Hemophilia: role of organ homografts

Marchioro, Thomas L.; Hougie, Cecil; Ragde, Haakon; Epstein, Robert B.; Thomas, E D

doi:10.1097/00007890-196910000-00035

Cited by 26 publications

(43 citation statements)

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“…16,17 The conclusion was based on studies in 3 dogs, although one of these died 34 days after BM transplantation with allograft-related complications, suggesting rejection. Up to 5% plasma FVIII activity was detected after BM transplantation in the first dog but one-stage clotting assay detected FVIII activity in untreated dogs as well.…”

Section: Discussionmentioning

confidence: 99%

“…Up to 5% plasma FVIII activity was detected after BM transplantation in the first dog but one-stage clotting assay detected FVIII activity in untreated dogs as well. 16 In 2 subsequent dogs, myeloid and lymphoid lineages were replaced by donor BM, and the animals survived for 7 months and 2 years, the former dying after bleeding from iliac crest BM aspiration. 17 Despite plasma FVIII activity up to 8% normal, definitive information regarding plasma FVIII by one-stage clotting assay was unavailable.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 For instance, low plasma FVIII activity levels, up to 8% of normal, were observed, but could not be differentiated from untreated controls. One dog died of transplantrelated complications after 34 days, 16 another died of bleeding after BM aspiration, which suggests that FVIII activity was not corrected to high levels, but 1 dog remained healthy for Ͼ 2 years. 17 Despite the impact of these dog studies on the field, whether FVIII could be replaced by cell types originating from donor BM was unresolved, that is, through production of endothelial cells, 20 which could potentially have arisen from the shared hematopoietic and endothelial stem cell, the hemangioblast.…”

Section: Introductionmentioning

confidence: 98%

“…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, and other issues. 16,17 For instance, low plasma FVIII activity levels, up to 8% of normal, were observed, but could not be differentiated from untreated controls.…”

mentioning

confidence: 99%

“…[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, and other issues. 16,17 For instance, low plasma FVIII activity levels, up to 8% of normal, were observed, but could not be differentiated from untreated controls. One dog died of transplantrelated complications after 34 days, 16 another died of bleeding after BM aspiration, which suggests that FVIII activity was not corrected to high levels, but 1 dog remained healthy for Ͼ 2 years.…”

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

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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Orthotopic liver transplantation in a patient with combined hemophilia A and B

et al. 1990

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A 38-year-old man with severe factor IX and mild factor VIII deficiencies complicated by cirrhosis secondary to chronic non-A non-B hepatitis underwent orthotopic liver transplantation as treatment for both the cirrhosis and his congenital coagulopathy. Intraoperative hemostasis was obtained with factor VII-depleted prothrombin complex concentrate and fresh frozen plasma. Factor VIII and factor IX levels were assayed frequently in the perioperative period, and both returned to normal within 24 hr and remained normal postoperatively. Liver transplantation can be considered as definitive therapy for hemophilia A and/or B with transfusion-related liver disease.

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