The search for the origin of factor VIII synthesis and its impact on therapeutic strategies for hemophilia A

Arruda, Valder R.

doi:10.3324/haematol.2015.129858

Cited by 15 publications

(8 citation statements)

References 20 publications

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“…Angiogenesis is essential in the improvement of gastric mucosa healing and prevention of ulcer relapse [24]. Factor VIII is a blood-clotting protein produced by the liver and some epithelial cells; its activation is in response to cellular injury and malignancy [48]. Ulcer base angiogenesis is an essential factor in ulcer healing; several factors are responsible for accelerated angiogenesis which promote healing, and one of such consideration is factor VIII [49,50].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Studies of Age-Related Changes in Cell Proliferation and Angiogenesis during the Healing of Acetic Acid-Induced Gastric Ulcers in Rats

Ajayi

Olaleye

2020

The Scientific World Journal

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Cell proliferation and angiogenesis are of utmost importance for healing to take place. The KI67 and EGFR proteins are markers of cell proliferation, while CD31 and factor VIII are markers of angiogenesis. To elucidate the mechanism responsible for delayed healing of the gastric injury in old age, we analyzed the expression of these markers in rats of different months during the healing of an acetic acid-induced gastric ulcer. Male Wistar rats (aged 3, 6, 12, and 18 months) divided into four groups, according to their ages, formed the experimental animals. Stomach tissue samples were collected on days 3, 7, 14, and 21 after induction for assessment of ulcer healing. The area of gastric mucosa healed was inversely proportional to age. The expression of markers of proliferation (KI67 and EGFR) and angiogenesis (factor VIII and CD31) decreased significantly (p<0.05) in older rats when compared with younger ones (3 months > six months > 12 months > 18 months) on days 7, 14, and 21 after induction of gastric ulcer. This study revealed that the slower gastric ulcer healing rate in older rats might be due to reduced epithelial cell proliferation and angiogenic activities.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical Studies of Age-Related Changes in Cell Proliferation and Angiogenesis during the Healing of Acetic Acid-Induced Gastric Ulcers in Rats

Ajayi

Olaleye

2020

The Scientific World Journal

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“…Factor VIII is synthesized mainly by endothelial cells, not hepatocytes. 10 As such, most patients with normalmild liver iron overload had normal aPTT, although their PT was abnormal. It is important to note that technical factors may cause false positive results of PT and aPTT prolongation.…”

Section: Discussionmentioning

confidence: 99%

Hemostatic abnormalities in children with thalassemia major and liver iron overload

Wahidiyat

Iskandar

Chozie

et al. 2018

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Background Thalassemia major (TM) patients are susceptible to liver dysfunction due to iron deposition. Pediatric TM patients often present with bleeding. Blood loss necessitates transfusions, leading to increased iron absorption from the gut. Objective To study hemostatic abnormalities in children with TM and iron deposition in the liver. Methods This cross-sectional study involved 190 non-splenectomized children with TM. Liver iron deposition was evaluated using T2* MRI. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet counts were assessed from blood specimens. Results Most subjects were diagnosed with β-thalassemia and β-thalassemia/HbE. The majority of subjects were on deferiprone (DFP) treatment. Approximately 89.5% of subjects had liver iron overload. Prolongation of PT and aPTT, as well as thrombocytopenia were observed in 60%, 27.9%, and 19.5% of subjects, respectively. Prolonged aPTT and thrombocytopenia were observed three times more frequently in subjects with moderate - severe liver iron overload than in subjects with normal - mild liver iron overload (P=0.04 and 0.001, respectively). Conclusion Most TM subjects have liver iron overload ranging from mild to severe. Prothrombin time and prolongation, as well as aPTT prolongation, and thrombocytopenia are easily found in TM children. There were significantly more moderate - severe liver iron deposition patients with aPTT prolongation and thrombocytopenia than normal – mild patients with these conditions. Hence, we suggest that pediatric TM patients undergo liver iron deposition evaluations and use iron chelators in an optimal manner, in order to limit the risk of bleeding.

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“…The liver is an ideal target organ for gene therapy for hemophilia. FVIII and FIX are normally synthetized by liver sinusoidal endothelial cells (LSECs) and hepatocytes, respectively ( 77 ). Both cell types can efficiently secrete proteins into circulation.…”

Section: Hepatic Gene Therapy For Tolerance Inductionmentioning

confidence: 99%

Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

2017

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Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors”) remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg), in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A.

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The search for the origin of factor VIII synthesis and its impact on therapeutic strategies for hemophilia A

Cited by 15 publications

References 20 publications

Immunohistochemical Studies of Age-Related Changes in Cell Proliferation and Angiogenesis during the Healing of Acetic Acid-Induced Gastric Ulcers in Rats

Immunohistochemical Studies of Age-Related Changes in Cell Proliferation and Angiogenesis during the Healing of Acetic Acid-Induced Gastric Ulcers in Rats

Hemostatic abnormalities in children with thalassemia major and liver iron overload

Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

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