Fresh-frozen plasma, pathogen-reduced single-donor plasma or bio-pharmaceutical plasma?

Three types of therapeutic plasma are available that differ in their manufacturing processes, composition, clinical efficacy, and side effects. Quarantine-stored, not pathogen-reduced fresh-frozen plasma (QFFP) is prepared from single whole blood or plasma donations. The manufacture of pathogen-reduced single-donor plasmas such as methylene blue-light treated (MLP) or amotosalen-ultraviolet light treated plasma (ALP) involves the addition of a chemical followed by irradiation and subsequent removal of the chemical. Both plasma types show substantial fluctuation of clotting factor and inhibitor levels according to interindividual variations, and both carry the risk of inducing transfusion-associated lung injury (TRALI). Photo-oxidation in pathogen-reduced single-donor plasmas reduces clottable fibrinogen and other clotting factors markedly, and there is a lack of clear evidence showing whether this is harmful or not. MLP also appears to be less effective clinically than QFFP. Like clotting factor or inhibitor concentrates, solvent/detergent-treated plasmas (SDP) are bio-pharmaceutical preparations derived from large plasma pools, and variations in plasma protein levels from batch-to-batch are for that reason low. The SD manufacturing process inevitably involves a considerable reduction of plasmin inhibitor (PI), and moderate reduction of all other clotting factors and inhibitors in the final plasma bags. Clinical studies and broad clinical use have however shown that this does not significantly reduce clinical efficacy or increase adverse events. SDPs obviously do not induce TRALI and the risk of allergic reactions is significantly lower than for QFFP. Common to all three plasma types is that the time between donation and freezing the plasma, and whether plasma from whole blood or apheresis plasma is used as starting material, are decisive determinants for the clotting factor and inhibitor potencies in the final bags. Plasma frozen 3-6h after donation, and apheresis plasma, contain markedly greater amounts of clotting factors and inhibitors than plasma frozen 15-24h after collection or plasma from whole blood. Lyophilisation and the pooling of single-donor plasma units with ABO blood group in suitable proportions (Uniplas) facilitate SDP handling and logistics without loss of clinical efficacy. SDP is obviously at least as cost-effective as QFFP if non-infectious adverse events including TRALI are taken into account, at least in younger patients and patients with good prognosis.     

Partial plasma protein replacement in therapeutic plasma exchange

We wished to determine whether subtotal replacement of protein in plasma removed at plasma exchange would be adequate to prevent hypovolemia and hypoproteinemia. Seven well nourished outpatients with chronic progressive multiple sclerosis underwent 60 plasma exchanges in which two liters of plasma were replaced with 750 ml saline followed by 1250 ml of a 5% albumin solution (62.5% albumin replacement). Total serum protein, protein electrophoresis, and immunoglobulin levels were measured before and after each exchange. Clinically, the exchanges were well tolerated. Total serum protein dropped by a mean of only 18% during the study and mean preexchange serum albumin levels were unchanged, even though immunoglobulins decreased by 57–72%. We conclude that in well nourished patients, partial albumin replacement of this magnitude is an adequate substitute for plasma removed in a plasma exchange.     

Range of fractionated plasma products to optimize plasma resources

<正>HUMAN PLASMA is a source material that is crucial for the production of unique therapeutic fractionated products.Indeed,plasma contains hundreds of proteins ensuring many physiological functions.The most abundant proteins,albumin and immunoglobulin G (IgG),are present at about 35 and 10 g/L,respectively,representing about 80% of all plasma proteins.However,other important therapeutic proteins include the coagulation factors (factor Ⅷ (FⅧ); FⅨ; Von Willebrand Factor (VWF),fibrinogen) various protease inhibitors (alpha 1-antitrypsin; antithrombin; C1-esterase) and anticoagulants (protein C) which exhibit potent physiological activity.Currently over 10 different protein therapeutics can be extracted from plasma to treat life-threatening diseases or injuries associated to bleeding and thrombotic disorders,immunological diseases,infectious conditions as well as tissue degenerating diseases,thus addressing the clinical needs of many patients.Considering that plasma is a very valuable resources available in limited supply at national levels,it is important,for ethical,medical,and economical reasons,to optimize its use by producing,at satisfactory yields,an appropriate range of safe products meeting the needs of patients.     

Dissemination of contact activation in plasma by plasma kallikrein

The dissemination of contact activation of plasma was examined by measuring the cleavage of Hageman factor (HF) molecules on two separate sets of kaolin particles, one of which contained all of the components of the contact activation system, HF, prekallikrein (PK) and high molecular weight kininogen (HMWK) in whole normal plasma, and the second set of particles containing only HF and HMWK, being prepared with PK-deficient plasma. After mixing of the particles, cleavage of HF on the second set of particles occurred at a rate similar to that occurring on the first set of particles. This indicated that rapid dissemination and burst of activity of the contact reaction takes place in fluid phase. A supernatant factor, responsibel for the dissemination of the contact reaction, was identified as kallikrein. A rapid appearance of cleaved PK (kallikrein) and HMWK on both the kaolin surface and in the supernate was observed. Within 40 s, > 70-80% of the PK and HMWK in the supernate was cleaved. On the surface, approximately 70% of each radiolabeled protein was cleaved at the earliest measurement. Cleavage of PK by activated HF occurred at least 17 times faster on the surface than in the fluid phase, as virtually no cleavage of PK occurred in fluid phase. Each molecule of surface-bound, activated HF was calculated to cleave at a minimum, 20 molecules of PK per minute. It is concluded that the contact activaton of plasma may be divided into three phases: (a) the reciprocal activation of a few molecules of zymogen HF and PK on the surface, with HMWK acting as cofactor to bring these molecules into apposition; (b) the rapid release of kallikrein into the fluid phase and the continued conversion of PK to kallikrein by each surface-bound molecule of activated HF; and (c) the activation by fluid-phase kallikrein of multiple surface-bound HF molecules, and the cleavage of multiple molecules of MHWK both in fluid phase and on the surface by the soluble kallikrein. The evidence suggests that steps b and c account for a great majority of the generation of contact activation of plasma.     

Modern plasma fractionation

Protein products fractionated from human plasma are an essential class of therapeutics used, often as the only available option, in the prevention, management, and treatment of life-threatening conditions resulting from trauma, congenital deficiencies, immunologic disorders, or infections. Modern plasma product production technology remains largely based on the ethanol fractionation process, but much has evolved in the last few years to improve product purity, to enhance the recovery of immunoglobulin G, and to isolate new plasma proteins, such as alpha1-protease inhibitor, von Willebrand factor, and protein C. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risk associated to plasma products is the transmission of blood-borne infectious agents. A complete set of measures--and, most particularly, the use of dedicated viral inactivation and removal treatments--has been implemented throughout the production chain of fractionated plasma products over the last 20 years to ensure optimal safety, in particular, and not exclusively, against HIV, hepatitis B virus, and hepatitis C virus. In this review, we summarize the practices of the modern plasma fractionation industry from the collection of the raw plasma material to the industrial manufacture of fractionated products. We describe the quality requirements of plasma for fractionation and the various treatments applied for the inactivation and removal of blood-borne infectious agents and provide examples of methods used for the purification of the various classes of plasma protein therapies. We also highlight aspects of the good manufacturing practices and the regulatory environment that govern the whole chain of production. In a regulated and professional environment, fractionated plasma products manufactured by modern processes are certainly among the lowest-risk therapeutic biological products in use today.     

Effects of replacement fluids used for therapeutic plasma exchange on plasma viscosity and plasma oncotic pressure.

INTRODUCTION: Apheresis is a procedure in which one of the components of blood is removed. The aim of therapeutic plasma exchange (TPE) is to remove a large fraction of the patient's plasma from the body, and to exchange this with replacement solutions using automatic devices. With this procedure circulating pathogens and toxins are reduced. Before each TPE results of a baseline basal complete blood count, serum protein electrophoresis, coagulation tests and serum electrolytes must be known. The efficacy of this therapy is assessed only by these values. The proteins responsible for disease may be monoclonal proteins, cryoglobulins, lipoproteins, auto or allo antibodies or toxins. In this study, we aimed to compare the effects of several replacement fluids on plasma viscosity and oncotic pressure. At the same time, we evaluated the correlation between plasma viscosity and oncotic pressure. MATERIAL AND METHODS: 111 TPE were performed on 42 patients. Before TPE, the patients whose veins were not suitable were catheterised either by using a subclavian or jugular 11F dialysis catheter. At each session, approximately 1-1.5L of plasma was exchanged. The procedure was performed with albumin in patients whose albumin was under 3gr/dl. Over this value, the exchange fluids were randomised. RESULTS: When the overall results were analysed, there was no statistically significant difference between groups 1 (HES+albumin) and group 3 (albumin). The statistical difference between group 2 and 3 was significant, but no difference was observed between group 1 and 2. According to the decreasing plasma viscosity, there was a significant difference between group 2 and group 3, but there was no difference between group 1 and group 2. CONCLUSIONS: The replacement solutions used for plasmapheresis are similar when compared for hemorheologic effects, but we have chosen fresh frozen plasma because of fewer side effects.     

Selective plasma exchange

Selective plasma exchange (SePE) is a new modality of simple plasma exchange that uses a selective membrane plasma separator Evacure EC-4A10 (EC-4A) (Kawasumi Laboratories Inc., Tokyo, Japan). EC-4A has a relatively small pore size of 0.03 μm, which is around one-tenth that of conventional plasma separators. The sieving coefficients of albumin, immunoglobulin G (IgG), factor XIII (FXIII), and fibrinogen using EC-4A have been shown to be 0.73, 0.5, 0.17, and 0, respectively. Therefore, one session of SePE can remove approximately 50% of IgG regardless of the IgG subclasses while retaining coagulation factors, such as FXIII and fibrinogen. SePE may lower the risk of bleeding when compared with other plasmapheresis modalities. SePE cannot remove large molecular substances, including IgM. When only IgG is targeted by plasmapheresis, SePE is a useful and safe option. When various immunoglobulins are targeted by plasmapheresis, PE can be combined with SePE, which results in both the unspecific removal of pathogens by PE and the retention of coagulation factors by SePE. Careful selection of the modality is important, and when necessary, appropriate plasmapheresis modalities should be combined on the basis of the characteristics and removal kinetics of the pathogenic substances.     

The concentration of plasma fibronectin in burns patients treated with fresh frozen plasma or plasma protein fraction

A group of 10 patients with 30-70% burns were given intravenous infusions during the first 48 h following hospital admission either with fresh frozen plasma (FFP) or human plasma protein fraction ( HPPF ). FFP contained 300-400 mg/dl plasma fibronectin whereas none was detectable in HPPF . Circulating plasma fibronectin levels fell quickly in those patients receiving HPPF and levels remained low for 2-3 weeks. In those receiving FFP, plasma fibronectin remained normal during the 48-h transfusion period but fell subsequently. Fibronectin may be an important determinant in the resistance to shock and infections. Consideration should therefore be given to the use of blood products which contain fibronectin and to the monitoring of plasma levels both during the acute and recovery periods after burn injury.     

Therapeutic plasma exchange

The improvement in design and biocompatibility of continuous renal replacement therapy equipment has made it possible to perform therapeutic plasma exchange (TPE) in the intensive care unit. The purpose of this article is to outline the general principles of apheresis, including a historical perspective, current indications, and complications. Replacement fluid, membrane filtration, anticoagulation, and vascular access will be presented. A summary of the nursing care associated with TPE, potential complications, and methods to reduce the risk of their occurrence are summarized.