Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These... Show moreHaploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (+/- 9.2) to 1.9 (+/- 3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study. Show less
Orlova, V.V.; Nahon, D.M.; Cochrane, A.; Cao, X.; Freund, C.; Hil, F. van den; ... ; Mummery, C.L. 2022
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent... Show moreHereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENG(c.)(1678C>)(T)) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1(c.)(1678C)(>T)-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays. Show less
We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is... Show moreWe identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and a proangiogenic-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development. Show less
Background: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of... Show moreBackground: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL(-1)) NT-proBNP. Methods and results: Hemodynamically stable outpatients with acute PE and NT-proBNP level < 500 pg mL(-1) were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of readmission due to PE or its treatment and the patient's satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3-month follow-up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow-up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS-A anxiety score did not change significantly between day 0 and day 10. The PSQ-18 showed a high score for satisfaction with home treatment. Conclusion: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL(-1)) NT-proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. Show less
Lebrin, F.; Srun, S.; Raymond, K.; Martin, S.; Brink, S. van den; Freitas, C.; ... ; Mummery, C.L. 2010
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their... Show moreHereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations. Show less
Post, S.; Smits, A.M.; Broek, A.J. van den; Sluijter, J.P.G.; Hoefer, I.E.; Janssen, B.J.; ... ; Goumans, M.J. 2010
Aims Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to... Show moreAims Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1a (SDF-1 alpha) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs. Methods and results CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1 alpha was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1 alpha gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein. Conclusion We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1 alpha. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism. Show less
