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CHAPTER 143 PREPARATION AND CLINICAL USE OF PLASMA AND PLASMA FRACTIONS

CHAPTER 143 PREPARATION AND CLINICAL USE OF PLASMA AND PLASMA FRACTIONS
Williams Hematology

CHAPTER 143 PREPARATION AND CLINICAL USE OF PLASMA AND PLASMA FRACTIONS

KENNETH D. FRIEDMAN
JAY E. MENITOVE

Preparation and Fractionation of Plasma Components and Derivatives
Plasma Components

Fresh-Frozen Plasma

Plasma Frozen within 24 h of Collection

Liquid Plasma

Cryo-Poor Plasma

Solvent-Detergent–Treated Plasma

Donor Retested Plasma

Cryoprecipitate

Clinical Use of Plasma and Cryoprecipitate

Plasma Derivatives

Factor VIII Concentrates

Concentrates for Treatment of Patients with Factor VIII Inhibitors

Adverse Events Associated with Factor VIII Therapy

Clinical Use of Factor VIII Concentrates

Prothrombin Complex Concentrates and Factor IX Concentrates

Clinical Use of Prothrombin Complex Concentrates, Coagulation Factor IX Concentrates, Recombinant Factor IX, and Factors XI and XIII and Protein C Concentrates

Albumin and Plasma Protein Fractions

Immunoglobulins

Serine Protease Inhibitors
Chapter References

Plasma collected from blood donors is provided as a blood component following minimal manipulation or as a plasma derivative after an extensive fractionation process. Plasma components include fresh-frozen plasma and the precipitate remaining after frozen plasma is thawed at 4°C (39.2°F), cryoprecipitate. Plasma components are used to replace inherited or acquired coagulation factor deficiencies, reverse the effects of warfarin when hemostasis is required urgently, and to replete plasma removed during plasma exchange therapy for thrombotic thrombocytopenic purpura. Cryoprecipitate serves as a source of fibrinogen and as a substrate for fibrin sealant. Plasma derivatives include albumin; immunoglobulin preparations; coagulation factors VIII, IX, XI, and XIII and prothrombin complex concentrates; and replacement products for antithrombin III, Cl esterase inhibitor, and a-proteinase inhibitor deficiencies.

Acronyms and abbreviations that appear in this chapter include: aPCC, activated prothrombin complex concentrate; API, a1-proteinase inhibitor; AT-III, antithrombin III; BU, Bethesda unit; CMV, cytomegalovirus; DDAVP, desmopressin; DEAE, diethylaminoethyl; DIC, disseminated intravascular coagulation; DR-FFP, donor retested fresh-frozen plasma; FDA, U.S. Food and Drug Administration; FFP, fresh-frozen plasma; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HTLV, human T lymphocytotropic virus; IL, interleukin; INR, international normalized ratio; ITP, immune-mediated thrombocytopenia; IVIg, intravenous immunoglobulin; MHC, major histocompatibility complex; PCC, prothrombin complex concentrate; PCR, polymerase chain reaction; PEG, polyethylene glycol; PT, prothrombin time; PTT, partial thromboplastin time; SD, solvent-detergent treated; TNBP, tri-(n-butyl)-phosphate; TNF-a, tumor necrosis factor a; TTP, thrombotic thrombocytopenic purpura; vWD, von Willebrand disease; vWF, von Willebrand factor.

PREPARATION AND FRACTIONATION OF PLASMA COMPONENTS AND DERIVATIVES
Plasma used for transfusion is separated from whole blood by centrifugation, tested, stored, and infused without significant modification. Plasma derivatives, including albumin, factor VIII, other hemostatic proteins, and immunoglobulins, are prepared in concentrated form following large-scale plasma fractionation procedures. This chapter addresses the preparation and clinical uses of plasma components and plasma derivatives.
PLASMA COMPONENTS
Blood banks and transfusion services provide various plasma components containing the fluid portion of donated whole blood. Plasma components are prepared from whole blood by separating the cellular and liquid portions of blood by centrifugation or by apheresis technology in which plasma and not cellular elements are collected.
FRESH-FROZEN PLASMA
Fresh-frozen plasma (FFP) is separated within 8 h of whole-blood collection, frozen at –18°C (–0.4°F) or colder, and stored in the frozen state for up to 1 year. FFP volume varies between 180 and 300 ml. FFP contains plasma proteins and all coagulation factors. Since idealized plasma contains 1 unit of each coagulation factor, a unit of FFP contains approximately 200 units of each coagulation factor, or 7 percent of the coagulation factor activity of a 70-kg patient.1,2,3 and 4
PLASMA FROZEN WITHIN 24 H OF COLLECTION
Plasma that is frozen within 24 h of whole-blood collection contains stable coagulation factors at the same concentration as present in FFP. The levels of factors V and VIII are reduced approximately 15 percent compared to those in FFP.4
LIQUID PLASMA
Liquid plasma is plasma that is separated no more than 5 days after the expiration date of the whole blood. Stable coagulation factor levels are similar to those in FFP, but levels of labile factors, V and VIII, are reduced significantly.5
CRYO-POOR PLASMA
The supernatant plasma remaining after the removal of cryoprecipitated material is referred to as cryo-poor plasma. It is relatively deficient in fibrinogen, factor VIII, and von Willebrand factor (vWF) multimers.4,7
SOLVENT-DETERGENT–TREATED PLASMA
Solvent-detergent–treated (SD) plasma is a pooled plasma product that undergoes treatment with the solvent tri-(n-butyl)-phosphate (TNBP) and the detergent Triton X-100 to inactivate lipid-enveloped viruses, such as hepatitis B and C and the human immunodeficiency virus (HIV).8,9 and 10 Plasma treated with the SD process is obtained from up to 2500 donations that are pooled together and subsequently aliquoted into 200-ml volumes. The process is not effective against nonenveloped viruses, such as hepatitis A and parvovirus, and is partially effective against emerging viruses, such as the TT virus.11,12 The SD process does not alter or inactivate labile coagulation factors or other plasma proteins, such as fibrinogen or immunoglobulin. It lacks the largest vWF multimers.9 SD plasma is stored in the frozen state. The cost-effectiveness of this product is unclear.13
DONOR RETESTED PLASMA
Donor retested plasma (DR-FFP) refers to single units of FFP prepared from repeat blood donors. DRP is prepared by making FFP from a single unit of whole blood, quarantining the plasma in the frozen state, and releasing the frozen plasma for use when the donor returns at least 112 days later and again has negative test results for hepatitis B and C and HIV. The 112-day time frame was chosen because it exceeds the “window period” interval during which viral transmission may occur despite negative test results for hepatitis B, C, and HIV.14
CRYOPRECIPITATE
Cryoprecipitate is prepared by thawing FFP at 1 to 6°C (33.8 to 42.8°F) and recovering the precipitated material. The cold-insoluble precipitate is then refrozen and stored at –18°C (–0.4°F) or colder for up to 1 year. Cryoprecipitate contains more than 150 mg of fibrinogen, more than 80 units of factor VIII, significant amounts of vWF (including the high-molecular-weight multimers), and some fibronectin and factor XIII in less than 15-ml volume.2,6
CLINICAL USE OF PLASMA AND CRYOPRECIPITATE
Contemporary guidelines for the use of FFP and cryoprecipitate appeared first in 1985 in a National Institutes of Health–sponsored consensus conference.3 Subsequently, professional associations established panels and issued reports.1,2,4,15,16 and 17 In general, there is agreement about use of FFP for replacement of coagulation factors to treat specific coagulopathies and for use as a replacement fluid for patients with thrombotic thrombocytopenic purpura (TTP) undergoing plasma exchange therapy.
The indications for FFP, SD plasma, and donor retested plasma are similar. SD plasma is not licensed for treatment of patients with disseminated intravascular coagulation (DIC) or for use in patients with coagulation factor deficiencies related to massive blood transfusion, although it has been used successfully in these situations.10
INDICATIONS FOR LIQUID PLASMA AND PLASMA FROZEN WITHIN 24 H OF COLLECTION
(Table 143-1) gives the indications for the use of liquid plasma and plasma frozen within 24 h of whole-blood collection.

TABLE 143-1 INDICATIONS FOR PLASMA TRANSFUSIONS*

Congenital or Acquired Coagulation Factor Deficiencies FFP, DR-FFP, and SD plasma is indicated for the correction of known congenital or acquired coagulation factor deficiencies, such as factor II, V, VII, X, XI, and XIII deficiencies; in patients with hemorrhage; or for an anticipated surgery or invasive procedure for which specific concentrates are not available.1,2,3 and 4,15,16 and 17
Hemostasis occurs when coagulation factor concentrations are at least 20 to 30 percent of normal and when fibrinogen levels are greater than 75 mg/dl. Coagulopathy is unusual until the prothrombin time (PT) and partial thromboplastin time (PTT) exceed 1.5 to 1.8 times control values.15,16
Urgent Reversal of Warfarin Effect In the setting of active bleeding, pending emergency surgery, or an invasive procedure, plasma infusion is indicated if insufficient time (approximately 6 h) is available for parenteral administration of vitamin K to reverse warfarin anticoagulation [PT greater than 18 s or international normalized ratio (INR) greater than 1.6].1,2,3 and 4,15,16 and 17
Treatment of Hemorrhage in the Presence of Elevated PT or PTT1,2,3 and 4,15,16 Clinical settings in which hemorrhage and elevated (greater than 1.5 times normal) PT or PTT occur include chronic liver disease, DIC, and dilutional coagulopathy.18,19,20,21,22 and 23 A clear correlation between elevated PT and PTT levels and INR values has not been established. Despite this relationship, in Canada, an INR of 2.0 has been selected as the threshold INR for recommending plasma infusion for patients with severe liver disease with active bleeding or for whom surgery or other invasive procedures are planned.4 In general, INR should be employed as an index in patients receiving warfarin who are in steady state.
Treatment of Bleeding in the Setting of Massive Blood Transfusion When PT and PTT Are Not Obtained in a Timely Manner20,21,22 and 23 In general, the use of plasma to replace coagulation factor deficiencies should be based on timely laboratory test results. If such results cannot be obtained, plasma is indicated to treat microvascular bleeding in the setting of massive transfusion (more than one blood volume) on the basis of clinical judgment alone.
Plasma Exchange for TTP FFP has been used empirically for plasma exchange therapy or as an infusion to treat patients with TTP.24,25 Plasma therapy effectiveness may be related to the presence of autoantibodies against a metalloprotease that degrades large vWF multimers in patients with acute TTP.26,27 Plasma removal in the exchange process removes antibody and large multimers, while replacement with normal plasma restores normal-sized multimers. In some patients with chronic, relapsing TTP, the protease is absent. Large vWF multimers serve as a platelet-aggregating cofactor in TTP. Thus, degradation of these multimers has therapeutic implications. In this regard, cyro-poor plasma has been recommended in lieu of routine plasma-exchange therapy, since cryo-poor plasma is relatively deficient in large vWF multimers.28 The metalloprotease is present in patients with hemolytic uremic syndrome and thus may explain why plasma therapy is usually ineffective in treating patients with this syndrome.26
Other Uses Plasma infusions are effective in preventing acute complications of protein C deficiency and have been used in neonates with purpura fulminans. Warfarin therapy should be instituted in both disorders for therapy.29,30 DIC and severe acquired protein C deficiency are characteristic of meningococcemia and purpura fulminans.31 An unlicensed monoclonal antibody–purified, vapor heat–treated protein C concentrate32 has shown remarkable promise in these patients, with control of DIC, reversal of organ dysfunction, and reduction in morbidity and mortality rates.33,34
Plasma is used to replace protein S during surgery or when anticoagulants cannot be given. Treatment with oral anticoagulants is effective long-term therapy.30
DOSE AND MONITORING FOR PLASMA TRANSFUSIONS
The volume of the infused plasma component should be sufficient to achieve at least 30 percent coagulation factor levels, 10 to 15 ml plasma per kilogram of body weight (Fig. 143-1). Urgent reversal of warfarin may require 5 to 8 ml plasma per kilogram of body weight.2,15 Plasma is present in platelet concentrates and should be considered in calculating the plasma dose when platelets and plasma are given simultaneously. Plasma components are labeled with the ABO and Rh type of the donor; infused plasma should be ABO compatible with the recipient’s red cells. Compatibility testing for plasma transfusion is not necessary.

FIGURE 143-1 The decision pathway for plasma transfusions requires an evaluation of coagulation test results and clinical evidence of hemorrhage or an impending invasive procedure.
*If yes, infuse plasma, 10 to 15 ml/kg body weight. Monitor laboratory results to decide whether additional transfusions are necessary.
**If yes, infuse plasma, 5 to 8 ml/kg body weight.
***Plasma or cryo-poor plasma for exchange transfusion.

Following infusion, subsequent dosing should be based on coagulation factor intravenous recovery half-lives, the results of repeat coagulation testing, and clinical parameters.2
CONTRAINDICATIONS TO PLASMA TRANSFUSIONS
Plasma components should not be used for plasma expansion, albumin supplementation, correction of hypogammaglobulinemia, treatment of hemophilia or von Willebrand disease [vWD; where desmopressin (DDAVP) or virally inactivated concentrates are available], or treatment of other congenital procoagulant or anticoagulant factor deficiencies where virally inactivated or recombinant factor concentrates are preferred.4
ADVERSE EVENTS ASSOCIATED WITH PLASMA TRANSFUSIONS
Plasma transfusions present the same risk as transfusion of other blood components for transmitting viral infection. The risk of viral transmission is decreased with SD-treated plasma and DR-FFP. However, hepatitis A superinfection of hepatitis C–infected patients is associated with fulminant hepatitis.35 Intracellular viruses, such as cytomegalovirus (CMV) and HTLV-1, are not transmitted by plasma.
Allergic or anaphylactic reactions and transfusion-related acute lung injury occur infrequently. Volume overload may occur in patients with impaired cardiac reserve.38
Rh alloimmunization was reported following massive plasma infusion during plasma exchange therapy, presumably related to small amounts of contaminating red cells.39 In general, plasma has a white blood cell content below that considered to cause human leukocyte antigen (HLA) alloimmunization or graft-versus-host disease, although significant numbers of leukocytes have been found in some plasma units.40
INDICATIONS FOR CRYOPRECIPITATE AND DOSAGE
Hypofibrinogenemia Fibrinogen is concentrated 15- to 20-fold in cryoprecipitate compared to plasma. Commercially prepared fibrinogen concentrates are not available in the United States. Thus, cryoprecipitate is the component of choice for correction of hypofibrinogen-related bleeding or those at risk for bleeding. It is also indicated as prophylaxis in those at risk of bleeding as a result of marked hypofibrinogenemia (fibrinogen concentrations <80–100 mg/dl) facing an imminent invasive procedure or surgery.
In many instances, patients with severe hypofibrinogenemia have concomitant DIC. FFP alone may not raise the fibrinogen level to hemostatic levels (>100 mg/dl). Infusion of cryoprecipitate in doses of 1 bag per 5 kg body weight will augment fibrinogen levels by at least 75 mg/dl. Fibrinogen has a half-life of 3 to 5 days, and 50 percent of infused fibrinogen is recovered postinfusion. Additional doses should be given on the basis of laboratory measurements. For patients with inherited hypofibrinogenemia, infusions are given every other day.1,2,15,16 and 17
von Willebrand Factor Replacement Desmopressin is the preferred treatment option for patients with type I vWD. In those patients with other types of vWD or in those unresponsive to DDAVP, virally inactivated factor VIII concentrates containing adequate amounts of vWF (e.g., Humate-P) are indicated therapy. Cryoprecipitate represents an additional option for prophylactic therapy of those unresponsive to DDAVP or treatment of bleeding. About 50 percent of the vWF contained in the initial plasma is recovered in cryoprecipitate. Infusion of 1 bag of cryoprecipitate per 10 kg body weight is recommended.2,15,16 and 17 Subsequent dosing should be based on an analysis of ristocetin cofactor activity, factor VIII antigen, or vWF multimer levels after transfusion. Measurement of the bleeding time to assess further dosing is not recommended.2
Hemophilia A Cryoprecipitate is used infrequently for factor VIII replacement therapy in hemophilia A patients. In a 70-kg patient, factor VIII procoagulant activity levels increase approximately 2 percent for each bag of cryoprecipitate infused. Since the half-life of factor VIII is 8 to 12 h, repeat doses should be given at approximately this interval.
Fibrin Sealant Fibrin sealants prepared by blood banks or by surgeons in operating suites, so-called homemade fibrin sealants, are prepared by mixing bovine thrombin (1000 U/ml) with an equal volume of cryoprecipitate. In May 1998, a commercial preparation was licensed by the U.S. Food and Drug Administration (FDA). This and other commercially formulated fibrin sealant preparations (Tisseel) contain fibrinogen prepared from pooled human plasma (40–150 mg/dl), human factor XIII (20–210 U/ml), human thrombin (200–600 U/ml), and bovine aprotinin (0–10,000 KIU/ml). Viral inactivation techniques include vapor heat, wet heat, SD treatment, nanofiltration, and ultraviolet C exposure.41,42 and 43
Fibrin sealants have hemostatic and adhesive properties and are used primarily during cardiovascular and thoracic surgical procedures as adjuncts to hemostasis and for sealing anastomoses. Additional clinical situations in which hemostatic properties of fibrin sealant are useful include liver and spleen lacerations, dental extractions in hemophilic patients, connection sites for extracorporeal membrane oxygenators, gastric ulcers, and carotid endarterectomy. Fibrin sealant adhesive properties augment sealing of dural leaks in neurosurgery, union of middle ear bones, skin grafting following burn injuries, sealing of bronchopleural fistulas, and repair of lung defects and serve as alternatives to sutures in plastic surgery. Fibrin sealants have been proposed as wound bandages and as a self-expanding foam for body-cavity administration to stop internal bleeding.41,42 and 43
Other Uses for Cryoprecipitate Approximately 50 percent of uremic patients receiving 10 units of cryoprecipitate have normalization of abnormal bleeding times 1 h postinfusion. However, aggressive dialysis and DDAVP have replaced cryoprecipitate for treatment or prophylaxis of uremic bleeding.44 Although cryoprecipitate contains factor XIII, FFP (5 ml/kg body weight every 4–6 weeks) is used for treatment of patients with congenital factor XIII deficiency.9,45
ADVERSE EVENTS ASSOCIATED WITH CRYOPRECIPITATE TRANSFUSIONS
Adverse effects associated with cryoprecipitate and fibrin sealant are similar to those associated with plasma infusion. In addition, some patients exposed to bovine thrombin develop autoantibodies to factor V that lead to hemorrhagic complications 7 to 14 days after exposure. Treatment of this complication includes infusion of FFP; possibly platelet concentrates, since platelets contain approximately 20 percent of the factor V in plasma; and immunosuppression with methylprednisolone.46
PLASMA DERIVATIVES
The Cohn-Oncley process is the prototype method of plasma fractionation.47 Plasma subcomponents are separated by adding alcohol, altering the pH and temperature, and using additional chromatographic steps. The source plasma used in the fractionation process derives from volunteer and commercial donors. All donors are screened for risk factors associated with transfusion-transmitted infections, and all donations are tested for evidence of HIV and hepatitis (Fig. 143-2).48

FIGURE 143-2 The cold ethanol plasma fractionation process involves multiple steps that result in various plasma derivative products. (Modified from PR Foster, B Cuthbertson: Procedures for the prevention of virus transmission by blood products, in Blood, Blood Products and HIV, edited by R Madhok, CD Forbes, BL Evatt, p 207, Chapman and Hall Medical, London, 1994; and DBL McClelland,48 with permission.)

FACTOR VIII CONCENTRATES (See Table 143-2)

TABLE 143-2 FACTOR VIII PRODUCTS AVAILABLE IN THE UNITED STATES

Lyophilized factor VIII concentrates prepared from plasma pools containing as many as 20,000 donations have been distributed in the United States since the early 1970s (Table 143-2). The nomenclature for purity and the processes followed by various pharmaceutical companies to prepare various coagulation concentrates are not standardized.49 Intermediate-purity preparations contain residual vWF, and some of these products are useful in the treatment of patients with vWD. Other contaminating proteins include fibrinogen, fibronectin, IgA, and IgG, while affinity-purified plasma-derived factor VIII preparations and recombinant products are essentially free of these contaminants.50 Posttransfusion recovery and half-life are identical among the various preparations.51 Major issues have been purity and viral safety.
PURIFICATION PROCEDURES49,52,53
Cryoprecipitation and Alcohol Precipitation: Intermediate Purity The specific activity of factor VIII concentrates made from Cohn fraction I or from cryoprecipitate ranges from 1 to 6 units of factor VIII per milligram protein (Humate-P, Centeon). Use of polyethylene glycol (PEG) precipitation increases the specific activity to 6 to 10 units of factor VIII per milligram of protein (Profilate SD, Alpha Therapeutics).
Gel and Ion-Exchange Chromatography: High Purity Gel and ion-exchange chromatography procedures increase the specific activity of factor VIII preparations to approximately 50 to 150 units factor VIII per milligram protein prior to the addition of albumin for stabilization (Koate HP, Bayer).
Affinity Chromatography: Very High Purity PEG precipitation followed by affinity chromatography of factor VIII/vWF complex on heparin-agarose is employed as one method for very high level purification of both factor VIII and vWF (Alphanate, Alpha Therapeutic). Monoclonal antibody–based affinity chromatography allows purification of factor VIII to more than 3000 factor VIII units per milligram of protein. Antibodies directed either against the vWF molecule (Monoclate-P, Centeon) or against the procoagulant factor VIII:C (Hemophil-M, Baxter; and Monarc-M, American Red Cross) are used to capture factor VIII. Factor VIII:C is released from the solid phase–bound vWF–factor VIII complex by addition of an aqueous solution of calcium, followed by gel chromatography and freeze drying. Alternatively, factor VIII:C is eluted from the column containing anti-VIII:C by an aqueous solution of 40% ethylene glycol followed by ion-exchange absorption and lyophilization. Purified human albumin is added to very high purity factor VIII preparations to stabilize the material.
Viral Inactivation In response to transmission of hepatitis and HIV by earlier concentrates, viral inactivation methods were devised and introduced during the 1980s for pooled and/or processed plasma-derived blood products. Unfortunately, most severe hemophilic patients alive in the early 1980s had already been exposed to these infectious agents.54 Subsequently, the efficiency of inactivation of viruses containing lipid envelopes was shown through prospective longitudinal studies of previously untransfused patients. However, transmission of nonenveloped agents, such as the hepatitis A virus, by some concentrates led to a recommendation to vaccinate patients likely to be exposed to clotting factor concentrates against hepatitis A. Hepatitis B vaccination was recommended previously.55
“Dry”-heated concentrates are lyophilized concentrates heated at 68°C (154.4°F) for 32 to 72 h to eliminate hepatitis risk. While partially effective against HIV,56 “dry” heating of concentrate was not completely effective for eliminating the risk of hepatitis viruses or HIV.49,57,58 Prolonged dry heat ( 68°C for 144 h) is used in the treatment of some prothrombin complex concentrates (Proplex-T, Baxter; and Autoplex T, NABI), with dry heat at higher temperature [80°C (176°F) for 72 h] conferring viral safety for another (Konyne-80, Bayer).59
“Moist”-heated concentrates involve viral inactivation of lyophilized product by heating under a pressurized vapor phase (60°C for 10 h under 1190 mbar). Two prothrombin complex concentrates available in United States are so prepared (Feiba VH, Baxter; and Bebulin VH, Baxter).
Pasteurized, or “wet” heat–treated, factor concentrates include two available factor VIII concentrates (Humate-P, Centeon; and Monoclate-P, Centeon). Pasteurized concentrates do not appear to transmit HIV or hepatitis C.49,52,60,61 However, transmission of parvovirus B19 has been reported.62 An increase in the incidence of antibodies to factor VIII (inhibitors) found with the introduction of one pasteurized, controlled-pore, silica-adsorbed factor VIII led to a suggestion that clinicians treating hemophilia should follow serial inhibitor test results when patients change coagulation factor preparations63; this has not been observed with other concentrates.
SD-treated factor concentrates became popular because they preserve the biologic activity of clotting factors. The SD process prevents viral transmission though disruption of viral lipid membranes, by destruction of cell receptor recognition sites, or by killing virus. TNBP and Tween 80, Triton X-100, or sodium cholate are used in various SD treatments. Solvents and detergents are eliminated by chromatographic steps, and residual material does not appear to be toxic despite repeated use in hemophilic patients. No transmission of hepatitis B or C or HIV has occurred with SD-treated factor VIII concentrates.49,57,58,64 Hepatitis G is not transmitted by virally infected factor concentrates.65 The majority of currently available factor concentrates are treated by SD methods to reduce viral transmission (including Profilate SD, Alpha Therapeutic; Koate HP, Bayer; Hemophil-M, Baxter; and Monarc-M, American Red Cross). However, hepatitis A superinfection of hepatitis C–infected patients is associated with fulminant hepatitis.35
RECOMBINANT-DERIVED FACTOR VIII CONCENTRATES
The factor VIII gene has been cloned and sequenced, and its cDNA inserted into mammalian cell cultures.66,67 Recombinant factor VIII concentrates hold the promise of continuous supply and viral safety.68,69 However, concerns linger because the cell lines are of animal origin, cultures are nourished with fetal calf serum, and proteins are purified on monoclonal immunoaffinity columns and then may be stabilized with human albumin. In fact, concern over Creutzfeldt-Jakob disease has resulted in product withdrawals of recombinant factor VIII, despite the absence of evidence that this infection has occurred in hemophiliac patients as a result of transfusion.70 Products are in development that do not require albumin stabilization.71
Two recombinant factor VIII concentrates are available in the United States: Recombinate (Baxter; also sold as Bioclate, Centeon) and Kogenate (Bayer; also sold as Helixate, Centeon).49,72,73 The former product is prepared in Chinese hamster ovary cells cotransfected with factor VIII and vWF genes and purified by immunoaffinity and ion-exchange chromatography.74,75 The latter product is derived from a baby hamster kidney cell line transfected with human coagulant factor VIII cDNA. The secreted protein is purified by ion-exchange chromatography and immunochromatography. Recombinant-derived factor VIII–specific activity ranges from 4000 to 7000 units of factor VIII per milligram protein prior to addition of albumin. Following infusion, the recombinant factor VIII binds to circulating vWF.68,76 In vivo recovery and survival are similar to those for plasma-derived factor VIII.77
Development of factor VIII inhibitors following treatment is one of the most serious consequences of factor replacement therapy and was an early concern with the recombinant products.68,77 Subsequent studies indicate that the cumulative incidence of inhibitors is not increased in patients treated with recombinant factor.78,79 Although hamster and mouse proteins are present in trace amounts in the final preparations, antibodies to these proteins have not been detected.68,72
CONCENTRATES FOR TREATMENT OF PATIENTS WITH FACTOR VIII INHIBITORS
ACTIVATED PROTHROMBIN COMPLEX CONCENTRATES
Activated prothrombin complex concentrate (aPCC) preparations are activated spontaneously or deliberately during the manufacturing process and have been used to treat patients with inhibitors to factor VIII.80,81 The active component or components were postulated to be either activated clotting factors (Xa or VIIa) or factor VIII complexed with phospholipid. The products are standardized by their ability to correct the clotting time of factor VIII–deficient plasma or factor VIII inhibitor plasma. Autoplex T (NABI) is dry heated at 60°C (140°F) for 144 h, and FEIBA VH (Baxter) is subject to steam heat under pressure to reduce virus transmission.49
RECOMBINANT FACTOR VIIa CONCENTRATE
Factor VII cDNA has been isolated and cloned into baby hamster kidney cells cultured in media supplemented with calf serum. Recombinant protein is purified using a combination of immunoaffinity and ion-exchange chromatography. Factor VII spontaneously activates during purification, and the final material is stabilized without albumin (Novo Nordisk). This factor VII product has been used in clinical trials82 and now is licensed for use.
PORCINE FACTOR VIII
Since patients’ antibodies to human factor VIII often cross-react weakly or not at all with porcine factor VIII, purified porcine factor VIII has been used to treat patients with factor VIII inhibitor.83 Porcine cryoprecipitate is depleted of vitamin K–dependent factors by passage over alumina; then factor VIII is purified by polyelectrolyte adsorption chromatography, followed by concentration and lyophilization. The resultant concentrate (HYATE:C, Speywood) has a specific activity of 140 U/mg, with minimal residual porcine vWF. Although no cases of human transmission of porcine parvovirus were found by the manufacturer or the Centers for Disease Control and Prevention, source material is now screened by polymerase chain reaction (PCR) for this virus.84
ADVERSE EVENTS ASSOCIATED WITH FACTOR VIII THERAPY
Plasma-derived factor VIII concentrates are prepared from pools containing up to 20,000 units of human plasma. Prior to viral-inactivation procedures, 60 to 100 percent of patients with severe hemophilia A treated with commercially prepared concentrates were infected with HIV,60,135 and at least 80 percent were infected with hepatitis B, C, or G.60,136,137 The risk of nonenveloped viral disease persists despite viral-inactivation procedures.12,62,64 Recombinant technology should eliminate the risk of human transfusion-transmitted disease.
CLINICAL USE OF FACTOR VIII CONCENTRATES
SELECTION OF LEVEL FOR REPLACEMENT THERAPY
Information essential to patient management includes accurate diagnosis, the hemostatic level of factor required to achieve the therapeutic goal, the recovery of transfused factor, and the half-life of factor after transfusion. The goal of replacement therapy is to achieve hemostatic levels of the replaced factor using the lowest dose of replacement required. Guidelines for factor replacement have evolved over time; the dosage of factor VIII for various types of bleeding is discussed in Chap. 123) (also see Table 143-3 and Fig. 143-3).

TABLE 143-3 INITIAL REPLACEMENT THERAPY FOR COAGULATION FACTOR DEFICIENCY

FIGURE 143-3 The flow diagram presents a generalized approach to the choice of replacement products for patients with factor VIII deficiency (hemophilia A) or von Willebrand disease. The algorithm may require modification based on specific patient variables and the patient’s response to therapy.

BIOLOGIC HALF-LIFE AND RECOVERY
The biologic half-life of the factor replaced is used to determine the time interval for additional dosage if needed. For factor VIII, the biologic half-life is 8 to 12 h,85 and a dose of 1 U/kg body weight will raise the circulating factor VIII level 2 percent. Factor VIII may be given twice daily. Reconstituted factor VIII concentrate loses little biologic activity at room temperature over several days86 and does not favor bacterial growth,86,87 allowing for continuous infusion of factor VIII. Continuous infusion avoids the unnecessarily high levels of factor VIII that occur immediately after intermittent administration and may decrease clearance of factor VIII, allowing a reduction in the total amount of factor VIII administered.86,88 This method of administration is increasing in popularity.
CHOICE OF PRODUCT
DDAVP is the treatment of choice for patients with mild and moderate hemophilia A who respond with an appropriate rise in plasma factor VIII levels.89 For patients with severe hemophilia A and those with mild or moderate hemophilia A who do not respond to DDAVP, factor VIII replacement is indicated. Plasma can theoretically be used to treat any factor deficiency, but the dose required to obtain a hemostatic level and the required frequency of therapy to sustain a hemostatic level would result in circulatory overload.90 Cryoprecipitate has largely been abandoned for treatment of hemophilia A because of the lack of viral attenuation. Concentrates offer convenience and predictability in dose response. Currently available data suggest little difference regarding safety, efficacy, or convenience.50 The choice of concentrate is problematic, since the potentially safest product, recombinant factor VIII, is both formulated with plasma-derived albumin and more expensive. Cost is a significant issue in product selection. Most physicians who treat hemophilia strongly prefer recombinant factor VIII for those patients who have never been exposed to blood products or have no evidence of transfusion-transmitted viral infections, such as hepatitis or HIV. For patients who are HIV-infected, consideration was initially given to use of highly purified factor VIII, since it caused less immunosuppression,91,92 but other studies have shown no benefit.93 Furthermore, these studies were all done before the advent of HIV-protease inhibitors, and other studies have shown that the progression to AIDS in hemophilia patients is similar to that in other HIV-infected individuals after age is considered.50 For HIV-negative patients who have already been exposed to hepatitis B and C, the choice between intermediate- or high-purity factor VIII concentrate is also unclear; there is currently no evidence to suggest that exposure to the diversity of protein antigens in intermediate-purity concentrates has any negative effect on clinical course.
PRESENCE OR ABSENCE OF AN INHIBITOR
Development of an inhibitor (alloantibody) to the congenitally deficient factor is one of the most serious complications of replacement therapy. Approximately 10 to 15 percent or more of patients with hemophilia A develop an inhibitor to factor VIII, and approximately 2.5 percent of hemophilia B patients develop an antibody to factor IX.94,95,96 and 97 Patients with inhibitors have severely reduced factor half-life. Patients refractory to replacement therapy require alternative means to control bleeding episodes and are candidates for induction of immune tolerance.98,99 Most inhibitors are suspected when a patient fails to respond to replacement therapy appropriately; inhibitor titer is then quantified in vitro by the Bethesda assay.69
Evaluation of Acute Bleeding Episodes in Hemophilia A Patients with Inhibitors Patients with factor VIII inhibitors are categorized as those unlikely to mount an anamnestic antibody response when exposed to allogeneic factor VIII (low responders) and those with a propensity to make such antibodies (high responders).
“Low-responder” patients usually have factor VIII inhibitors of low titer [<5–10 Bethesda units (BU)]. Hemorrhage in these patients is treated with factor VIII concentrates at a dose sufficient to overcome the effect of the anti–factor VIII antibody (20–50 U/kg plus 20 U/kg for every Bethesda unit of inhibitory activity). Following infusion, factor VIII levels should be followed to ensure that the desired effect has been attained.
“High-responder” patients have been treated with numerous approaches, and none has been entirely successful. Porcine factor VIII is used as the primary treatment modality for many “high-responder” patients if the anti–porcine antibody titer is low. Factor VIII concentrates may be effective in treating serious hemorrhage or surgical emergencies in high-responder hemophilic patients whose current inhibitor titers have decayed to less than 5 BU, but even in these patients there is the risk of anamnestic titer increases after factor VIII reexposure. When factor VIII is used, a bolus of 75 to 100 U/kg followed by continuous factor VIII infusion at 4 to 14 U/kg body weight per hour may be successful,100 thereby taking advantage of the time dependence of inhibitor activity. Other options include prothrombin complex concentrates (PCCs), aPCC, or experimentally available recombinant factor VIIa.101,102
Therapeutic Options for Hemophilia A Patients with Inhibitors Porcine factor VIII infusion may produce a persistent, measurable level of factor VIII. In general, patients with inhibitors have a lower anti–porcine factor VIII titer than anti–human factor VIII titer.103 An assay of the patient’s inhibitor titer against porcine factor VIII and its ratio to the inhibitory effect against human factor VIII (cross-reactivity determination) should be performed and used for deciding treatment strategies. Porcine factor VIII concentrate is considered the treatment of choice for life- or limb-threatening bleeding episodes and for surgical procedures in patients with inhibitor titers less than 50 BU without antibodies to porcine factor VIII or with anti–porcine antibody levels less than 20 BU. The starting dose is 100 to 150 U/kg. Additional doses are determined by the patient’s measured factor VIII response. Recovery is less and the half-life of porcine factor VIII is reduced in patients with anti–porcine inhibitor activity; measuring the 10-min posttransfusion factor VIII level rather than residual preinfusion factor VIII levels is recommended for determining efficacy in patients with low-level porcine inhibitors.103
Side effects include mild temperature elevation, nausea, headache, flushing, and occasional vomiting and thrombocytopenia. Patients susceptible to reactions or who have received the product previously are often treated with hydrocortisone and antihistamines intravenously. Increases of anti–porcine factor VIII titer have been reported. Porcine factor VIII is not known to transmit hepatitis or HIV.
PCCs are often used for first-line treatment of routine hemorrhages or for patients with factor VIII inhibitors that cannot be overridden (i.e., anti–human factor VIII inhibitor titer >50 BU and anti–porcine factor VIII titer >15–20 BU),104 since prothrombin complex concentrate may bypass the deficiency in factor VIII. PCC infusions effectively control approximately 50 percent of bleeding episodes experienced by hemophilia A and B inhibitor patients,81,105,106 but the utility of this intervention is limited by the unpredictability and short duration of some responses. Clinical parameters are followed, since there are no laboratory tests to monitor effectiveness.
The initial dose of PCC is 75 to 100 U/kg. Infusions are repeated once or twice at 8- to 12-h intervals if needed. Prolonged treatment should be avoided because of the possibility of thrombotic complications. If repeated doses are given, monitoring of the antithrombin level and for DIC is recommended; concurrent treatment with antifibrinolytic therapy should be avoided.
In one study, aPCC given as a single dose was no more effective than PCC for treatment of acute hemarthroses.106 However, another study found that one or two doses of aPCC controlled 64 percent of mucocutaneous joint and muscle bleeding, compared to 52 percent of similar episodes in which PCC was used.81 There are no laboratory tests to measure the effectiveness of aPCC.
Therapeutic plasma exchange has been used to transiently lower the inhibitor titer107; factor VIII is infused immediately following the plasmapheresis. Hemapheresis techniques, in which the patient’s plasma is perfused over immunoabsorption columns containing staphylococcal protein A, have been used to reduce factor VIII and IX inhibitor levels.98
Recombinant factor VIIa concentrate has been used successfully in the management of acute bleeding and as perioperative prophylaxis in patients with factor VIII and XI inhibitors. The response was judged to be excellent or effective in 81 to 86 percent of surgical bleeds and 92 percent of dental extractions, with very few possible adverse events reported.82 No markers of systemic activation of the hemostatic system were observed during the studies82; one patient made antibody to factor VII.108 It is postulated that the recombinant factor VIIa interacts with tissue factor expressed at the site of vascular injury, resulting in factor X activation, thus “bypassing” the inhibited coagulation factors VIII or IX.109 FDA approval of this product has made it a preferred treatment option.
Immune tolerance induction aimed at suppression of alloantibody production and restoration of responsiveness to factor VIII replacement therapy offers the best long-term approach for patients with inhibitors. International registry data on 158 available patients indicate a 68 percent response rate, with best responses in patients given high-dose daily factor VIII (>100 U/kg body weight per day) and with initial inhibitor titers of less then 10 BU.110 Tolerance was generally long lasting. Dosing schedules and adjunctive maneuvers to optimize this expensive approach to therapy are still being evaluated.104
Treatment of Nonhemophilic Patients with Factor VIII Inhibitors Bleeding problems in nonhemophilic patients with inhibitors are treated with infusion of factor VIII concentrates, PCC, aPCC, or porcine factor VIII.111,112 and 113 The antiporcine inhibitor level should be measured at presentation, and, if it is low, porcine factor VIII should be considered.113 Since most of these patients have not previously received clotting factor concentrates, they are at risk for developing hepatitis B and should be immunized against hepatitis B. High-dose intravenous gamma globulin was reported to be effective in patients with autoantibodies, but not alloantibodies against factor VIII.114,115 Unlike hemophilic patients with inhibitors, most nonhemophilic patients with inhibitors are responsive to prednisone or prednisone plus cytotoxic therapy.116,117
von WILLEBRAND DISEASE
vWD is a heterogeneous set of related bleeding conditions due to quantitative and/or qualitative abnormality of vWF. Normal vWF is required for normal plasma factor VIII levels, and decreased plasma factor VIII levels may be seen in vWD (see Chap. 135).
The most common form of vWD is type I, which accounts for approximately 80 percent of all patients with vWD.118 The vast majority of these patients can avoid treatment with plasma-derived therapeutic products by using the drug DDAVP.89 The optimal dose is 0.3 µg/kg DDAVP intravenously over 30 min or intranasally at a dose of 300 µg for adults or 150 µg for children. Plasma vWF and factor VIII levels are increased two- to fourfold after DDAVP, reaching a peak 30 min to 60 min after intravenous and 60 to 90 min after intranasal administration.119 A DDAVP trial with postinfusion testing is useful, since patients’ responses are variable. Doses may be repeated at intervals of 12 to 24 h, but tachyphylaxis may occur after three or four doses.120 Patients should be counseled to avoid drinking large amounts of water for 18 h after receiving DDAVP because the residual antidiuretic activity of the drug can result in hyponatremia and seizure.121 The risk of inducing acute thrombosis with DDAVP in patients with a predisposing factor is uncertain.122 In patients with severe type I vWD or complete absence of vWF (type III), DDAVP will not be effective, and replacement therapy must be used.
In qualitative variants of vWD (type II vWD), DDAVP induces the release of abnormal vWF. DDAVP may be ineffective to briefly beneficial in type IIA vWD.123 Its use is controversial in type IIB vWD, since thrombocytopenia may worsen.124,125 In general, replacement therapy with a vWF-containing concentrate is used in these patients.
Replacement therapy with pasteurized or SD-treated factor VIII concentrates demonstrated to contain the high-molecular-weight vWF multimers is preferred over nonvirally attenuated cryoprecipitate. Data from an international retrospective study support the efficacy of this approach.126 Filtration during the SD treatment process removes high-molecular-weight multimers of vWF, and thus cryoprecipitate made from SD-treated plasma is not recommended.9 Monoclonal antibody–derived factor VIII concentrates and recombinant factor VIII do not contain vWF and should not be used.127,128 The minimal hemostatic level for vWF is not as clearly established as that for factor VIII, and the role of bleeding time monitoring is unclear.90,129 Most physicians attempt to increase the level of vWF and factor VIII to within the normal range for surgery (80–100 U/dl) and maintain it above 50 U/dl during the postoperative period. The level of correction and duration of treatment in type II variants is less clear, and often treatment must be given on an empirical basis. Factor VIII concentrates (Humate-P) are FDA licensed for this indication but are not assayed for their vWF concentration; published reports of the ratio of vWF ristocetin cofactor activity to factor VIII content help guide therapy (0.53 for Alphanate, Alpha; 2–2.7 for Humate-P, Centeon).130,131 If the patient has had major surgery, replacement therapy must usually be given every 8 to 12 h, as in treatment of severe hemophilia. Similarly to factor VIII, infusion of 1 U/kg body weight will increase the plasma level by approximately 2 U/dl. Since the patient with vWD is fully capable of synthesizing factor VIII if normal vWF is present to stabilize the vWF/factor VIII complex, the apparent survival time of transfused factor VIII is 24 to 36 h, which is longer than the 12 h found in the hemophilic patient.132 The transfused vWF has a normal biologic half-life in the vWD patient of 12 h.118 A recombinant vWF product is in development.133
For dental extractions, a single treatment with DDAVP (for type I vWD) or replacement therapy (for type II or III vWD), together with 5 to 10 days of oral adjunctive treatment with antifibrinolytic agents (e-aminocaproic acid or tranexamic acid) is usually adequate.
“Platelet-type” pseudo-vWD is the result of a defective vWF receptor (GPIb) on platelets and is clinically similar to type IIB vWD,134 with loss of the plasma high-molecular-weight vWF multimers (see Chap. 135). Platelet transfusion is recommended as replacement therapy in these patients.118
PROTHROMBIN COMPLEX CONCENTRATES AND FACTOR IX CONCENTRATES
Table 143-4 summarizes the PCC and factor IX concentrates currently available in the United States.

TABLE 143-4 PROTHROMBIN COMPLEX CONCENTRATES AND FACTOR IX PRODUCTS AVAILABLE IN THE UNITED STATES

PROTHROMBIN COMPLEX CONCENTRATES
PCCs were first developed in 1959, became available in the United States in 1969, and quickly became the mainstay of hemophilia B therapy. Prepared by barium sulfate precipitation followed by column chromatography on various adsorbents,138 these intermediate-purity concentrates of vitamin K–dependent proteins had large amounts of prothrombin and thus acquired the name PCC. Although labeled by factor IX content, currently available PCCs contain variable amounts of factors II, VII, and X; thus, PCC may be useful for therapy of other inherited vitamin K–dependent factor deficiencies.139 PCCs are prepared by DEAE absorption of the Cohn fraction I effluent (Konyne 80, Bayer), DEAE-Sephadex absorption, PEG precipitation (Proplex T, Baxter), or other procedures (Profilnine HT, Alpha; Bebulin VH, Baxter).49,140
Prolonged and repeated use of PCC is associated with adverse events, such as thrombotic complications.141 Potential explanations included contamination with either activated coagulation factors or phospholipid.142,143 In order to prevent these complications, second-generation factor IX concentrates contain only traces of other prothrombin complex factors.144 Thermal stability of factor IX allowed implementation of methods to reduce the risk of virus transmission by PCC and subsequent concentrates; HIV transmission has not been associated with currently available products.49,140
COAGULATION FACTOR IX CONCENTRATES
AlphaNine SD (Alpha) is prepared by ion-exchange and carbohydrate ligand affinity chromatography.145,146 Specific activity levels of 84 to 256 units of factor IX per milligram of protein have been achieved. Mononine (Centeon) is prepared by monoclonal antibody affinity chromatography. Sodium thiocyanate is used to elute factor IX from the column and also destroys HIV. Viral retention ultrafiltration, used in the preparation of both coagulation factor IX concentrates, confers additional viral safety.64 The specific activity is approximately 180 units of factor IX per milligram of protein.147 The recovery of factor IX for each of these products is at least equal to that achieved with PCC. Purified factor IX concentrates entail significantly less risk of thrombogenicity than do PCCs148,149 and are the preferred product when more then one dose of factor is anticipated.150 Antibody to mouse IgG or inhibitors to factor IX have not been reported to date.147
RECOMBINANT FACTOR IX CONCENTRATE
The challenges of producing an extensively posttranslationally modified protein such as factor IX have recently been overcome.151 Genes for factor IX and a soluble form of a paired basic amino acid–cleaving protein (PACE-SOL) were expressed in Chinese hamster ovary cells grown in a bovine protein-free system. The expressed factor IX (BeneFix, Genetics Institute) is purified by serial nonimmunoaffinity chromatographic steps and does not require albumin stabilization, thus avoiding bovine, murine, and human protein exposure during production. Although the half-life of transfused recombinant factor IX is identical to that of plasma-derived factor, the recovery is approximately 28 percent less, requiring dose adjustment for patients switched from plasma-derived factor therapy.152 Although minor differences in phosphorylation and sulfation of the recombinant protein have been noted, inhibitor development has not yet been a concern.
CLINICAL USE OF PROTHROMBIN COMPLEX CONCENTRATES, COAGULATION FACTOR IX CONCENTRATES, RECOMBINANT FACTOR IX, AND FACTORS XI AND XIII AND PROTEIN C CONCENTRATES
Currently, recombinant factor IX or highly purified coagulation factor IX concentrates are preferred to PCC for hemophilia B patients. Although less expensive PCCs are occasionally used when a single dose is sufficient, PCCs are inappropriate in situations where repeated replacement therapy is anticipated (e.g., perioperatively, with large-muscle hematomas, or in situations of life-threatening hemorrhage) or in individuals at increased risk of thrombotic complications, such as patients with liver dysfunction. PCCs are not advised for newborns due to hepatic immaturity; neonates should be considered for recombinant product to avoid the risks of exposure to plasma-derived products. PCC is still a good choice for patients with factor II, VII, or X deficiency when specific viral-inactivated clotting factor concentrates are not available or treatment with plasma is not feasible or ineffective. The levels of factors II, VII, and X vary with manufacturer and lot139 (see Table 143-3).
SELECTION OF DESIRED LEVEL NEEDED FOR REPLACEMENT THERAPY
The biologic half-life of factor IX is 18 to 24 h once equilibrium is established,153 and a dose of 1 U/kg body weight will raise the circulating factor IX level approximately 1 percent. Factor IX may be given in a single daily dose. Calculation of doses of factor IX is discussed in Chap. 123. Increasing the factor IX level to 30 to 40 percent is effective in stopping most routine hemorrhages.146 If the bleeding is limb- or life-threatening, the factor IX level should be raised to 50 to 80 percent and maintained at 30 to 40 percent levels for 7 to 14 days with coagulation factor IX concentrates. For major surgery, the factor IX levels should be increased to 60 to 80 percent just prior to surgery and then maintained above 30 percent for 5 to 7 days and above 15 to 20 percent for 7 to 10 additional days until healing occurs. For prophylaxis against hemorrhage during times of extensive physical activity, the plasma factor IX levels should be raised to 15 to 30 percent. Levels are maintained above 1 percent for patients on primary prophylaxis to prevent the development of joint disease, usually requiring bolus therapy every 2 to 3 days.
ADVERSE EFFECTS ASSOCIATED WITH FACTOR IX THERAPY
Prior to treatment with virally attenuated products, 45 to 57 percent of patients with severe hemophilia B had developed antibodies to HIV, and more than 80 percent were infected with hepatitis.60,135,136 and 137,140,146 These risks have been greatly reduced by the viral attenuation procedures49,57 and are probably eliminated through use of recombinant product.
Following administration of PCC, some patients develop transient fever, chills, headache, flushing, or tingling. PCC administration has been associated with activation of the hemostatic system, thrombosis, and sudden death from myocardial infarction.140,141,154,155 and 156 Factor IX concentrate or recombinant factor IX use should significantly reduce this risk. PCCs are not recommended for treatment of hemostatic abnormalities occurring in patients with liver disease, since thrombotic complications have occurred following PCC infusion in some, but not all, patients. e-Aminocaproic acid should be avoided during PCC or aPCC use.
Between 2.5 and 16 percent of hemophilia B patients develop inhibitors in response to replacement therapy,157 which may present as failure to respond appropriately to replacement therapy or as anaphylaxis.158 Similar to hemophilia A patients with inhibitors, those with titers less than 10 BU may respond to higher-dose therapy,140 and those with titers over 10 BU are usually treated with PCC, aPCC, or recombinant factor VIIa. Induction of immune tolerance has been disappointing in hemophilia B, and several cases of nephrotic syndrome have developed in this setting.159
FACTOR XI CONCENTRATE
There is significant variability in the occurrence of bleeding episodes in patients with factor XI deficiency, which is generally a milder condition than hemophilia A or B. Hemorrhage is reported following surgical procedures in the mouth and oral pharynx or urinary tract, possibly because of the associated high levels of plasminogen activators in these areas.207,208 and 209
Hemorrhage is treated with plasma infusion (»10–20 ml/kg body weight) to raise factor XI activity to 20 to 30 percent. The biologic half-life of infused factor XI is 40 to 84 h, and the half-disappearance time is approximately 2 days. Factor XI concentrates are under development and have been used in Europe.210,211 Consumptive coagulopathy and thrombotic complications have been reported with two European concentrates.212,213
FACTOR XIII CONCENTRATE
Factor XIII deficiency is characterized by delayed wound healing and bleeding with injuries. The very low levels required for normal function (»5%)214 and a long half-life (288 h)215 permit replacement therapy with plasma or cryoprecipitate.10 Factor XIII concentrate is available in Europe.216
PROTEIN C CONCENTRATE
Purpura fulminans may be a presenting symptom complex of either congenital homozygous protein C deficiency32 or acquired disorders, such as meningococcal sepsis.33 Experience with an investigational monoclonal antibody–purified, vapor heat–treated protein C concentrate32 has shown remarkable promise,2,34 and studies are underway to expand this initial experience. Infusion of activated protein C into baboons was demonstrated to prevent septic shock and death in animals challenged with bacterial infusion,12 and studies of recombinant activated protein C therapy are in clinical trial.

FIGURE 143-4 The flow diagram presents a generalized approach to the choice of replacement products for patients with factor IX deficiency (hemophilia B) or other vitamin K–dependent factor deficiencies. The algorithm may require modification based on the specific patient’s response to therapy.

ALBUMIN AND PLASMA PROTEIN FRACTIONS
Albumin and plasma protein fractions are referred to as protein colloid solutions, in contrast to nonprotein colloid solutions, such as hetastarch, dextran, and other synthetic colloid products. Albumin and plasma protein fractions are prepared from plasma, serum, or human placentas. At least 96 percent of the total protein in albumin products is albumin, while a minimum of 83 percent of the total protein in plasma protein fractions is albumin, with immunoglobulins constituting the remaining protein content. Albumin and plasma protein fractions are heated for 10 h or more at 60°C (140°F) to inactivate contaminating viruses. Despite concern about transmission of classic Creutzfeldt-Jakob disease by plasma derivatives, there is no evidence to indicate this has occurred.48
CLINICAL USE OF ALBUMIN AND PLASMA PROTEIN FRACTIONS
The purported benefits of albumin in the treatment of patients with burns or hypoalbuminia and possibly with hypovolemia were questioned in a meta-analysis of 30 randomized, controlled trials comparing recipients of albumin or plasma protein fraction with those receiving no fluid or those receiving crystalloid solution.160 The relative risk of death after albumin administration was 1.46 for hypovolemia, 2.40 for burns, and 1.69 for hypoalbuminemia. The pooled risk of death between albumin and nonalbumin recipients was 6 percent, or 1 additional death for every 17 patients treated with albumin or plasma protein fraction.
In 26 randomized, controlled trials, there was an absolute mortality rate increase of 4 percent, or 4 extra deaths for every 100 patients resuscitated with colloids compared to crystalloids.161
One possible explanation for the adverse events associated with albumin administration is cardiac decompensation secondary to rapid volume replacement and edema, including pulmonary edema, because of albumin leakage from capillaries with increased permeability. In addition, colloid solutions may exert antihemostatic effects and exacerbate thrombocytopenic complications that increase blood loss. Albumin resuscitation during hypovolemic shock also impairs sodium and water excretion and thus may lead to renal insufficiency.162
The University Hospital Consortium guidelines for albumin usage include plasma exchange involving more than 20 ml/kg body weight and short-term usage in conjunction with diuretic therapy for patients with nephrotic syndrome and acute, severe peripheral or pulmonary edema as the only first-line indications for albumin.163,164 These guidelines state that (1) the effectiveness of colloid solutions in the treatment of sepsis has not been demonstrated in clinical trials, (2) crystalloids are considered the initial resuscitation fluid of choice for hemorrhagic shock, (3) colloids should be used in thermal injury after the first 24 h if crystalloids fail to correct hypovolemia, (4) crystalloids are preferred to colloids to prevent complications associated with large-volume paracentesis, and (5) there is limited or inconclusive published supportive evidence for using albumin for patients with severe hypoalbuminemia.
If 25% albumin is diluted to a 5% solution, 0.9% NaCl or 5% dextrose solution should be used. Reports of hemolysis in recipients, including fatal episodes, have been associated with the use of sterile water as a diluent.165
IMMUNOGLOBULINS
Immunoglobulin preparations for intravenous administration are made by cold ethanol fractionation, the Cohn-Oncley process, from plasma pooled from 3000 to 10,000 donations.166,167,168 and 169 The product is treated at pH 4.0 to 4.25 and stabilized with albumin, glucose, maltose, glycerin, or sucrose. The latter has been implicated in the etiology of acute renal failure resulting from osmotic injury to proximal renal tubules.170 Intravenous immunoglobulin (IVIg) products contain more than 95 percent IgG, less than 2.5 percent IgA, and small amounts of IgM. IgG1 varies between 55 to 70 percent, and IgG2 from 0.7 to 2–6 percent.166 The half-life of infused IVIg ranges from 15 to 25 days.
IVIg preparations contain antibodies against multiple infectious agents and anti-idiotype antibodies. In contrast to native IgG, 40 percent of the IgG in IVIg is present as dimers binding double-arm and single-arm F(ab’)2 domains. Sixty percent of the IgG is in monomeric form. IVIg also contains immunomodulating proteins, such as soluble CD4, CD8, and HLA molecules.166
Currently, IVIg is considered to have a minimal risk of transmitting known viruses. Donors are screened and tested for transmissible agents, and HIV and hepatitis B virus are inactivated by the fractionation process. Treatment with the SD process inactivates hepatitis C virus and other lipid-enveloped viruses, such as GBV-C and hepatitis G virus.171 Prior to SD treatment and following donor testing for anti–hepatitis C virus, at least 100 cases of hepatitis C transmission occurred from one IVIg preparation, possibly because removal of donors with anti–hepatitis C antibodies resulted in a reduction of neutralizing hepatitis C antibody.172,173 Transmission of Creutzfeldt-Jakob disease and other spongiform encephalopathy agents is theoretically possible, but the risk is considered minimal.174 Nonetheless, batches of IVIg have been withdrawn because one or more of the donors to a large pool developed the disease subsequent to donation. This factor, production impediments related to regulatory compliance issues, and increases in usage led to shortages of IVIg products in the late 1990s.175
The postulated mechanisms of the immunomodulatory action of IVIg include anti-idiotypic antibody neutralization of pathologic autoantibodies; down-regulation of antibody production; suppression of cytokine activity, since IVIg contains neutralizing antibodies against IL-1a, IL-6, and TNF-a; prevention of Fc receptor–mediated phagocytosis by saturating or altering the affinity of Fc receptors; interfering with the membranolytic attack complex of complement by preventing incorporation of C3 molecules into the C5 convertase assembly; and interfering with antigen recognition by T cells through the actions of soluble CD4, CD8, and MHC-II molecules.166
CLINICAL USE OF INTRAVENOUS IMMUNOGLOBULINS
The FDA-approved indications for IVIg products include treatment of primary immunodeficiency, immune-mediated thrombocytopenia (ITP), Kawasaki syndrome, marrow transplantation in adults, chronic B-cell lymphocytic leukemia, and pediatric HIV-1 infection. In addition, IVIg is used for treatment of “off-label” conditions, such as posttransfusion purpura and chronic inflammatory demyelinating polyneuropathy.166,167 and 168,175,176,177,178,179,180,181,182 and 183
Other uses include prevention of infections in patients with stable multiple myeloma, CMV-negative recipients of CMV-positive organs, hypogammaglobulinemic neonates at risk for infection, intractable epilepsy, systemic vasculitic syndromes, warm-type autoimmune hemolytic anemia, immune-mediated neutropenia, anemia caused by parvovirus B19, neonatal alloimmune thrombocytopenia unresponsive to other treatments, dermatomyositis, polymyositis, decompensation in myasthenia gravis, and severe thrombocytopenia unresponsive to other treatments.166,167 and 168,175,184,185,186,187,188,189 and 190
In light of difficulties in obtaining supplies of IVIg, alternative approaches have been used to reduce IVIg usage. These include infusion of anti-D antibodies, but not monoclonal anti-D, to Rh D–positive patients with ITP and plasmapheresis for patients with autoimmune neuropathies. Intravenous anti-D has been reported to increase the platelet count by more than 50,000/µl in 46 percent of nonsplenectomized patients with ITP or HIV-related ITP.192 Splenectomized patients with chronic ITP had minimal or no response to anti-D therapy.
ADVERSE EFFECTS OF IVIg THERAPY
Mild to moderate headaches occur in up to 10 percent of patients. Chills, myalgias, or chest discomfort may develop following the onset of therapy but respond to slowing the infusion rate. Fatigue, nausea, and fever may persist for 24 h. Anaphylactic reactions occur rarely. Aseptic meningitis has been reported with infusions ranging from 0.2 to 2 g/kg body weight. This syndrome occurs within several hours to 2 days following IVIg administration and resolves within a few days of discontinuing IVIg treatment.193 Acute renal failure, including fatal cases, has been reported predominantly in association with higher doses of preparations containing sucrose that were used during consecutive days. This finding led to recommendations to ensure that patients are adequately hydrated, to consider the risk of sucrose-containing preparations in patients with risk factors for renal insufficiency, to limit the rate at which sucrose-containing preparations are infused, and to monitor renal function in patients receiving IVIg.170
SERINE PROTEASE INHIBITORS
Plasma protease inhibitors are members of the serine protease inhibitor (serpin) superfamily. They play a crucial role in regulation of the coagulation, fibrinolytic, complement, and kinin systems, as well as regulation of cellular proteases. Deficiency of certain serpins is associated with disease states; thus, several serpins have been purified from plasma and made available for therapeutic uses as concentrate.
ANTITHROMBIN
Lyophilized preparations are prepared by subfractionation using cold ethanol precipitation techniques and pasteurization. There has been no evidence of virus transmission associated with infusion of this product.194
Antithrombin inactivates serine proteases of the coagulation cascade through a 1:1 stoichiometric complex of the protease serine-active site and an arginine residue on antithrombin.
Antithrombin is an important regulator of factors Xa and IIa. Their deficiency is associated with increased risk for thrombosis. Standard care of patients with antithrombin deficiency and thrombosis is anticoagulation.195 Concentrates were licensed in the United States for use limited to treatment of patients with hereditary antithrombin deficiency as prophylaxis against thrombosis following surgery or obstetric procedures and for therapeutic use when these patients had thromboembolic events.194
In stable patients with antithrombin deficiency, the half-life of infused antithrombin varies between 60 and 91 h, with an initial half-disappearance time of approximately 22 h. In acute DIC, antithrombin recovery is approximately one-half that achieved in stable patients; the half-life may be as short as 4 h.
Antithrombin concentrates are indicated in patients with hereditary deficiency in the peripartum period and perioperatively to minimize the risk of thrombosis and in certain acute thrombotic conditions.196 There is debate about indications for antithrombin III (AT-III) replacement therapy in patients with acquired AT-III deficiency. Antithrombin supplementation is associated with improved heparin responsiveness in patients requiring extracorporeal circulation during surgery,197 but the heparin resistance seen in patients incurring a thrombosis is rarely due to antithrombin deficiency.198 Definitive clinical results have yet to be established a benefit in DIC or in liver transplantation.196
AT-III replacement dosage is designed to achieve an AT-III level of 120 percent following infusion. Subsequent doses (»60 percent of the loading dose) are determined empirically to maintain levels of 70 to 120 percent.199
C1 ESTERASE INHIBITOR
C1 esterase inhibitor regulates activation of the kinin and complement systems.200 Hereditary deficiency results in hereditary angioedema. A concentrate available in Europe is prepared by anion-exchange chromatography, several precipitation steps, and viral inactivation by a “moist heat” treatment method.201
Hereditary angioedema is characterized by well-circumscribed subepithelial edema involving the extremities, face, larynx, or bowel. Complications may include acute abdominal pain or respiratory distress. Autosomal dominant C1 esterase inhibitor deficiency underlies this condition.202 While androgens and antifibrinolytic medications may prevent attacks, replacement therapy is the only intervention shown to shorten attacks already in progress. FFP has been used successfully during acute attacks,203,204 but the volume of FFP required and the time required for thawing are limitations. Concentrate is available in Europe and has been shown to be effective and safe in a clinical trial.
a1-PROTEINASE INHIBITOR
Originally called antitrypsin, a1-proteinase inhibitor (API) is the primary physiologic inhibitor of neutrophil elastase. Autosomal recessive hereditary deficiency presents with panacinar emphysema.205 Panacinar emphysema due to destruction of alveolar wall develops in the third to fourth decade in the patients with hereditary absence of a1-proteinase; disease develops earlier in smokers.
A commercially prepared concentrate is made from plasma via Cohn fractionation followed by PEG anion-exchange chromatography and pasteurization (Proelastin, Bayer).
The infused material has a terminal-phase half-life of 4.4 days. After infusion, a1-proteinase diffuses into alveolar walls, and sustained levels are found 1 week later in alveolar lavage fluid.206 Weekly replacement therapy is indicated in individuals with hereditary a1-proteinase deficiency and clinically evident panacinar emphysema.
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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