Endothelial Function in Patients with Severe and Moderate Haemophilia A and B

Böhmert, Stephanie; Schubert, Ralf; Fichtlscherer, Stephan; Alesci, S.; Miesbach, Wolfgang

doi:10.1055/s-0038-1673415

Cited by 7 publications

(30 citation statements)

References 28 publications

(40 reference statements)

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“…The high expression of miRNA-155 in CAD and haemophilia patients are consistent with the significantly elevated sICAM-1 levels in haemophilia patients in our previous study. 2 and the positive correlation between miRNA-155 and sICAM-1 as described earlier. This outlines the involvement of miRNA-155 and miRNA-21 in pro-inflammatory processes leading to atherosclerosis by upregulations of VCAM-1, ICAM-1 and MCP1 through targeting different pathways.…”

Section: Discussionsupporting

confidence: 63%

Endothelial dysfunction and atherosclerosis related miRNA‐expression in patients with haemophilia

et al. 2022

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Introduction: Elevated markers of endothelial dysfunction and inflammation indicate worse endothelial function in the aging haemophilia population. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Several miRNAs have been shown to be involved in the process of endothelial dysfunction and atherosclerosis. Aim: The aim of this study was to determine the underlying molecular pathways of endothelial dysfunction and inflammation in haemophilia patients. Methods: A total of 25 patients with severe or moderate haemophilia A (20 patients) or B (5 patients), 14 controls and 18 patients with coronary artery disease (CAD) after myocardial infarction were included in this study. Expression of miRNA-126, -155, -222, -1, -let7a, -21 and -197 were analysed using a real time polymerase chain reaction. Network-based visualisation and analysis of the miRNA-target interactions were performed using the MicroRNA ENrichment TURned NETwork (MIENTURNET).Results: Expression of miRNA-126 (p < .05) and miRNA-let7a (p < .05) were significantly higher in CAD patients compared to haemophilia patients and controls.MiRNA-21 (p < .05) was significantly elevated in CAD patients compared to controls.MiRNA-155 (p < .05), miRNA-1 (p < .05) and miRNA-197 (p < .05) were significantly higher expressed in CAD and haemophilia patients compared to controls and showed a strong correlation with increased levels of interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1). The network analysis revealed interactions in the cytokine signalling, focal adhesion and VEGFA-VEGFR2 pathway (Vascular endothelial growth factor, -receptor). Conclusion:This study characterises miRNA expression in haemophilia patients in comparison to CAD patients and healthy controls. The results imply comparable biological processes in CAD and haemophilia patients.

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Section: Discussionsupporting

confidence: 63%

Endothelial dysfunction and atherosclerosis related miRNA‐expression in patients with haemophilia

et al. 2022

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“…Indeed, abnormal endothelial function was recently recognized in patients with hemophilia. 23 Our current findings will inspire future investigations looking at the molecular mechanism underlying loss of endothelial fenestration associated with FVIII deficiency and whether or how this possibly could be affecting liver gene therapy in hemophilia.…”

Section: Resultsmentioning

confidence: 79%

Defenestrated endothelium delays liver-directed gene transfer in hemophilia A mice

Kamiński

Gudapati

et al. 2022

Blood Advances

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Hemophilia A is an inherited bleeding disorder caused by defective or deficient coagulation factor-VIII (FVIII) activity. Until recently, the only treatment for prevention of bleeding involved intravenous administration of FVIII. Gene therapy with adeno associated vectors (AAV) has shown some efficacy in hemophilia A patients. However, limitations persist due to AAV-induced cellular stress, immunogenicity, and reduced durability of gene expression. Herein, we examined the efficacy of liver-directed gene transfer in FVIII knock out mice by AAV8-GFP. Surprisingly, compared to control mice, FVIII knockout (F8TKO) mice showed significant delay in AAV8-GFP transfer in the liver. We found that the delay in liver directed gene transfer in F8TKO mice was associated with absence of liver sinusoidal endothelial cell (LSEC) fenestration, which led to aberrant expression of several sinusoidal endothelial proteins causing increased capillarization and decreased permeability of LSECs. This is the first study to link impaired liver-directed gene transfer to liver-endothelium maladaptive structural changes associated with FVIII deficiency in mice.

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“…In our study a lower than expected number of CVD events was observed. From previous studies it is known that haemophilia does not protect against atherosclerosis 6,[22][23][24] . We hypothesized that lower clotting factor levels diminish pathologic clot formation at sites of unstable plaques in PWH.…”

Section: Discussionmentioning

confidence: 99%

Reduced cardiovascular morbidity in patients with hemophilia: results of a 5-year multinational prospective study

et al. 2022

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Hemophilia is a congenital bleeding disorder caused by low clotting factor VIII or IX levels. Life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased. In retrospective studies there are conflicting data if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH with the predicted incidence. This prospective, multicenter, observational study included adult PWH (>30y) from the Netherlands and United Kingdom (UK). They were followed for a 5-year period and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary endpoint was the observed fatal and nonfatal CVD incidence after 5 years compared to the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years follow up or reached an endpoint. For 108 patients the QRISK score could not be calculated at inclusion. For the remaining 579 fewer CVD events were observed than predicted: 9 versus 24 (RR 0.38; 95% CI: 0.18 - 0.80 p=0.01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistical significant relation between severity of hemophilia and incidence of CVD. In hemophilia a lower than predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov (identification number NCT01303900).

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Endothelial Function in Patients with Severe and Moderate Haemophilia A and B

Cited by 7 publications

References 28 publications

Endothelial dysfunction and atherosclerosis related miRNA‐expression in patients with haemophilia

Endothelial dysfunction and atherosclerosis related miRNA‐expression in patients with haemophilia

Defenestrated endothelium delays liver-directed gene transfer in hemophilia A mice

Reduced cardiovascular morbidity in patients with hemophilia: results of a 5-year multinational prospective study

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