Dialysis and Renal Transplant in a Hemophiliac

Gomperts, Edward D.; Malekzadeh, Mohammed H.; Fine, Richard Ν.

doi:10.1055/s-0038-1653433

Cited by 19 publications

(18 citation statements)

References 1 publication

(1 reference statement)

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“…We studied liver further, because LSECs are known to produce FVIII and previous reports indicated that BM cells too could generate hepatocytes. 35 However, we found only rare GFP ϩ hepatocytes, including in mice given J0-2 or MCT plus CCl 4 . No proliferation of donor-derived hepatocytes was observed, which is consistent with lack of hepatocyte selection.…”

Section: Identity Of Donor Bm-derived Cell Type(s) Imparting Therapeumentioning

confidence: 68%

“…2 However, the cell-type origin of FVIII has been controversial. 3 Correction of hemophilia after orthotopic liver transplantation (OLT) but not after kidney transplantation, despite FVIII mRNA expression in both organs, 3,4 indicated that liver was a major site for FVIII production. Recently, the cell transplantation approach established that of various liver cell types, liver sinusoidal endothelial cells (LSECs) replaced FVIII in hemophilia mice.…”

Section: Introductionmentioning

confidence: 99%

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Role of bone marrow transplantation for correcting hemophilia A in mice

Follenzi

Raut

Merlin

et al. 2012

Blood

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To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)-derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. IntroductionHemophilia A is characterized by inability to clot blood because of FVIII gene mutations and deficiency of this coagulation factor. 1 The potential for cell and gene therapy in hemophilia A is highly attractive because even small amounts of FVIII may substantially decrease bleeding risk. This requires sound knowledge of cell types capable of replacing FVIII, especially within proximity of von Willebrand factor (vWF), which protects FVIII from degradation. 2 However, the cell-type origin of FVIII has been controversial. 3 Correction of hemophilia after orthotopic liver transplantation (OLT) but not after kidney transplantation, despite FVIII mRNA expression in both organs, 3,4 indicated that liver was a major site for FVIII production. Recently, the cell transplantation approach established that of various liver cell types, liver sinusoidal endothelial cells (LSECs) replaced FVIII in hemophilia mice. 5,6 Nonetheless, extrahepatic organs probably contributed in FVIII production, as indicated by FVIII synthesis in spleen, lungs, or pancreatic islets. [6][7][8] This was in agreement with lack of plasma FVIII deficiency after OLT with donor liver from dogs or people with hemophilia A because such donor liver cells would not have synthesized or secreted FVIII. 9,10 Therefore, whether nonendothelial cells, and cells in extrahepatic organs, could also produce FVIII was not excluded. For instance, macrophages, which originate in bone marrow (BM), and contained FVIII mRNA, 11 could be such a candidate. Although FVIII was cloned from T cells, 12 and transplantation of lymphatic tissue was thought to correct hemophilia in dogs, 13 whether lymphocytes did express FVIII was uncertain, because correction of hemophilia by transplanted organs (eg, spleen) included other cell types. 7,14,15 Because BM cells may generate multiple lineages, the potential of BM-derived cells in FVIII production seemed relevant to us. Previously, BM transplantation studies in hemophilia A, 40 years ago, were limited to just 3 dogs and 2 persons. [16][17][18][19] BM transplantation in hemophilia dogs was carefully performed, although there were limitations, such as suboptimal allograft tolerance, lack of studies showing engraftment and generation of various BM cell types, absence of FVIII expression analysis in donor BM-derived cells,...

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Section: Identity Of Donor Bm-derived Cell Type(s) Imparting Therapeumentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Role of bone marrow transplantation for correcting hemophilia A in mice

Follenzi

Raut

Merlin

et al. 2012

Blood

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“…Gomperts et al. [19] described a 15‐year‐old boy with moderate haemophilia who had persistent haematuria beginning at 5 years of age, developed proteinuria at age 13 years and subsequently required haemodialysis and later renal transplantation.…”

Section: Haematuria and Renal Diseasementioning

confidence: 99%

Renal disease among males with haemophilia

2003

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Haematuria is common among persons with haemophilia (PWH), but its long-term effects on the kidney and renal function are not well defined. In addition, infection with human immunodeficiency virus (HIV) or hepatitis C, or exposure to nephrotoxic agents as therapy for these infections may place PWH at increased risk for renal disease. To examine factors associated with chronic renal disease (CRD) and acute renal disease (ARD) in PWH, we analysed data collected from the medical records of 3422 males with haemophilia living in six US states from 1993 to 1998. Renal disease cases were ascertained from among 2075 persons who were hospitalized at least once over the 6-year period. Of these, 60 (2.9%) were diagnosed during one or more hospitalizations with either ARD (29/60) or CRD (31/60). In multivariate analyses, we examined associations between renal disease and demographic and clinical factors including age, race, haemophilia type and severity, hypertension, diabetes, history of recent renal bleeds, presence of an inhibitor, and infection with hepatitis C or HIV. HIV infection and hypertension were strongly associated with both ARD and CRD. PWH who had ARD were also more likely to have an inhibitor than those without this diagnosis. PWH who had CRD were more likely to be older and non-white and to have had a recent admission for a kidney bleed than those without diagnosed CRD. In summary, we found that HIV infection and haemophilia-related factors including inhibitors and kidney bleeds were associated with renal disease in a cohort of males with haemophilia.

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“…One earlier report described a renal transplantation in a patient with mild haemophilia that was complicated by the occurrence of an intravesicular bleeding resulting in an allograft rejection 8. In another case report, FVIII plasma concentrations were kept >0.70 IU/mL for >2 weeks and afterwards >0.20 IU/mL with long-term successful transplantation of the allograft 9.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-guided dosing of factor VIII concentrate in a patient with haemophilia during renal transplantation

et al. 2016

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A 29-year-old man with severe haemophilia A and end-stage renal disease underwent a renal transplantation. To prevent bleeding, patient was treated with replacement therapy using factor VIII (FVIII) concentrate, according to National guidelines. Bayesian analysis was performed by combining observed FVIII concentrations with a population pharmacokinetic (PK) model for patients with severe haemophilia A in a perioperative setting. Application of Bayesian analysis led to accurate prediction of observed concentrations after prescribing dosing advice. We believe that PK-guided dosing of factor concentrates is a valuable step towards further individualisation of treatment in patients with bleeding disorders, especially in those patients requiring precise targeting of coagulation factor levels due to high risk of either bleeding or thrombosis, as illustrated by this patient undergoing a major surgical procedure.

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Dialysis and Renal Transplant in a Hemophiliac

Cited by 19 publications

References 1 publication

Role of bone marrow transplantation for correcting hemophilia A in mice

Role of bone marrow transplantation for correcting hemophilia A in mice

Renal disease among males with haemophilia

Pharmacokinetic-guided dosing of factor VIII concentrate in a patient with haemophilia during renal transplantation

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