Choice of human plasma preparations for transfusion

Choice of Human Plasma Preparations for Transfusion Celso Bianco

HE RECENT licensure of pooled plasma, solvent/detergent treated (PLAS + SD| V.I. Technologies, Melville, NY) by the US Food and Drug Administration (FDA) brings to three the number of plasma preparations available for transfusion in the United States. The other two preparations are fresh frozen plasma, donor-retested (FFPDR), and the traditional fresh frozen plasma (FFP) product. The newer products have been developed to address concerns about infectious disease transmission by transfusion. Although the therapeutic indications of these three plasma products are fundamentally the same, they differ in their potential to transmit infectious agents, in cost, and in availability. An ad hoc Committee of the American Association of Blood Banks summarized the current knowledge about pooled plasma, solvent detergent treated, x The current review considers the characteristics of the three products (Table 1), the theoretical risks associated with each product (Table 2), elements required for a rational decision, and a pragmatic approach to the prescription of plasma products (Table 3).

T

THE PRODUCTS

The United States Food and Drug Administration has licensed the three products described below. Fresh Frozen Plasma Fresh frozen plasma (FFP), obtained from voluntary donations, is available in volumes of approximately 220 mL (derived from whole blood donations) and 600 mL (derived from apheresis). Both products are frozen within 8 hours of collection (needle in vein) and are subjected to routine donor screening. When the results are negative, they are released for transfusion. 2 From the New York Blood Center, New York, NY. CB is Vice President, Medical Affairs of the New York Blood Center (NYBC). NYBC has a minority financial interest in EL Technologies, the manufacturer of Solvent Detergent Plasma. The American Red Cross is the exclusive distributor of this product in North America. Address reprint requests to Celso Bianco, MD, New York Blood Center, 310 East 67~hSt, New York, N Y 10021. Copyright 9 1999 by W.B. Saunders Company 0887-7963/99/1302-000253.00/0 84

Fres'h Frozen Plasma, Donor Retested Fresh frozen plasma, donor retested (FFP-DR) is collected from individual donors as described above for FFP, either from a whole blood donation (220 mL) or by apheresis into 600-mL bags. Such units are placed in quarantine until the donor returns and is retested at least 112 days (16 weeks) after the initial donation. If the donor is negative on retest, the earlier donation is released for transfusion. The quarantine period and the retesting minimize the risk associated with window period seroconversion for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Pooled Plasma, Solvent~Detergent Treated Pooled plasma, solvent/detergent treated (S/D-P), is prepared from frozen plasma that is thawed, pooled into blood type-specific lots containing no more than 2,500 donations, and treated with tri(nbutyl)phosphate and Triton X-100. These reagents are removed by vegetable oil extraction followed by chromatography. The final product is sterile filtered into 200-mL plastic bags and refrozen. 3 S/D-P has been available in Western Europe for some years. Horowitz, Prince, and Neurath developed the solvent/detergent procedure at the New York Blood Center in the early 1980s. The technology used with whole plasma is similar to that used for the various plasma derivatives, including coagulation factor concentrates. Currently, approximately 70% of plasma products used in the world are subjected to viral inactivation by solvent/detergent technology. The first such product (factor VIII) was licensed by the Food and Drug Administration (FDA) in 1985. 4 The generic properties of the three licensed plasma products are compared in Table 1. INDICATIONS FOR THE TRANSFUSION OF PLASMA PRODUCTS

For the past 15 years, there has been a perception that a proportion of fresh frozen plasma transfusions is unnecessary. The College of American Pathologists in 1994 published practice guidelines for the use of FFP, cryoprecipitate, and platelets. 5 FFP is considered appropriate for the treatment of patients with: (1) history or clinical course suggesTransfusion Medicine Reviews, Vo113, No 2 (April), 1999: pp 84-88

PLASMA PREPARATIONS FOR TRANSFUSION

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Table 1. Characteristics of the Various Plasma Products Available for Transfusion Characteristic

FFP

Synonyms

Fresh frozen plasma

Volume (mL/unit) ABO type specific Source Estimated cost (US$/mL)

220 or 600 Yes Whole blood or apheresis 0.25

FFP-DR

S/D-P

Delayed-release, quarantined, fresh frozen p l a s m a ~ o n o r retested 600 Yes Apheresis 0.40

Pooled plasma, solvent/detergent treated (PLAS + SD| 200 Yes Whole blood or apheresis 0.65

Abbreviations: FFP, fresh frozen plasma; FFP-DR, fresh frozen plasma, donor-retested; S/D-P, pooled plasma, solvent/detergent treated.

tive of coagulopathy congenital or acquired, with active bleeding or before an invasive procedure; (2) a massive transfusion of red blood cells with evidence of coagulation deficiency; (3) a need for reversal of warfarin effect; and (4) management of bleeding and prophylaxis of patients with a congenital deficiency of factor II, V, VII, X, XI, or XIII, clinical evidence of abnormal bleeding (bleeding from venipuncture sites or generalized oozing), and the treatment of patients with thrombotic thrombocytopenic purpura (TTP). PROPERTIES OF THE VARIOUS PLASMA PRODUCTS

According to studies carried out by the manufacturer of S/D plasma for submission to the FDA, the levels of prothrombin, factors V, VII, VIII, IX, X, XI, XIII, and antithrombin were found to be similar to those of pooled FFP (-- 1 unit/mL). Protein C and protein S levels were reduced by 20% to 40%, and Table 2. Summary of Theoretical Risks of Plasma Products Available for Transfusion Risk

Risk for nonenveloped viruses Risk of allergic reactions Risk of TRALI Donor exposures per unit

TTP. 6

Table 3. A Pragmatic Approach to the Choices Available in the Prescription of Plasma Product

Procoagulant/Anticoagulant/Inhibitor Levels in Pooled FFP and in S/D-P

Risk for enveloped viruses

the fibrinogen levels were 2.46 mg/mL for pooled FFP and 2.57 mg/mL for S/D-P. The manufacture release specification is 0.7 units/mL for factors V, VII, X, XI, and XIII, and 1.8 mg/mL of fibrinogen. The levels of high-molecular-weight multimers of von Willebrand factor are substantially diminished in S/D-E making it similar to that of cryosupernatant-poor plasma sometimes used for treatment of

FFP

FFP-DR

S/D-P

Very small (for HIV, 1:675,000; for HCV, 1:103,000") Remote

Remote

None reported

Remote

Small

Small

Small

Small

Small One

Small 1/3

Remote 2,500

Abbreviations: FFP, fresh frozen plasma; FFP-DR, fresh frozen plasma, donor-retested; S/D-P, pooled plasma, solvent/ detergent treated. *Risk per unit.

Indication Thrombotic thrombocytopenic purpura ('l-I'P) Congenital deficiency* of factors II, V, VII, X, XI, XIII Massive transfusion with coagulation deficiencies, multiple blood products Severe liver disease with active bleeding or before invasive procedure, patient negative for hepatitis C virus infection Severe liver disease with active bleeding or before invasive procedure, patient positive for hepatitis C virus infection Reversal of warfarin effect, unlikely to receive other blood products

FFP

FFP-DR

S/DP

+

++

+++

+

++

+++

+++

+

+

+

+++

+++

+++

+

+

+

+

+++

NOTE. + + + , excellent; ++, good; +, satisfactory. Abbreviations: FFP, fresh frozen plasma; FFP-DR, fresh frozen plasma, donor-retested; S/D-P, pooled plasma, solvent/ detergent treated. *Some physicians prefer to prescribe prothrombin complex or purified factor IX concentrates for deficiencies other than those of factor V and XI. It should be noted that these commercial products are virally inactivated but are prepared with much larger plasma pools than S/D-P.

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Comparison of Potential Adverse Reactions (Noninfectious) There are no differences between the three plasma products in terms of expected potential for allergic reactions, headaches, fever, chills, nausea, and so forth. Obviously, in case of an allergic reaction, a different lot of product may be tried in subsequent transfusions. The three plasma products contain immunoglobulin A (IgA) and should not be administered to IgA-deficient patients who possess antibodies to IgA. Theoretically, S/D-P has lower risk of inducing transfusion-related acute lung injury (TRALI), a rare, noncardiogenic pulmonary edema observed following the administration of blood products. TRALI is caused by high-titer antibodies to HLA or to granulocyte-specific antigens. 7 Plasma pooling in the course of S/D-P manufacture dilutes these antibodies. The maximum amount of solvent-detergent reagents present in the final S/D-P product is less than 3 pg/mL (or less than 3 parts per million). The plastic containers used for S/D-P are the same as those used for FFP and FFP-DR. The risk associated with the processing chemicals and bag plasticizers is extremely small.

Risk of Transmission of Infectious Disease The major objective for the development of S/D-P and FFP-DR was the reduction of risk of transmission of infectious diseases associated with the window of seroconversion, that is, the period between donor infectivity and ability of screening tests to detect the infection. The HIV risk in the United States has been estimated recently as 1:675,000 (with the 95% confidence intervals, or CIs, between 1:202,000 and 1:2,777,000) per transfused unit, subsequent to the addition of HIV-l p24 antigen in March 1996. 8 The risk for HCV is 1:103,000 (with the 95% CIs between 1:27,700 and 1:288,000) and for HBV 1:66,000 (with 95% CIs between 1:31,300 and 1:147,000). HTLV does not appear to be transmitted by the transfusion of plasma. The risk of transmission of infection is cumulative and increases proportionally with the number of infusions. Thus, the actual risk of HCV transmission may be 1:1,000 for an individual receiving 100 individual units of FFP. FFP-DR is released only after the donor returns and tests negative for HIV-1/2, HBV, HCV, HTLV-I, and HTLV-II. It is possible, however, that on rare occasions individuals may take longer than the quarantine period to seroconvert. Also, the risk of

CELSO BIANCO

transmission of diseases for which there are no screening tests is the same as that of FFE Solvent-detergent is a highly effective inactivation procedure for lipid-enveloped viruses. S/D-P does not transmit HIV-1/2, HBV, HCV, HTLV-I, HTLV-II, HGV, undetectable mutants of these viruses, or unknown lipid-enveloped viruses. The solvent-detergent procedure, however, is not effective against non-lipid-enveloped viruses, and cases of transmission of hepatitis A and parvovirus B19 by solvent-detergent-treated clotting factor concentrates devoid of IgG (eg, factor VIII) have been documented. 9 As yet, no cases of transmission of HAV or parvovirus B19 have been attributed to S/D-P. Blood donors are not screened for HAV or parvovirus B 19, because these infections are highly prevalent in the general population (30% to 60%) and usually benign. Approximately 1:3,000 units of whole blood contains parvovirus B19 particles detectable by DNA polymerase chain reaction. 1~ Parvovirus B 19 infection is associated with the fifth exanthematous disease of childhood. On rare occasions it affects erythropoiesis and can have serious consequences for pregnant women and for immunocompromised patients. 11 However, the likelihood of transmission of HAV or of parvovirus B19 by S/D-P is remote because pooling guarantees the presence of protective antibodies. For instance, recipients of 10 to 15 mL/kg of S/D-P receive 480 to 1,800 IU of anfi-HAV, a dose that exceeds the dose of intramuscular immunoglobulin recommended for HAV prophylaxis. 12 The protective dose of antibodies to parvovirus B19 in vivo has not been determined. However, anti-B 19 antibodies have been shown to effectively neutralize in vitro infection of erythroid cells. 13 No B19 DNA or hematologic sequelae have been found in patients with hemophilia. 14Immunization of chronic recipients of pooled plasma products against HAV is also recommended using commercially available vaccines. Concern has been expressed that pooling increases the risk of exposure of recipients to known and unknown nonenveloped viruses. Mathematical modeling of pools suggests that units from individual donors (FFP and FFP-DR) carry less risk of transmission of unknown agents than S/D-P, a pooled product. 15 However, the pool size used in the manufacture of S/D-P (up to 2,500 units/lot) is at least one order of magnitude (10- to 20-fold) smaller than that used in the manufacture of

PLASMA PREPARATIONS FOR TRANSFUSION

clotting factor concentrates. Consequently, risks associated with S/D-P pooling are much smaller than those estimated to be associated with the use of clotting factor concentrates. Differences between FFP and the new safetyenhanced products will be reduced even further when genetic amplification technologies for HCV and HIV are applied routinely to blood donor screening. 8 CAN A RATIONALE FOR PRODUCT SELECTION BE DEVELOPED?

The selection of a plasma preparation for prescription to patients is very difficult because none of the available products (or any other biological product) is perfectly safe. Each has its pros and cons. For instance, the risk of HCV transmission is higher for FFP and FFP-DR than for S/D-P. However, the risk of transmission of nonenveloped viruses is higher for S/D-P than for FFP and FFP-DR. Pooling increases the risk of transmission of unknown agents, but most of the agents that threatened the safety of the blood supply in recent years were lipid-enveloped (eg, HIV, HTLV, HCV, HGV). In addition, the multiplicity of plasma products available for transfusion increases the complexity of product management tasks in blood centers and hospital blood banks and theoretically increase the opportunity for errors. The following are issues that may be considered in the choice of a plasma product: 9 The medical indication for the plasma transfusion 9 The total number of units of plasma and noninactivated cellular blood products that the patient is likely to receive in his/her lifetime (the risk of transmission of HIV is 1:675,000 per unit transfused or 1:6,750 per 100 units transfused) 9 Preexisting infection with HCV, common among patients with chronic liver disease who need plasma transfusions 9 Patient concerns about unknown diseases (eg, Creutzfeldt-Jakob Disease, or CJD) and pooled products 9 Product availability 9 Product cost

Basis for a Pragmatic Approach to the Prescription of Plasma Preparations 9 FFP should be considered for patients who are likely to need up to 25 to 50 units of plasma in

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their lifetime. At that level of usage, the maximum cumulative risk of window transmission of HCV is less than 1:2,000 to 1:4,000 for the lifetime of the patient. It should be noted that some physicians believe that even patients with such low risk should receive virally inactivated products. Such physicians reason that even though their lifetime chance of infection is negligible, these patients should be exposed to the minimum possible risk. 9 S/D-P or FFP-DR should be considered for large-volume, long-term users of plasma, such as patients with coagulation factor deficiencies who are likely to receive small amounts of non-virally inactivated blood products. 9 The age of the patient should be taken into consideration. Young patients who are likely to survive their primary disease are more likely to be affected by the morbidity of HCV and HIV associated with transfusion transmission. 9 S/D-P appears to be preferable for the treatment of patients with TTP because of the large number of units required for the treatment of such patients; plasma is the only product transfused; and because of the reduced contents of multimeric yon Willebrand factor in S/D-P. 9 Patient preferences regarding pooled products should always be taken into consideration. Appropriate informed consent is important. A recent publication provides a very useful approach to the communication of transfusion risks, t6 9 Costs: Enhanced safety plasma products are more expensive than FFP (Table 1). A study performed recently suggested that the costs of S/D-P for patients exposed to a limited number of units of product in their lifetime exceeded the acceptable range in terms of additional quality-adjusted life-years obtained. 17 Hopefully, the authors of this study will redo their calculations for chronic, large-volume, multiple-infusion plasma users. Such recalculation should yield more favorable cost/ benefit ratios. FFP-DR is more expensive than FFP because of the quarantine requirements. Table 3 describes one pragmatic approach to the prescription of plasma products based on these considerations. Obviously, different choices also

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CELSO BIANCO

can be supported by the information currently available in the literature.

Issues of Availability Finally, the newer plasma products might not always be available for transfusion. Plasma is obtained from volunteer donors, and shortages occur, particularly of plasma of the AB type. The quarantine and retest of donors of FFP-DR imposes burdensome additional requirements for storage and logistics that at least initially will restrict its availability. Fortunately, the differences in risk of transmission of infectious diseases between FFP, FFP-DR, and S-DP are relatively small, rendering choices based on availability ethically acceptable.

CONCLUSION

The recent licensure of S/D-P and of FFP-DR have increased the choices of plasma products available for transfusion. The selection of the plasma preparation for administration to a given patient has become very difficult, because none of the available products (or any other biological product) is perfectly safe. However, several objective factors will contribute to appropriate decision making, including: the clinical indication for plasma transfusion; the number of units of plasma and noninactivated cellular blood products that the patient is likely to receive; preexisting infection with HCV; patient concerns about pooled products; product availability; and finally, cost.

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concentrates treated with organic solvent and detergent to inactivate viruses. The Italian Collaborative Group. Ann Intern Med 120:1-7, 1994 10. McOmish F, Yap PL, Jordan A, et al: Detection of parvovirus B 19 in donated blood: A model system for screening by polymerase chain reaction. J Clin Microbiol 31:323-328, 1993 11. Zanella A, Rossi F, Cesana C, et al: Transfusion transmitted human parvovirus B19 infection in a thalassemic patient. Transfusion 35:769-772, 1995 12. Protection against viral hepatitis: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 39:2-26, 1990 13. Kurtzman GJ, Cohen BJ, Field AM, et al: Immune response to B19 parvovirus and an antibody defect in persistent viral infection. J Clin Invest 84:1114-1123, 1989 14. Ragni MV, Koch WC, Jordan JA: Parvovirus B19 infection in patients with hemophilia. Transfusion 36:238-241, 1966 15. Lynch TJ, Weinstein DL, Tankersley/(2, et al: Considerations of pool size in the manufacture of plasma derivatives. Transfusion 36:770-775, 1996 16. Lee DH, Paling JE, Blajchman MA: A new tool for communicating transfusion risk information. Transfusion 38:184188, 1998 17. Anbuchon JP, Birkmeyer JD: Safety and cost-effectiveness of solvent-detergent treated plasma. JAMA 272:12101214, 1994