No abstract

SummaryA rabbit antibody against human protein C was used for the quantitative estimation of protein C in plasma. In healthy individuals protein C antigen ranged from 0.65-1.45 U/ml. Plasma protein C antigen was found to be independent of either age or sex. Under influence of oral anticoagulant treatment the protein C antigen concentration decreased to 0.47 U/ml (at low intensity treatment) or 0.33 U/ml (at high intensity treatment). Using normal ranges of protein C and protein C/factor II and protein C/factor X ratios criteria were developed for the assessment of protein C deficiency. In a Dutch family with a history of thrombotic disease two members were found to have an isolated protein C deficiency, while a third one is suspected of protein C deficiency. In one case it was possible to confirm the diagnosis of suspected protein C deficiency during temporary withdrawal of the anticoagulant therapy.

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterzygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.

SummaryProtein S, a vitamin K-dependent coagulation factor, is involved in the regulation of the anticoagulant activity of activated protein C.Using an immunoradiometric assay for total protein S in plasma we identified 14 patients (7 male and 7 female) in three unrelated Dutch families as fulfilling the criteria for an isolated protein S deficiency. In 9 patients who were not receiving oral anticoagulant treatment the mean total protein S antigen concentration was 0.50 ± 0.08 U/ml (± S.D.) and the calculated free protein S concentration was 0.15 ± 0.01 U/ml (± S.D.). In the five patients who were on oral anticoagulant treatment the mean total protein S antigen was 0.23 ± 0.05 U/ml (± S.D.).Seven of the 14 patients had a history of venous thromboembolism occurring at a mean age of 25 years and often without an apparent cause. Protein S deficiency is inherited as an autosomal dominant trait.

Advanced therapy medicinal products (ATMPs) hold promise as treatments for previously untreatable and high-burden diseases. Expectations are high and active company pipelines are observed, yet only 10 market authorizations were approved in Europe. Our aim was to identify challenges experienced in European ATMP clinical development by companies. A survey-based cohort study was conducted among commercial ATMP developers. Respondents shared challenges experienced during various development phases, as well as developer and product characteristics. Descriptions of challenges were grouped in domains (clinical, financial, human resource management, regulatory, scientific, technical, other) and further categorized using thematic content analysis. A descriptive analysis was performed. We invited 271 commercial ATMP developers, of which 68 responded providing 243 challenges. Of products in development, 72% were in early clinical development and 40% were gene therapies. Most developers were small- or medium-sized enterprises (65%). The most often mentioned challenges were related to country-specific requirements (16%), manufacturing (15%), and clinical trial design (8%). The European ATMP field is still in its early stages, and developers experience challenges on many levels. Challenges are multifactorial and a mix of ATMP-specific and generic development aspects, such as new and orphan indications, novel technologies, and inexperience, adding complexity to development efforts.