Interest in Africa on therapeutic use of COVID-19 convalescent plasma (CCP) has increased with continental spread of the pandemic of SARS -CoV-2. Consequently, blood organisations in several countries have established governmentally... more
Interest in Africa on therapeutic use of COVID-19 convalescent plasma (CCP) has increased with continental spread of the pandemic of SARS -CoV-2. Consequently, blood organisations in several countries have established governmentally approved investigational protocols for collection and use of CCP. However, other countries still seek advice in this area. Sources of guidance can be found in recent publications by the Working Party on Global Blood Safety of the International Society of Blood Transfusion (ISBT), the ISBT Convalescent Plasma Working Group, and the World Health Organization. Additionally, resources on CCP policies and protocols can be found at an ISBT open-access website: http://isbtweb.org/coronaoutbreak/convalescent-plasma-covid-19-resources/.The effectiveness and safety of CCP remain uncertain based on limitations of the available controlled studies and reported case series and fundamental questions regarding optimal use in patient management are unanswered. Neverthele...
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The world is regularly exposed to emerging infections with the potential to burst into a pandemic. One possible way to treat patients, when no other treatment is yet developed,is passive immunization performed by transfusing blood, plasma... more
The world is regularly exposed to emerging infections with the potential to burst into a pandemic. One possible way to treat patients, when no other treatment is yet developed,is passive immunization performed by transfusing blood, plasma or plasma immunoglobul infractions obtained from convalescent donors who have recovered from the disease and have developed protective antibodies. The most recent on-going epidemic is caused by the Ebola virus, a filovirus responsible for Ebola virus disease, a severe, often lethal, hemorrhagic fever. Recently, the use of convalescent blood products was proposed by the WHO as one early option for treating patients with Ebola virus disease. This publication provides an overview of the various convalescent blood products and technological options that could theoretically be considered when there is a need to rely on this therapeutic approach.In countries without access to advanced blood-processing technologies, the choice may initially be restricted ...
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This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international requirements for the production and control of vaccines and other biologicals and the... more
This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international requirements for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the Committee's attention and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, and endocrinological substances. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains recommendations for the production and quality control of meningococcal group C conjugate vaccines, guidelines for regulatory expectations for clinical evaluation of vaccines, guidelines for the production and quality control of inactivated oral cholera vaccines and guidelines ...
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This paper describes the increasingly unique and powerful role that affinity chromatography is occupying both as a tool for the treatment of extracorporeal plasma exchange (to discard biological compounds with noxious metabolic or... more
This paper describes the increasingly unique and powerful role that affinity chromatography is occupying both as a tool for the treatment of extracorporeal plasma exchange (to discard biological compounds with noxious metabolic or immunologic effects in patients) and as a purification tool in the production of therapeutic plasma protein derivatives. Management of both applications requires careful monitoring of the parameters applied to the plasma material, to avoid immunological stimulation or activation of the coagulation cascade. Examples of direct current applications of affinity ligands in therapeutic removal and industrial production of plasma compounds are presented.
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Inter-alpha-trypsin inhibitor (ITI) is a serine-proteinase inhibitor of human plasma enzymes. ITI is composed of three polypeptide chains covalently linked: bikunin, responsible for the antiprotease activity and two heavy chains H1 and... more
Inter-alpha-trypsin inhibitor (ITI) is a serine-proteinase inhibitor of human plasma enzymes. ITI is composed of three polypeptide chains covalently linked: bikunin, responsible for the antiprotease activity and two heavy chains H1 and H2. Human plasma also contains other components immunologically related to ITI such as pre-alpha-trypsin inhibitor (paI), inter-alpha-like inhibitor (IalphaLI) and free bikunin. The ELISA procedure we propose exclusively measures native ITI within the range 12.5-200 microgram/l. The intra- and interassay coefficients of variation were less than 5.6% and 8.7%, respectively. When ITI was added to plasma samples, full recovery was obtained. EDTA-plasma from 30 healthy individuals revealed a mean level of 241.5 mg/l (range 145.5-506). The high specificity, sensitivity, reproducibility and accuracy of the present assay should facilitate the specific measurement of native ITI in blood and thus might represent a useful tool for further physiopathological stu...
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Industrial-scale chromatographic fractionation and purification methods have been used increasingly in the last few years for plasma fractionation. This has resulted in the development of a new generation of therapeutic plasma... more
Industrial-scale chromatographic fractionation and purification methods have been used increasingly in the last few years for plasma fractionation. This has resulted in the development of a new generation of therapeutic plasma derivatives, especially coagulation factors, protease inhibitors and anticoagulants. Implementation and combination of ion-exchange, affinity and size-exclusion chromatography have allowed the development of new therapeutic products with improved purity and safety for treating congenital or acquired plasma protein deficiencies in patients. More recently, the benefit of chromatographic purification of plasma proteins in the removal of plasma-borne viruses has been revealed. Development of packing materials with improved characteristics for industrial applications, including higher capacity and rigidity, should further promote the use of chromatography as an essential plasma fractionation tool and confine more and more the traditional ethanol precipitation metho...
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The risk of transmission of bovine spongiform encephalopathy cannot be excluded from the use of bovine-derived products. The present study was undertaken to evaluate the performance of a new fibrin glue free of bovine-derived components... more
The risk of transmission of bovine spongiform encephalopathy cannot be excluded from the use of bovine-derived products. The present study was undertaken to evaluate the performance of a new fibrin glue free of bovine-derived components in vas anastomosis and to compare this product to conventional vas anastomosis with fibrin glue. Bilateral delayed vas anastomosis was performed in 40 Sprague-Dawley rats. All animals underwent a fibrin glue-assisted vas anastomosis with three transmural sutures tied prior to fibrin glue application. The composition and preparation of fibrin glue was similar for all vas anastomoses except the fibrinolysis inhibitor component which was aprotinin (3,000 KUI/ml) in group 1 and tranexamic acid (10 mg/ml) in group 2. The animals (20 rats in both groups) were sacrificed 7 weeks postoperatively and evaluated for gross patency, presence of sperm granuloma and tensile strength measurements at the anastomosis site. No difference was found between the 2 groups for all parameters evaluated whether a bovine-derived or a synthetic fibrinolysis inhibitor component was used. This study showed that tranexamic acid, a fibrinolysis inhibitor, can be substituted for conventional fibrin glue thereby avoiding the risks of bovine products.
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Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with... more
Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub-Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to de...
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Polymorphism of human platelet antigens (HPAs) leads to alloimmunizations and immune-mediated platelet disorders including fetal-neonatal alloimmune thrombocytopenia (FNAIT), posttransfusion purpura (PTP), and platelet transfusion... more
Polymorphism of human platelet antigens (HPAs) leads to alloimmunizations and immune-mediated platelet disorders including fetal-neonatal alloimmune thrombocytopenia (FNAIT), posttransfusion purpura (PTP), and platelet transfusion refractoriness (PTR). HPA typing and knowledge of antigen frequency in a population are important in particular for the provision of HPA-matched blood components for patients with PTR. We have performed allele genotyping for HPA-1 through -6 and -15 among 998 platelet donors from 6 blood centers in Taiwan using sequence-specific primer polymerase chain reaction. The HPA allele frequency was 99.55, and 0.45% for HPA-1a and -1b; 96.49, and 3.51% for HPA-2a and -2b; 55.81, and 44.19% for HPA-3a and -3b; 99.75, and 0.25% for HPA-4a and -4b; 98.50, and 1.50% for HPA-5a and -5b; 97.75 and 2.25% for HPA-6a and -6b; 53.71 and 46.29% for HPA-15a and -15b. HPA-15b and HPA-3a, may be considered the most important, followed by HPA-2, -6, -1, -5, and -4 systems, as a c...
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Fibrin sealant is a complex plasma-derived product which is increasingly used as a biodegradable tissue adhesive or sealant to stop or control bleeding or provide air and fluid tightness in many surgical situations. This review describes... more
Fibrin sealant is a complex plasma-derived product which is increasingly used as a biodegradable tissue adhesive or sealant to stop or control bleeding or provide air and fluid tightness in many surgical situations. This review describes the historical development of current fibrin sealant preparations and the scientific rationale behind the alleged physiological benefits of its major plasma-derived components. A comparison in the extraction methods and viral reduction treatments applied to current commercial products and autologous preparations, and their respective advantages and limits, are discussed. Application devices used for surgical applications are described. A survey of the major clinical applications in various surgical areas is presented. Current issues in terms of viral safety, definition of optimal fibrin sealant composition, and regulatory concerns, especially to demonstrate clinical efficacy, are also included.
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Major technical developments have been made in recent years to improve the quality and safety of human plasma for transfusion and fractionation. The present study was performed to assess, for the first time, the feasibility of applying a... more
Major technical developments have been made in recent years to improve the quality and safety of human plasma for transfusion and fractionation. The present study was performed to assess, for the first time, the feasibility of applying a nanofiltration process, using 75-nm and 35-nm mean pore size membranes (Planova) 75N and Planova 35N), to human plasma. Ten apheresis plasma units were obtained from 10 plasma donors. Within 4 h of collection, plasma was subjected to leucoreduction and filtration (using 75-nm and 35-nm mean pore size membranes) at 35 degrees C, at less than 1 bar pressure. Aliquots of plasma were taken at all steps of the filtration procedure and numerous plasma quality parameters were measured. In addition, six hepatitis C virus (HCV)-positive plasma donations were experimentally subjected to the same filtration sequence and subsequently assessed by RNA polymerase chain reaction (PCR) and branched-chain DNA-quantification assays. Leucoreduced plasma can be reproducibly nanofiltered onto a sequence of 75-nm and 35-nm membranes, at a flow rate of 450 ml/h and a temperature of 35 +/- 0.5 degrees C. Some protein dilution, or loss, was found during filtration, but the plasma filtered through membranes with a mean pore size of 75 nm and 35 nm met in vitro specifications for use in transfusion or fractionation. There were no signs of activation of the coagulation system. HCV-positive plasma donations became negative, as judged by PCR and branched-chain DNA assay results, after filtration through the 35-nm membrane. It is possible to apply a 75 + 35-nm filtration process to leucoreduced human plasma. This technology may have important future benefits in improving the quality and safety of plasma, by removing blood cell debris and infectious agents.
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Research Interests: Risk, Prion Diseases, Safety, Humans, Nanofiltration, and 13 moreExperimental Infection, Clinical Sciences, Bovine Spongiform Encephalopathy, Prions, Fractionation, Epidemiological Surveillance, Blood Donors, Therapeutic Use, Immunoglobulin, Prion Protein, Blood component transfusion, Plasma exchange, and Blood Donor
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We compare delayed vasectomy reversals performed in rats using fibrin glue combined with 3 transmural sutures or a conventional microsurgical technique. Forty Sprague-Dawley rats underwent bilateral vasectomy followed 2 weeks later by... more
We compare delayed vasectomy reversals performed in rats using fibrin glue combined with 3 transmural sutures or a conventional microsurgical technique. Forty Sprague-Dawley rats underwent bilateral vasectomy followed 2 weeks later by bilateral vasovasostomy using fibrin glue or a conventional microsurgical suture technique. Our protocol evaluated fertility rates after a 3-week mating period, sperm granuloma formation, histological changes at the anastomotic site, longitudinal tensile strength and mean testicular weight. The fibrin glue technique required significantly reduced operative time (p < 0.0005) and showed statistically lower tensile strength performance (p < 0.0005). All other parameters showed no statistical difference between the two techniques. Fibrin-glued vasovasostomy is efficient in a delayed protocol and deserves further clinical experience.
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ABSTRACT The first plasma fractionation process was developed in the 1940s by Cohn and co‐workers to prepare albumin and immunoglobulins. It relies on sequential precipitation steps at negative temperatures, different ethanol... more
ABSTRACT The first plasma fractionation process was developed in the 1940s by Cohn and co‐workers to prepare albumin and immunoglobulins. It relies on sequential precipitation steps at negative temperatures, different ethanol concentrations and various pH to segregate bulk plasma proteins. The ‘Cohn procedure’ has been modified over the years but largely remains the core fractionation process in use up to now. The introduction of cryoprecipitation (thawing of plasma at 2–4°C), as the first plasma fractionation step, to isolate a crude factor‐VIII fraction, and the integration of chromatographic steps to extract labile plasma or trace plasma proteins, have eventually shaped the modern fractionation technologies into complex procedures. Viral inactivation and removal treatments are performed to prevent the risks of transmission of enveloped and non‐enveloped viruses. Viral inactivation steps are applied most often on pre‐purified fractions, the downstream steps being used to remove protein contaminants and viral inactivation agents. Depending upon products and protein stability, treatments include incubations with combinations of solvent (TnBP) and detergent (e.g. Tween 80 or Triton X‐100) (S/D), pasteurization (heat‐treatment in the liquid state at 60°C for 10 h in the presence of stabilizers), as well as low pH or caprylic acid treatments (these last two treatments are restricted to immunoglobulins). Nanofiltration, to capture viruses on nm‐membranes, is typically performed on the final purified protein fractions prior to sterile filtration and aseptic filling. Terminal dry‐heat treatment at 80–100°C is used for some coagulation factor preparations. Modern plasma protein products have an unprecedented level of quality and safety when there is careful process control and monitoring together with sensitive test methods to detect potentially harmful contaminants, such as procoagulant impurities. Since the implementation of validated robust viral reduction treatments, plasma products have a high viral safety profile including against emerging agents (WNV, Dengue virus, Chikungunya virus). Experimental spiking studies suggest that several fractionation steps are capable of removing prions causing variant Creutzfeldt‐Jakob disease. Alternative fractionation processes based exclusively on chromatography have been developed at pilot scale and need further validations to demonstrate the quality, safety and consistency of resulting plasma products. A mini‐pool viral inactivation and fractionation process relying on single‐use equipment is also being developed to facilitate the access to safer plasma components, including plasma for transfusion, cryoprecipitate, prothrombin complex, immunoglobulins and fibrin sealant, in particular in developing countries.
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To compare fibrin-glued vasovasostomy to a conventional microsurgical technique in a protocol of delayed vasovasostomy. Forty male Sprague-Dawley rats underwent bilateral vasectomy through a midline abdominal incision. Two weeks later all... more
To compare fibrin-glued vasovasostomy to a conventional microsurgical technique in a protocol of delayed vasovasostomy. Forty male Sprague-Dawley rats underwent bilateral vasectomy through a midline abdominal incision. Two weeks later all animals underwent a bilateral vasectomy reversal through a bilateral inguino-scrotal incision, following two different protocols. Invariably, the proximal segment had a larger lumen. The control group (20 rats) had a conventional modified one-layer sutured vasal anastomosis with 10/0 nylon. The experimental group (20 rats) underwent vasal anastomosis using fibrin glue and consisting of three transmural sutures with 10/0 nylon followed by the application of fibrin glue circumferentially to seal the anastomosis. The fibrin-tissue adhesive was obtained from pooled donor plasma and was virally inactivated by a solvent-detergent treatment. Seven weeks after surgery all animals were killed and the vasal specimens were evaluated for gross patency and the incidence of sperm granuloma. The control group had a patency rate of 85% and half had sperm granuloma. The experimental group had a patency rate of 92% and 40% had sperm granuloma; neither difference was significant. The mean operative time was significantly shorter for the fibrin glue-assisted vasovasostomy (P < 0.001). This study showed that a delayed fibrin-glued vasovasostomy gave a comparable anatomical success and an incidence of sperm granuloma similar to that using a conventional microsurgical technique, but with the advantages of a shorter operative time and a less technically demanding anastomosis.
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This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international requirements for the production and control of vaccines and other biologicals and the... more
This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international requirements for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the Committee's attention and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, and endocrinological substances. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains recommendations for the production and quality control of meningococcal group C conjugate vaccines, guidelines for regulatory expectations for clinical evaluation of vaccines, guidelines for the production and quality control of inactivated oral cholera vaccines and guidelines ...
Research Interests: Vaccines, Cytokines, International Cooperation, Quality Control, Antibodies, and 13 moreHumans, Animals, Hormones, Advisory Committees, Peptides, Anti-Bacterial Agents, Public health systems and services research, World Health Organization, Blood Transfusion, Biological Factors, Recombinant Proteins, Antigens, and Blood Proteins
In March 2003, an outbreak of severe acute respiratory syndrome started in Hong Kong. A 57-year-old woman had a typical presentation, including fever, non-productive cough, malaise, lymphopenia, and raised liver aminotransferases. The... more
In March 2003, an outbreak of severe acute respiratory syndrome started in Hong Kong. A 57-year-old woman had a typical presentation, including fever, non-productive cough, malaise, lymphopenia, and raised liver aminotransferases. The clinical course and successful treatment with convalescent plasma, ribavirin, and corticosteroids are discussed.
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The approach followed in the design of a large-scale pasteurization treatment (60 degrees C for 10 hours in the liquid state) of fresh frozen plasma is presented. Various aspects thought to influence the viral safety of such a product are... more
The approach followed in the design of a large-scale pasteurization treatment (60 degrees C for 10 hours in the liquid state) of fresh frozen plasma is presented. Various aspects thought to influence the viral safety of such a product are discussed. They are based largely upon the fact that, although it is subjected to a specific viral inactivation treatment, this plasma does not benefit from any fractionation steps known to participate in the potential elimination of infectious agents during the manufacture of plasma derivatives. Consequently, the plasma is obtained from regular plasmapheresis donors, and the plasma donations used to make the pool must be negative for anti-HIV-1 and -2, anti-HCV, anti-HBc, anti-HTLV-1 and -2, HBs antigen and parvovirus B19 antigen, and have a normal level of ALT. The batch size is limited to 100 plasma units to limit the potential infectious risk associated with very large batches, especially if an infectious agent, resistant to pasteurization, is ...
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... Angel Montoya*. Laboratorio Integrado de Bioingeniería, Universidad Politécnica de Valencia, Camino de Vera s/n, 46022 Valencia, Spain. J. Agric. ... Abad, A.; Montoya, A. Production of monoclonal antibodies for carbaryl from a hapten... more
... Angel Montoya*. Laboratorio Integrado de Bioingeniería, Universidad Politécnica de Valencia, Camino de Vera s/n, 46022 Valencia, Spain. J. Agric. ... Abad, A.; Montoya, A. Production of monoclonal antibodies for carbaryl from a hapten preserving the carbamate group. J. Agric. ...
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Instituto Clodomiro Picado has developed an immunoglobulin G (IgG) plasma fractionation process combining a polyethylene glycol/phosphate aqueous two-phase system (ATPS), caprylic acid precipitation and anion-exchange membrane... more
Instituto Clodomiro Picado has developed an immunoglobulin G (IgG) plasma fractionation process combining a polyethylene glycol/phosphate aqueous two-phase system (ATPS), caprylic acid precipitation and anion-exchange membrane chromatography. We evaluated the purity and in vitro thrombogenicity of such IgG, in line with current international requirements. Contributions of the different production steps to reduce thrombogenicity were assessed at 0·2 l-scale, and then the methodology was scaled-up to a 10 l-scale and final products (n = 3) were analysed. Purity, immunoglobulin composition, and subclass distribution were determined by electrophoretic and immunochemical methods. The in vitro thrombogenic potential was determined by a thrombin generation assay (TGA) using a Technothrombin fluorogenic substrate. Prekallikrein activator (PKA), plasmin, factor Xa, thrombin and thrombin-like activities were assessed using S-2302, S-2251, S-2222, S-2238 and S-2288 chromogenic substrates, respectively, and FXI by an ELISA. The thrombogenicity markers were reduced mostly during the ATPS step and were found to segregate mostly into the discarded liquid upper phase. The caprylic acid precipitation eliminated the residual procoagulant activity. The IgG preparations made from the 10 l-batches contained 100% gamma proteins, low residual IgA and undetectable IgM. The IgG subclass distribution was not substantially affected by the process. TGA and amidolytic activities revealed an undetectable in vitro thrombogenic risk and the absence of proteolytic enzymes in the final product. Fractionating human plasma by an ATPS combined with caprylic acid and membrane chromatography resulted in an IgG preparation of high purity and free of a detectable in vitro thrombogenic risk.
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Polyvalent immunoglobulin G (IgG) products obtained by fractionation of human plasma are used to treat a broad range of conditions, including immunodeficiency syndromes and autoimmune, inflammatory, and infectious diseases. Recent... more
Polyvalent immunoglobulin G (IgG) products obtained by fractionation of human plasma are used to treat a broad range of conditions, including immunodeficiency syndromes and autoimmune, inflammatory, and infectious diseases. Recent incidences of increased thromboembolic events (TEEs) associated with intravenous (IV) IgG (IVIG) led to recalls of some products and increased regulatory oversight of manufacturing processes in order to ensure that products are essentially free of procoagulant/thrombogenic plasma protein contaminants. Laboratory investigations have now identified activated factor XI (FXIa) as the likely causative agent of IVIG-related TEEs. Quantification of the thrombogenic potential is becoming a requirement made to fractionators (a) to validate the capacity of IVIG and subcutaneous IgG manufacturing processes to remove procoagulant contaminants and (b) to establish the safety of the final products. However, in the absence of a recommended test by the main regulatory authorities, several analytical approaches have been evaluated by fractionators, regulators, and university groups. This review focuses on the scientific rationale, merits, and applications of several analytical methods of quantifying the thrombogenic potential of IgG products and intermediates to meet the latest regulatory requirements.