Plasma is the liquid portion of blood, containing nutrients, electrolytes (dissolved salts), gases, albumin, clotting factors, hormones, and wastes. Many components of plasma are used, and include treatments for the trauma of burns and surgery and for replacing blood elements that are lacking as a result of disease, such as hemophilia. Table 1 lists the plasma components that are currently available in the United States and their primary uses. The various plasma-derived products are purified from the plasma pool by a process known as fractionation. This process separates plasma proteins based on the inherent differences of each protein. Fractionation involves changing the conditions of the pool (for example, the temperature or the acidity) so that proteins that are normally dissolved in the plasma fluid become insoluble, forming large clumps called precipitate. The insoluble protein can be collected by spinning the solution at high speeds or through filtration. One of the most effective ways for carrying out this process is the addition of alcohol to the plasma pool while simultaneously cooling the pool. For this reason, the process is sometimes called cold alcohol fractionation or ethanol fractionation. This procedure is carried out in a series of steps so that a single pool of plasma yields several different protein products such as albumin and immune globulins. It is estimated that each year, as many as a million patients rely on products manufactured from human plasma: more than 400,000 are given albumin, 15,000 to 18,000 are given factor VIII, 3,000 to 5,000 receive factor IX, greater than 20,000 receive immune globulin intravenous (IGIV), and an estimated 100,000 to 500,000 receive immune globulin intramuscular (IGIM). Additional patients receive a variety of hyperimmune globulins and other specialized products. Plasma used for plasma-derived products manufactured and distributed in the United States can only be collected at facilities registered with the FDA. Centers require donors to provide proof that they are legally in the United States and have a local permanent residence. About 85 percent of plasma is collected from paid donors in a commercial setting and is known as source plasma. Through a process known as plasmapheresis, the plasma is removed and the red cells are reinfused into the donor. The remaining 15 percent of plasma is collected from volunteer donors and is known as recovered plasma. From the whole blood, plasma is “recovered”—that is, the red cells, platelets, and cryoprecipitate are separated for transfusion and the unused plasma is either transfused as plasma or sent for further manufacturing into plasma products. On the basis of a European Union policy position, many European countries are working toward self-sufficiency in plasma products using an all-volunteer system, although most countries continue to depend on U.S. products made from paid donors and on source plasma obtained from U.S. donations. Units of plasma collected as source plasma contain approximately 825 milliliters, while recovered plasma from whole blood donations contain approximately 250 milliliters. Thus, more than three times as many donated units of recovered plasma are required to make up a pool of equal volume to one made up of only source plasma. Approximately 370 paid plasma collection centers annually collect about 11 million liters of plasma from 1.5 million donors, involving a total of approximately 13 million separate donations each year. The industry, through its trade organization, the American Blood Resources Association, maintains a limited national donor deferral registry that is checked for each first-time donor. This is a list of known donors who are unsuitable for further donations because of positive test results. Repeat donors’ records are checked at the plasmapheresis center where the plasma is removed. Most of these centers also ensure that donors are not migrating from one center to another over the 48-hour minimum donation interval.The vast majority of source plasma is processed by four companies: Alpha Therapeutic Corporation, Baxter Healthcare Corporation, Bayer Corporation, and Centeon LLC. An additional 1.8 million liters of plasma are collected annually from approximately 8 million volunteer (not paid) donors who contribute 12 to 13 million whole blood donations. Volunteer donors give blood at American Red Cross blood centers and independent blood centers represented by America’s Blood Centers; the plasma is recovered for further manufacturing. Plasma collected by the American Red Cross is fractionated under contract by Baxter Healthcare and the Swiss Red Cross and returned to the American Red Cross for distribution. Plasma collected at member facilities of America’s Blood Centers is currently sold only to the Swiss Red Cross, which manufacturers the various plasma products and sells them through U.S. distributors. Paid donors typically receive between $15 and $20 for the 2 hours required to remove whole blood, separate the plasma from the cells and serum, and reinfuse the latter back into the donor. Source plasma donors may donate once every 48 hours but no more than twice a week. Whole blood donors can donate only once every 56 days since their red cells are not reinfused as is done with the paid donor. Donor screening is designed to prevent the donation of blood by persons who have known risk factors or other conditions such as low blood pressure. All prospective donors, both paid and volunteer, are screened for medical history and risk behaviors. High-risk donors, those whose blood or plasma may pose a health hazard, are encouraged to exclude themselves. Everyone who seeks to donate plasma must answer a series of behavioral and medical questions. If the answers indicate high risk, the prospective donor is deferred from donating. The screening requirements are completed before the donor is allowed to give plasma. Additionally, paid donors must pass an annual physical examination and a brief medical examination each time they donate. Similarly, volunteer donors undergo a brief medical examination each time they donate. The American Blood Resources Association’s National Donor Deferral Registry is one method by which the plasma industry has attempted to ensure that donors who are presenting to donate for the first time at a plasma center are checked for past deferrals at other centers. The American Red Cross has a similar system that is a national list of those deferred through their blood collection system. Each member facility of America’s Blood Centers maintains its own donor deferral list against which donors are checked. All donors are tested for certain viruses known to be transmissible through blood, including HBV, HCV, and HIV. The specific screening tests check for the presence of hepatitis B surface antigen (HBsAg), antibodies to hepatitis C (anti-HCV), HIV-1 antigen (Ag) and antibodies to HIV types 1 and 2 (anti-HIV). Donors with repeatedly reactive test results are rejected from further donations. (See app. II for more information on testing procedures.) For units found to be reactive on HIV tests, the positive units and all previously donated plasma units not pooled for manufacture in the preceding 6 months are retrieved, and those professional services who receive the plasma products are notified according to federal regulations (21 C.F.R. 610.46). All of the plasma fractionation companies have also received permission from the FDA to begin clinical trials of the polymerase chain reaction (PCR) technique, a more sensitive test that is now available, to detect viral material for HIV, HBV, and HCV. PCR is used to amplify the number of copies of a specific region of DNA or RNA in order to produce enough DNA or RNA to be adequately tested. This technique appears to be able to identify, with a very high probability, disease-causing viruses such as HIV, HBV, and HCV. Because PCR testing detects virus particles at the genetic level, infected donors can be identified days or even months sooner than if only traditional antibody or antigen testing is performed, thus shortening the window period. PCR testing is being investigated using minipools that can combine over 500 individual donations. All plasma used in the manufacturing process that undergoes PCR testing must be nonreactive for that specific test. We calculated the risk of incorporating an infectious unit of plasma into a plasma pool for HIV, HBV, and HCV for both volunteer and paid plasma donors. Overall viral marker rates for HIV, HBV, and HCV are higher among individuals who present themselves to donate at paid plasma centers than among those who come to volunteer blood centers. This is due to higher HCV rates among paid donors. Units that test positive are excluded. The incidence rate of collecting infectious units from donors who are in the window period between the time they become infected and the time they test positive is much higher among paid plasma donors than among volunteer donors. However, a number of safety initiatives have been instituted by paid plasma centers that greatly reduce the likelihood of infectious units being pooled for manufacturing. Nevertheless, the final—or residual—risk of an infectious unit entering a plasma pool remains somewhat higher for paid donors than for volunteer donors. There are at least four potential ways in which viral agents go undetected during donation and may thus be transmitted through blood products.First, there exists a very rare chronic carrier state in which a clinically asymptomatic, yet infectious, donor will persistently test negative on a donation screening test. Second, a viral agent may have a large degree of genetic diversity so that laboratory screening tests fail to identify some infectious donors who harbor an atypical genetic variant. Third, laboratory error in performing screening tests may occur, allowing positive units to be made available for transfusion. Finally, the donor may have a negative laboratory test during the window period before the virus is detected by currently licensed screening tests. The majority of cases in which an infectious donation will be included in a plasma pool is a result of this last circumstance. As a result, modeling techniques have been developed to determine the risk estimates of incorporating these infectious window period units into the blood supply. To determine the marker rate for HIV in plasma donations, we obtained data from California’s Department of Health Services (DHS), which collects information on these rates for volunteer blood donors and paid donors at plasma collection facilities. We obtained information on HIV, HBV, and HCV viral marker rates from the American Red Cross for donors who donate at their centers.