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.
Fibrinogen
A virally inactivated fibrinogen concentrate prepared from human plasma is now available commercially and is approved by the FDA for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency [108–110]. The concentrate is recommended for use in situations when the fibrinogen level is less than 100 mg/dL. Although fibrinogen concentrate is approved only for use in congenital fibrin deficiency [109], small studies of its use in patients with low fibrinogen levels and massive bleeding from obstetric complications, cardiovascular surgery, intra‐abdominal surgery, trauma [108], and an aortic ascending aorta replacement [110] have demonstrated substantially reduced bleeding, and these situations have become its major use [111].
Immune serum globulins
Immune serum globulin (Ig or gamma globulin) prepared by the traditional plasma fractionation technique has been very effective in preventing bacterial infections in patients with agammaglobulinemia and in preventing certain viral infections in immunologically normal persons. Immune globulin is administered intramuscularly because it contains aggregated or oligomeric molecules of Ig, which, when injected intravenously, activate complement, resulting in severe reactions [112]. The limitations of intramuscular Ig are dose, painful injections because of the volume required, and difficulty maintaining plasma levels of IgG. To overcome these issues, immune globulin suitable for intravenous administration is prepared from the plasma of normal donors and thus can be expected to have an antibody content reflective of normal healthy individuals in a large population. There are some differences among different products in the IgA content, the relative proportions of IgG subclasses, and in vitro activity against some viruses. The differences in IgA content are clinically important, because brands that contain much IgA may cause a reaction if given to an IgA‐deficient patient with anti‐IgA. The importance of the other differences among the brands has not been established. The intravenous half‐life of the intravenous immunoglobulin (IVIG) is 21–25 days, which is similar to native IgG.
All IVIG products that are approved by the FDA are labeled for treatment of individuals with impaired humoral immunity, specifically for primary (congenital) immune deficiency. Individual products are additionally labeled for use in (idiopathic) autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, Kawasaki syndrome, HIV infection during childhood, bone marrow transplant, and B‐cell chronic lymphocytic leukemia [113–115]. The availability of IVIG makes it possible to maintain the serum IgG level near normal in immunodeficient patients. The amount required varies with the size of the patient and the indication. Usually 100–200 mg/kg per month is used as a starting dosage for patients with primary immunodeficiencies.
Administration of IVIG in autoimmune situations may seem odd. The mechanism of action is thought to be macrophage Fc receptor blockage by immune complexes formed between the IVIG and native antibodies. IVIG is effective for patients with autoimmune thrombocytopenia. Specific IV anti‐Rh(D) is used in Rh‐positive patients with autoimmune thrombocytopenia [113, 116]. This is thought to cause immune complexes with anti‐Rh and the patient’s Rh‐positive red cells, resulting in Fc receptor blockade. Larger doses are usually used for patients with autoimmune thrombocytopenic purpura compared with immune deficiency. IVIG is now used in other immune deficiency or autoimmune states (see Chapter 10).
Adverse reactions to IVIG occur with 2–10% of injections [113]. These are local, such as erythema, pain, phlebitis, or eczema. Systemic symptoms include fever, chills, myalgias, back pain, nausea, and vomiting. Some reactions in some patients are dose related and can be reduced or eliminated by slowing the rate of infusion. The nature and frequency of adverse reactions may differ among the different products, but this is not clear and is beyond the scope of this chapter.
Because IVIG is made from large pools of human plasma, it contains a variety of antibodies, including those against blood groups and possibly anti‐HBs, anti‐HBc, anti‐cytomegalovirus, and so on [113]. Donor screening should eliminate some of these (i.e., anti‐HIV), but patients may have transiently positive tests for certain antibodies, especially ABO, that are passively acquired from the IVIG [117], and some patients may develop a positive direct antiglobulin test. Transient hemolysis has been reported in patients with autoimmune thrombocytopenic purpura and others being treated with IVIG (see Chapter 16). Thus, although hemolysis is unusual, a large proportion of patients receiving IVIG will develop circulating or cell‐bound blood group antibodies. This should be considered if unexplained hemolysis occurs in patients being treated with IVIG.
5.9 Pathogen‐inactivated blood components
The approach to blood safety during the past 40 years has been very successful but is nearing the end of its effectiveness [118–121]. Addition of new tests and/or screening measures erodes the donor base unnecessarily and is reactive, allowing patients to be harmed before preventive steps are implemented. Several pathogen‐inactivated plasma products and two pathogen‐inactivated platelet products are widely used outside the United States, and one platelet and two plasma products are FDA licensed for domestic use. This technology is reviewed extensively by Prowse [121, 122] and in a Cochrane review [123]. Refer to Chapter 14 for additional information on Pathogen‐reduced blood products.
Solvent–detergent plasma (Octaplas)
Treatment of fresh plasma with a combination of solvent tri‐n‐butyl‐phosphate and the detergent Triton X‐100 inactivates lipid envelope viruses while retaining most coagulation factor activity. The process must be done on a large scale, and plasma from about 2,500 donors is pooled for the SD process. The product has little, if any, risk for transmitting lipid envelope viruses, such as HIV, hepatitis C virus, and hepatitis B virus, but can transmit nonlipid envelope viruses such as parvovirus [124]. Reports of thrombosis in patients with thrombotic thrombocytopenic purpura who are undergoing plasma exchange with SD plasma [125] and deaths in patients receiving SD plasma while undergoing liver transplantation led to withdrawal of an earlier version of that product from the market. It is postulated that these thrombotic complications were due to decreased protein S and plasmin inhibitor activity in SD plasma [125]. A different SD plasma, Octaplas (Octapharma, Vienna, Austria) (Table 5.11), has higher, although not normal, levels of protein S and plasmin inhibitor [126] and has not been associated with thrombotic events. This form of SD‐treated plasma is in rather wide use in Europe [127, 128] and is now available in the United States.
Fresh frozen plasma
Three pathogen‐inactivated FFP products are in use in Europe. Methylene blue can be added to plasma, and subsequent exposure to visible light inactivates most viruses and bacteria [129, 130]. The plasma can then be frozen as an FFP product. Three other pathogen inactivation methods are used for both plasma and platelets [118–122]. One uses a psoralen compound and ultraviolet A (UV‐A) light [131], one uses riboflavin and ultraviolet B (UV‐B) light [132], and a third method uses ultraviolet C (UV‐C)