Page 1987 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 116 Preparation of Plasma-Derived and Recombinant Human Plasma Proteins 1761

above, intramuscular and later IV injection became the preferred
Albumin and Plasma Protein Fraction methods. Recently, however, two immune globulin concentrates for
subcutaneous injection have been marketed, Hizentra and HyQvia.
Albumin remains one of the major products of human plasma frac- HyQvia is also formulated with recombinant hyaluronidase to
tionation. Literally tons of albumin have been isolated and millions improve dispersion and absorption of the immune globulins in
of units have been infused. Albumin, recovered in very pure form subcutaneous infusion. These products are intended for patients who
in fraction V, is pasteurized in the final vial for 10 hours at 60°C have problems with IV infusion.
with sodium acetyltryptophanate and sodium caprylate added as
stabilizers.
Albumin is a commodity product, with little to distinguish one COAGULATION FACTOR CONCENTRATES
manufacturer’s product from another’s. There are small differences in
purity, but those are only clinically relevant in rare cases. Three Transfusion of whole blood was shown in the mid-1800s to curtail
albumin products are manufactured in the United States: albumin bleeding in patients with hemophilia, and by 1940, bleeding episodes
(human) 25% solution, albumin (human) 5% solution, and plasma were being routinely treated with plasma. However, large amounts of
protein fraction (human) or PPF. In albumin (human), more than plasma were needed, and this method of therapy could not provide
96% of the protein content must be albumin. PPF, obtained by normal levels of coagulation factors without producing hypervolemia.
coprecipitating fraction IV-4 with fraction V, has a lower purity of The development of more highly purified plasma-derived coagulation
greater than 83% albumin. PPF is more economical to produce than factor concentrates and more recently of recombinant concentrates
albumin, but the rapid infusion of PPF has been associated with has resulted in dramatic increases in the quality of life and life
hypotensive episodes. expectancy for patients with hemophilia. Hemophilia treatment is a
large market, and the development of improved coagulation factor
concentrates continues to be a major focus of research.
Immune Globulins and Hyperimmune Globulins

Since the early 1950s, immune globulin products have been prepared Factor VIII Concentrates
from Cohn fraction II + III by the method developed by Oncley, a
collaborator of Cohn. The Oncley process uses additional ethanol Factor VIII is the protein that is missing or defective in patients with
precipitations to remove lipoproteins, immunoglobulins A and M hemophilia A. Factor VIII concentrates, generically termed antihemo-
(IgA and IgM), and other plasma proteins, leaving fraction II, which philic factor (human) or AHF, for the treatment of hemophilia A have
contains purified immunoglobulin G (IgG). Whereas immune globu- evolved from cryoprecipitates to very high-purity plasma-derived
lin is prepared from the plasma of unselected normal donors, products to recombinant products. The various AHF concentrates
hyperimmune globulins are prepared from the plasma of donors with available in the United States are listed in Table 116.3.
high antibody titers against specific antigens [e.g., rho(D), hepatitis
B, rabies, and tetanus]. These donors may be identified during con-
valescent periods after infection or transfusion, or they may be specifi- Cryoprecipitate
cally immunized to produce the desired antibodies. The immune
globulin products are listed in Tables 116.1 and 116.2. In a landmark discovery for hemophilia A treatment, cryoprecipitate
was discovered in the mid-1950s to contain much of the factor VIII
activity of the original plasma. By 1965, single-donor cryoprecipitate
Intravenous Immune Globulin Concentrates with factor VIII concentrations five to 30 times that of plasma
became widely available for use in the treatment of patients with
The original immune globulin concentrates, initially termed immune hemophilia A. Single-donor cryoprecipitate is still available from
serum globulin and currently immune globulin (human), were admin- many blood banks but does carry a risk of viral transmission.
istered by the intramuscular route, with the associated problems of
limited injectable volume, poor bioavailability, and discomfort at the
injection site. Intravenous (IV) injection of immune globulin Intermediate- and High-Purity Antihemophilic
(human) causes serious clinical reactions, which are attributed to Factor Concentrates
complement-activating aggregates in these products.
To overcome these limitations, immune globulin intravenous The development of AHF concentrates purified approximately 3000-
(human) (IGIV) products were developed using a variety of methods fold over plasma was the next significant advance in the treatment of
to remove or inactivate anticomplementary aggregates. Today most hemophilia A. Cryoprecipitate was used as the starting material, and
intramuscular immune globulin usage is limited to hyperimmune a variety of methods were developed to remove fibrinogen, immuno-
products. Although immune globulin products tend to be self- globulins, and other contaminating proteins. These were the mainstay
protecting from viral transmission because of the large pools of of hemophilia A treatment for many years and are still available, their
antibodies they contain, infections have occurred, and as a result all chief advantage being lower cost. Some of these products are also
manufacturers have incorporated viral inactivation or removal steps indicated as a source of vWF, which circulates in a complex with
in their production processes. factor VIII. Products purified 5000-20,000–fold over plasma were
The development of IGIV has permitted the administration of subsequently developed using various chromatographic methods, but
much higher doses, with a subsequent expansion in immunoglobulin they have primarily been supplanted by immunoaffinity-purified
therapy. Although immune globulin products were originally also products in the United States.
considered commodity products, the increased usage has led manu-
facturers to distinguish their products in various ways. As shown in
the tables, products are available in both lyophilized and liquid forms, Immunoaffinity-Purified Concentrates
with various strengths and purities. IgA content and product formu-
lation are also distinguishing factors. The next major advance in the preparation of AHF concentrates was
the use of murine monoclonal antibodies (mAbs) immobilized on a
chromatographic column for the purification of factor VIII. Factor
Subcutaneous Immune Globulin Concentrates VIII concentrates partially purified by conventional means are applied
to an immunoaffinity column that binds either factor VIII directly
The first patient treated for primary immune deficiency was actually or the factor VIII/vWF complex. The columns are washed extensively
given subcutaneous injections of immunoglobulins, but as described to remove unwanted proteins and then eluted with a solution that