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Medicine » Medical Genetics » "Targets in Gene Therapy", book edited by Yongping You, ISBN 978-953-307-540-2, Published: August 23, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 20

Using Factor VII in Hemophilia Gene Therapy

By Bahram Kazemi
DOI: 10.5772/17695

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External and internal pathways of blood coagulation process. (Reference phonetically
Figure 1. External and internal pathways of blood coagulation process. (Reference phonetically
Genetic mutation in intron 22 of FVIII (Schwartz et al., 2011)
Figure 2. Genetic mutation in intron 22 of FVIII (Schwartz et al., 2011)
The Map of FVIII on the long arm of chromosome X (Schwartz et al., 2011)
Figure 3. The Map of FVIII on the long arm of chromosome X (Schwartz et al., 2011)
Genetic map of FVIII (White & Shoemaker, 1989)
Figure 4. Genetic map of FVIII (White & Shoemaker, 1989)
The domains organization of FVIII (Schwartz et al., 2011)
Figure 5. The domains organization of FVIII (Schwartz et al., 2011)
Mutagenesis method to create furin digestion site on the FVII protein (Proposed based on Emamgholipour et al., 2009; Margaritis, 2010)
Figure 6. Mutagenesis method to create furin digestion site on the FVII protein (Proposed based on Emamgholipour et al., 2009; Margaritis, 2010)

Using Factor VII in Hemophilia Gene Therapy

Kazemi Bahram1

1. Introduction

Human blood at physiological conditions is kept as fluid through precise system called homeostasis, if damage to the vessel, causing the system will be restored by vessel wall. Cases no regulation or homeostasis disorders, thrombosis (intravascular coagulation) or bleeding occur. In normal conditions, the secretion of vascular endothelial heparin-like and trmbomodulin molecules prevent blood coagulation and secretion of nitric oxide and prostacyclin prevent platelet aggregation and blood brings the liquid keeps. Homeostasis has three stages: vasoconstriction, platelet plug formation and blood coagulation, blood coagulation are reactions in which plasma zymogens become active enzymes that create the clotting reaction. Coagulation reactions will be set with inhibitory and stimulatory mechanisms. Coagulation is a regulatory process that keeps the blood flowing. Blood coagulation has two external and internal pathways (Figure 1), tissue factor and FVII form the external pathway, internal pathway is formed of FVIII, FIX and FXI (Ramanarayana et al., 2011; Ellison, 1977).

2. Hemophilia

Hemophilia had recognized in the fifth century BC, first the Jews law passed that when a woman has two dead boys doing the circumcision her third son should not be circumcised, they showed the mother will transmit the disease to her sons (History of hemophilia, 2011). Genetic and hereditary pattern of hemophilia was carefully described in 1803 by the American physician John Conrad Otto. He supposed that the bleeding was occurring due to lack of blood anti hemophilic factor (Cahill & Colvin, 1997). Glossary of hemophilia was developed for this disease in 1828 at the University of Zurich. Anti-hemophilia globin was discovered in 1937 by Patek and Tylor at Harvard University (History of Hemophilia Disease, 2011). The two forms of hemophilia A and B were distinguished in 1952 by Pavlosky, the Brazilian physician. Both diseases are sex-dependent and occur in males (Cahill & Colvin, 1977).

3. Causes hemophilia

Hemophilia is a genetic disorder happens in coagulation FVIII (hemophilia A) or FIX (hemophilia B) and are related to the X chromosome. Hemophilia A is a disease due to genetic defects in coagulation FVIII (Furie et al., 1994; White & Shoemaker, 1989) It is identified by Hoyer and Breckenridge (Hoyer & Breckenridge, 1968) and then by Denson for the first time (Denson et al., 1969). They showed that there was not FVIIIa in the plasma of the most people with hemophilia. Hemophilia B caused by genetic defects occur in the coagulation FIX; the FIX deficiency will inhibit the activation of FX by FVIIa through external coagulation pathway (Furie et al., 1994; Thompson, 1986). About half The patients who suffer from severe hemophilia A there is a large inversion in intron 22 of their FVIII mRNA (Figure 2) which it is repeated (Arruda et al., 1995; Deutz-Terlouw et al., 1995; Okamoto et al., 1995; Pieneman et al., 1995; Van de Water et al., 1995; Goodeve et al., Jenkins et al., 1994; 1994; Naylor et al., 1993; Naylor et al., 1992). Different alleles of the VNTR (di nucleotides) have observed in intron 13 of FVIII in people with hemophilia A (Kochhan et al., 1994).


Figure 1.

External and internal pathways of blood coagulation process. (Reference phonetically

Hemophilia A is occurring one for 5000-10000 birthday boys and hemophilia B one for 20,000 to 34,000 birthday boys (Dimitrios et al., 2009). The bleeding in joints of hemophilia patients the wound bleeding is longer continued (Petkova et al., 2004). The position of FVIII gene is Xq28 and of FIX is Xq27.1 location on distal long arm of chromosome X (Figure 3). The FVIII gene has 186 kb organized in 26 exons (about 9 kb) (Figure 4). There are detected some gene mutations on FVIII as insertion, deletions or point mutations which involved in the reduced or cut up in FVIII activation (Ramanarayana et al., 2011; Salviato et al., 2002; Cahill & Colvin, 1997; Arruda et al., 1995; Naylor et al., 1991; Higuchi et al., 1989; Youssoufian et al., 1987; Gitschier et al., 1985;). The FVIII organized in A, B and C domains (Figure 5), which B domain is highly glycosylated and do not involve in FVIII activities (Eaton et al., 1986).


Figure 2.

Genetic mutation in intron 22 of FVIII (Schwartz et al., 2011)


Figure 3.

The Map of FVIII on the long arm of chromosome X (Schwartz et al., 2011)


Figure 4.

Genetic map of FVIII (White & Shoemaker, 1989)


Figure 5.

The domains organization of FVIII (Schwartz et al., 2011)

4. Diagnosis of hemophilia

Laboratory diagnosis of hemophilia is done based on activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count and bleeding time. There is an abnormally in the initial section of internal coagulation pathway at the prolonged aPTT and normal PT. The normal aPTT should not be reject the FVIII deficiencies (hemophilia A), the aPTT is not enough sensitive too reduced amount of FVIII C. Prolonged PT alone, or PT and aPTT do not specify of hemophilia A, the liver diseases, overdose of warfarin or heparin and the distribution intravascular coagulation (DIC) can cause this coagulophaty. Thrombocytopenia alone cannot cause of hemophilia A. The nature and severity of bleeding is performed with cell blood counts (CBC) and differentiation also check for blood in the stool and urine (Schwartz et al., 2011). Knights and Ingram in 1967 were used thromboplastin time assay for hemophilia A and B differentiation. Based on their test when alumina is added to normal plasma do not see the harm of FVIII, but FIX is deleted, remove the alumina from plasma FIX will re- back up. If thromboplastin time is increased in males with a history of prolonged bleeding, test is repeated after adding or removing alumina from the plasma. If thromboplastin time is shorter than the control, the patient is suffering from hemophilia A, but if thromboplastin time is shortened after the removal of the alumina, patient is suffering from hemophilia B (Knights & Ingram, 1967). Stites et al (1971) and Essien and Ingram (1967) were distinguished hemophilia A and B by FVIII inhibitory antibodies.

The test results in children and adults are different. Clotting Index and coagulability in hemophilia patients significantly lower than non-hemophilia one. In this test, coagulability of FVIII treated blood varies by the replaced FVIII type. rFVIII clotting index is lower than of derived plasma one (Goldenberg et al., 2006). Firshein and colleagues were diagnosed prenatal hemophilia A using radioimmunometric by fetal plasma and fetoscope by amniotic fluid at second trimester in pregnancy women (Firshein et al., 1979), other researchers were developed radoimmunometric method for measurements of FVIII antibody (Hoyer et al., 1985; Hellings et al., 1982; Ljung R, Holmberg, 1982). Antonarakis et al were analyzed FVIII gene for possibility detection of prenatal and hemophilia carrier through gene cloning method (Antonarakis et al., 1985), the problems and limitations of these methods were evaluated by other researchers (Graham et al., 1985). The PCR RFLP method was used for prenatal diagnosis and hemophilia A carrier for the first time in 1990s (Rudzki et al., 1996; Herrmann et al., 1988; Kogan et al., 1987;). Missense and nonsense point mutations in FVIII gene of hemophilia A patient, prenatal and carrier hemophilia A were detected using DGGE method (Gitschier, 1989). Ball and colleagues were used oral cells, urine and hair follicles samples to identify prenatal and carrier hemophilia A (Ball et al., 1990). Various polymorphism and mutations have been detected in FVIII gene of hemophilia A patients (Wacey et al., 1996Antonarakis et al, 1995; Naylor et al., 1991; Baranov et al., 1990; Gécz et al., 1990; Jedlicka et al., 1990; Sadler et al., 1990; Surin et al., 1990; Wehnert et al., 1990a; Wehnert et al., 1990b). Establishment the PCR technique in diagnostic laboratories was a large change in DNA analysis of FVIII gene for detecting carriers and individuals with hemophilia A (Song et al., 1993; Feng, 1991; Wadelius et al., 1991; Wu, 1991). Detection of unknown mutations is performed by universal mutation detection system methods such as SSCP (Arruda et al., 1995; Pieneman et al., 1995; David et al., 1994). Hemophilia diagnosis with PGD method was used by Michaelides (2006) and colleagues For the first time in 2006; they were diagnosed two point mutations in FVIII gene of donor (IVF) blastomere. Acquired hemophilia due to FVIII autoantibody is a rare disease and occurs one in a million, yearly; its mortality is 20 percent (Shetty et al., 2010).

5.1. Treatment of hemophilia A

Hemophilia treatment doing by replacing the natural (Brackmann & Gormsen, 1977) or recombinant FVIII (Kaufman, 1991) via intravenous injection. The half life of transfused FVIII in normal individuals or patients with hemophilia is 8 to 12 hours (White & Shoemaker, 1989). Using recombinant serum proteins in the treatment of hemophilia began in 1990 (Liras, 2008), but Homate P / humate-P is a derived pasteurized human plasma which was approved in Germany in 1981 and used administered intravenous injection for 25 years to control bleeding in patients with hemophilia A and von Willebrand disease (Berntorp, 2009; Carter & Scott, 2007; Czapek et al, 1988). The main presentation following hemophilia treatment is creating inhibitory antibodies against the FVIII which observed 5% in patients with hemophilia B and 40 -20 percent in patients with severe hemophilia A (Hong & Stachnik, 2010; Kempton et al., 2010; Eckhardt et al., 2009; Ghosh & Shetty, 2009; von Auer et al., 2005; Sharathkumar wt al., 2003; Scharrer, 1999; de Biasi et al., 1994). Complication inhibitory antibodies seem to produce with plasma-derived FVII severe than with recombinant one (Lusher, 2002; Lusher, 2000), also with FVIII (Qadura et al., 2009; Delignat et al., 2007; Goudemand et al., 2006; Yoshioka et al., 2003; Fijnvandraat et al, 1997). The B cell epitopes mutated, produced FVIII inhibitory antibody is reduced, and some one proposed that this phenomenon is safe vaccine for people with hemophilia (Parker et al, 2004). Antibody production against FVIII has been studied in hemophilia patients and indicates that most nonsense mutations and large deletions in FVIII gene and chromosomal recombination lead to produce FVIII inhibitory antibody (Schwaab et al., 1995). Treatment of hemophilia by FVIII overdose administration is effective for producer antibodies hemophilia patients (Scandella et al., 2000).

The OBI (BDD- rpFVIII) was introduced by Ipsen and Inspiration Biopharmaceuticals Inc Company and passed clinical trial phases 1 and 2. It shows porcine FVIII biochemical properties and procoagulant activity and less immunogenicity than plasma derived pFVIII (Toschi, 2010).

In 1960 Los Angeles Red Cross Blood Center was treated hemophilia patients using anti hemophilic globin (Rapaport et al., 1960). 1-Deamino-8-d-arginine vasopressin (DDAVP) (a FVII autologous) have been used instead of plasma derived factors for treatment of hemophilia A and B (Mannucci et al., 1977). Hultin and colleagues were used cyclophosphamide as immunosuppression drug for antibody producer hemophilia patients (Hultin et al., 1976). Lian et al. were treated hemophilia using cyclophosphamide, vincristine and prednisone (CVP) (Lian et al., 1989). Blatt et al were removed FVIII inhibitory antibody with prothrombin complex concentrates (PCC) (Blatt et al., 1977). Paleyanda and colleagues were transferred FVIII cDNA into pig lactate system; the pig was produced FVIII more than 10 times as normal plasma (Paleyanda et al., 1997). Specific thrombin anticoagulant Bivalirudin (Krolick, 2005) and monoclonal antibody Retoximab (Franchini, 2007; Wiestner et al., 2002) are also used for hemophilia treatment and patients with FVIII autoantibody, respectively. Idiotype vaccines will neutralize anti human FVIII antibody in hemophilia A patients (Lacroix-Desmazes et al., 2002).

Production and characterization of recombinant FVIII for the treatment of hemophilia was conducted in 1984 for the first time (Toole et al., 1984; Wood et al., 1984). Use of recombinant proteins to replace clotting factors and treatment of hemophilia opened a new arena in treatment of disease. Circulating blood factors are the first generation recombinant proteins and second generation drugs made by recombinant DNA and protein engineering technology cause changes in proteins for specific applications, like FVIIa (Levy & Levi, 2009; Pipe, 2008). FVII alone or in combination with its analogues have been used to reduce bleeding (Lauritzen el al., 2008a; Lauritzen et al., 2008b; Allen et al., 2007). Use of recombinant FVIIa for hemophilia patients with FVIII antibody (Obergfell et al., 2010; Margaritis, 2010; Margaritis et al., 2010), also people who have bleeding into the joint or prevent bleeding in surgery is economically efficient (Stephens et al., 2007).

5.2. Gene therapy of hemophilia A

For the first time in 1996, Connelly et al were administrated intravenous hemophilia dog by adenovirus containing hFVIII gene in which related protein was detectable in plasma for two weeks (Connelly et al., 1996a). Connelly and colleagues were injected adenovirus containing BDD- hFVIII gene through the tail artery into mice; hFVIII was detected in plasma by ELISA method (Connelly et al., 1999; Connelly et al. 1995). Dwarki and colleagues were transfected fibroblast by retrovirus containing BDD- FVIII gene, transfected fibroblasts were transferred into mice, human FVIII was observed in plasma after one week (Dwarki et al., 1995). Connelly et al were transferred adenovirus containing hFVIII gene into mice, hFVIII was stable in mouse for five months. (Connelly et al., 1996b). Ill et al were prepared suitable plasmid with necessary elements for FVIII expression in liver cells (Ill et al., 1997). Zhang et al were prepared a mini-adenovirus containing FVIII -equipped human albumin gene promoter for hemophilia A gene therapy. This structure was transferred to cell line; the hFVIII was consistently produced in mouse transferred ell line (Zhang et al., 1999). Gene therapy of hemophilia were done by liver cell transfected by adeno associated viruses or lentiviral viruses containing FVIII and FIX. Also use non-viral vector is also considered. Antibody production in gene therapy of hemophilia with FVIII and FIX can be depended on vector serotype (viral), expression rate (a long time, especially in the liver), the promoter used, method of gene delivery and transduced cell types (Margaritis et al., 2009; Ohmori et al., 2008; VandenDriessche et al., 2003; Chuah et al., 2001).

To overcome adenovirus toxicity phenomena, Andrews and colleagues were used adenovirus defected early genes E1, E2a, E3, E4 (four-generation defected vector), and transferred albumin promoter –controlled FVIII gene into mice, but was not suitable for use in vivo (Andrews et al., 2001). Chuah et al were inhibited bleeding in hemophilia A SCID mice using intravenous injection of adenovirus carrying BDD -FVIII gene (Chuah et al., 2003). Shi et al believed that platelet/ megakaryocyte is a target for hemophilia A gene therapy, they were transferred equipted specific platelet glycoprotein IIb promoter BDD- hFVIII to Domi cells, hFVIII was biosynthesised (Shi et al., 2003). Sarkar and colleagues were transferred AAV carrying hFVIII to deficient FVIII mice through portal, intravenous and spleen injections, they observed secreted hFVIII in transgenic animals but no in neonatal animal (Sarkar et al., 2003). Scallan et al were transferred FVIII gene into mice by AAV2 vector. The construct was equipped with liver cell specific promoter (Scallan et al., 2003). Kang and colleagues were used liver specific promoter equipted FIV retrovirus containing BDD- hFVIII gen for intravenous injection in hemophilia mice, hFVIII was secreted in mice for months without anti FVIII antibody production (Kang et al., 2005). Kumaran et al were treated hemophilia mice by cell therapy, a mixture of hepatocytes, liver endothelial sinusoids and liver kupffer cells was injected into mice peritoneum, FVIII was observed in mouse blood (Kumaran et al., 2005). Jiang et al were transferred FVIII in to hemophilia dog by AAV types 2, 5, 6 and 8, their report indicated that the performance of virus types 2 and 5 for gene therapy is more than viruses type 6 and 8 (Jiang et al., 2006). Sarkar et al believed that gene therapy duration in the dog with AAV8 containing FVIII have prolonged up to two years (Sarkar et al., 2006). Durable gene therapy based on AAV containing FVIII have also been reported by McCormack and colleagues (McCormack et al., 2006). Shi and colleagues findings suggest that targeted FVIII gene expression by platelets specific promoter is effective in the treatment of hemophilia A (Shi et al., 2006). Shi and colleagues were suggested that ectopic expression of FVIII in platelets with lentiviral virus via bone marrow gene therapy is effective for human hemophilia treatment They were transferred lentiviral vector containing FVIII - Induced glycoprotein IIb platelet specific promoter into null mice bone marrow, the permanent secretion of FVIII in platelets lysates mice was observed. (Shi et al., 2007). Liu and colleagues were targeted rDNA of HL7702 hepatocytes by non-viral vector pHrneo containing FVIII gene for treatment of hemophilia (Liu et al., 2007). Doering has been transferred swine FVIII gene into mouse bone marrow mesenchymal cells for hemophilia treatment (Doering, 2008). Ishiwata and colleagues have been treated hemophilia mice using AAV8 vector containing canine BDD -FVIII gene (Ishiwata et al., 2009). Sabatino and colleagues report indicated that canine BDD- FVIII dogs is stable than human BDD- FVIII, it can be considered in the hemophilia treatment (Sabatino et al., 2009). Doering et al were transferred hFVIII - sFVIII hybrid in to hematopoietic stem cells with lentiviral vector; cells expressed FVIII more than 100-8 times of cells transfected with hFVIII only (Doering et al., 2009). Zatloukal and colleagues report suggested that expressed FVIII would be observed if the adenovirus containing FVIII -transfected fibroblasts or mayoblasts move into liver or spleen cells, but do not observe in the transfected muscle cells (Zatloukal et al., 1995). Because there are no acceptable phenotypic correction of hemophilia mice, Liars was used induced pluri potent stem cell therapy technology, these cells suggested converting into all cells and can be transfected by recombinant AAV or lentiviral vectors (Liars, 2011). Studies conducted so far suggest that blood factors gene therapy with AAV in animal muscle (dogs and mice) was healthy for FIX, but did not sufficiently much success for FVIII (Haurigot et al., 2010; Wang & Herzog, 2005). It is believed that the clinical correction of hemophilia B depends on the dose of vector transfer into muscular hosts (mice and dogs) (Hagstrom et al., 2000; Kay et al., 2000).

5.3. Hemophilia gene therapy with factor VII

Activated FVII is used as recombinant factor VII (rFVII) can go around process dependent coagulation FVIII and FIX (Mackman et al., 2007), it helps blood coagulation through extrinsic pathway. It is an ideal choice in the treatment of patients with FVIII producing antibodies and hemophilia patients to be considered (Johannessen etal., 2000; Lauritzen et al., 2008a). FVII is used in patient`s surgery with hemophilia A (Lauritzen et al., 2008a) also effective in term of homostatic process (Hedner et al., 2000; Kenet et al., 1999). The VIIa (Novoseven; rhFVIIa) has been achieved great success in treating patients with hemophilia. On the FVIII or FIX defects or presence of inhibitory antibodies, FVIIa – tissue factor complex will activate coagulation FX. FVIIa can activate coagulation cascade which cause clot formation and bleeding is inhibited (Hong & Stachnik, 2010; Levy & Levi, 2009). The main drug problems are short half-life (3-6 hours) and highly price (Ramanarayana et al., 2011; Puetz, 2010; Agersø et al., 2011; ), more than one full dose of medication, especially for homeostasis regulation during surgeries are required. Hence, research groups around the world are trying different methods of gene transfer to express stable FVIIa in cells without the need to drug re administration (Ramanarayana et al., 2011). After biosynthesis of rhFVII as zymogen, it will be cut by proteases and biologically active through purification process (Huntington, 2009). The produced protein will breaks down at Arg152 and Ile153 to FVIIa. It is proposed that FVII gene transfer eliminates short half-life of rFVII and FVIII inhibitory antibody production (Ramanarayana et al., 2011). Emamgholipour et al (2009) and Margaritis (2010) established furin enzyme digestion site between Arg152 and Ile153 to generate FVIIa from FVII zymogene break down inside the targeted cell during FVII gene therapy strategy (Figure 6). Margaritis and colleagues were successfully corrected canine hemophilia B with this method


Figure 6.

Mutagenesis method to create furin digestion site on the FVII protein (Proposed based on Emamgholipour et al., 2009; Margaritis, 2010)

(Margaritis et al., 2004). Margaritis and colleagues were injected the mice through gene therapy by AAV contained FVII gene, FVII was produced in host cells (Margaritis et al., 2004). Miller et al were injected mice muscle myoblasts with plasmids coding FVIII and FVII cDNA (muscle specific elements and poly A were placed on both sides of genes); they were observed FVII and related antibody after 4-5 days. They believed that post translation modification process was occurred in the muscle cells (Miller et al., 1995). Tomokiyo and colleagues showed that the composition of plasma FVIIa and FXa in the treatment of monkeys hemophilia B more effective than FVIIa alone (Tomokiyo et al., 2003). Ohmori et al have been used ectopic expression FVIIa in platelets to hemophilia A treatment, they were transferred SIV containing platelet glycoprotein Ib alpha specific promoter into bone marrow cells, was lead to FVII expression on the platelets surface. This construct was corrected mouse hemophilia A phenotype (Ohmori et al., 2008). Margaritis have been treated canine hemophilia by AAV containing FVII through the portal vein (Margaritis et al., 2009). To overcome the repeated injection problem, Obergfell and colleagues were studied hemophilia treatment and suggested permanent expression of FVII in canine hemophilia model through gene therapy method (Obergfell et al., 2010).

6. Conclusion

There are some reported of FVIII and FIX gene transfer by viral vectors in animal models, but no evidence so far reported successful treatment of human hemophilia gene therapy by this method. Researchers have used FVII to overcome antibody production in treatment of FVIII deficiency. Despite several reports of curing hemophilia A with FVII in animals, there is no yet successful reported in human.

Methods proposed for the future: reviewing the history of hemophilia gene therapy by viral vectors, identified several reasons that cannot be sure of the viruses used for gene transfer:

  1. Application of viruses is associated with inappropriate chromosomal insertion and makes the undesirable point mutations (Nakai et al., 2003; Miller et al., 2002).

  2. Viruses are carcinogens (Check, 2003).

  3. The viruses will cause the host immune response (Lefesvre et al., 2003) which is temporarily being transgene.

  4. Because viruses genome are great than non-viral vectors the sequences of the viruses cannot be controlled by reseaechers.

  5. Preparation of this vector requires a lot of time and money.

Although non-viral gene transfer is less efficient than virus vector but have been told no above disadvantages and their use for gene transfer in human can be safer than viruses. Vectors are suggested to be prepared as non-viral vector for targeting the rDNA locus of human genome by homologous recombination method, and as ex vivo gene transfer in humans to be done with them.


This work was supported by Iran National Science Foundation (project no.843083) and was done in Cellular and Molecular Biology Research Center of Shahid Beheshti University of Medical Sciences, the author’s thanks directors.


1 - H. Agersø, D. F. Brophy, H. Pelzer, J. Martin, M. Carr, U. Hedner, M. Ezban, 2011Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients. J Thromb Haemost; 9 2 333 338 1538-7933
2 - G. A. Allen, E. Persson, R. A. Campbell, M. Ezban, U. Hedner, AS Wolberg, 2007A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Arterioscler Thromb Vasc Biol ;27 3 683 689 1049-8834
3 - J. L. Andrews, MJ Gorziglia. M. I. Kadan, M. Kaleko, S. Connelly, 2001Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII. Mol Ther; 3 3 329 336 1525-0016
4 - S. E. Antonarakis, P. G. Waber, S. D. Kittur, AS Kazazian. H. H. Patel, MA Counts. R. B. Jr Mellis, G. Stamatoyannopoulos, E. J. Bowie, D. N. Fass, et al. 1985Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med; 313 14 842 848 0028-4793
5 - Antonarakis SE, Kazazian HH, Tuddenham EG 1995Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat; 5 1 1 22 1059-7794
6 - V. R. Arruda, W. C. Pieneman, P. H. Reitsma, P. P. Deutz-Terlouw, J. M. Annichino-Bizzacchi, E. Briët, F. F. Costa, 1995Eleven novel mutations in the factor VIII gene from Brazilian hemophilia A patients. Blood; 86 8 3015 3020 0006-4971
7 - J. Ball, L. J. Warnock, F. E. Preston, 1990Rapid assessment of haemophilia A carrier state by non-invasive techniques using the polymerase chain reaction. J Clin Pathol; 43 6 505 507 0021-9746
8 - Baranov VS, Aseev MV, Gorbunova VN, Ivashchenko TE, Mikhaĭlov AV, Gornostaeva NI, Surin VL 1990Use of molecular and genetic approaches in prenatal diagnosis and prevention of hemophilia A and Duchenne muscular dystrophy. Akush Ginekol (Mosk) ;(11): 26-28. 0002-3906 0002 3906
9 - A. Bartlett, K. M. Dormandy, C. M. Hawkey, P. Stableforth, A. Voller, 1976Factor-VIII-related antigen: measurement by enzyme immunoassay. Br Med J; 1 6016 994 996 0959-8138
10 - E. Berntorp, 2009Haemate P/Humate-P: a systematic review. Thromb Res;124 Suppl 1: S11 4 0049-3848
11 - Blatt PM, White GC 2nd, McMillan CW, Roberts HR 1977Treatment of anti-factor VIII antibodies. Thromb Haemost; 38 2 514 523 0340-6245
12 - H. H. Brackmann, J. Gormsen, 1977Massive factor-VIll infusion in haemophiliac with factor-VIll inhibitor, high responder. Lancet; 2: 933. 0140-6736 0140 6736
13 - Cahill MR, Colvin BT 1997Haemophilia. Postgrad Med J; 73 201 206 0022-3859
14 - Carter NJ, Scott LJ 2007Human Plasma von Willebrand Factor/Factor VIII Complex (Haemate(R) P/Humate-P(R)): In von Willebrand Disease and Haemophilia A. Drugs: 67 10 1513 1519 0012-6667
15 - E. Check, 2003Cancer risk prompts US to curb gene therapy. Nature. Mar 6;422(6927):7. 0028-0836 0028 0836
16 - M. K. Chuah, D. Collen, Driessche. T. Vanden, 2001Gene therapy for hemophilia. J Gene Med; 3 1 3 20 0109-9498X
17 - M. K. Chuah, G. Schiedner, L. Thorrez, B. Brown, M. Johnston, V. Gillijns, S. Hertel, N. Van Rooijen, D. Lillicrap, D. Collen, Driessche. T. Vanden, S. Kochanek, 2003Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors. Blood;101 5 1734 1743 0006-4971
18 - S. Connelly, J. Mount, A. Mauser, J. M. Gardner, M. Kaleko, A. Mc Clelland, C. D. Lothrop, Jr , 1996aComplete short-term correction of canine hemophilia A by in vivo gene therapy. Blood; 88 10 3846 3853 0006-4971
19 - S. Connelly, T. A. Smith, G. Dhir, J. M. Gardner, M. G. Mehaffey, K. S. Zaret, A. Mc Clelland, M. Kaleko, 1995In vivo gene delivery and expression of physiological levels of functional human factor VIII in mice. Hum Gene Ther; 6 2 185 193 1043-0342ISSN: 1043-0342
20 - S. Connelly, J. M. Gardner, R. M. Lyons, A. Mc Clelland, M. Kaleko, 1996bSustained expression of therapeutic levels of human factor VIII in mice. Blood ; 87 11 4671 4677 0006-4971
21 - S. Connelly, J. L. Andrews, A. M. Gallo-Penn, L. Tagliavacca, R. J. Kaufman, M. Kaleko, 1999Evaluation of an adenoviral vector encoding full-length human factor VIII in hemophiliac mice. Thromb Haemost; 81 2 234 239 0340-6245
22 - Czapek EE, Gadarowski JJ Jr, Ontiveros JD, Pedraza JL 1988Humate-P for treatment of von Willebrand disease [letter]. Blood; 72: 1100. 0006-4971 0006 4971
23 - D. David, I. Moreira, M. R. Lalloz, H. A. Rosa, R. Schwaab, S. Morais, MJ Deus. G. Diniz de, M. Campos, J. Lavinha, et al. 1994Analysis of the essential sequences of the factor VIII gene in twelve haemophilia A patients by single-stranded conformation polymorphism. Blood Coagul Fibrinolysis; 5 2 257 264 1473-5733
24 - R. de Biasi, A. Rocino, M. L. Papa, E. Salerno, L. Mastrullo, D. De Blasi, 1994Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost; 71 5 544 7 0340-6245
25 - S. Delignat, S. Dasgupta, S. André, A. M. Navarrete, S. V. Kaveri, J. Bayry, M. H. André, S. Chtourou, Z. Tellier, S. Lacroix-Desmazes, 2007Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A. Haematologica ;92 10 1423 1426ISSN is 0390-6078
26 - K. W. Denson, R. Biggs, ME Borrett. R. Haddon, K. Cobb, 1969Two types of haemophilia (A+ and A-): a study of 48 cases. Br J Haematol; 17 2 163 171 0007-1048
27 - P. P. Deutz-Terlouw, M. Losekoot, R. Olmer, W. C. Pieneman, d. de Vries-v, S. Weerd, E. Briët, E. Bakker, 1995Inversion in the factor VIII gene: improvement of carrier detection and prenatal diagnosis in Dutch haemophilia A families. J Med Genet; 32 4 296 300 0148-7299
28 - P. Dimitrios, Robert. A. Agaliotis, Saduman. Zaiden, Ozturk, 2009Hemophilia, Overview.
29 - C. B. Doering, G. Denning, K. Dooriss, B. Gangadharan, J. M. Johnston, K. W. Kerstann, D. A. Mc Carty, H. T. Spencer, 2009Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A. Mol Ther; 17 7 1145 1154 1525-0016
30 - Doering CB 2008Retroviral modification of mesenchymal stem cells for gene therapy of hemophilia. Methods Mol Biol; 433 203 212 1064-3745
31 - V. J. Dwarki, P. Belloni, T. Nijjar, J. Smith, L. Couto, M. Rabier, S. Clift, A. Berns, L. K. Cohen, 1995Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice. Proc Natl Acad Sci U S A; 92 4 1023 1027ISSN
32 - D. L. Eaton, W. I. Wood, D. Eaton, P. E. Hass, P. Hollingshead, K. Wion, J. Mather, R. M. Lawn, G. A. Vehar, C. Gorman, 1986Construction and characterization of an active factor VIII variant lacking the central one-third of the molecule. Biochemistry; 25 26 8343 8327 0174-2464X
33 - C. L. Eckhardt, L. A. Menke, C. H. van Ommen, J. H. van der Lee, R. B. Geskus, P. W. Kamphuisen, M. Peters, K. Fijnvandraat, 2009Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost; 7 6 930 937 1538-7933
34 - N. Ellison, 1977Diagnostic and management of Bleeding disorders. Anesthesiology; 47 2 171 180 0003-3022
35 - S. Emamgholipour, M. Bandehpour, P. Shabani, L. Maghen, B. Yaghmaee, B. Kazemi, 2009Mutagenesis in sequence encoding of human factor VII for gene therapy of hemophilia. DARU; 17 4 294 298 1560-8115
36 - Essien EM, Ingram GI 1967Diagnosis of haemophilia: use of an artificial factor-VIII-deficient human plasma system. J Clin Pathol; 20 4 620 623 0021-9746
37 - Feng J (1991). Gene diagnosis of hemophilia A by PCR. Zhongguo Yi Xue Ke Xue Yuan Xue Bao; 0376-2491 5 13 384 388
38 - M. Franchini, 2007Rituximab in the treatment of adult acquired hemophilia A: a systematic review. Crit Rev Oncol Hematol; 63 1 47 52 1040-8428
39 - Fijnvandraat K, Turenhout EA, van den Brink EN, ten Cate JW, van Mourik JA, Peters M, Voorberg J (1997). The missense mutation Arg593--> Cys is related to antibody formation in a patient with mild hemophilia A. Blood; 0006-4971 12 89 4371 2377
40 - S. I. Firshein, L. W. Hoyer, J. Lazarchick, B. G. Forget, J. C. Hobbins, L. P. Clyne, F. A. Pitlick, W. A. Muir, I. R. Merkatz, MJ Mahoney, 1979Prenatal diagnosis of classic hemophilia. N Engl J Med; 300 17 937 941 0028-4793
41 - C. D. Forbes, J. King, C. R. Prentice, G. P. Mc Nicol, 1972Serum enzyme changes after intramuscular bleeding in patients with haemophilia and Christmas disease. J Clin Patho; 25 12 1034 1037 0021-9746
42 - B. Furie, S. A. Limentani, C. G. Rosenfield, 1994A Practical Guide to the Evaluation and Treatment of Hemophilia. Blood; 84 1 3 9 0006-4971
43 - J. Gécz, L. Kádasi, H. Poláková, V. Ferák, 1990Use of DNA analysis in the diagnosis and prevention of hemophilia A. Bratisl Lek Listy; 91 3 219 224 0006-9248
44 - K. Ghosh, S. Shetty, 2009Immune response to FVIII in hemophilia A: an overview of risk factors. Clin Rev Allergy Immunol; 37 2 58 66 1080-0549
45 - J. Gitschier, 1989Molecular genetics of hemophilia A. Schweiz Med Wochenschr; 119 39 1329 1331ISSN, 0036-7672
46 - J. Gitschier, W. I. Wood, E. G. Tuddenham, MA Goralka. T. M. Shuman, E. Y. Chen, R. M. Lawn, 1985Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature; 315 6018 427 430 0028-0836
47 - N. A. Goldenberg, W. E. Hathaway, L. Jacobson, et al. 2006Influence of Factor VIII on Overall Coagulability and Fibrinolytic Potential of Haemophilic Plasma as Measured by Global Assay: Monitoring in Hemophilia A.” Haemophilia.; 12 605 614 1351-8216
48 - A. Goodeve, F. E. Preston, I. R. Peake, 1994Factor VIII gene rearrangements in patients with severe haemophilia A. Lancet; 343 329 330 0140-6736
49 - J. Goudemand, C. Rothschild, V. Demiguel, C. Vinciguerrat, T. Lambert, H. Chambost, A. Borel-Derlon, S. Claeyssens, Y. Laurian, T. Calvez, 2006Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood; 107 1 46 51 0006-4971
50 - Graham JB, Green PP, McGraw RA, Davis LM 1985Application of molecular genetics to prenatal diagnosis and carrier detection in the hemophilias: some limitations. Blood; 66 4 759 764 0006-4971
51 - J. N. Hagstrom, L. B. Couto, C. Scallan, M. Burton, M. L. Mc Cleland, P. A. Fields, V. R. Arruda, R. W. Herzog, K. A. High, 2000Improved muscle-derived expression of human coagulation factor IX from a skeletal actin/CMV hybrid enhancer/promoter. Blood; 95 8 2536 42 0006-4971
52 - V. Haurigot, F. Mingozzi, G. Buchlis, D. Hui, Y. Chen, E. B. Tschakarjan, V. Arruda, A. Radu, H. G. Franck, J. F. Wright, S. Zhou, H. H. Stedman, D. A. Bellinger, T. C. Nichols, K. A. High, 2010Safety of AAV Factor IX Peripheral TransvenularGene Delivery to Muscle in Hemophilia B Dogs. Mol Ther; 18 7 1318 1329 1525-0016
53 - U. Hedner, 2000NovoSeven as a universal haemostatic agent. Blood Coagul Fibrinolysis; 11 Suppl 1: S107 111 0957-5235
54 - J. A. Hellings, F. R. van Leeuwen, J. Over, J. A. van Mourik, 1982Immunoradiometric assay of VIII:CAg, a potential tool to detect human anti-VIII:C antibodies. Thromb Res 15; 26 4 297 302 0049-3848
55 - F. H. Herrmann, T. Kruse, M. Wehnert, G. Vogel, K. Wulff, 1988First experiences in application of RFLP analysis for carrier detection in preparation of prenatal diagnosis of hemophilia A in the GDR. Folia Haematol Int Mag Klin Morphol Blutforsch; 115 4 489 93 1087-0156
56 - M. Higuchi, L. Kochhan, R. Schwaab, H. Egli, H. H. Brackmann, J. Horst, K. Olek, 1989Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis. Blood; 74 3 1045 1051 0006-4971
58 - History of HemophiliaDisease.
59 - Hong I, Stachnik J (2010). Unlabeled uses of factor VIIa (recombinant) in pediatric patients. Am J Health Syst Pharm; 0815-9319 22 67 1909 19
60 - Hoyer LW, Breckenridge RT 1968Immunologic studies of antihemophilic factor (AHF, factor VIII): cross-reacting material in a genetic variant of hemophilia A. Blood; 32 6 962 971 0006-4971
61 - Hoyer LW, Carta CA, Golbus MS, Hobbins JC, Mahoney MJ 1985Prenatal diagnosis of classic hemophilia (hemophilia A) by immunoradiometric assays. Blood; 65 6 1312 1317 0006-4971
62 - M. B. Hultin, S. S. Shapiro, H. S. Bowman, F. M. Gill, A. T. Andrews, J. Martinez, E. M. Eyster, W. C. Sherwood, 1976Immunosuppressive therapy of Factor VIII inhibitors. Blood; 48 1 95 108 0006-4971
63 - Huntington JA. 2009Slow thrombin is zymogen-like. J Thromb Haemost; Suppl 1 159 64 1538-7933
64 - C. R. Ill, C. Q. Yang, S. M. Bidlingmaier, J. N. Gonzales, DS Bartholomew. R. M. Burns, P. Scuderi, 1997tion of the human factor VIII complementary DNA expression plasmid for gene therapy of hemophilia A. Blood Coagul Fibrinolysis; Suppl 2:S23 30 0957-5235
65 - A. Ishiwata, J. Mimuro, H. Mizukami, Y. Kashiwakura, K. Takano, T. Ohmori, S. Madoiwa, K. Ozawa, Y. Sakata, 2009Liver-restricted expression of the canine factor VIII gene facilitates prevention of inhibitor formation in factor VIII-deficient mice. J Gene Med ; 11 11 1020 1029 0109-9498X
66 - P. Jedlicka, S. Greer, DS Grundy. C. B. Millar, E. Jenkins, M. Mitchell, R. S. Mibashan, V. V. Kakkar, D. N. Cooper, 1990Improved carrier detection of haemophilia A using novel RFLPs at the DXS115 (767) locus. Hum Gene; 85 3 315 318 0340-6717
67 - Jenkins PV, Collins PW, Goldman E, McCraw A, Riddell A, Lee CA, Pasi KJ (1994). Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling. Blood; 0006-4971 7 84 2197 2201
68 - H. Jiang, D. Lillicrap, S. Patarroyo-White, T. Liu, X. Qian, C. D. Scallan, S. Powell, T. Keller, M. Mc Murray, A. Labelle, D. Nagy, J. A. Vargas, S. Zhou, L. B. Couto, G. F. Pierce, 2006Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood; 108 1 107 115 0006-4971
69 - M. Johannessen, R. B. Andreasen, O. Nordfang, 2000Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven. Blood Coagul Fibrinolysis; 11 3 239 242 0957-5235
70 - Y. Kang, L. Xie, D. T. Tran, C. S. Stein, M. Hickey, B. L. Davidson, P. B. Mc Cray, Jr , 2005Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer. Blood; 106 5 1552 1558 0006-4971
71 - Kaufman RJ 1991Developing rDNA products for treatment of hemophilia A. Trends Biotechnol; 9 10 353 359 0167-7799
72 - MA Manno. C. S. Kay, M. V. Ragni, P. J. Larson, L. B. Couto, A. Mc Clelland, B. Glader, A. J. Chew, S. J. Tai, R. W. Herzog, V. Arruda, F. Johnson, C. Scallan, E. Skarsgard, A. W. Flake, K. A. High, 2000Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet; 24 3 257 261 1061-4036
73 - Kempton CL, Soucie JM, Miller CH, Hooper C, Escobar MA, Cohen AJ, Key NS, Thompson AR, Abshire TC (2010). Non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. J Thromb Haemost; 10 8 2224 2231
74 - Kenet G, Walden R, Eldad A, Martinowitz U (1999). Treatment of traumatic bleeding with recombinant factor VIIa. Lancet; 0140-6736 0140 6736
75 - Knights SF, Ingram GIC 1967Partial thromboplastin time test with kaolin: diagnosis of haemophilia and Christmas disease without natural reference plasmas. J clin. Path; 20 616 619 0021-9746
76 - L. Kochhan, M. R. Lalloz, J. Oldenburg, J. H. Mc Vey, K. Olek, H. H. Brackmann, E. G. Tuddenham, R. Schwaab, 1994Haemophilia A diagnosis by automated fluorescent DNA detection of ten factor VIII intron 13 dinucleotide repeat alleles. Blood Coagul Fibrinolysis; 5 4 497 501 0957-5235
77 - S. C. Kogan, M. Doherty, J. Gitschier, 1987An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med; 317 16 985 990 0028-4793
78 - Krolick MA 2005Successful percutaneous coronary intervention in a patient with severe haemophilia A using bivalirudin as the sole procedural anticoagulant. Haemophilia; 11 4 415 417 1351-8216
79 - Kumaran V, Benten D, Follenzi A, Joseph B, Sarkar R, Gupta S (2005). Transplantation of endothelial cells corrects the phenotype in hemophilia A mice. J Thromb Haemost; 1538-7933 9 3 2022 2031
80 - S. Lacroix-Desmazes, J. Bayry, N. Misra, S. V. Kaveri, MD Kazatchkine, 2002The concept of idiotypic vaccination against factor VIII inhibitors in haemophilia A. Haemophilia;8 Suppl 2 55 59 1351-8216
81 - B. Lauritzen, M. Tranholm, M. Ezban, 2008arFVIIa and a new enhanced rFVIIa-analogue, NN1731, reduce bleeding in clopidogrel-treated and in thrombocytopenic rats. J Thromb Haems; 7 4 651 657 1538-7933
82 - B. Lauritzen, U. Hedner, P. B. Johansen, M. Tranholm, M. Ezban, 2008bRecombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost; 6 5 804 811 1538-7933
83 - Lefesvre P, Attema J, Lemckert A, Havenga M, van Bekkum D (2003). Genetic heterogeneity in response to adenovirus gene therapy. BMC Mol Biol. 5; 4: 4. 1471-2199
84 - J. H. Levy, M. Levi, 2009A modified recombinant factor VIIa: can we make it work Harder, Better, Faster, Stronger?. J Thromb Haemost; 7 9 1514 1516 1538-7933
85 - Lian EC, Larcada AF, Chiu AY 1989Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med; 110 10 774 778 0003-4819
86 - Liars A (2011). Induced human pluripotent stem cells and advanced therapies Future perspectives for the treatment of haemophilia?Thromb Res; 2011 Mar 9. [Epub ahead of print] 0049-3848
87 - A. Liras, 2008Recombinant proteins in therapeutics: haemophilia treatment as an example. Int Arch Med, 1:4 1755-7682 1755 7682
88 - X. Liu, M. Liu, Z. Xue, Q. Pan, L. Wu, Z. Long, K. Xia, D. Liang, J. Xia, 2007Non-viral ex vivo transduction of human hepatocyte cells to express factor VIII using a human ribosomal DNA-targeting vector. J Thromb Haemost; 5 2 347 351 1538-7933
89 - R. Ljung, L. Holmberg, 1982Immunoradiometric assay of inhibitors of antihaemophilic factor A. Acta Paediatr Scand; 71 6 1019 1023 0000-1656X
90 - Lusher JM 2000Hemophilia treatment. Factor VIII inhibitors with recombinant products: prospective clinical trials. Haematologica; 85(10 Suppl): 2 5discussion 5-6. 0390-6078
91 - Lusher JM 2002First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Hemost; 28 3 273 276 0094-6176
92 - N. Mackman, R. E. Tilley, N. S. Key, 2007Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol; 27 8 1687 1693 1049-8834
93 - P. M. Mannucci, Z. M. Ruggeri, F. I. Pareti, A. Capitanio, 1977Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands’ diseases. Lancet; 1 8017 869 872 0140-6736
94 - P. Margaritis, V. R. Arruda, M. Aljamali, R. M. Camire, A. Schlachterman, K. A. High, 2004Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII. Clin Invest; 113 7 1025 1031 0021-9738
95 - P. Margaritis, 2010Long-term expression of canine FVIIa in hemophilic dogs. Thromb Res; 125 Suppl 1:S60 62 0049-3848
96 - P. Margaritis, E. Roy, M. N. Aljamali, H. D. Downey, U. Giger, S. Zhou, E. Merricks, A. Dillow, M. Ezban, T. C. Nichols, K. A. High, 2009Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood; 113 16 3682 3689 0006-4971
97 - W. M. Mc Cormack, M. P. Jr Seiler, T. K. Bertin, K. Ubhayakar, D. J. Palmer, P. Ng, T. C. Nichols, B. Lee, 2006Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model. J Thromb Haemost; 4 6 1218 1225 1538-7933
98 - K. Michaelides, E. G. Tuddenham, C. Turner, B. Lavender, S. A. Lavery, 2006Live birth following the first mutation specific pre-implantation genetic diagnosis for haemophilia A. Thromb Haemost; 95 2 373 379 1538-7933
99 - G. Miller, R. A. Steinbrecher, P. J. Murdock, E. G. Tuddenham, CA Pasi. K. J. Lee, G. Goldspink, 1995Expression of factor VII by muscle cells in vitro and in vivo following direct gene transfer: modelling gene therapy for haemophilia. Gene Ther; 2 10 736 742 0969-7128
100 - Miller DG, Rutledge EA, Russell DW 2002Chromosomal effects of adeno-associated virus vector integration. Nat Genet; 30 2 147 8 1061-4036
101 - H. Nakai, E. Montini, S. Fuess, T. A. Storm, M. Grompe, MA Kay, 2003AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet; 34 3 297 302 1061-4036
102 - J. Naylor, A. Brlnke, S. M. Hassock, P. Green, F. Giannelll, 1993Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Human Molecular Genetics; 2 11 1773 1778 0964-6906
103 - J. A. Naylor, P. M. Green, A. J. Montandon, C. R. Rizza, F. Giannelli, 1991Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene. Lancet; 337 8742 635 639 0140-6736
104 - J. A. Naylor, P. M. Green, C. R. Rizza, F. Giannelli, 1992Factor VIII gene explains all cases of haemophilia A. Lancet; 340 8827 1066 1067 0140-6736
105 - C. Nowotny, H. Niessner, E. Thaler, K. Lechner, 1976Sonography: a method for localization of hematomas in hemophiliacs. Haemostasis; 5 3 129 135 0301-0147
106 - A. Obergfell, T. Nichols, M. Ezban, 2010Animal models of FVIIa gene expression: their role in the future development of haemophilia treatment. Haemophilia; 16 Suppl 2 24 27 1351-8216
107 - T. Ohmori, A. Ishiwata, Y. Kashiwakura, S. Madoiwa, K. Mitomo, H. Suzuki, M. Hasegawa, J. Mimuro, Y. Sakata, 2008Phenotypic correction of hemophilia A by ectopic expression of activated factor VII in platelets. Mol Ther; 16 8 1359 1365 1525-0016
108 - Y. Okamoto, T. Kojima, A. Katsumi, T. Yamazaki, M. Hamaguchi, M. Nishida, K. Suzumori, H. Saito, 1995Carrier detection and prenatal diagnosis for hemophilia A using the inversion analysis of the factor VIII gene. Rinsho Ketsueki; 36 11 1252 1256 0485-1439
109 - R. K. Paleyanda, W. H. Velander, T. K. Lee, D. H. Scandella, F. C. Gwazdauskas, J. W. Knight, L. W. Hoyer, W. N. Drohan, H. Lubon, 1997Transgenic pigs produce functional human factor VIII in milk. Nat Biotechnol;15 10 971 997 1087-0156
110 - E. T. Parker, J. F. Healey, R. T. Barrow, H. N. Craddock, P. Lollar, 2004Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope. Blood; 104 3 704 710 0006-4971
111 - Petkova R, Chakarov S, Kremensky I (2004). Genetic analysis of haemophilia A in Bulgaria. BMC Blood Disord; 4(1): 2. ISSN 1471-23261471-2326 1471 2326
112 - J. Puetz, 2010Optimal use of recombinant factor VIIa in the control of bleeding episodes in hemophilic patients. Drug Des Devel Ther; 4 127 337 1177-8881
113 - W. C. Pieneman, P. P. Deutz-Terlouw, P. H. Reitsma, E. Briët, 1995Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol; 90 2 442 449 0007-1048
114 - Pipe SW 2008Recombinant clotting factors. Thromb Haemost ; 99 840 850
115 - J. Ramanarayana, G. S. Krishnan, Factor. V. I. Hernandez-Ilizaliturri, VII.
116 - M. Qadura, B. Waters, E. Burnett, R. Chegeni, S. Bradshaw, C. Hough, M. Othman, D. Lillicrap, 2009Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood ; 114 4 871 880 0006-4971
117 - Rapaport SI, Patch MJ, Casey JE 1960The antihemophilic globulin in plasma; content of freshly frozen single-donor plasma units prepared by the Los Angeles Red Cross Blood Center. Calif Med; 93 208 210 0008-1264
118 - Z. Rudzki, S. E. Rodgers, L. J. Sheffield, J. V. Lloyd, 1996Detection of carriers of haemophilia A: use of bioassays and restriction fragment length polymorphisms (RFLP). Aust N Z J Med; 26 2 195 205 0004-8291
119 - D. E. Sabatino, C. F. Freguia, R. Toso, A. Santos, E. P. Merricks, H. H. Kazazian, T. C. Jr Nichols, R. M. Camire, V. R. Arruda, 2009Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood; 114 20 4562 4565 0006-4971
120 - Sadler JE 1990Recombinant DNA methods in hemophilia A: carrier detection and prenatal diagnosis. Semin Thromb Hemost ; 16 4 341 347 0094-6176
121 - R. Salviato, D. Belvini, A. Are, P. Radossi, G. Tagariello, 2002Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs. Haemophilia; 8 1 17 21 1351-8216
122 - R. Sarkar, M. Mucci, S. Addya, R. Tetreault, D. A. Bellinger, T. C. Nichols, H. H. Kazazian, Jr , 2006Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Hum Gene Ther; 17 4 427 439 1043-0342
123 - R. Sarkar, W. Xiao, H. H. Kazazian, Jr , 2003A single adeno-associated virus (AAV)-murine factor VIII vector partially corrects the hemophilia A phenotype. J Thromb Haemost; 1 2 220 226 1538-7933
124 - C. D. Scallan, T. Liu, A. E. Parker, S. L. Patarroyo-White, H. Chen, H. Jiang, J. Vargas, D. Nagy, S. K. Powell, J. F. Wright, R. Sarkar, H. H. Kazazian, A. Mc Clelland, L. B. Couto, 2003Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII. Blood; 102 12 3919 3926 0006-4971
125 - D. Scandella, H. Reyes, M. Felch, Y. Sakurai, 2000Characterization of antibodies to factor VIII in hemophilia A patients treated by immune tolerance therapy. Haematologica; 85(10 Suppl): 86 88 0390-6078
126 - I. Scharrer, 1999Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. Haemophilia; 5 4 253 259 1351-8216
127 - R. Schwaab, H. H. Brackmann, C. Meyer, J. Seehafer, M. Kirchgesser, A. Haack, K. Olek, E. G. Tuddenham, J. Oldenburg, 1995Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost ; 74 6 1402 1406 0340-6245
128 - Schwartz RA, Klujszo E, McKenna Ri. FVIII.
129 - A. Sharathkumar, D. Lillicrap, VS Kern. M. Blanchette, J. Leggo, A. M. Stain, L. Brooker, MD Carcao, 2003Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost; 1 6 1228 1236 1538-7933
130 - Shetty S, Bhave M, Ghosh K (2010). Acquired hemophilia A: Diagnosis, aetiology, clinical spectrum and treatment options. Autoimmun Rev. 2010 Nov 27. [Epub ahead of print]. 1568-9972
131 - Shi Q, Wilcox DA, Fahs SA, Weiler H, Wells CW, Cooley BC, Desai D, Morateck PA, Gorski J, Montgomery RR (2006). Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest; 0021-9738 7 116 1974 1982
132 - Q. Shi, D. A. Wilcox, S. A. Fahs, J. Fang, BD D. U. L. M. Johnson, D. Desai, R. R. Montgomery, 2007Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A. J Thromb Haemost; 5 2 352 361 1538-7933
133 - Q. Shi, D. A. Wilcox, S. A. Fahs, P. A. Kroner, R. R. Montgomery, 2003Expression of human factor VIII under control of the platelet-specific alphaIIb promoter in megakaryocytic cell line as well as storage together with VWF. Mol Genet Metab; 7 9 1 25 1096-7192
134 - K. S. Song, C. H. Lee, C. S. Chung, K. Lee, Y. H. Yang, K. Y. Kim, 1993The prevalence study on restriction fragment length polymorphism analysis for the detection of hemophilia A carrier. Yonsei Med J; 34 3 239 242 0513-5796
135 - J. M. Stephens, A. V. Joshi, M. Sumner, M. F. Botteman, 2007Health economic review of recombinant activated factor VII for treatment of bleeding episodes in hemophilia patients with inhibitors. Expert Opin Pharmacother; 8 8 1127 1136 1465-6566
136 - Stites DP, Hershgold EJ, Perlman JD, Fudenberg HH 1971Factor 8 detection by hemagglutination inhibition: hemophilia A and von Willebrand’s disease. Science; 171 967 196 197 0036-8075
137 - Surin VL, Zhukova EL, Krutov AA, Solov’ev GIa, Likhacheva EA, Pliushch OP, Grineva NI 1990Detection of hemophilia A carriers by testing polymorphic Bcl I and HINDIII sites using the PCR method with internal splitting control]. Gematol Transfuziol; 35 3 3 6 0234-5730
138 - Thompson AR 1986Structure, function, and molecular defects of factor IX. Blood; 67 565 572 0006-4971
139 - K. Tomokiyo, Y. Nakatomi, T. Araki, K. Teshima, H. Nakano, T. Nakagaki, S. Miyamoto, A. Funatsu, S. Iwanaga, 2003A novel therapeutic approach combining human plasma-derived Factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone. Vox Sang; 85 4 290 299 0042-9007
140 - J. J. Toole, J. L. Knopf, J. M. Wozney, L. A. Sultzman, J. L. Buecker, D. D. Pittman, R. J. Kaufman, E. Brown, C. Shoemaker, E. C. Orr, et al. 1984Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature ; 312 5992 342 347 0028-0836
141 - V. Toschi, 2010OBI-1, porcine recombinant Factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human Factor VIII. Curr Opin Mol Ther; 12 5 617 625 1464-8431
142 - L. Toy, E. A. Young, J. B. Longenecker, 1983Ascorbic acid, vitamin A, folic acid, and amino acids in blood of patients with hemophilia. Blood; 62 3 532 537 0006-4971
143 - N. S. Van de Water, R. Williams, J. Nelson, P. J. Browett, 1995Factor VIII gene inversions in severe hemophilia A patients. Pathology; 27 1 83 85 0031-3025
144 - Driessche. T. Van den, D. Collen, M. K. Chuah, 2003Gene therapy for the hemophilias. J Thromb Haemost; 1 7 1550 1558 1538-7933
145 - Auer. von, Oldenburg. J. Ch, Depka. M. von, C. Escuriola-Ettinghausen, K. Kurnik, H. Lenk, I. Scharrer, 2005Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates. Ann N Y Acad Sci; 1051 498 505 0077-8923
146 - A. I. Wacey, G. Kemball-Cook, H. H. Kazazian, S. E. Antonarakis, R. Schwaab, P. Lindley, E. G. Tuddenham, 1996 The haemophilia A mutation search test and resource site, home page of the factor VIII mutation database: HAMSTeRS.Nucleic Acids Res; 24 1 100 102 0305-1048
147 - C. Wadelius, M. Blombäck, P. Goonewardena, M. Anvret, M. Lindstedt, K. H. Gustavson, U. Pettersson, 1991Evaluation of DNA-based diagnosis for haemophilia A. Scand J Clin Lab Invest ; 51 7 625 633 0036-5513
148 - Wang L, Herzog RW (2005). AAV-mediated gene transfer for treatment of hemophilia. Curr Gene Ther. 2005 Jun; 1566-5232 3 5 349 360
149 - M. Wehnert, E. L. Shukova, V. L. Surin, W. Schröder, G. Solovjev, Herrmann. F. H. Ya, 1990aPrenatal diagnosis of haemophilia A by the polymerase chain reaction using the intragenic hind III polymorphism. Prenat Diagn; 10 8 529 532 0197-3851
150 - M. Wehnert, E. L. Shukova, V. L. Surin, W. Schröder, G. Solovjev, Grinjeva. N. I. Ya, F. H. Herrmann, 1990bGenomic carrier detection and prenatal diagnosis of haemophilia A in families at risk using the polymerase chain reaction (PCR). Folia Haematol Int Mag Klin Morphol Blutforsch; 117 4 617 622 0323-4347
151 - White GC, Shoemaker CB. 1989Factor VIII Gene and Hemophilia A. Blood; 73 10 1 12 0006-4971
152 - A. Wiestner, H. J. Cho, AS Michelis. Asch, MA J. A. Zeller, E. I. Peerschke, B. B. Weksler, G. P. Schechter, 2002Rituximab in the treatment of acquired factor VIII inhibitors. Blood; 100 9 3426 3428 0006-4971
153 - W. I. Wood, D. J. Capon, C. C. Simonsen, D. L. Eaton, J. Gitschier, B. Keyt, P. H. Seeburg, D. H. Smith, P. Hollingshead, K. L. Wion, et al. 1984Expression of active human factor VIII from recombinant DNA clones. Nature; 312 5992 330 337 0028-0836
154 - Wu G (1991). Prenatal diagnosis of hemophilia A by DNA analysis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao; 0376-2491 6 13 428 434
155 - A. Yoshioka, K. Fukutake, J. Takamatsu, A. Shirahata, Post. Kogenate-Marketing, Study. Surveillance, Group, 2003Clinical evaluation of a recombinant factor VIII preparation (Kogenate) in previously untreated patients with hemophilia A. Int J Hematol; 78 5 467 474 0925-5710
156 - H. Youssoufian, S. E. Antonarakis, S. Aronis, G. Tsiftis, D. G. Phillips, H. H. Kazazian, 1987Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci U S A; 84 11 3772 3776 0027-8424
157 - K. Zatloukal, M. Cotten, M. Berger, W. Schmidt, E. Wagner, M. L. Birnstiel, 1994In vivo production of human factor VII in mice after intrasplenic implantation of primary fibroblasts transfected by receptor-mediated, adenovirus-augmented gene delivery. Proc Natl Acad Sci U S A; 91 11 5148 5152 0027-8424
158 - W. W. Zhang, S. F. Josephs, J. Zhou, X. Fang, R. Alemany, C. Balagué, Y. Dai, D. Ayares, E. Prokopenko, Y. C. Lou, E. Sethi, D. Hubert-Leslie, M. Kennedy, L. Ruiz, S. Rockow-Magnone, 1999Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A. Thromb Haemost; 82 2 562 571 1538-7933