Stepwise options for preparing therapeutic plasma proteins from domestic plasma in low- and middle-income countries.

Industrial plasma fractionation, a complex and highly regulated technology, remains largely inaccessible to many low- and middle-income countries (LMICs). This, combined with the limited availability and high cost of plasma-derived medicinal products (PDMPs), creates deficiency of access to adequate treatment for patients in resource-limited countries, and leads to their suffering. Meanwhile, an increasing number of LMICs produce surplus plasma, as a by-product of red blood cell preparation from whole blood, that is discarded because of the lack of suitability for fractionation. This article reviews pragmatic technological options for processing plasma collected from LMICs into therapies and supports a realistic stepwise approach aligned with recent World Health Organization guidance and initiatives launched by the Working Party for Global Blood Safety of the International Society of Blood Transfusion. When industrial options based on contract or toll plasma fractionation programme and, even more, domestic fractionation facilities require larger volumes of quality plasma than is produced, alternative methods should be considered. In-bag minipool or small-scale production procedures implementable in blood establishments or national service centres are the only realistic options available to gradually reduce plasma wastage, provide safer treatments for patients currently treated with non-pathogen-reduced blood products and concurrently improve Good Manufacturing Practice (GMP) levels with minimum capital investment. As a next step, when the available volume of quality-assured plasma reaches the necessary thresholds, LMICs could consider engaging with an established fractionator in a fractionation agreement or a contract in support of a domestic fractionation facility to improve the domestic PDMP supply and patients' treatment.

Rationale for supporting stepwise access to safe plasma proteins through local production in low- and middle-income countries: A commentary of an international workshop.

This document provides a commentary and further elaboration on the conclusions reached during a recent international workshop on plasma protein therapies organized by the Working Party for Global Safety of the International Society of Blood Transfusion (ISBT). The workshop addressed the profound deficiency in access to safe plasma protein therapies that persists in low- and middle-income countries (LMICs). We provide additional factual economic and technological information that highlights why local production of small-scale virus-inactivated concentrates of clotting factors and immune globulins from domestic recovered plasma through stepwise introduction of available validated technologies is a pragmatic approach to gradually improve the care of patients with bleeding disorders and immune deficiencies in LMIC while supporting progress toward fractionation of plasma. This strategy is in line with a recent WHO guidance. We stress that the active involvement of international blood donor and blood transfusion organizations, patient organizations, governments and industry will be essential in supporting stepwise and sustainable improvements in access to safe, effective, and quality assured plasma protein therapies.

Apheresis in developing countries around the World.

At the combined American Society for Apheresis (ASFA) Annual Meeting/World Apheresis Association (WAA) Congress in San Francisco, California, in April of 2014, the opening session highlighted the status of apheresis outside of the United States. The organizers invited physicians active in apheresis in countries not usually represented at such international gatherings to give them a forum to share their experiences, challenges, and expectations in their respective countries with regard to both donor and therapeutic apheresis. Apheresis technology is expensive as well as technically and medically demanding, and low and median income countries have different experiences to share with the rest of the world. Apheresis procedures also require resources taken for granted in the developed world, such as reliable electrical power, that can be unpredictable in parts of the developing world. On the other hand, it was obvious that there are significant disparities in access to apheresis within the same country (such as in Brazil), as well as between neighboring nations in Africa and South America. A common trend in the presentations from Brazil, Indonesia, Malaysia, Nigeria, and South Africa, was the need for more and better physicians and practitioners' training in the indications of the various apheresis modalities and patient oversight during the procedures. As ASFA and WAA continue to work together, and globalization allows for increased knowledge-sharing, improved access to apheresis procedures performed by qualified personnel with safety and high-quality standards will be increasingly available.

Plasmapheresis rescue therapy in progressive systemic ANCA-associated vasculitis: single-center results of stepwise escalation of immunosuppression.

OBJECTIVE: We evaluated 26 patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) with progressive disease despite treatment with cyclophosphamide and steroids treated with additional plasmapheresis and compared outcome with 50 matched-disease controls. METHODS: Patients diagnosed with AAV and treated with cyclophosphamide from January 1990 to December 2009 (n = 272) were included when plasmapheresis was not started at diagnosis but added for progressive disease during initial standard therapy (n = 26). We selected controls equal for age, Birmingham vasculitis activity score, and creatinine at diagnosis. Primary endpoint was estimated glomerular filtration rate (eGFR) or death. RESULTS: Plasmapheresis was added 18 days (range 5-41) after start of therapy. In 11 patients, a rise in serum creatinine >30% led to plasmapheresis; insufficient response to induction (n = 11), progressive pulmonary disease (n = 3), or progressive necrotic lesions (n = 1) were other indications.In the plasmapheresis group, six patients were in need of renal replacement therapy (RRT), and three controls. Five years after diagnosis, four patients had died in the plasmapheresis against eight controls (P = 0.94). At baseline, mean eGFR was 44 ml/min/1.73 m(2) in plasmapheresis group versus 43 ml/min/1.73 m(2) in controls. At start of plasmapheresis, eGFR was 26 ml/min/1.73 m(2) (P = 0.003), at 6 months mean eGFR had significantly improved to 44 ml/min/1.73 m(2) (P = 0.0003), comparable to eGFR in controls, 48 ml/min/1.73 m(2). During long-term follow-up, there was no difference in renal function between the groups. CONCLUSION: AAV patients with progressive disease despite standard induction therapy in whom plasmapheresis was added had significant improvement in renal function and similar long-term outcome in both renal and patient survival as matched disease controls.

Role of glycoprotein Ibalpha in phagocytosis of platelets by macrophages.

BACKGROUND: Platelet (PLT) storage at 0 to 4 degrees C suppresses bacterial multiplication, but induces clusters of glycoprotein (GP) Ibalpha that trigger their phagocytosis by macrophages and reduce their survival after transfusion. A method was sought that detects cold-induced changes in GPIbalpha involved in phagocytosis. STUDY DESIGN AND METHODS: Human PLTs were isolated and stored for up to 48 hours at 0 degrees C. Binding of a phycoerythrin (PE)-labeled antibody directed against amino acids (AA) 1-35 on GPIbalpha (AN51-PE) was compared with phagocytosis of PLTs by matured monocytic THP-1 cells, analyzed by fluorescence-activated cell sorting. RESULTS: Freshly isolated PLTs were detected as a single population of AN51-PE-positive particles and showed less than 5 percent phagocytosis. Cold storage led to a decrease in AN51-PE binding and an increase in phagocytosis. N-Acetylglucosamine, known to interfere with macrophage recognition of GPIbalpha clusters, restored normal AN51-PE binding to cold-stored PLTs and suppressed phagocytosis. CONCLUSIONS: It is concluded that binding of an antibody against AA 1-35 on GPIbalpha reflects changes in GPIbalpha that make PLTs targets for phagocytosis by macrophages.

Platelet binding and phagocytosis by macrophages.

BACKGROUND: Earlier it was reported that metabolic arrest followed by incubation at 4 degrees C reduces the platelet (PLT) storage defect. Here it is reported that this treatment also reduces binding and phagocytosis by macrophages. STUDY DESIGN AND METHODS: Phagocytosis of mepacrine-labeled PLTs by macrophages changes the latter into bright fluorescent particles easily detected by fluorescence-activated cell sorting. RESULTS: In combination with conventional binding analysis it was found that binding to phorbol 12-myristate 13-acetate-matured THP-1 cells is primarily regulated by PLT P-selectin expression and phagocytosis by combined phosphatidylserine (PS) exposure and glycoprotein (GP) Ibalpha clustering. It was found that trapping of PLT Ca2+ and raising cAMP reduces phagocytosis by lowering PS exposure. Chilling of PLTs leads to an increase in binding and PS- and GPIbalpha-mediated phagocytosis. Prior depletion of PLT energy stores prevents this increase by preserving low Ca2+ concentration, PS exposure, and PS-mediated phagocytosis. CONCLUSION: These data characterize the individual factors that control PLT binding and phagocytosis and might help to define conditions that improve the survival of stored PLTs after transfusion.