014 (online)

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Abstract

Molecular genetic analysis is widely applied in inherited bleeding disorders. The outcome of genetic analysis allows genetic counselling in affected families and helps to find a link between the genotype and phenotype. Genetic analysis in hemophilia A (HA) has tremendously improved in the past decades. Many new techniques and modifications as well as analysis software have become available, which has enabled genetic analysis and interpretation of data to become faster and more accurate. The advances in mutation detection strategies facilitate the identification of the causal mutation in up to 97% of patients with HA. This review discusses the milestones in genetic analysis of HA and highlights the importance of identification of the causative mutations for genetic counseling and particularly for the interpretation of the clinical presentation of HA patients.

Keywords

hemophilia A - genetic analysis - F8 gene mutations - historic overview

* This article is dedicated to Dr. Hans-Hermann Brackmann in recognition of his pioneering work for hemophilia patients.


 

  • References

  • 1 Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
    CrossrefPubMedGoogle Scholar
  • 2 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost 2001; 86 (1) 57-65
    PubMedGoogle Scholar
  • 3 Oldenburg J, El-Maarri O. New insight into the molecular basis of hemophilia A. Int J Hematol 2006; 83 (2) 96-102
    CrossrefPubMedGoogle Scholar
  • 4 Levinson B, Kenwrick S, Lakich D, Hammonds Jr G, Gitschier J. A transcribed gene in an intron of the human factor VIII gene. Genomics 1990; 7 (1) 1-11
    CrossrefPubMedGoogle Scholar
  • 5 Levinson B, Kenwrick S, Gamel P, Fisher K, Gitschier J. Evidence for a third transcript from the human factor VIII gene. Genomics 1992; 14 (3) 585-589
    CrossrefPubMedGoogle Scholar
  • 6 Peters MF, Ross CA. Isolation of a 40-kDa Huntingtin-associated protein. J Biol Chem 2001; 276 (5) 3188-3194
    CrossrefPubMedGoogle Scholar
  • 7 Lakich D, Kazazian Jr HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 5 (3) 236-241
    CrossrefPubMedGoogle Scholar
  • 8 Naylor JA, Buck D, Green P, Williamson H, Bentley D, Giannelli F. Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum Mol Genet 1995; 4 (7) 1217-1224
    CrossrefPubMedGoogle Scholar
  • 9 Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1) 168-174
    CrossrefPubMedGoogle Scholar
  • 10 Schröder J, El-Maarri O, Schwaab R, Müller CR, Oldenburg J. Factor VIII intron-1 inversion: frequency and inhibitor prevalence. J Thromb Haemost 2006; 4 (5) 1141-1143
    CrossrefPubMedGoogle Scholar
  • 11 Biggs R, Rizza CR. The sporadic case of haemophilia A. Lancet 1976; 2 (7983) 431-433
    PubMedGoogle Scholar
  • 12 Kasper CK, Lin JC. Prevalence of sporadic and familial haemophilia. Haemophilia 2007; 13 (1) 90-92
    CrossrefPubMedGoogle Scholar
  • 13 Oldenburg J, Schwaab R, Grimm T , et al. Direct and indirect estimation of the sex ratio of mutation frequencies in hemophilia A. Am J Hum Genet 1993; 53 (6) 1229-1238
    PubMedGoogle Scholar
  • 14 Vogel F. A probable sex difference in some mutation rates. Am J Hum Genet 1977; 29 (3) 312-319
    PubMedGoogle Scholar
  • 15 Strauss HS. The perpetuation of hemophilia by mutation. Pediatrics 1967; 39 (2) 186-193
    PubMedGoogle Scholar
  • 16 Becker J, Schwaab R, Möller-Taube A , et al. 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 (4) 657-670
    PubMedGoogle Scholar
  • 17 Tuddenham EG. Flip tip inversion and haemophilia A. Lancet 1994; 343 (8893) 307-308
    PubMedGoogle Scholar
  • 18 Leuer M, Oldenburg J, Lavergne JM , et al. Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet 2001; 69 (1) 75-87
    CrossrefPubMedGoogle Scholar
  • 19 Oldenburg J, Rost S, El-Maarri O , et al. De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism. Blood 2000; 96 (8) 2905-2906
    PubMedGoogle Scholar
  • 20 Gitschier J, Wood WI, Goralka TM , et al. Characterization of the human factor VIII gene. Nature 1984; 312 (5992) 326-330
    CrossrefPubMedGoogle Scholar
  • 21 Toole JJ, Knopf JL, Wozney JM , et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312 (5992) 342-347
    CrossrefPubMedGoogle Scholar
  • 22 Schwaab R, Oldenburg J, Higuchi M , et al. Haemophilia A: carrier detection by DNA analysis. Blut 1988; 57 (2) 85-90
    CrossrefPubMedGoogle Scholar
  • 23 Schwaab R, Oldenburg J, Brackmann HH, Hanfland P. Hemophilia A: molecular biology and carrier diagnosis [in German]. Infusionsther Transfusionsmed 1994; 21 (2) 116-125
    PubMedGoogle Scholar
  • 24 Peake IR, Lillicrap DP, Boulyjenkov V , et al. Haemophilia: strategies for carrier detection and prenatal diagnosis. Bull World Health Organ 1993; 71 (3-4) 429-458
    PubMedGoogle Scholar
  • 25 Bernardi F, Marchetti G, Bertagnolo V , et al. RFLP analysis in families with sporadic hemophilia A. Estimate of the mutation ratio in male and female gametes. Hum Genet 1987; 76 (3) 253-256
    PubMedGoogle Scholar
  • 26 Harper K, Winter RM, Pembrey ME, Hartley D, Davies KE, Tuddenham EG. A clinically useful DNA probe closely linked to haemophilia A. Lancet 1984; 2 (8393) 6-8
    PubMedGoogle Scholar
  • 27 Gitschier J, Lawn RM, Rotblat F, Goldman E, Tuddenham EG. Antenatal diagnosis and carrier detection of haemophilia A using factor VIII gene probe. Lancet 1985; 1 (8437) 1093-1094
    PubMedGoogle Scholar
  • 28 Wion KL, Tuddenham EG, Lawn RM. A new polymorphism in the factor VIII gene for prenatal diagnosis of hemophilia A. Nucleic Acids Res 1986; 14 (11) 4535-4542
    CrossrefPubMedGoogle Scholar
  • 29 Lalloz MR, McVey JH, Pattinson JK, Tuddenham EG. Haemophilia A diagnosis by analysis of a hypervariable dinucleotide repeat within the factor VIII gene. Lancet 1991; 338 (8761) 207-211
    CrossrefPubMedGoogle Scholar
  • 30 Lalloz MR, Schwaab R, McVey JH, Michaelides K, Tuddenham EG. Haemophilia A diagnosis by simultaneous analysis of two variable dinucleotide tandem repeats within the factor VIII gene. Br J Haematol 1994; 86 (4) 804-809
    CrossrefPubMedGoogle Scholar
  • 31 Lin SY, Su YN, Hung CC , et al. Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM. BMC Med Genet 2008; 9: 53
    CrossrefPubMedGoogle Scholar
  • 32 Schwaab R, Ludwig M, Oldenburg J , et al. Identical point mutations in the factor VIII gene that have different clinical manifestations of hemophilia A. Am J Hum Genet 1990; 47 (4) 743-744
    PubMedGoogle Scholar
  • 33 Schwaab R, Oldenburg J, Tuddenham EG, Brackmann HH, Olek K. Mutations in haemophilia A. Br J Haematol 1993; 83 (3) 450-458
    CrossrefPubMedGoogle Scholar
  • 34 Schwaab R, Oldenburg J, Schwaab U , et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol 1995; 91 (2) 458-464
    CrossrefPubMedGoogle Scholar
  • 35 Higuchi M, Antonarakis SE, Kasch L , et al. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A 1991; 88 (19) 8307-8311
    CrossrefPubMedGoogle Scholar
  • 36 Higuchi M, Kazazian Jr HH, 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 (16) 7405-7409
    CrossrefPubMedGoogle Scholar
  • 37 Lakich D, Kazazian Jr HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet. 1993; 21 (2) 236-241
    PubMedGoogle Scholar
  • 38 Liu Q, Nozari G, Sommer SS. Single-tube polymerase chain reaction for rapid diagnosis of the inversion hotspot of mutation in hemophilia A. Blood 1998; 92 (4) 1458-1459
    PubMedGoogle Scholar
  • 39 Rossetti LC, Radic CP, Larripa IB, De Brasi CD. Genotyping the hemophilia inversion hotspot by use of inverse PCR. Clin Chem 2005; 51 (7) 1154-1158
    CrossrefPubMedGoogle Scholar
  • 40 Brinke A, Tagliavacca L, Naylor J, Green P, Giangrande P, Giannelli F. Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia. Hum Mol Genet 1996; 5 (12) 1945-1951
    CrossrefPubMedGoogle Scholar
  • 41 Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 1987; 155: 335-350
    PubMedGoogle Scholar
  • 42 Mullis KB. Target amplification for DNA analysis by the polymerase chain reaction. Ann Biol Clin (Paris) 1990; 48 (8) 579-582
    PubMedGoogle Scholar
  • 43 Lin SW, Lin SR, Shen MC. Characterization of genetic defects of hemophilia A in patients of Chinese origin. Genomics 1993; 18 (3) 496-504
    CrossrefPubMedGoogle Scholar
  • 44 Williams IJ, Abuzenadah A, Winship PR , et al. Precise carrier diagnosis in families with haemophilia A: use of conformation sensitive gel electrophoresis for mutation screening and polymorphism analysis. Thromb Haemost 1998; 79 (4) 723-726
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Waseem NH, Bagnall R, Green PM, Giannelli F ; Haemophilia Centres. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Thromb Haemost 1999; 81 (6) 900-905
    PubMedGoogle Scholar
  • 46 Oldenburg J, Ivaskevicius V, Rost S , et al. Evaluation of DHPLC in the analysis of hemophilia A. J Biochem Biophys Methods 2001; 47 (1-2) 39-51
    CrossrefPubMedGoogle Scholar
  • 47 Antonarakis SE, Kazazian HH, Gitschier J, Hutter P, de Moerloose P, Morris MA. Molecular etiology of factor VIII deficiency in hemophilia A. Adv Exp Med Biol 1995; 386: 19-34
    PubMedGoogle Scholar
  • 48 Pezeshkpoor B, Zimmer N, Marquardt N , et al. Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. J Thromb Haemost 2013; 11 (9) 1679-1687
    CrossrefPubMedGoogle Scholar
  • 49 Voelkerding KV, Dames S, Durtschi JD. Next generation sequencing for clinical diagnostics-principles and application to targeted resequencing for hypertrophic cardiomyopathy: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2010; 12 (5) 539-551
    CrossrefPubMedGoogle Scholar
  • 50 Acquila M, Pasino M, Di Duca M, Bottini F, Molinari AC, Bicocchi MP. MLPA assay in F8 gene mutation screening. Haemophilia 2008; 14 (3) 625-627
    CrossrefPubMedGoogle Scholar
  • 51 Rost S, Löffler S, Pavlova A, Müller CR, Oldenburg J. Detection of large duplications within the factor VIII gene by MLPA. J Thromb Haemost 2008; 6 (11) 1996-1999
    CrossrefPubMedGoogle Scholar
  • 52 Oldenburg J, Schröder J, Schmitt C, Brackmann HH, Schwaab R. Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the severe haemophilia A phenotype. Thromb Haemost 1998; 79 (2) 452-453
    PubMedGoogle Scholar
  • 53 Youssoufian H, Antonarakis SE, Bell W, Griffin AM, Kazazian Jr HH. Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet 1988; 42 (5) 718-725
    PubMedGoogle Scholar
  • 54 El-Maarri O, Olek A, Balaban B , et al. Methylation levels at selected CpG sites in the factor VIII and FGFR3 genes, in mature female and male germ cells: implications for male-driven evolution. Am J Hum Genet 1998; 63 (4) 1001-1008
    CrossrefPubMedGoogle Scholar
  • 55 Tavassoli K, Eigel A, Horst J. A deletion/insertion leading to the generation of a direct repeat as a result of slipped mispairing and intragenic recombination in the factor VIII gene. Hum Genet 1999; 104 (5) 435-437
    CrossrefPubMedGoogle Scholar
  • 56 Woods-Samuels P, Kazazian Jr HH, Antonarakis SE. Nonhomologous recombination in the human genome: deletions in the human factor VIII gene. Genomics 1991; 10 (1) 94-101
    CrossrefPubMedGoogle Scholar
  • 57 Vidal F, Farssac E, Tusell J, Puig L, Gallardo D. First molecular characterization of an unequal homologous alu-mediated recombination event responsible for hemophilia. Thromb Haemost 2002; 88 (1) 12-16
    PubMedGoogle Scholar
  • 58 Rossetti LC, Goodeve A, Larripa IB, De Brasi CD. Homeologous recombination between AluSx-sequences as a cause of hemophilia. Hum Mutat 2004; 24 (5) 440
    PubMedGoogle Scholar
  • 59 Van de Water N, Williams R, Ockelford P, Browett P. A 20.7 kb deletion within the factor VIII gene associated with LINE-1 element insertion. Thromb Haemost 1998; 79 (5) 938-942
    PubMedGoogle Scholar
  • 60 Sheen CR, Jewell UR, Morris CM , et al. Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication. Hum Mutat 2007; 28 (12) 1198-1206
    CrossrefPubMedGoogle Scholar
  • 61 Pezeshkpoor B, Rost S, Oldenburg J, El-Maarri O. Identification of a third rearrangement at Xq28 that causes severe hemophilia A as a result of homologous recombination between inverted repeats. J Thromb Haemost 2012; 10 (8) 1600-1608
    CrossrefPubMedGoogle Scholar
  • 62 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55 (1) 1-18
    CrossrefPubMedGoogle Scholar
  • 63 Young M, Inaba H, Hoyer LW, Higuchi M, Kazazian Jr HH, Antonarakis SE. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet 1997; 60 (3) 565-573
    PubMedGoogle Scholar
  • 64 Leyte A, van Schijndel HB, Niehrs C , et al. Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. J Biol Chem 1991; 266 (2) 740-746
    PubMedGoogle Scholar
  • 65 Leyte A, Voorberg J, Van Schijndel HB, Duim B, Pannekoek H, Van Mourik JA. The pro-polypeptide of von Willebrand factor is required for the formation of a functional factor VIII-binding site on mature von Willebrand factor. Biochem J 1991; 274 (Pt 1) 257-261
    PubMedGoogle Scholar
  • 66 Gilles JG, Lavend'homme R, Peerlinck K , et al. Some factor VIII (FVIII) inhibitors recognise a FVIII epitope(s) that is present only on FVIII-vWF complexes. Thromb Haemost 1999; 82 (1) 40-45
    PubMedGoogle Scholar
  • 67 Stoylova SS, Lenting PJ, Kemball-Cook G, Holzenburg A. Electron crystallography of human blood coagulation factor VIII bound to phospholipid monolayers. J Biol Chem 1999; 274 (51) 36573-36578
    CrossrefPubMedGoogle Scholar
  • 68 Zimmermann MA, Gehrig A, Oldenburg J, Müller CR, Rost S. Analysis of F8 mRNA in haemophilia A patients with silent mutations or presumptive splice site mutations. Haemophilia 2013; 19 (2) 310-317
    CrossrefPubMedGoogle Scholar
  • 69 Pahl S, Pavlova A, Driesen J, Oldenburg J. Effect of F8 B domain gene variants on synthesis, secretion, activity and stability of factor VIII protein. Thromb Haemost 2014; 111 (1) 58-66
    PubMedGoogle Scholar
  • 70 Castaman G, Giacomelli SH, Mancuso ME , et al. Deep intronic variations may cause mild hemophilia A. J Thromb Haemost 2011; 9 (8) 1541-1548
    CrossrefPubMedGoogle Scholar
  • 71 Ogata K, Selvaraj SR, Miao HZ, Pipe SW. Most factor VIII B domain missense mutations are unlikely to be causative mutations for severe hemophilia A: implications for genotyping. J Thromb Haemost 2011; 9 (6) 1183-1190
    CrossrefPubMedGoogle Scholar
  • 72 Oldenburg J, Brackmann HH, Schwaab R. Risk factors for inhibitor development in hemophilia A. Haematologica 2000; 85 (10, Suppl): 7-13 , discussion 13–14
    PubMedGoogle Scholar
  • 73 Schwaab R, Brackmann HH, Meyer C , et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74 (6) 1402-1406
    PubMedGoogle Scholar
  • 74 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22
    PubMedGoogle Scholar
  • 75 Schwaab R, Pavlova A, Albert T, Caspers M, Oldenburg J. Significance of F8 missense mutations with respect to inhibitor formation. Thromb Haemost 2013; 109 (3) 464-470
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Schwaab R, Oldenburg J, Kemball-Cook G , et al. Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family. Br J Haematol 2000; 109 (3) 523-528
    CrossrefPubMedGoogle Scholar
  • 77 Rodgers SE, Duncan EM, Barbulescu DM, Quinn DM, Lloyd JV. In vitro kinetics of factor VIII activity in patients with mild haemophilia A and a discrepancy between one-stage and two-stage factor VIII assay results. Br J Haematol 2007; 136 (1) 138-145
    CrossrefPubMedGoogle Scholar
  • 78 Oldenburg J, Pavlova A. Discrepancy between one-stage and chromogenic factor VIII activity assay results can lead to misdiagnosis of haemophilia A phenotype. Hamostaseologie 2010; 30 (4) 207-211
    PubMedGoogle Scholar
  • 79 Pavlova A, Delev D, Pezeshkpoor B, Müller J, Oldenburg J. Haemophilia A mutations in patients with non-severe phenotype associated with a discrepancy between one-stage and chromogenic factor VIII activity assays. Thromb Haemost 2014; 111 (5) 851-861
    Article in Thieme ConnectPubMedGoogle Scholar
  • 80 Hakeos WH, Miao H, Sirachainan N , et al. Hemophilia A mutations within the factor VIII A2-A3 subunit interface destabilize factor VIIIa and cause one-stage/two-stage activity discrepancy. Thromb Haemost 2002; 88 (5) 781-787
    Article in Thieme ConnectPubMedGoogle Scholar
  • 81 Pipe SW, Saenko EL, Eickhorst AN, Kemball-Cook G, Kaufman RJ. Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa. Blood 2001; 97 (3) 685-691
    CrossrefPubMedGoogle Scholar
  • 82 Pavlova A, Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost 2013; 39 (7) 702-710
    Article in Thieme ConnectPubMedGoogle Scholar
  • 83 Santagostino E, Gringeri A, Tagliavacca L, Mannucci PM. Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin. Thromb Haemost 1995; 74 (2) 619-621
    PubMedGoogle Scholar
  • 84 Zimmermann MA, Oldenburg J, Müller CR, Rost S. Characterization of duplication breakpoints in the factor VIII gene. J Thromb Haemost 2010; 8 (12) 2696-2704
    CrossrefPubMedGoogle Scholar
  • 85 Uen C, Oldenburg J, Schröder J , et al. 2% Haemophilia A patients without mutation in the FVIII gene [in German]. Hamostaseologie 2003; 23 (1) 1-5
    PubMedGoogle Scholar
  • 86 El-Maarri O, Herbiniaux U, Graw J , et al. Analysis of mRNA in hemophilia A patients with undetectable mutations reveals normal splicing in the factor VIII gene. J Thromb Haemost 2005; 3 (2) 332-339
    CrossrefPubMedGoogle Scholar
  • 87 Pezeshkpoor B, Pavlova A, Oldenburg J, El-Maarri O. F8 genetic analysis strategies when standard approaches fail. Haemostaseologie 2014; 34 (2) 167-173
    PubMedGoogle Scholar
  • 88 Zhang B, Cunningham MA, Nichols WC , et al. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet 2003; 34 (2) 220-225
    CrossrefPubMedGoogle Scholar
  • 89 Nichols WC, Seligsohn U, Zivelin A , et al. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 1998; 93 (1) 61-70
    CrossrefPubMedGoogle Scholar
  • 90 Spreafico M, Peyvandi F. Combined FV and FVIII deficiency. Haemophilia 2008; 14 (6) 1201-1208
    CrossrefPubMedGoogle Scholar
  • 91 Zhang B, McGee B, Yamaoka JS , et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 2006; 107 (5) 1903-1907
    CrossrefPubMedGoogle Scholar