Hemophilia treatment in historical perspective: a review of medical and social developments

Rosendaal, Frits R.; Smit, Cees; Briët, E.

doi:10.1007/bf01714977

Cited by 71 publications

(48 citation statements)

References 107 publications

(25 reference statements)

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“…The clotting activity of the blood can be raised at a sufficient level by infusion with factor concentrates. With the introduction of effective treatment methods at the end of the 1960's (the use of clotting factor Substrates and the possibility of prophylactic treatment) and then home treatment in the early 1970's, haemophilia became a controllable disorder that ceased to automatically result in severe levels of joint impairment, disablement and early death (Rosendaal et al, 1991;Nilsson et al, 1992;Triemstra et al, 1995).…”

Section: Haemophiliamentioning

confidence: 99%

Well-being of haemophilia patients: a model for direct and indirect effects of medical parameters on the physical and psychosocial functioning

Triemstra

Ploeg

Smit³

et al. 1998

Social Science & Medicine

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Abstract-This study outlines the development and evaluation of a structural equation model for establishing the consequences of haemophilia. The hereditary disorder is characterized by a high tendency to haemorrhages, with recurrent bleeding mto the joints causing irreversible joint damage. The model is, in general, an attempt to answer the following questions: what is the effect of haemophilia on the wellbeing (i.e. satisfaction, health, somatic complaints and self-esteem) of patients and what is the additional or mediating role of other individual characteristics in this pathway? Disease severity, joint impairment and disability are defined äs antecedents of well-being and the mediating roles of appraisal (i.e. the personal evaluation of the disease), health beliefs (i.e. locus of control), psychological characteristics (i.e. anxiety, anger, depression and optimism) and social Support are investigated. Psychological variables turned out to be the strengest determinants of well-being and partly mediated the detrimental effect of disability on well-being. The role of appraisal remained somewhat unclear, äs no significant relationship was established between this personal evaluation of haemophilia and well-being. Nevertheless, appraisal very well reflected the level of disability. An internal locus of control and favourable psychological characteristics appeared to reduce the perceived seriousness of haemophilia. No evidence was found for social Support to act äs a mediator between disability and well-being. The perception of support did show moderately strong associations with psychological characteristics (i.e. anxiety and depression) and satisfaction ratings. The study merits further research on quantifying the relationships between clinical parameters and psychosocial outcomes in patients with a chronic disease.

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Section: Haemophiliamentioning

confidence: 99%

Well-being of haemophilia patients: a model for direct and indirect effects of medical parameters on the physical and psychosocial functioning

Triemstra

Ploeg

Smit³

et al. 1998

Social Science & Medicine

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“…46 Hemophilia A is an X-linked disorder of variable severity that is due to mutations in the fVIII gene, which is 187 kb long and contains 26 exons. The genetic lesions resulting in hemophilia A include deletions, exon inversions and translocations, nonsense frame shifts, premature stops, and a large number of missense point mutations, all of which can cause defects in the expression, secretion, and/or half-life of fVIII in circulation.…”

Section: Hemophilia a Mutationsmentioning

confidence: 99%

The tertiary structure and domain organization of coagulation factor VIII

Shen

Spiegel

Chang

et al. 2008

Blood

229

258

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Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 do IntroductionThe principal mechanism used to stop the loss of blood in mammals following vascular injury consists of a pair of overlapping proteolytic cascades called the extrinsic and intrinsic pathways. [1][2][3][4] The process of blood coagulation requires extraordinary spatial and temporal regulation, which is accomplished by assembling and tethering the central proteolytic activities of these cascades at the location of transiently exposed biomolecules and cellular surfaces ( Figure 1A). This includes an integral membrane protein called "tissue factor" that initiates the rapid up-regulation of the short-lived extrinsic pathway, 5 and the surfaces of activated platelets, which modulate the activation of the longer-lived intrinsic pathway. 6 A total of 2 homologous procoagulants, factors V and VIII (fV and fVIII), are each localized on the surface of these platelets, where they nucleate the assembly of multiprotein proteolytic complexes.When fVIII is bound to activated platelets at the site of vascular injury, it recruits the serine protease fIXa into a complex that then catalyzes the proteolytic activation of fX. 1,4,7 The proteolytic activity of fIXa is enhanced by approximately 200 000-fold through its interaction with fVIII, calcium, and the phospholipid bilayer, 8 corresponding to an increase of approximately 10 9 in k cat /K M .The full-length, unprocessed fVIII protein consists of 2332 amino acid residues and has the domain structure A1-A2-B-A3-C1-C2 9-12 ( Figure 1B). The 3 A domains are each approximately 330 residues, and approximately 40% identical to each other and to the copper-binding protein ceruloplasmin. 13 The C domains are smaller (approximately 160 residues) and are more distantly related to various members of the discoidin protein fold family, such as galactose oxidase. [14][15][16][17] The B domain has no known structural homologs, is heavily glycosylated, and is relatively dispensible for procoagulant activity. fVIII is initially processed by proteolytic cleavage events that remove a large portion of the B domain, generating a heterodimer that circulates in a tight complex with von Willebrand factor (VWF). 18 This interaction is essential for maintaining stable levels of fVIII in circulation. 19 Upon vascular injury, further proteolytic processing generates activated factor VIIIa (fVIIIa), a heterotrimer (A1/A2/A3-C1-C2) that is released from VWF and binds to activated platelets. 18 The carboxy-terminal 159 amino acids of fVIII comprise its C2 domain, which is invo...

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“…Von Willebrand factor and platelet function is not affected in hemophilia. Until the 1960s, before the introduction of cryoprecipitate, hemophilia could not be adequately treated, and most patients died of bleeding at a young age (17). Since clotting preparations became available, the life expectancy has increased to an almost normal life span, which makes it possible to study the occurrence of other causes of death, i.e.…”

Section: Studies In Heniophilia Patientsmentioning

confidence: 99%