Publications - Fresh Frozen Plasma: Two New Options

Transfusion Medicine Bulletin
Vol. 1, No. 1 - February 1998
Provided in conjunction with America's Blood Centers�.

Despite fresh frozen plasma's (FFP) exceedingly low risk of infectious disease transmission¹, there soon will be two additional transfusion choices for treating patients who need plasma: solvent/detergent treated FFP (SD Plasma) and Fresh Frozen Plasma, donor retested (FFP-DR). A direct, data based, comparison of the theoretical benefits, risks, and costs of SD plasma vs. FFP-DR is not available, but both have potential advantages over the current product (FFP). With licensure of SD Plasma by the Food and Drug Administration (FDA) imminent, it is appropriate to review this product and its alternative, FFP, Donor Retested.

SD Plasma is designed to reduce: (1) the already-low risk of viral transmission by FFP from donors in the infectious, seronegative window period of currently screened viral infections, and (2) the risk of transmission of lipid enveloped viruses not currently recognized as potential threats to transfusion safety.

SD Plasma is to be produced by pooling large numbers of FFP units from volunteer donors. The resulting pools are treated with the solvent tri(N-butyl) phosphate and the detergent triton x-100 to disrupt, with very high efficiency, the lipid envelopes of those viruses most relevant to transfusion medicine. These include HIV-1 and HIV-2, HTLV-I and HTLV-II, HCV, and HBV. Clinical trials and extensive clinical experience world-wide with SD treated clotting factor concentrates, immunoglobulin preparations, and SD Plasma have not documented transmission of enveloped viruses.

Neutralizing activity of antibody in plasma pools may provide protection against some non-enveloped pathogens as well. SD Plasma appears clinically equivalent to FFP for the indications studied, primarily correction of coagulation defects and treatment of thrombotic thrombocytopenic purpura (TTP).

Disadvantages of SD Plasma are also recognized. Most obviously, it is a pooled plasma product. A single donor infected with a pathogen not inactivated by SD treatment can contaminate an entire pool and potentially infect many or all recipients exposed to the pool. For SD Plasma this risk appears vanishingly low from lipid enveloped viruses, but outbreaks of Hepatitis A, a non-enveloped virus, have already been attributed to SD treated Factor VIII concentrates. This is despite the theoretical neutralizing activity of antibody to Hepatitis A Virus from immune donors in very large plasma pools. Hepatitis A Virus generally produces low mortality and only moderate short term morbidity (although recent data suggest a high rate of fulminant hepatitis in patients with chronic HCV who are superinfected with HAV²). However, HAV may be a model for other recognized or unrecognized transmissible pathogens contaminating products derived from plasma pools. These may include Parvovirus B19, new agents of hepatitis, the agent(s) of the spongiform encephalopathies like Creutzfeld-Jakob disease, and unexpected future pathogens.

According to Harvey Alter, MD, of the National Institutes for Health's Department of Transfusion Medicine "...the risk of pooling is greater than the risk of the infections SD technology aims to prevent. Viral inactivation has great potential, but it should not be at the expense of converting single units to pooled products...."³ It is an important perspective that FDA does not view the incremental safety of SD plasma as sufficient to justify removal of FFP from the market.

In an analysis using a baseline incremental cost of SD plasma over FFP of only $20,⁴ the marginal cost-effectiveness was $289,300 per quality-adjusted life-year (QALY) saved by the use of SD Plasma instead of FFP. Most medically accepted interventions fall below $50,000/QALY. In fact, this threshold was exceeded at an incremental cost of $4.04 per unit for SD Plasma. The price of SD Plasma is unknown prior to licensure, but recent estimates fall in ranges twice (or more) those of FFP. Further, the cost-effectiveness model assumed rates of HCV infection more than 10 fold higher than current estimates, and of HIV infection 2-3 fold higher than contemporary rates.

As single-donor testing using gene amplification technology is brought into blood establishments in the next several years, the increment in transfusion safety afforded by SD Plasma and its marginal cost-effectiveness will erode further.

Given the potential risks that SD Plasma, as a pooled product, may transmit non-enveloped viruses and is not cost-effective by usual standards, many independent community blood centers are developing an alternative to FFP.

"Fresh Frozen Plasma, Donor Retested" (FFP-DR) is produced as FFP from single, volunteer, whole blood or apheresis donations by the usual methods. The "standard" FFP is held in quarantine beyond the estimated infectious, seronegative window period for recognized transfusion associated viral pathogens and until the donor returns, is retested and found to be negative by all required tests.

According to the Retrovirus Epidemiology Donor Study (REDS),⁵ the estimated infectious, sero-negative intervals for transfusion-associated viruses are 22 days for HIV (now 16 days with HIV p24 antigen testing), 51 days for HTLV, 82 days for HCV and 59 days for HBV. Accordingly, quarantine for a minimum of 90 days before donor retesting can qualify a unit as FFP-DR is proposed. (FDA will be the final arbiter of the minimum quarantine duration.) Because FFP-DR is biologically identical in all respects to FFP, the important issues raised by FDA in discussions of licensure relate to standard operating procedures at blood establishments adequate to assure appropriate quarantine and release from quarantine of FFP-DR.

The advantages of FFP-DR are straightforward. First, by using only individual repeat donors and maintaining quarantine beyond current estimates of the infectious, seronegative window period, transmission of HIV, HCV, HTLV, and HBV should be minimized.

Second, as a single donor derived product, the disadvantages of plasma pools are not an issue. A donor, and this product, infected with a hypothetical agent not inactivated by SD treatment, will expose only a single recipient.

Third, the incremental costs of producing FFP-DR will be only those of assuring appropriate segregation and storage of quarantined product, the process controls needed to allow accurate labeling and release of the product, and the effort to assure return of donors for a second donation beyond the quarantine minimum. The latter is the most difficult. The experience of centers that have already produced this component suggests that recruitment of frequent repeat donors is the most effective means of accomplishing this. No formal estimates of the costs of such programs are yet available.

Finally, FFP-DR should be readily convertible to cryo-poor plasma which may represent the preferred component for the treatment of TTP, a major indication for the use of frozen plasma. This has not been demonstrated for SD plasma.

It is expected that with the licensure of SD plasma sometime this year, a great deal of effort will be put into the sale of this new product. However, one must keep in mind the relative risks and benefits involved compared with current or other options.

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