Haemophilias

PA S1 S01.214 Coagulation factor IXa Possible target for gene therapy of haemophilia B... 

Factor VIII 2332 amino acids Mammalian cells Treatment of haemophilia Normally obtained from plasma but now concern over potential contamination with AIDS virus... 

Primary prophylaxis is expensive, but historical cohorts show progressively better outcomes (e.g., joint function and radiologic appearances) with more treatment, and prophylaxis thus is recommended as optimal therapy by the WFH, the World Health Organization (WHO), the U.K. Haemophilia Centre Doctors Organization, and the National Hemophilia... 

Blanchette VS, Manco-Johnson M, Santagostino E, Ljung R. Optimizing factor prophylaxis for the haemophilia population Where do we stand Haemophilia 2004 10(suppl 4) 97-104. 

Mitchell M, Keeney S, Goodeve A. The molecular analysis of haemophilia B A guideline from the UK Haemophilia Centre Doctors Organization Haemophilia Genetics Laboratory Network. Haemophilia 2005 11 398 404. 

Severe local bleeding, e.g. haemophilia (joint, muscle)... 

Blood products (e.g. coagulation factors) Treatment of blood disorders such as haemophilia AorB... 

Despite the undoubted advantages of recombinant production, it remains the case that many protein-based products extracted directly from native source material remain on the market. In certain circumstances, direct extraction of native source material can prove equally/more attractive than recombinant production. This may be for an economic reason if, for example, the protein is produced in very large quantities by the native source and is easy to extract/purify, e.g. human serum albumin (HSA Chapter 12). Also, some blood factor preparations purified from donor blood actually contain several different blood factors and, hence, can be used to treat several haemophilia patient types. Recombinant blood factor preparations, on the other hand, contain but a single blood factor and, hence, can be used to treat only one haemophilia type (Chapter 12). 

Haemophilia A Haemophilia A Haemophilia B Haemophilia A Haemophilia A Some forms of haemophilia Haemophilia A Haemophilia A... 

Haemophilia A (classical haemophilia, often simply termed haemophilia) is an X-linked recessive disorder caused by a deficiency of factor VIII. Von Willebrand disease is a related disorder, also caused by a defect in the factor VIII complex, as discussed below. 

Persons suffering from haemophilia A exhibit markedly reduced levels (or the complete absence) of factor VIII complex in their blood. This is due to the lack of production of factor VIII C. 

Several companies have expressed the cDNA coding for human factor VIII C in a variety of eukaryotic production systems (human VIII C contains 25 potential glycosylation sites). CHO cells and BHK cell lines have been most commonly used, in addition to other cell lines, such as various mouse carcinoma cell lines. The recombinant factor VIII product generally contains only VIII C (i.e. is devoid of vWF). However, both clinical and preclinical studies have shown that administration of this product to patients suffering from haemophilia A is equally as effective as administering blood-derived factor VIII complex. The recombinant VIII C product appears to bind plasma... 

Some patients, particularly those suffering from severe haemophilia A (i.e. those naturally producing little or no VIII C), will mount an immune response against injected factor VIII C whatever its source. 

Individuals who display a deficiency of factor IX develop haemophilia B, also known as Christmas disease. Although its clinical consequences are very similar to that of a deficiency of factor VIII, its general incidence in the population is far lower. Persons suffering from haemophilia B are treated by i.v. administration of a concentrate of factor IX. This was traditionally obtained by fractionation of human blood. Recombinant factor IX is now also produced in genetically engineered CHO cells (Table 12.2 and Box 12.1). 

Some 5-25 per cent of individuals suffering from haemophilia A develop anti-factor VIII antibodies, and 3-6 per cent of haemophilia B sufferers develop anti-factor IX antibodies. This complicates treatment of these conditions and, as mentioned previously, one approach to their treatment is direct administration of factor Vila. The therapeutic rationale is that factor Vila could directly activate the final common steps of the coagulation cascade, independently of either factor VIII or IX (Figure 12.1). Factor Vila forms a complex with tissue factor that, in the presence of phospholipids and Ca2+, activates factor X. 

Thrombolytic agent Thrombolytic agent Anticoagulant Haemophilia B Anti-cancer agent Cystic fibrosis Gaucher s disease Fabry disease Hyperuricaemia Mucopolysaccharidosis Oxygen toxicity Pompe disease... 

Bowen, D. 2002. Haemophilia a and haemophilia b molecular insights. Journal of Clinical Pathology - Molecular Pathology 55(1), 1-18. 

Farrugia, A. 2004. Safety and supply of haemophilia products worldwide perspectives. Haemophilia 10(4), 327-333. 

Graw, J., Brackmann, H.H., Oldenburg, J., Schneppenheim, R., Spannagl, M., and Schwaab, R. 2005. Haemophilia A from mutation analysis to new therapies. Nature Reviews Genetics 6(6), 488-501. 

Kingdon, H. and Lundblad, R. 2002. An adventure in biotechnology the development of haemophilia A therapeutics - from whole blood transfusion to recombinant DNA technology to gene therapy. Biotechnology and Applied Biochemistry 35, 141-148. 

Haemophilia is characterised by repeated, spontaneous and traumatic haemorrhages. It is divided into two classes, haemophilia A and haemophilia B. 

Haemophilia A is also known as classical and is caused by lack of factor VIII. It is now treated by replacement with factor VIII which, when prepared from human blood, was not without its problems. It is now prepared by genetic engineering. 

Haemophilia B is also known as Christmas disease. It is caused by absence of factor K. It was called Christmas disease because this was the surname of the first patient diagnosed with type B and the case was first published in the Christmas edition of the British Medical Journal. 

Both are due to mutations in genes in the X-chromosome. Haemophilia is inherited as an X-finked recessive trait and females do not suffer from the disease (since the other X-... 

Heparin, which has an anticoagulation action, may give rise to heparin-induced thrombocytopenia, which is an immune-mediated condition that usually develops 5-10 days after the administration of the drug. When heparin is used, a platelet count should be measured before treatment and if administration is repeated, platelet counts should be monitored regularly. Signs of thrombocytopenia include a reduction in platelet count. It may present with spontaneous haemorrhage and heparin should be stopped. Factor VIII is used in the treatment and prophylaxis of haemorrhage in patients with haemophilia. 

Q59 Hepatitis B vaccination is recommended to individuals with haemophilia. Hepatitis B vaccination requires one single dose. 

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