Effectiveness of long-term prophylaxis using pdFVIII/VWF concentrate in patients with inherited von Willebrand disease.

BACKGROUND: Patients with symptomatic von Willebrand disease (VWD) should be offered long-term prophylaxis (LTP) to prevent recurrent bleedings. Our objective was to evaluate the effectiveness and safety of Voncento®, a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), administrated in LTP. METHODS: We included patients from the OPALE study (May 2016 to April 2021), a French multicenter observational study following patients with inherited VWD, who received a Voncento® LTP during the study period. RESULTS: Among the 130 OPALE-study patients, 23 patients (12 women) received a LTP and were therefore included. The median (range) age was 16 (1-85) years; 16 patients were type 3, 1 was type 2A, 6 were type 2B. Before inclusion, 19 (83%) were under LTP and 4 (17%) received on-demand (OD) treatment. The indications for initiating prophylaxis in the overall population were joint bleeding (43%), ear, nose, and throat (ENT) bleeding including epistaxis or oral bleeding (39%), and recurrent muscle hematoma (22%). The medians (ranges) dose of Voncento® per infusion, frequency, and weekly dose were 45 (33-109) IU/kg, 2 infusions per week, and 96 (44-222) IU/kg/week, respectively. The median (range) annualized bleeding rate (ABR) was 0.8, 0.7 (0-3.5), and 0 (0-2.3) for type 2A, 2B, 3 patients, respectively. There was no difference regarding to the dose, frequency of infusion, or in terms of ABR in 9/19 patients who replaced previous concentrates with Voncento®. During the study period, no adverse event was reported. CONCLUSION: These results suggest that Voncento® is effective to prevent recurrent bleedings in patients symptomatic VWD.

Effectiveness and safety of hFVIII/VWF concentrate (Voncento®) in patients with inherited von Willebrand disease requiring surgical procedures: the OPALE multicentre observational study.

BACKGROUND: In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento® (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD. MATERIALS AND METHODS: The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento® who underwent surgery. RESULTS: In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1-9), the pre-operative loading dose was 41 IU VWF:RCo kg-1 (range: 18-147), and the total dose was 63 (range: 18-594). During major surgeries, the number of infusions was 4 (range: 1-23), the pre-operative loading dose was 43 (range: 25-66) IU VWF: RCo kg-1, and the total dose was 155 (range: 40-575). The median FVIII:C levels ranged from 78 to 165 IU dL-1 during 5 days after minor surgeries and from 86 and 167 IU dL-1 during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL-1 and between 34 and 76 IU dL-1 after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as "excellent" or "good" in 99% of patients. No thrombotic events related to Voncento® were recorded. DISCUSSION: The present study suggests that Voncento® is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.

Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2.

BACKGROUND: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS: We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS: Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.

Potential role of the (pro)renin receptor in cardiovascular and kidney diseases.

The discovery of a (pro)renin receptor ((P)RR) and the introduction of renin inhibitors in the clinic has brought prorenin, the inactive proenzyme form of renin, back into the spotlight. The (P)RR binds both renin and its inactive precursor prorenin, and their binding triggers intracellular signaling that up-regulates the expression of profibrotic genes. Furthermore, binding of prorenin unmasks its active site and endows prorenin with angiotensin I-generating activity. Many studies have attempted to establish a link between (P)RR and hypertension, (P)RR and tissue fibrosis associated with hypertension and with diabetic nephropathy. Models of transgenic rats overexpressing (P)RR develop high blood pressure and have glomerulosclerosis, suggesting a link between increased (P)RR and these pathologies, but no definite proof of any role of (P)RR in other models of cardiovascular or renal diseases could be established because of the absence of any specific (P)RR antagonist and of tissue-specific (P)RR null mice. Nevertheless, a study in a large cohort of Japanese men has shown a correlation between a polymorphism in the (P)RR gene and increased ambulatory blood pressure. Finally, a mutation in the (P)RR gene is responsible for mental retardation and epilepsy, indicating that (P)RR is essential during brain development.

Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma.

The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for alpha1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-alpha protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.

[The prorenin receptor]. / Le récepteur de la prorénine.

The renin-angiotensin system (RAS) is one of the most important systems in physiology and in pathology. The (pro)renin receptor [(P)RR] is a new component of the system that has attracted much attention, being potentially a new therapeutic target, because the binding of renin and of prorenin triggers the activation of the mitogen-activated protein kinase p42/p44 followed by up-regulation of the expression of profibrotic genes. and because prorenin bound to (P)RR becomes catalytically active. The introduction of a renin inhibitor in the treatment of hypertension and of organ damages, together with the discovery of (P)RR, has revived the interest for the RAS and for potential new RAS blockers, in order to optimize RAS blockade in tissues.