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Aahi- Asociación Argentina de Hemoterapia e Inmunohematología

Aahi- Asociación Argentina de Hemoterapia e Inmunohematología

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    Aahi- Asociación Argentina de Hemoterapia e Inmunohematología

    bueno, aca les dejo la pagina de la asociacion, ya muchos la deben conocer, y ademas les dejo dos boletines muy interesantes, uno sobre sangre autologa y otro sobre hepatitis C

    www.aahi.org.ar


    Hoy puede ser un gran dia planteatelo asi, aprovecharlo o que pase de largo depende en parte de ti....
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    Plasma derivatives and recombinant DNA-produced coagulation factors

    Arthur J Silvergleid, MD

    UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.2 is current through April 2007; this topic was last changed on June 13, 2006. The next version of UpToDate (15.3) will be released in October 2007.
    INTRODUCTION — Plasma derivatives are products manufactured from human plasma by plasma fractionation techniques. Although dozens of proteins can be so purified, some are considered orphan drugs, and many are not widely used or available. The most commonly used plasma derivatives, including those manufactured using recombinant DNA techniques, will be discussed here (eg, immune globulins, coagulation proteins, and protease inhibitors, show table 1).
    The use of plasma "components" (ie, those prepared by differential centrifugation techniques, including fresh frozen plasma and cryoprecipitate) is discussed separately. (See "Preparation of blood components" and see "Transfusion of plasma components").
    Fibrin sealant (fibrin "glue"), a two-component system in which a solution of concentrated fibrinogen and factor XIII is combined with a solution of thrombin and calcium in order to form a coagulum, is discussed separately. (See "Fibrin sealant").
    HISTORY AND METHODOLOGY — During World War I surgeons developed a better understanding of shock when organ failure resulted from large volume blood loss, and by the late 1930s methods for freeze-drying plasma had been developed. The use of such plasma required mixing, under battlefield conditions, with sterile water, a time-consuming process. In addition, pooled, freeze-dried plasma frequently transmitted serum hepatitis.
    The development of plasma fractionation took place under the pressure of devising products for the treatment of war casualties in the early 1940s. Harvard biochemist Edwin J. Cohn and a team of scientists developed what became known as the Cohn plasma fractionation process [1] . Dr. Cohn and his team prepared plasma from Red Cross blood donations in Boston, separated the plasma at the Massachusetts Public Health Laboratory and took the raw material to their laboratories. By various trials, they devised methods for separating plasma proteins that remain the mainstay of plasma fractionation today, publishing their work in 1950 [2] .
    The Cohn process, also known as cold ethanol fractionation, uses five variables to obtain differential solubility of plasma proteins in mixtures of ethanol and water, including [3] :
    • <LI class=MsoNormal style="mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l3 level1 lfo1">ethanol concentrations from 8 to 40 percent <LI class=MsoNormal style="mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l3 level1 lfo1">pH between 4.5 and 7.4 <LI class=MsoNormal style="mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l3 level1 lfo1">temperatures from 0ºC to -6ºC <LI class=MsoNormal style="mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l3 level1 lfo1">ionic strength differentials of 0.14 to 0.01
    • protein concentrations ranging from 5.1 to 0.8 percent
    Additional methods for purifying certain proteins involve ion exchange, immune affinity chromatography, and other separation techniques, but modifications of the original cold ethanol process remain the mainstay for the production of plasma derivatives.
    ALBUMIN — Human serum albumin became the mainstay of the treatment of shock on the battlefield and in the emergency department for decades and is still in widespread use, although, for reasons of efficacy and expense, non-plasma-derived crystalloids (eg, saline, Ringer's solution) and colloids (eg, hydroxyethyl starch, dextran) have generally supplanted albumin for the primary treatment of hypovolemic shock (see "Indications" below).
    Available preparations — Human serum albumin is available in both 5 and 25 percent solutions, the former being isosmotic with plasma. Both have been pasteurized and do not transmit any known infectious diseases [4] . The 25 percent albumin solution should never be used for shock alone without other fluid volume replacement, since the hyperosmotic 25 percent solution will draw fluids from the extravascular space into the vascular space.
    The 25 percent solution is sometimes diluted by pharmacies or nursing staff to a volume of 250 mL of 5 percent solution from its original 50 mL volume. This must be done only with normal saline. A number of cases of hemolysis in patients undergoing therapeutic plasmapheresis due to dilution of 25 percent albumin with sterile water have been reported. At least one death and five cases of acute renal insufficiency were attributed to this practice, which results in a solution whose osmolarity is approximately one-fifth that of plasma [5] .
    Plasma protein fraction — The product called "plasma protein fraction" contains primarily albumin (about 90 percent) and is somewhat cheaper to prepare than albumin. It is available in 5 percent solutions and contains some globulins as well as albumin. Prekallikrein activation, with attendant development of anaphylactic shock, caused some problems many years ago, but the manufacturing process now removes these proteins. The indications for use of plasma protein fraction are similar to those for albumin.
    Indications — The major indications for use of albumin include the following:
    • Plasma volume expansion and maintenance of cardiac output in shock. However, a well-conducted randomized study has shown that, for intensive care unit patients, 28-day mortality and other clinical outcomes did not differ following fluid resuscitation with albumin versus saline solutions [6] . (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on Choice of replacement fluid).
    • Albumin and fresh frozen plasma are the principal replacement fluids for therapeutic plasma exchange and/or plasmapheresis. (See "Prescription and technique of therapeutic plasma exchange", section on Replacement fluids).
    Albumin may be of value in the following situations:
    • As an adjunct to large volume paracentesis in the treatment of diuretic-resistant ascites in cirrhosis. (See "Treatment of diuretic-resistant ascites in patients with cirrhosis", section on colloid replacement).
    • For the prevention of ovarian hyperstimulation syndrome. (See "Prevention of ovarian hyperstimulation syndrome", section on Intravenous albumin).
    • Treatment of the hepatorenal syndrome [7] . (See "Diagnosis and treatment of hepatorenal syndrome", section on Medical therapy).
    Use of albumin solutions for nutritional supplementation is no longer an appropriate indication for this product. (See "Overview of parenteral and enteral nutrition"). Its value in pancreatitis, severe burns, the edema of nephrotic syndrome, and acute respiratory distress syndrome is unproven (see appropriate topic reviews).
    IMMUNE GLOBULINS — The original Cohn fractionation process precipitates immune globulins (and some coagulation factors) in fractions II and III, from which relatively pure concentrations of (primarily) IgG can be produced.
    Intramuscular immune serum globulinImmune serum globulin (ISG) is a 16 percent solution of immune globulins prepared for intramuscular injection, which contains, due to the large pool size of the plasma being fractionated, protective titers of antibodies to numerous infective agents, including hepatitis A and B viruses. ISG must be solvent/detergent treated, since cases of hepatitis C virus (HCV) transmission were noted in some preparations made by this process. (See "Transfusion of Plasma Components", section on Solvent- detergent method).
    ISG remains a mainstay for the prevention of hepatitis A in outbreaks, for the military and for travelers to regions endemic for hepatitis A. (See "Hepatitis A virus vaccination and postexposure prophylaxis", section on Postexposure prophylaxis). Since there is a higher demand for intravenous immune globulin preparations, many concerns no longer manufacture the intramuscular form, and it is currently in short supply.
    Intravenous immune globulinIntravenous immune globulin (IGIV, IVIG) is prepared as a 5 or 6 percent solution and has revolutionized the treatment of primary and acquired hypogammaglobulinemia in children and adults. It is also widely used for the treatment of refractory ITP, Kawasaki syndrome, and a variety of other conditions. (See "General principles of the use of intravenous immune globulin" and see "Use of intravenous immune globulin in hematologic disorders" and see "Use of immune globulin in primary immunodeficiency").
    Hyperimmune globulins — Hyperimmune globulins, prepared primarily for intramuscular use, but in some instances for use intravenously, are made by selecting plasma with high titers of the desired antibody or by specifically immunizing donors to produce such antibodies. Hyperimmune globulins are available for temporary, passive immunization against hepatitis B (HBIG), cytomegalovirus (CMVIG), varicella zoster (VZIG), respiratory syncytial virus (RSVIG), Rho (D), rabies, pertussis, vaccinia, and botulinum toxin (show table 1). It is theoretically possible to produce a hyperimmune globulin to any organism which can safely be used to immunize humans.
    Although recombinant DNA techniques have supplanted coagulation factor production from human plasma, at least for factors VII, VIII and IX, such techniques will not soon replace immune globulins from human sources, given the variety of proteins needed to be made to replicate the protective effect of human immune globulins against a wide variety of human infectious diseases.
    COAGULATION FACTORS
    Fibrinogen — The first cold-ethanol precipitated fraction from the Cohn process contains high concentrations of fibrinogen. Freeze-dried fibrinogen from this source was widely used for two decades, primarily for treating the hypofibrinogenemia associated with the "consumption" coagulopathies, especially those seen in obstetrics. However, hepatitis B virus co-precipitates with fibrinogen in this process. Accordingly, large-pool fibrinogen concentrates are no longer made in the United States using this methodology.
    Cryoprecipitate is the current source for fibrinogen replacement. (See "Transfusion of plasma components", section on Cryoprecipitate).
    Prothrombin complex concentrates — The discovery of cryoprecipitate in 1964 thoroughly revolutionized the treatment of hemophilia [8] . (See "Preparation of blood components", section on Cryoprecipitate). A decade later, using the cryoprecipitated fraction of large plasma pools as starting material, several processes for isolating and purifying factor VIII were developed, along with concentrates of the prothrombin complex of proteins, factors II,VII, IX, and X. Subsequent ability to purify factor IX from the prothrombin complex led to an improved source of factor IX for the treatment of hemophilia B.
    Since varying degrees of activation of factor X, the critical protein in the common pathway of the coagulation cascade, occur during isolation of the prothrombin complex, such concentrates can be used to bypass the intrinsic pathway of the coagulation process and be used to treat patients with inhibitors of factor VIII, as can recombinant DNA factor VIIa (show figure 1). (See "Overview of hemostasis").
    However, prior to purification of factor IX, many patients suffered significant morbidity or mortality from excessive clotting (eg, disseminated intravascular coagulation, deep vein thrombosis, pulmonary embolus, myocardial infarction) generated by the presence of activated factors in prothrombin complex concentrates. The risk of thrombosis using this product appears to be especially high in patients receiving high or multiple doses as well as those with liver disease who are unable to adequately clear these activated products from the circulation. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on Prothrombin complex concentrates and activated prothrombin complex concentrates).
    Activated prothrombin complex concentrates — Several products (Autoplex® T, Feiba VH Immuno® [factor eight inhibitor bypassing activity]) are available in which components of the prothrombin complex have been purposefully activated during the fractionation process. These products are intended for use in bleeding patients with circulating inhibitors, although controlled trials have shown variable improvement over standard prothrombin complex concentrates. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on Prothrombin complex concentrates and activated prothrombin complex concentrates).
    Factor VIII and IX concentrates — Purification of factor VIII using glycine or polyethylene glycol yielded concentrates of increased purity. Using immunoaffinity chromatography very high purity concentrates of factors VIII and IX can be prepared and S/D treated to remove infectivity from HBV, HCV, and HIV. These S/D processes do not kill HAV, however, and an outbreak of hepatitis A related to the use of a Factor IX concentrate has been reported [9] .
    Currently, one factor VIII (AHF) concentrate available for use in the United States (Humate P™) is known to contain large von Willebrand factor multimers. It is labeled with ristocetin cofactor activity units. Newer products, such as recombinant von Willebrand factor, are in clinical trials. (See "Treatment of von Willebrand disease", section on Replacement therapy with vWF).
    Porcine factor VIII — Porcine factor VIII concentrates (Hyate:C®, Speywood) are manufactured from porcine plasma, using methodologies similar to those used for isolation of factor VIII from human plasma. This product is used in patients with a high titer of antibodies to human factor VIII, which either do not cross-react, or which minimally cross-react, with the porcine factor VIII molecule. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on Porcine factor VIII concentrates).
    Protein C concentrate — A protein C concentrate is available in the United States and Canada on a compassionate use basis for the treatment of homozygous protein C deficiency. It is in extremely short supply, and is therefore mostly used in infants and small children. (See "Protein C deficiency", section on Warfarin-induced skin necrosis).
    Viral inactivation and risks of pooled plasma — A major public health concern regarding plasma derivatives is the source of the plasma used for further manufacture, a corollary of which is the size (number of donor units) of the batch of plasma pooled for fractionation. Some argue that current viral inactivation procedures (see below) render the plasma source irrelevant. Most authorities agree that adherence to strict standards of donor recruitment and donor screening are still necessary for safety. (See "Blood donor medical history" and see "Laboratory testing of donated blood" and see "Procedures used for blood donor screening: Protection of potential blood donors and recipients").
    Plasma pools in industry currently range from 500 to 10,000 liters. Each liter of plasma represents about four units of plasma from four whole blood donations, or about 1.7 donations of source plasma (600 mL donation size) from plasmapheresis donors. Thus, several thousand individual units of plasma, containing the personal infectious disease history of each donor in the form of antibodies (and sometimes infectio us particles), are pooled into one vat for fractionation. It is clear that healthy, honest, well-motivated donors are key to the safety of such products. Such was not always the case. (See "Procedures used for blood donor screening: Protection of potential blood donors and recipients", section on Predonation screening).
    Viral inactivation methods reduce/kill viruses in log ratios, not absolutely; these methods affect only lipid-enveloped viruses, and no known sterilization procedure usable with human plasma has any effects on prions such as are associated with Creutzfeldt-Jakob disease (CJD). There is no evidence that CJD can be transmitted by transfusion of blood, its components or derivatives, and considerable evidence to the contrary. However, having been reassured about acquired immune deficiency and clotting factors in the early 1980's, the hemophilia community, and many governmental regulators, have no trust in the pronouncements of science with regard to CJD transmission. Accordingly, current and proposed FDA regulations bar from donation anyone who might have contracted the disease while living in areas in which such infections have been reported. (See "Blood donor medical history", section on Creutzfeldt-Jakob disease).
    The S/D method of viral inactivation has a good safety record, and manufacturers consistently are required to document efficacy. However, if viral inactivation techniques reduce a target virus by five logs (ie, to 0.001 percent of the starting concentration) it is still mathematically possible that the inadvertent inclusion of one or more high titered infectious units of plasma could render the product infectious.
    In addition to HAV, a non-lipid enveloped virus, parvovirus B19 is also not affected by current viral inactivation methods. Parvovirus B19 has been related to aplastic crises in transfused patients with chronic hemolysis and to spontaneous abortion. (See "Transfusion of plasma components", section on Viral inactivation of FFP).
    Continuing health concerns — Although clinical use of human-derived coagulation factors is considered far less risky than in the past, members of the hemophilia community (patients, families, and care providers) are acutely aware of the tragedy of HIV infection that has occurred following their use. Since human derived plasma products cannot be said to be without any risk, the preferred treatment for hemophilia A and B now consists of the use of recombinant DNA-produced coagulation factors, although at a higher cost. (See "Treatment of hemophilia", section on Replacement therapy).
    Even with requirements for PCR testing now being implemented for plasma products, one can see that there remains a level of scientific concern about what the next unknown intruder into the plasma fractionation system might be, and how we would recognize it in time [10] . In this regard, our hemophilia patients, in particular, are at risk. This is why recombinant DNA techniques, the production in transgenic animals of coagulation factors in (and isolation from) maternal milk, and the use of cloning techniques to produce biologically active proteins for human medicine have become important.
    RECOMBINANT COAGULATION PRODUCTS
    Factors VIII and IX — A major step towards reducing the risk (but substantially increasing the cost) of hemophilia treatment occurred with the cloning of the gene for, and subsequent expression of the protein, antihemophilic factor, factor VIII. Successful products, now with proven safety and efficacy records, have been made by two manufacturers [11,12] . A recombinant Factor IX has also been produced for the treatment of hemophilia B [13] . (See "Treatment of hemophilia", sections on Recombinant human factor VIII and Recombinant factor IX).
    Initial studies led to some concerns that these highly purified, highly specific proteins would lead to an increase in the development of antibodies to coagulation factors, which currently are seen in about 15 percent of patients using human plasma-derived Factor VIII. Although antibody development is somewhat more frequent, in the range of 25 percent, the antibodies do not have the inhibitory effect seen previously, and do not necessarily increase in titer with repeated use. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on Incidence).
    Factor VIIa — A recombinant DNA-produced activated factor VII (VIIa) is commercially available (Novo-Seven®). Its FDA-approved indication in the United States is for bypassing inhibitors to factors VIII and IX in patients with hemophilia A and B, respectively. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on Recombinant human factor VIIa). This product is currently licensed in Europe for the above indications as well as for treatment of congenital factor VII deficiency and Glanzmann's thrombasthenia [14] .
    Clinical use of this product, including "off-label" uses, is discussed separately. (See "Clinical uses of recombinant coagulation factor VIIa").
    Activated protein C — Activated protein C has both anticoagulant, as well as anti-inflammatory activity. An activated, recombinant form of protein C is commercially available (Xigris™, drotrecogin alfa) for reduction of mortality from severe sepsis associated with organ dysfunction in adults at high risk of death (eg, APACHE II score 25). (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults", section on Activated protein C and see "Management of severe sepsis and septic shock in adults", section on Recombinant human activated protein C).
    Potential risks — Recombinant products, manufactured from non-human living cells (eg, Chinese hamster ovary cells), may eventually pose different risks from those noted with plasma derivatives, although none are yet recognized. As an example, it is theoretically possible that a mutant virus, with an affinity for Chinese hamster ovary cells, could cause problems for future generations of patients receiving these products.
    PROTEASE INHIBITORS — Human plasma contains a variety of protease inhibitors designed to inhibit, or modulate, the activation of coagulation, fibrinolysis, complement activation, and other functions. Three protease inhibitors isolated from human plasma are commercially available and have important clinical applications. These include antithrombin (AT), C1-esterase inhibitor, and alpha-1-antitrypsin.
    AntithrombinAntithrombin (AT, Thrombate III, formerly called antithrombin III) is a major inhibitor of thrombin and of activated Factor X (Xa), and also has an effect on activated Factors IX and XI. It has a strong affinity for heparin, which enhances its anticoagulant effects. There are heritable deficiencies of AT leading to thrombotic tendencies, as well as acquired deficits such as disseminated intravascular coagulation [15] . (See "Antithrombin (ATIII) deficiency" and see "Management of inherited thrombophilia", section on Antithrombin deficiency).
    A human recombinant antithrombin has been developed using transgenic technology [16] . It has been successfully employed in five patients with antithrombin deficiency undergoing surgical procedures.
    C1-esterase inhibitor — C1-esterase inhibitor limits the activity of C1-esterase on complement activation; a deficiency of this factor is associated with hereditary angioneurotic edema. The transfusion of C1-esterase inhibitor (or fresh frozen plasma) is effective for the emergency treatment of glottal edema [17] . (See "Inherited and acquired disorders of the complement system", section on C1 inhibitor deficiency and see "An overview of angioedema", section on Treatment).
    Alpha-1-antitrypsin — Alpha-1-antitrypsin prepared from human plasma (Prolastin) has been used to treat the autosomal defect characterized by an increased risk for emphysema [18] and is currently available in the United States. (See "Clinical manifestations, diagnosis, and natural history of alpha-1-antitrypsin deficiency" and see "Treatment of alpha-1-antitrypsin deficiency").

    Use of UpToDate is subject to the Subscription and License Agreement.
    REFERENCES
    1. Starr, D. Again and again in World War II, blood made the difference. The Smithsonian Magazine, Washington DC, March 1995. p.124.
    2. Cohn, EJ, Gurd, FRN, Surgenor, DM, et al. A system for the separation of the components of human blood. Qualitative procedures for the separation of the protein components of human plasma. J Am Chem Soc 1950; 72:465.
    3. Van Aken, WG. Preparation of plasma derivatives. In: Principles of Transfusion Medicine, 2nd edition, Rossi, EC, Simon, TL, Moss, GS, Gould, SA (Eds). Williams and Wilkins, Baltimore 1996. p.403.
    4. Blumel, J, Schmidt, I, Willkommen, H, Lower, J. Inactivation of parvovirus B19 during pasteurization of human serum albumin. Transfusion 2002; 42:1011.
    5. Hemolysis associated with 25% human albumin diluted with sterile water--United States, 1994-1998. MMWR Morb Mortal Wkly Rep 1999; 48:157.
    6. Finfer, S, Bellomo, R, Boyce, N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247.
    7. Arroyo, V, Guevara, M, Gines, P. Hepatorenal syndrome in cirrhosis: Pathogenesis and treatment. Gastroenterology 2002; 122:1658.
    8. Pool, JG, Gershgold, EJ, Pappenhagen, AR. High-potency antihaemophilic factor concentrate prepared from cryoglobulin precipate. Nature 1964; 203:312.
    9. Hepatitis A among persons with hemophilia who received clotting factor concentrate--United States, September-December 1995. MMWR Morb Mortal Wkly Rep 1996; 45:29.
    10. Ludlam, CA, Powderly, WG, Bozzette, S, et al. Clinical perspectives of emerging pathogens in bleeding disorders. Lancet 2006; 367:252.
    11. Lusher, JM, Arkin, S, Abidgaard, CF, et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy and development of inhibitors. N Engl J Med 1993; 328:453.
    12. Gomperts, E. Recombinate study. Ann Hematol 1994; 68 Suppl 3:S51.
    13. White GC, 2nd, Beebe, A, Nielsen, B. Recombinant factor IX. Thromb Haemost 1997; 78:261.
    14. Kessler, C. Haemostasis.com: clinical experiences in the investigational use of rFVIIa in the management of severe haemorrhage. Br J Haematol 2004; 127:230.
    15. Menache, D. Replacement therapy in patients with hereditary antithrombin III deficiency. Semin Hematol 1991; 28:31.
    16. Konkle, BA, Bauer, KA, Weinstein, R, et al. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion 2003; 43:390.
    17. Vogelaar, EF, Brummelhuis, HG, Krijnen, HW. Contributions to the optimal use of human blood. 3. Large-scale preparation of human c1 esterase inhibitor concentrate for clinical use. Vox Sang 1974; 26:118.
    18. Wewers, T, Casolaro, MA, Sellers, SE, et al. Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316:1055.
    Hoy puede ser un gran dia planteatelo asi, aprovecharlo o que pase de largo depende en parte de ti....

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