Page 1995 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 117

TRANSFUSION THERAPY FOR COAGULATION FACTOR

DEFICIENCIES

Elizabeth Roman, Peter J. Larson, and Catherine S. Manno

This chapter reviews products available to treat deficiencies of plasma hemophilia B affects 1 : 30,000. This difference in incidence is
coagulation proteins. The development of blood component therapy roughly correlated with the size of the genes, and more than 30% of
and subsequently protein concentrates that are enriched in particular cases arise from spontaneous mutations.
coagulation factors and other proteins made possible the effective The major morbidity of the severe hemophilias A and B is
treatment of bleeding episodes in patients with hemophilia and other arthropathy, a result of recurrent joint bleeding developing over the
diatheses. In the 1940s, a collaborative effort funded by the US course of years in those with inhibitors or those who are untreated
government was undertaken among protein scientists with the goal or undertreated. The major cause of hemorrhagic mortality is bleed-
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of rapidly developing a method to isolate albumin from human ing into critical closed spaces (e.g., intracranial). Central nervous
plasma to provide a lyophilized intravascular volume expander for use system (CNS) bleeding occurs in 3% to 14% of patients, and mortal-
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in the military. As part of this effort, Dr. Edwin Cohn developed an ity from CNS hemorrhage ranges from 20% to 50% with neuro-
ethanol fractionation procedure that was amenable to large-scale logic sequelae (including seizures, motor impairment, or mental
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manufacture. Building on the foundation of the Cohn fractionation retardation) observed in 40% to 50% of survivors. CNS bleeding
procedure (see Chapter 116), the first coagulation factor concentrates episodes occur predominantly in patients with severe disease (<1%
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were developed in the mid-1960s and provided a safer and more factor level). A more detailed discussion of the hemophilias and
effective treatment for patients with the X-linked coagulation defi- the molecular biology of factors VIII and IX can be found in
ciencies, hemophilia A and B. Given the limited human plasma Chapter 135.
resource as a raw material for production of all but a few coagulation
protein concentrates, manufacturers of human plasma–based prod-
ucts attempt to derive the maximum yield from each pool of plasma. TRANSFUSION THERAPY FOR HEMOPHILIA A AND B
Manufacturers of plasma-derived products strive to maximize the
therapeutic potential of pooled human plasma by deriving more History of Transfusion for Hemophilia
products from these processes.
Development of recombinant products was fueled by infectious Transfusion was first proposed by Schönlein and his student Hopf in
disease transmission through human plasma–derived products. Cur- 1832 as a treatment for “bleeders” who were suffering from exsan-
rently licensed products are produced in mammalian cell culture to guinating hemorrhage, and these two were likely the first to have used
6,7
optimize necessary posttranslational modifications required for bio- the term Haemophilie to describe the disease. The first effective
logic activity. These recombinant expression processes are complicated transfusion-based intervention for hemophilia is credited to Samuel
and expensive. Transgenic recombinant technology has been explored Lane who, in 1840, infused 10–12 ounces of fresh human blood into
as a way to decrease or eliminate reliance on the human plasma a 12-year-old boy with postoperative hemorrhage after eye surgery
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resource and the technically rigorous production of recombinant for correction of a squint. Subsequently, a variety of interventions,
proteins using mammalian cell culture methods. using the infusion of human and animal blood and blood derivatives,
Recombinant technology has made significant progress recently were used in the therapy of hemorrhage in patients with congenital
in the evolution of long-acting factor VIII and IX preparations, which bleeding diatheses (Table 117.1). Citrated plasma was first used in
are effective in preventing as well as treating bleeding episodes; 1923 for the treatment of hemophilia by Feissly in a father-to-son
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however, the progress has been more significant in the extension of transfusion. Development of modern blood banking in the 1930s
the factor IX half-life. By conjugation to fusion protein (immuno- and expansion of transfusion during and after World War II allowed
globulin Fc) the half-lives of these coagulation proteins have been for more widespread use of whole blood and subsequently frozen
extended. This has had a great impact on the daily life of patients plasma in the treatment of hemophilia. Because of limited availability,
with hemophilia who use factor concentrate as prophylaxis, as the use of whole blood and components of whole blood for the
extending the factor half-life has reduced the burden of numerous treatment of hemophilia and other diseases was initially confined to
weekly infusions, while maintaining factor efficacy. larger metropolitan areas. In addition, volume constraints associated
In addition, this new era holds vast promise in gene therapy for with the quantity of whole blood or plasma needed to achieve thera-
factor IX deficiency. Enhancing a patient’s ability to produce even a peutic levels of coagulation limited their usefulness. 10
modest increase in factor levels could transform the individual from The advent of modern transfusion therapy for hemophilia came
a severe to moderate hemophilia patient, eliminating the need for with the observation that the cold-insoluble precipitate remaining
routine prophylactic therapy and reducing the number of spontane- after thawing of frozen plasma at 4°C contains high concentrations
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ous or trauma-related bleeding episodes. of factor VIII. Application of this procedure to the separation of
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components of whole blood allowed for the production of a
reduced-volume blood product known as cryoprecipitate. Cryopre-
HEMOPHILIA A AND B cipitate derived from a single whole blood collection contains
approximately 125 units of factor VIII and quickly replaced frozen
The hemophilias are X-linked disorders caused by deficiencies of plasma as the therapy of choice for the treatment of bleeding episodes
either factor VIII (hemophilia A, or classic hemophilia) or factor IX in hemophilia A in the 1960s. The availability of cryoprecipitate
(hemophilia B, or Christmas disease). The genes for these coagulation made the treatment of bleeding episodes by patients in their homes,
factors are located in close proximity on the long arm of the X rather than at a hospital, a reality. In addition, the development of
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chromosome. Whereas hemophilia A affects 1 : 5000 males, quantitative assays for factor VIII and for factor IX meant that the
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