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Although coagulation factor concentrates were known to transmit hepatitis when they first became available, the risk has been reduced over the years by improvements to the donor history, the addition of laboratory tests for transmissible agents, and the introduction in the mid‐1980s of methods to treat the concentrates to separate and inactivate viruses [95, 96, 99]. The major methods of viral inactivation for plasma‐derived concentrates are: (a) dry heating, in which the sealed final vial is heated between 80°C and 100°C; (b) pasteurization, in which the concentrate is heated to 60°C while still in solution before lyophilization; (c) vapor heating, in which the lyophilized powder is exposed to steam before bottling; and (d) solvent–detergent (SD) treatment, in which the organic solvent tri‐n‐butyl‐phosphate and the detergent Tween 80 or Triton X‐100 are added at intermediate processing steps. Currently, the SD method is most commonly used. The pasteurization and vapor heating methods result in substantial loss of factor VIII activity [99, 100].

Table 5.10 Plasma‐derivative products.

Source: From information provided by the Plasma Protein Therapeutics Association; and modified from Burnouf T. Transfus Med Rev 2007; 21(2):101–117.

Plasma product	Indication
Albumin
Serum human albumin Plasma protein fraction	Restoration of plasma volume subsequent to shock, trauma, surgery, burns, and therapeutic plasma exchange
Immunoglobulins
Immunoglobulin (intravenous and intramuscular)	Treatment of agammaglobulinemia and hypogammaglobulinemia; passive immunization for hepatitis A and measles
IgM‐enriched immune globulin	Treatment and prevention of septicemia and septic shock due to toxin liberation in the course of antibiotic treatment
Cytomegalovirus immune	Passive immunization subsequent to exposure to globulin cytomegalovirus
Hepatitis B immune globulin	Passive immunization subsequent to exposure to hepatitis B
Rabies immune globulin	Passive immunization subsequent to exposure to rabies
Rubella immune globulin	Passive immunization subsequent to exposure to German measles
Tetanus immune globulin	Passive immunization subsequent to exposure to tetanus
Vaccinia immune globulin	Passive immunization subsequent to exposure to smallpox
Varicella‐zoster immune	Passive immunization subsequent to exposure to globulin chicken pox
RhO(D) immune globulin	Treatment and prevention of hemolytic disease of fetus and newborn resulting from Rh incompatibility and incompatible blood transfusions
Protease inhibitors
Alpha1 proteinase inhibitor	Used in the treatment of emphysema caused by a genetic deficiency
C1‐esterase inhibitor	Hereditary angioneurotic edema
Coagulation proteins
Antithrombin III	Treatment of bleeding episodes associated with liver disease, antithrombin III deficiency, and thromboembolism
Antihemophilic factor	Treatment or prevention of bleeding in patients with hemophilia A
Anti‐inhibitor coagulant	Treatment of bleeding episodes in the presence of complex factor VIII inhibitor
von Willebrand factor/factor VIII concentrate	Treatment or prevention of bleeding in patients with von Willebrand factor
Unactivated prothrombin complex concentrate (PCC):
4‐Factor PCC includes vitamin K–dependent factors (factors II, VII, IX, X) 3‐Factor PCC includes factors II, IX,and X	Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonists therapy in patients with acute major bleeding or need for an urgent surgery/invasive procedure
Activated PCC: 4‐Factor PCC includes factors II, VII,IX, and X; only factor VII is mostly the activated form	Prevention or treatment of bleeding in patients with hemophilia A and B complicated by an inhibitor, acquired hemophilia A, or bleeding associated with certain anticoagulants
Factor IX	Prophylaxis and treatment of patients with factor IX deficiency
Factor X	Prophylaxis and treatment of patients with factor X deficiency
Factor XI	Prevention and treatment of bleeding associated with factor XI deficiency
Factor XIII	Treatment of bleeding and disorders of wound healing due to factor XIII deficiency
Fibrinogen	Treatment of hemorrhagic diathesis in hypofibrinogenemia, dysfibrinogenemia, and afibrinogenemia
Fibrinolysin	Dissolution of intravascular clots
Other proteins
Haptoglobin	Supportive therapy in viral hepatitis and pernicious anemia
Serum cholinesterase	Treatment of prolonged apnea after administration of succinyl choline chloride

Each of these methods uses a different strategy of viral inactivation. There are differing amounts of data about the effectiveness of these viral inactivation methods, because not all of their products have been subjected to randomized controlled trials. In general, it appears that the methods are effective in inactivating virus with a lipid envelope, but infections with nonlipid envelope viruses, such as parvovirus B19 [101] and hepatitis A [102], have been reported.

The first recombinant‐produced coagulation factor VIII concentrates became available in late 1992 and 1993 [103, 104]. It appears that these products transmit no diseases. The factor VIII is produced in murine cell lines, and both fetal calf serum and murine monoclonal antibodies are used in the production process. The products are subjected to viral inactivation steps, even though there should be no way that human viruses should contaminate the products. Although factor VIII is a very antigenic protein, it does not appear that recombinant factor VIII is more likely than plasma‐derived factor VIII to cause development of factor VIII inhibitors.

Coagulation factor VIII concentrates produced by recombinant DNA techniques are more expensive than those produced from plasma [105]. Despite this, the high‐purity (high‐cost) plasma‐derived and recombinant products are the most widely used.

Factor IX concentrates are also free of transmission of most viruses since 1991. Factor IX concentrates vary in purity, and most contain additional coagulation factor [106]. The less pure concentrates contain other coagulation factors and cause some degree of hypercoagulability [107]. Activated factor VII, fibrinogen, prothrombin complex concentrates, von Willebrand factor concentrate, and fibrin sealant are discussed in Chapter 10.