MASAC Recommendation # 99
MASAC Resolution on Creutzfeldt-Jakob Disease, new variant CJD, and Plasma-Derived Coagulation Products
The following resolution was approved by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation on May 6, 2000, and adopted by the NHF Board of Directors on June 10, 2000.
Creutzfeldt-Jakob disease (CJD) is a rare but fatal condition associated with a poorly understood transmissible agent that may arise from genetic mutations in the prion protein gene or may be contracted through exposure to infectious material, likely mutated prion proteins. A related disorder, termed new variant CJD (nvCJD), was first described in the United Kingdom in 1996 and was subsequently shown to be related to a CJD-like infection in cattle (mad cow disease). The mode of transmission and the factors that affect disease susceptibility have not been fully defined, and predictions regarding the eventual extent of the nvCJD epidemic are therefore highly imprecise. No confirmed cases of nvCJD have been identified in the United States to date. Collectively, all these diseases in animals and humans are termed transmissible spongiform encephalopathies (TSEs).
In December 1996, the FDA recommended the quarantine and destruction of single donor blood products and pooled plasma derivatives from donors with classic CJD or CJD risk factors. In September 1998, this policy was reversed for pooled plasma derivatives, although the withdrawal of all material from nvCJD donors continued to be advised. In October 1998, the NHF (MASAC Recommendation #88) objected to the decision to reverse policy on CJD-related donations until additional data relating to the infectivity of blood and blood products became available. Specifically, in view of the previously documented transmission of CJD through peripheral inoculation of purified human pituitary extracts, further research on the infectivity of plasma-derived products seemed warranted. In August 1999, the FDA issued a revised guidance for industry on CJD and nvCJD, consistent with the September 1998 policy reversal, and requested public comment. NHF provided supportive comments in the form of a letter to the FDA. New FDA recommendations pertaining to plasma derivatives from donors were issued in the form of Guidance to Industry in November 1999. At the same time, additional data using animal models of CJD appeared in the peer-reviewed literature that provided additional important insights into the natural history of human TSE and the infectivity of fractionated plasma. Extrapolating from these animal data, the authors concluded that the epidemiologic evidence of the absence of human disease transmission through the use of plasma derivatives could most likely be explained by the low levels of infectivity during symptomatic phases of CJD, the absence of infectivity during the preclinical phase of the disease, the reduction of infectivity during plasma processing, and the relatively large amount of infectious material required to produce disease via the i.v. route.
MASAC Resolution on CJD and nvCJD
1. MASAC is reassured by the results of the ongoing epidemiologic studies of CJD and the results of studies showing that levels of spiked TSE agents are greatly decreased during plasma fractionation. Taken together, these data indicate that the transmission of CJD through purified plasma-derived factor concentrates is unlikely. Nonetheless, MASAC supports continuing the FDA recommendations that potential donors diagnosed with CJD or with CJD risk factors should be deferred and that the blood components collected from such donors should not be used in the manufacturing of injectable products, unless they are already in the manufacturing pipeline.
2. In contrast to CJD, there is at present a critical lack of long-term epidemiologic data pertaining to nvCJD. Moreover, known differences in the biology of the two diseases, particularly the finding of the infectious agent of nvCJD in lymphoid tissue, are particularly worrisome. For these reasons, MASAC supports the deferral of donors diagnosed with or at higher risk for nvCJD. Similarly, MASAC agrees with proposed guidelines advising the withdrawal of pooled plasma and its derivatives from donors subsequently diagnosed with nvCJD. This policy should include patients clinically diagnosed with "suspected nvCJD" in cases where the neuropathological specimens are unavailable.
3. MASAC agrees with the FDA and the TSE Advisory Committee that until the scope of the nvCJD epidemic is more fully defined, persons who resided in the U.K. for more than six months during the period 1980 to 1996 should be considered at increased risk for developing nvCJD and therefore should be deferred as blood donors.
4. MASAC recognizes that there is, at present, no conclusive evidence that the infectious agents of CJD or nvCJD can be transmitted through blood or blood products in a clinically relevant setting. However, prion disease has been experimentally transmitted in this manner in animals, and the research is ongoing. MASAC strongly encourages this research including use of newly available murine models of human CJD and the rapid development of a screening test for abnormal prion proteins, its validation and implementation in the national blood collection system.
5. MASAC continues to support surveillance for CJD and nvCJD, particularly among chronic recipients of pooled plasma products.
6. MASAC urges the manufacturers of plasma-derived concentrates to adhere to the FDA recommendations on product labeling.
1. Brown, P et al. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 1998; 38:810-816.
2. Brown, P et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39:1169-1178.
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