TRANSFUSION Vol. 16
No. 3
May-June, 1976
Special Report
Single Donor Platelet Transfusions: Scientific, Legal, and Ethical Considerations M. WIECKOWICZ From ihe Puger Sound Blood Cenier. Seairle. Washington
W I T H T H E I N C R E A S I N G U S E of platelet transfusions, the development of alloantibodies is posing a serious problem, particularly in patients requiring long-term platelet support. The spectrum of antibody specificity often becomes so broad in these so-called “refractory” patients that only a few donors can be found whose platelets will achieve a therapeutic effect ( i e . , a sustained rise in platelet count associated with a decreased bleeding time). There appears to be little dispute that within families “full-house’’ HLA matched siblings nearly always provide an excellent source of compatible platelets. However, such siblings can be found only in about 25 per c e n t of t h e cases. When nonrelated full-house or fairly closely H L - A matched donors a r e used, the results a r e said to be better than when no attention is paid to H L - A matching. This situation has created some difficult questions regarding the scientific, clinical, legal, ethical, and economic a s p e c t s of developing large-scale programs for platelet support. For example, H L - A typing is costly, time consuming, and not always accurate.
Received for publication October 9, 1975, accepted December 26, 1975. Copies of the complete meeting report are available from the Puget Sound Blood Center, Terry a t Madison, Seattle, Washington 98104.
Furthermore, it may not be the H L - A loci which determine platelet antigenicity but, rather, a closely linked locus. Thus, i t might be preferable a t this time to develop methods for detecting the products of this other locus, leading potentially to accurate platelet crossmatching. Also, there a r e matters of clinical judgment. In thrombocytopenic patients, it may be difficult to distinguish between the refractory state due to allosensitization and i n c r e a s e d p l a t e l e t c o n s u m p t i o n which frequently accompanies infection, metastatic malignancy, o r vascular damage. Even if this distinction could be made in every instance, how should decisions about using selected donors be made to include additional factors such a s prognosis, donor inconvenience, patient consent, and economic burden? I n addition, there is the legal and ethical issue of individual autonomy. Is it appropriate to determine the H L - A type of random blood donors without their knowledge, especially if they will subsequently be requested to undergo repeated plateletpheresis? I f the answer is no, then how can these donors be educated so that if they do give their consent, it will reflect a real knowledge of the possible consequences? Can that consent include an agreement that information about their H L A types may be shared with transfusion centers in other parts of the country or even with organ transplantation teams?
193 Transfusion May-June 1976
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With these problems in mind, the National Heart and Lung Institute and the Division of Hematology of the University of Washington sponsored a two-day meeting in Seattle at the Puget Sound Blood Center on June 16 and 17, 1975. Research scientists holding grants or contracts from the National Institutes of Health for work on platelet collection, matching, and transfusion were invited to report their current results. Also invited were lawyers and social scientists known to be concerned with the special problems of tissue transplantation and informed consent. Summary of Presentations
Overview Dr. Dennis M. Donohue of the Puget Sound Blood Center, Seattle, introduced the conference by stressing that a sound scientific basis is needed for all procedures related to platelet transfusion. Well-controlled scientific data must be gathered to demonstrate that present equipment can produce platelets in sufficient number, that these platelets have physiological effectiveness when transfused, and, most important, that the procedure has a significant effect on morbidity and mortality. I n addition, the moral, ethical, and legal aspects must be considered as well as the education and motivation of donors, since the commitment asked of these donors is greater than that asked of whole blood donors.
Value of HL-A T,vpirtg Dr. Ronald Yankee of the Sidney Farber Cancer Research Institute in Boston reviewed his work of the past several years comparing t h e effects of giving HL-A matched, partially matched, and mismatched platelets to refractory patients. I n his opinion, the major cause of platelet refractoriness is sensitization to HL-A antigens, and specificity within this system needs to be further refined. When patients were given repeated transfusions of random platelets,
Transfusion May-June1976
evidence of alloimmunization usually appeared in about two months, but it could be seen as early as five days after the first transfusion. Predictions of the effectiveness of platelet transfusion based on lymphocyte cytotoxicity were generally successful. However, some patients lacking detectable humoral antibody showed evidence of direct cellular reaction against donor platelets as measured by the mixed lymphocyte culture and cell-mediated lympholysis tests. Dr. Roger Herzig of the National Cancer Institute described a study of 153 patients given 9,000 units of platelets from nonrelated donors selected by computer on the basis of HL-A types. The results were interpreted to establish the value of HL-A matching when transfusing platelet-refractory patients. Not all HL-A matched platelets were effective, however, and in 24 per cent of the cases matched platelets that were originally effective appeared to become incompatible. The duration of compatible response to platelets for all donor-recipient pairs regardless of HL-A match g r a d e was significantly prolonged by removal of the leukocytes, which also reduced the incidence of urticaria and fever. In vitro tests including serotonin release, complement-fixing antibody against platelets, lymphocyte cytotoxicity, and cellmediated lympholysis (direct cytotoxicity) were found not to be very helpful in the selection of donors o r in the prediction of transfusion response for alloimmunized patients. Dr. Herbert A. Perkins of the Irwin Memorial Blood Bank, San Francisco, discussed a study of 24 refractory patients primarily with acute leukemia who received 107 transfusions of platelet concentrates derived by plateletpheresis of HL-A-selected donors. Platelets from related donors matched by either one or both haplotypes and from nonrelated donors who were four-antigen matches almost always gave good results. When platelets from nonrelated donors with less than four antigens matched were used, there was little correlation between platelet
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PLATELET CONFERENCE
response and number of HL-A antigens shared. Nevertheless, platelets from HL-A matched donors tended to give good responses in patients refractory to pooled random platelets. Patients given platelets incompatible by the lymphocyte cytotoxicity test had very poor increments and often had platelet counts well below the preinfusion level. The incompatibility usually could not be detected until several transfusions after the patient became resistant, emphasizing the need for more sensitive techniques. Serial transfusions using the same donor-patient pair frequently resulted in progressively poorer responses even for HL-A identical siblings, suggesting immunization to nonHL-A antigens. The importance of other factors influencing platelet survival in these patients, particularly occult DIC, was emph asized. Dr. Rene J. Duquesnoy of the Milwaukee Blood Center summarized a study comparing degree of HL-A compatibility with transfusion response in refractory thrombocytopenic patients receiving platelets obtained by t h e Haemonetics model 30 procedure. Response was measured in terms of platelet count rise as well as hemostatic effectiveness (bleeding time correction). Results showed that a hemostatically effective platelet transfusion response occurred not just when patient-donor pairs had identical HL-A phenotypes but also when they were partially matched. When donor and patient were mismatched for more than one antigen, platelets were not hemostatically active. The implications are that the number of HL-A-typed donors available for plateletpheresis may not have to be as large as previously thought nor will the burden on individual donors be so great. It remains to be determined which antigens are most likely to be nonimmunogenic in patients of various phenotypes. Serologic crossreactivity, which has been used as an indicator of antigenic similarity, may not be a valid guide for predicting the likelihood of al loan ti body stimulation.
195
Neither is there a good method at the present time for the detection of antiplatelet antibodies. Dr. Kamal K. Mittal of Northwestern University described a study of 43 thrombocytopenic patients who received 69 transfusions of HI,-A matched o r mismatched platelets labeled with W r . The results appeared to confirm that survival of transfused platelets from HL-A matched single donors was consistently superior to those pooled from several grossly mismatched donors. Multiple infusions from matched donors did not appear to induc’e immunological sensitization or refractoriness in patients as determined by platelet survival. Survival of platelets infused when the patient had circulating lymphocytotoxic antibodies was consistently lower than when patients did not have such antibodies. Finally, platelets collected by the conventional method had lower average survival than those collected by Haemonetics, which in turn had lower average survival than those collected by Cell t rifuge. Dr. Paul Terasaki of the University of California at Los Angeles discussed the accuracy of HL-A typing and presented the results of a comparative study of 100 laboratories in Europe, Africa, Asia, and the United States. For many of the white blood cell specimens tested, the percentage of agreement among laboratories on the antigens of the first locus was high, with considerably less agreement on those of the second locus. The majority of the laboratories scored with 90 per cent or greater detection of the well-defined HL-A antigens. Results for antigens such as W5, W22, and W19 were much more variable, reflecting the difficulties of typing mixed antigens. Ten years after the discovery of HL-A the agreement among laboratories for perhaps half of the antigens is good. For the other half, definitions are constantly improving and it is hoped that international exchange will foster greater agreement. In the future, if
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wide-scale typing of donors for platelet transfusions is to occur, the system will have to be automated.
Value of Platelet Crossmatching Dr. John Hoak of the University of Iowa, Iowa City, described his use of the platelet aggregation test to select platelet donors for refractory patients. Family members whose p l a t e l e t s were not aggregated by t h e patient’s serum appeared to be superior as donors when compared with those whose platelets were aggregated. Donors selected in this manner also showed the best HL-A match. Similar tests with nonrelated donors have not yet been carried out. A high proportion (1 1 / 14) of patients refractory to random donor platelets were found to have antibodies causing platelet aggregation. Dr. Sherrill Slichter of the Puget Sound Blood C e n t e r , S e a t t l e , used fibrinogen turnover to differentiate causes of platelet transfusion refractoriness. I f refractoriness is due to consumptive states, both platelet and fibrinogen survival are shortened at a comparable rate, but if alloimmunization is the cause, only platelet survival is shortened. Because H L - A typing alone did not con si s t en t I y predict corn pa ti bl e p I a tel et donors, two platelet crossmatching tests were evaluated. One used the release of radiolabeled adenine and serotonin incorporated within the platelet as a measure of immune platelet injury. The other was a radioimmunoassay resembling the Coombs consumption t e s t except using column separation. Results indicated that the two tests tended to go in parallel and had predictive value. While platelet recovery was predicted quite well, the tests did not necessarily predict platelet survival. Dr. Jon P. Gockerman of the University of Kentucky, Lexington, pointed out that implementation of a large computer-based HL-A platelet matching program was beyond the financial capability of many medical centers. He described a technically simple and inexpensive test to predict platelet compati-
Transfusion May-June 1976
bility, the serotonin release assay. T h e assay measures the reactivity of the patient serum against the donor platelets through amount of radiolabeled serotonin released in the presence of antiplatelet antibodies. T h e test proved more sensitive than complement fixation and lymphocyte cytotoxicity in detecting platelet antibodies. When used with family members, the serotonin release assay, like the platelet aggregation test, appeared to be helpful in selecting compatible p l a t e l e t donors. Current Status of Plat eletpheresis
Dr. E. Alannah Ruder of Northwestern University compared two continuous flow centrifuge systems, the Aminco Celltrifuge and the Haemonetics model 30, which differ primarily in centrifuge speed and anticoagulant used. Both were reported to be efficient m e a n s for consistently producing l a r g e amounts of platelets from single donors. T h e Celltrifuge gave the highest platelet yield per hour. The cost per unit of platelets was also highest, exceeding that of Haemonetics and conventionally prepared platelets by $8 and $1 3, respectively. No significant donor complications occurred, and the ultrastructure of platelets collected by both machines was normal. Tests of ADP-, epinephrine-, and collagen-induced aggregation a s well a s serotonin uptake and release showed in vitro platelet function to be normal for platelets collected by the Celltrifuge but altered for those collected by Haemonetics. Final judgment on the utility of platelets collected by the Haemonetics model 30 will depend on in vivo evaluation of platelet function. Dr. John A. Koepke of the University of Iowa presented a comparison between the standard double plateletpheresis method and the Haemonetics model 10. Both systems had similar efficiency of harvest ( - 45%), and both harvested the smaller platelets which apparently survived equally well in normal recipients as measured by chromium techniques. White blood cell contamination using the Haemonetics technique (I5 to 20 per 10,-
Volume 16 Number 3
PLATELET CONFERENCE
000 platelets) was significantly lower than by the standard method, which may mean less antigenic stimulus to the recipient. With the Haemonetics procedure, there is less risk to the donor because of continuous connection with the machine. Similarly, there a r e fewer problems with immunoglobulin deficiencies and protein loss since nearly all plasma is returned to the donor. The Haemonetics provides cheaper production only if large numbers of platelets a r e required. Potential dangers to donors on a continuous platelet production program remain to be resolved. Existing Platelet Donor Progranis Dr. Robert G. C r a w of the National Cancer Institute described the development of the National Platelet Donor Pool funded by t h e National H e a r t and Lung Institute and t h e National C a n c e r Institute. Initially, t h e pool consisted of family and friends of NCI patients a s well a s platelet donors actively recruited through advertising. L a t e r HL-A-typed individuals from other institutions were incorporated to enable sharing of platelets and blood components selected by HL-A factors. Donors would be plateletpheresed in their local communities and platelets would be shipped for refractory patients. T o standardize HL-A typing among participating laboratories, results on test cells were compared and typing reagents exchanged. T h e computerprocessed file was structured to hide the identity of donors by using identification numbers known only to the local institution. Complications arose when it was desired to utilize the file for bone marrow transplantation donors. Subsequently t h e pool was separated into two groups: donors who agreed to have HL-A typing done a s a source of blood product transfusion and those who additionally consented to be contacted about other research studies. Expansion of the pool to interested blood banks and cancer centers is now being implemented on request. Dr. Herbert A. Perkins described the platelet program developed in collaboration
197
with Dr. Rose Payne a t the Irwin Memorial Blood Bank in San Francisco. Because of the routine performance of red blood cell phenotyping on blood donors without explicit permission, it was felt that permission to do HLA typing was not required. Approximately 3,000 voluntary blood donors have been typed to date. A confidential computer file is maintained a t the blood bank, and the HL-A types a r e entered by an in-house identification number into the National Platelet Donor Pool. I f a donor is needed for plateletpheresis for a specific patient, a physician makes the initial phone contact and a fully informed consent is obtained. About 80 to 90 per cent of the people called consent to the procedure. It remains to be seen whether the response will remain this excellent a s requests become more frequent. Dr. Donald J. Filip described the platelet program at the Milwaukee Blood Center developed two years ago to meet increasing needs for histocompatible platelets. Two fulltime technicians routinely HL-A type about 3,000 voluntary blood donors annually and also screen the serum of multigravida women for antibodies useful in tissue typing. Specific permission for HL-A typing is not obtained because the file is used only for another form of blood donation-plateletpheresis. When matched platelets a r e needed, a potential donor is contacted, the procedure described, and a consent obtained. Acceptance rate is 90 to 95 per cent. Nonrelated donors a r e used in preference to family members because emotional entanglements a r e avoided and a number of donors a r e available. While platelets have been shipped to other centers, the file has not been entered into the National Platelet Donor Pool. Dr. William Miller of the Red Cross Blood Center in Saint Louis summarized efforts within the Red Cross to develop a national p r o g r a m for providing h i s t o c o m p a t i b l e p l a t e l e t s . P a r t i c i p a t i n g c e n t e r s a r e enc o u r a g e d t o use existing H L - A typing facilities, but some a r e developing their own capability. To assure uniform typing results,
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WIECKOWICZ
procedures for quality control are being implemented, and a national typing tray is in development. T h e pheresis capability is already well established. Still to be confronted a r e i n t e r c e n t e r problems of shipment, charges, registry, and storage as well as donor motivation, consent, and whether information will be shared with non-Red Cross facilities.
Ethical and Legal Considerations Dr. Arno G. Motulsky of the Division of Medical Genetics, University of Washington, discussed the development of a platelet program in the context of current economic and social trends. First, the exponential growth of technoogy in the biomedical field has resulted in increasingly large allocations of resources to health care. Since the impact of this technology on morbidity and mortality of the adult population has not been striking, questions of accountability and cost effectiveness h a v e been raised. N e w platelet technology must be evaluated along these lines before c o m m i t m e n t to p r o g r a m development. T h e specific indications for platelet transfusions must be identified, the national need assessed, the costs computed, and the regional distribution of centers planned . Second, the centralization and depersonalization of urban society has resulted in a countertrend emphasizing individual rights and distrust of authority. These events, coupled with the broader implications of HL-A typing on transplantation research, require that a platelet program be based on full disclosure and careful evaluation of practices of donor motivation and consent. For example, the red blood cell program could be used to study the psychology of the volunteer donor and the motivating role of idealism, social recognition, or monetary payment. Control studies would be useful to compare responses of donors signing routine red blood cell consent forms, those consenting to participate in research studies, and those receiving detailed explanation of both forms. Based on
Transfusion May-June 1976
hard scientific data, it should be possible to design a platelet program that does not interfere with personal liberties. Dr. Judith Swazey of the Department of Sociomedical Sciences, Boston University, presented data from a two-year study of organ donor programs and related her findings to the platelet donor program. The pattern of interaction consistently observed in organ donation was that of gift exchange with reciprocal obligations of giving, receiving, and repayment. Complications arose over the magnitude of the gift. Within families there were strong pressures on the donor to give the gift, on the ill person to accept it, and great difficulties surrounding repayment. Debtor-creditor relationships frequently developed or the donor felt justified in exerting authoritarian control over the recipient. In the case of nonrelated donors, health care professionals had difficulty accepting altruism as the motivating factor and tended to suspect psychopathology. Despite elaborate screening and informed consent procedures, donors reported that their decision to donate was made almost instantaneously. What are the implications of these findings for platelet donation? The gift of life theme used in several existing platelet d o n o r r e c r u i t m e n t p r o g r a m s h a s established platelet donation as a form of gift exchange. Consequently problems similar to those encountered in organ donation will arise. One suggested approach has been to avoid family members as donors and to maintain donorrecipient anonymity. Whether payment for the donation will alter the obligations of gift exchange remains to be seen. Finally, informed consent is difficult to manage because the donor’s role has been inflated in an attempt to motivate him. M r . R o g e r Dworkin of t h e Indiana University School of Law discussed the informed consent doctrine, a tool by which the law a t t e m p t s after-the-fact regulation of technological development. In the medical treatment context, the current legal standard is that the patient must be given all infor-
Volume 16 Number 3
PLATELET CONFERENCE
mation that is material ( i . e . ,all that a responsible person would use to make a reasoned rather than emotional decision). In the experimental setting, requirements for informed consent must be met before a research proposal is approved. There must be fair explanation of procedures, risks, benefits, and alternative procedures, an offer to answer questions, and a stipulation that consent may be freely withdrawn. Whether platelet donation is characterized as experimental or nonexperimental, information on the purpose of HL-A typing, the potential physical, psychological, and social risks, and the probable benefits to the recipient must be given at the time of initial donation. Consenting to a procedure means only that the donor has agreed to having it competently done. Thus, if negligence occurs, the donor can recover a damage award. A signed consent form does not obligate the donor to continue in the program, even if termination injures the recipient. Mr. Michael Shapiro of the University of Southern California Law Center reviewed donor motivation and consent emphasizing the principle of personal autonomy. H e criticized the practice of paternalism in donor selection: potential d o n o r s a r e screened using unscientific judgments of motives or emotional stability. Instead, there should be a presumption of competence and a commitment to personal autonomy. This does not mean that donor selection is casual; rather, it necessitates the most rigid requirements of informed consent so that decisions are based on full and complete information. In the context of platelet donation, disclosure must be made at initial contact that blood will be HL-A typed and that the donor might be called repeatedly to undergo plateletpheresis. Since a matched platelet donor program requires computerized banks of information on donor locations and HL-A types, security measures must be carefully planned to guarantee that only authorized persons have
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access to the data. It is not enough to rely upon the honesty and good intentions of existing scientists and blood bank personnel.
Planning an Ideal Platelet Donor Program After the individual presentations, participants engaged in an open discussion of the following aspects of an ideal matched platelet donor program: 1 ) appropriate recruitment techniques; 2) a reliable donor education/information system; 3) mechanisms for informed consent; and 4) effective physician education. General consensus was apparent in several areas. First, while the development of effective educational programs for donor recruitment and consent is essential, the complexity of the information requires some staggering of delivery according to the level of commitment of the donor. However, if a follow-up request is plainly anticipated, the donor must be told. As computerized data sharing, plateletpheresis, and m a t c h e d platelet donor programs are developed, potential donors should receive much more detailed descriptions and explanations of the programs and signify their understanding by signing an informed consent document. I n this regard, a number of consent forms should be developed, including forms for HLA typing, information sharing and computer storage, plateletpheresis, matched platelet donor programs, and transplantation. Such forms should be circulated among participating scientists as well as to public and government agencies to insure maximum agreement and uniformity. At the same time, educational materials should be shared and evaluated by participating scientists t o develop ‘the most effective donor education possible. Finally, a plan for management of computer data is essential. Procedures for maintaining the confidentiality of donor typing information, names, and locations should continue to be discussed until a uniform policy is established.
No. 3
May-June, 1976
Special Report
Single Donor Platelet Transfusions: Scientific, Legal, and Ethical Considerations M. WIECKOWICZ From ihe Puger Sound Blood Cenier. Seairle. Washington
W I T H T H E I N C R E A S I N G U S E of platelet transfusions, the development of alloantibodies is posing a serious problem, particularly in patients requiring long-term platelet support. The spectrum of antibody specificity often becomes so broad in these so-called “refractory” patients that only a few donors can be found whose platelets will achieve a therapeutic effect ( i e . , a sustained rise in platelet count associated with a decreased bleeding time). There appears to be little dispute that within families “full-house’’ HLA matched siblings nearly always provide an excellent source of compatible platelets. However, such siblings can be found only in about 25 per c e n t of t h e cases. When nonrelated full-house or fairly closely H L - A matched donors a r e used, the results a r e said to be better than when no attention is paid to H L - A matching. This situation has created some difficult questions regarding the scientific, clinical, legal, ethical, and economic a s p e c t s of developing large-scale programs for platelet support. For example, H L - A typing is costly, time consuming, and not always accurate.
Received for publication October 9, 1975, accepted December 26, 1975. Copies of the complete meeting report are available from the Puget Sound Blood Center, Terry a t Madison, Seattle, Washington 98104.
Furthermore, it may not be the H L - A loci which determine platelet antigenicity but, rather, a closely linked locus. Thus, i t might be preferable a t this time to develop methods for detecting the products of this other locus, leading potentially to accurate platelet crossmatching. Also, there a r e matters of clinical judgment. In thrombocytopenic patients, it may be difficult to distinguish between the refractory state due to allosensitization and i n c r e a s e d p l a t e l e t c o n s u m p t i o n which frequently accompanies infection, metastatic malignancy, o r vascular damage. Even if this distinction could be made in every instance, how should decisions about using selected donors be made to include additional factors such a s prognosis, donor inconvenience, patient consent, and economic burden? I n addition, there is the legal and ethical issue of individual autonomy. Is it appropriate to determine the H L - A type of random blood donors without their knowledge, especially if they will subsequently be requested to undergo repeated plateletpheresis? I f the answer is no, then how can these donors be educated so that if they do give their consent, it will reflect a real knowledge of the possible consequences? Can that consent include an agreement that information about their H L A types may be shared with transfusion centers in other parts of the country or even with organ transplantation teams?
193 Transfusion May-June 1976
Volume 16 Number 3
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WIECKOWICZ
With these problems in mind, the National Heart and Lung Institute and the Division of Hematology of the University of Washington sponsored a two-day meeting in Seattle at the Puget Sound Blood Center on June 16 and 17, 1975. Research scientists holding grants or contracts from the National Institutes of Health for work on platelet collection, matching, and transfusion were invited to report their current results. Also invited were lawyers and social scientists known to be concerned with the special problems of tissue transplantation and informed consent. Summary of Presentations
Overview Dr. Dennis M. Donohue of the Puget Sound Blood Center, Seattle, introduced the conference by stressing that a sound scientific basis is needed for all procedures related to platelet transfusion. Well-controlled scientific data must be gathered to demonstrate that present equipment can produce platelets in sufficient number, that these platelets have physiological effectiveness when transfused, and, most important, that the procedure has a significant effect on morbidity and mortality. I n addition, the moral, ethical, and legal aspects must be considered as well as the education and motivation of donors, since the commitment asked of these donors is greater than that asked of whole blood donors.
Value of HL-A T,vpirtg Dr. Ronald Yankee of the Sidney Farber Cancer Research Institute in Boston reviewed his work of the past several years comparing t h e effects of giving HL-A matched, partially matched, and mismatched platelets to refractory patients. I n his opinion, the major cause of platelet refractoriness is sensitization to HL-A antigens, and specificity within this system needs to be further refined. When patients were given repeated transfusions of random platelets,
Transfusion May-June1976
evidence of alloimmunization usually appeared in about two months, but it could be seen as early as five days after the first transfusion. Predictions of the effectiveness of platelet transfusion based on lymphocyte cytotoxicity were generally successful. However, some patients lacking detectable humoral antibody showed evidence of direct cellular reaction against donor platelets as measured by the mixed lymphocyte culture and cell-mediated lympholysis tests. Dr. Roger Herzig of the National Cancer Institute described a study of 153 patients given 9,000 units of platelets from nonrelated donors selected by computer on the basis of HL-A types. The results were interpreted to establish the value of HL-A matching when transfusing platelet-refractory patients. Not all HL-A matched platelets were effective, however, and in 24 per cent of the cases matched platelets that were originally effective appeared to become incompatible. The duration of compatible response to platelets for all donor-recipient pairs regardless of HL-A match g r a d e was significantly prolonged by removal of the leukocytes, which also reduced the incidence of urticaria and fever. In vitro tests including serotonin release, complement-fixing antibody against platelets, lymphocyte cytotoxicity, and cellmediated lympholysis (direct cytotoxicity) were found not to be very helpful in the selection of donors o r in the prediction of transfusion response for alloimmunized patients. Dr. Herbert A. Perkins of the Irwin Memorial Blood Bank, San Francisco, discussed a study of 24 refractory patients primarily with acute leukemia who received 107 transfusions of platelet concentrates derived by plateletpheresis of HL-A-selected donors. Platelets from related donors matched by either one or both haplotypes and from nonrelated donors who were four-antigen matches almost always gave good results. When platelets from nonrelated donors with less than four antigens matched were used, there was little correlation between platelet
Volume 16 Number 3
PLATELET CONFERENCE
response and number of HL-A antigens shared. Nevertheless, platelets from HL-A matched donors tended to give good responses in patients refractory to pooled random platelets. Patients given platelets incompatible by the lymphocyte cytotoxicity test had very poor increments and often had platelet counts well below the preinfusion level. The incompatibility usually could not be detected until several transfusions after the patient became resistant, emphasizing the need for more sensitive techniques. Serial transfusions using the same donor-patient pair frequently resulted in progressively poorer responses even for HL-A identical siblings, suggesting immunization to nonHL-A antigens. The importance of other factors influencing platelet survival in these patients, particularly occult DIC, was emph asized. Dr. Rene J. Duquesnoy of the Milwaukee Blood Center summarized a study comparing degree of HL-A compatibility with transfusion response in refractory thrombocytopenic patients receiving platelets obtained by t h e Haemonetics model 30 procedure. Response was measured in terms of platelet count rise as well as hemostatic effectiveness (bleeding time correction). Results showed that a hemostatically effective platelet transfusion response occurred not just when patient-donor pairs had identical HL-A phenotypes but also when they were partially matched. When donor and patient were mismatched for more than one antigen, platelets were not hemostatically active. The implications are that the number of HL-A-typed donors available for plateletpheresis may not have to be as large as previously thought nor will the burden on individual donors be so great. It remains to be determined which antigens are most likely to be nonimmunogenic in patients of various phenotypes. Serologic crossreactivity, which has been used as an indicator of antigenic similarity, may not be a valid guide for predicting the likelihood of al loan ti body stimulation.
195
Neither is there a good method at the present time for the detection of antiplatelet antibodies. Dr. Kamal K. Mittal of Northwestern University described a study of 43 thrombocytopenic patients who received 69 transfusions of HI,-A matched o r mismatched platelets labeled with W r . The results appeared to confirm that survival of transfused platelets from HL-A matched single donors was consistently superior to those pooled from several grossly mismatched donors. Multiple infusions from matched donors did not appear to induc’e immunological sensitization or refractoriness in patients as determined by platelet survival. Survival of platelets infused when the patient had circulating lymphocytotoxic antibodies was consistently lower than when patients did not have such antibodies. Finally, platelets collected by the conventional method had lower average survival than those collected by Haemonetics, which in turn had lower average survival than those collected by Cell t rifuge. Dr. Paul Terasaki of the University of California at Los Angeles discussed the accuracy of HL-A typing and presented the results of a comparative study of 100 laboratories in Europe, Africa, Asia, and the United States. For many of the white blood cell specimens tested, the percentage of agreement among laboratories on the antigens of the first locus was high, with considerably less agreement on those of the second locus. The majority of the laboratories scored with 90 per cent or greater detection of the well-defined HL-A antigens. Results for antigens such as W5, W22, and W19 were much more variable, reflecting the difficulties of typing mixed antigens. Ten years after the discovery of HL-A the agreement among laboratories for perhaps half of the antigens is good. For the other half, definitions are constantly improving and it is hoped that international exchange will foster greater agreement. In the future, if
196
WIECKOWICZ
wide-scale typing of donors for platelet transfusions is to occur, the system will have to be automated.
Value of Platelet Crossmatching Dr. John Hoak of the University of Iowa, Iowa City, described his use of the platelet aggregation test to select platelet donors for refractory patients. Family members whose p l a t e l e t s were not aggregated by t h e patient’s serum appeared to be superior as donors when compared with those whose platelets were aggregated. Donors selected in this manner also showed the best HL-A match. Similar tests with nonrelated donors have not yet been carried out. A high proportion (1 1 / 14) of patients refractory to random donor platelets were found to have antibodies causing platelet aggregation. Dr. Sherrill Slichter of the Puget Sound Blood C e n t e r , S e a t t l e , used fibrinogen turnover to differentiate causes of platelet transfusion refractoriness. I f refractoriness is due to consumptive states, both platelet and fibrinogen survival are shortened at a comparable rate, but if alloimmunization is the cause, only platelet survival is shortened. Because H L - A typing alone did not con si s t en t I y predict corn pa ti bl e p I a tel et donors, two platelet crossmatching tests were evaluated. One used the release of radiolabeled adenine and serotonin incorporated within the platelet as a measure of immune platelet injury. The other was a radioimmunoassay resembling the Coombs consumption t e s t except using column separation. Results indicated that the two tests tended to go in parallel and had predictive value. While platelet recovery was predicted quite well, the tests did not necessarily predict platelet survival. Dr. Jon P. Gockerman of the University of Kentucky, Lexington, pointed out that implementation of a large computer-based HL-A platelet matching program was beyond the financial capability of many medical centers. He described a technically simple and inexpensive test to predict platelet compati-
Transfusion May-June 1976
bility, the serotonin release assay. T h e assay measures the reactivity of the patient serum against the donor platelets through amount of radiolabeled serotonin released in the presence of antiplatelet antibodies. T h e test proved more sensitive than complement fixation and lymphocyte cytotoxicity in detecting platelet antibodies. When used with family members, the serotonin release assay, like the platelet aggregation test, appeared to be helpful in selecting compatible p l a t e l e t donors. Current Status of Plat eletpheresis
Dr. E. Alannah Ruder of Northwestern University compared two continuous flow centrifuge systems, the Aminco Celltrifuge and the Haemonetics model 30, which differ primarily in centrifuge speed and anticoagulant used. Both were reported to be efficient m e a n s for consistently producing l a r g e amounts of platelets from single donors. T h e Celltrifuge gave the highest platelet yield per hour. The cost per unit of platelets was also highest, exceeding that of Haemonetics and conventionally prepared platelets by $8 and $1 3, respectively. No significant donor complications occurred, and the ultrastructure of platelets collected by both machines was normal. Tests of ADP-, epinephrine-, and collagen-induced aggregation a s well a s serotonin uptake and release showed in vitro platelet function to be normal for platelets collected by the Celltrifuge but altered for those collected by Haemonetics. Final judgment on the utility of platelets collected by the Haemonetics model 30 will depend on in vivo evaluation of platelet function. Dr. John A. Koepke of the University of Iowa presented a comparison between the standard double plateletpheresis method and the Haemonetics model 10. Both systems had similar efficiency of harvest ( - 45%), and both harvested the smaller platelets which apparently survived equally well in normal recipients as measured by chromium techniques. White blood cell contamination using the Haemonetics technique (I5 to 20 per 10,-
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000 platelets) was significantly lower than by the standard method, which may mean less antigenic stimulus to the recipient. With the Haemonetics procedure, there is less risk to the donor because of continuous connection with the machine. Similarly, there a r e fewer problems with immunoglobulin deficiencies and protein loss since nearly all plasma is returned to the donor. The Haemonetics provides cheaper production only if large numbers of platelets a r e required. Potential dangers to donors on a continuous platelet production program remain to be resolved. Existing Platelet Donor Progranis Dr. Robert G. C r a w of the National Cancer Institute described the development of the National Platelet Donor Pool funded by t h e National H e a r t and Lung Institute and t h e National C a n c e r Institute. Initially, t h e pool consisted of family and friends of NCI patients a s well a s platelet donors actively recruited through advertising. L a t e r HL-A-typed individuals from other institutions were incorporated to enable sharing of platelets and blood components selected by HL-A factors. Donors would be plateletpheresed in their local communities and platelets would be shipped for refractory patients. T o standardize HL-A typing among participating laboratories, results on test cells were compared and typing reagents exchanged. T h e computerprocessed file was structured to hide the identity of donors by using identification numbers known only to the local institution. Complications arose when it was desired to utilize the file for bone marrow transplantation donors. Subsequently t h e pool was separated into two groups: donors who agreed to have HL-A typing done a s a source of blood product transfusion and those who additionally consented to be contacted about other research studies. Expansion of the pool to interested blood banks and cancer centers is now being implemented on request. Dr. Herbert A. Perkins described the platelet program developed in collaboration
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with Dr. Rose Payne a t the Irwin Memorial Blood Bank in San Francisco. Because of the routine performance of red blood cell phenotyping on blood donors without explicit permission, it was felt that permission to do HLA typing was not required. Approximately 3,000 voluntary blood donors have been typed to date. A confidential computer file is maintained a t the blood bank, and the HL-A types a r e entered by an in-house identification number into the National Platelet Donor Pool. I f a donor is needed for plateletpheresis for a specific patient, a physician makes the initial phone contact and a fully informed consent is obtained. About 80 to 90 per cent of the people called consent to the procedure. It remains to be seen whether the response will remain this excellent a s requests become more frequent. Dr. Donald J. Filip described the platelet program at the Milwaukee Blood Center developed two years ago to meet increasing needs for histocompatible platelets. Two fulltime technicians routinely HL-A type about 3,000 voluntary blood donors annually and also screen the serum of multigravida women for antibodies useful in tissue typing. Specific permission for HL-A typing is not obtained because the file is used only for another form of blood donation-plateletpheresis. When matched platelets a r e needed, a potential donor is contacted, the procedure described, and a consent obtained. Acceptance rate is 90 to 95 per cent. Nonrelated donors a r e used in preference to family members because emotional entanglements a r e avoided and a number of donors a r e available. While platelets have been shipped to other centers, the file has not been entered into the National Platelet Donor Pool. Dr. William Miller of the Red Cross Blood Center in Saint Louis summarized efforts within the Red Cross to develop a national p r o g r a m for providing h i s t o c o m p a t i b l e p l a t e l e t s . P a r t i c i p a t i n g c e n t e r s a r e enc o u r a g e d t o use existing H L - A typing facilities, but some a r e developing their own capability. To assure uniform typing results,
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procedures for quality control are being implemented, and a national typing tray is in development. T h e pheresis capability is already well established. Still to be confronted a r e i n t e r c e n t e r problems of shipment, charges, registry, and storage as well as donor motivation, consent, and whether information will be shared with non-Red Cross facilities.
Ethical and Legal Considerations Dr. Arno G. Motulsky of the Division of Medical Genetics, University of Washington, discussed the development of a platelet program in the context of current economic and social trends. First, the exponential growth of technoogy in the biomedical field has resulted in increasingly large allocations of resources to health care. Since the impact of this technology on morbidity and mortality of the adult population has not been striking, questions of accountability and cost effectiveness h a v e been raised. N e w platelet technology must be evaluated along these lines before c o m m i t m e n t to p r o g r a m development. T h e specific indications for platelet transfusions must be identified, the national need assessed, the costs computed, and the regional distribution of centers planned . Second, the centralization and depersonalization of urban society has resulted in a countertrend emphasizing individual rights and distrust of authority. These events, coupled with the broader implications of HL-A typing on transplantation research, require that a platelet program be based on full disclosure and careful evaluation of practices of donor motivation and consent. For example, the red blood cell program could be used to study the psychology of the volunteer donor and the motivating role of idealism, social recognition, or monetary payment. Control studies would be useful to compare responses of donors signing routine red blood cell consent forms, those consenting to participate in research studies, and those receiving detailed explanation of both forms. Based on
Transfusion May-June 1976
hard scientific data, it should be possible to design a platelet program that does not interfere with personal liberties. Dr. Judith Swazey of the Department of Sociomedical Sciences, Boston University, presented data from a two-year study of organ donor programs and related her findings to the platelet donor program. The pattern of interaction consistently observed in organ donation was that of gift exchange with reciprocal obligations of giving, receiving, and repayment. Complications arose over the magnitude of the gift. Within families there were strong pressures on the donor to give the gift, on the ill person to accept it, and great difficulties surrounding repayment. Debtor-creditor relationships frequently developed or the donor felt justified in exerting authoritarian control over the recipient. In the case of nonrelated donors, health care professionals had difficulty accepting altruism as the motivating factor and tended to suspect psychopathology. Despite elaborate screening and informed consent procedures, donors reported that their decision to donate was made almost instantaneously. What are the implications of these findings for platelet donation? The gift of life theme used in several existing platelet d o n o r r e c r u i t m e n t p r o g r a m s h a s established platelet donation as a form of gift exchange. Consequently problems similar to those encountered in organ donation will arise. One suggested approach has been to avoid family members as donors and to maintain donorrecipient anonymity. Whether payment for the donation will alter the obligations of gift exchange remains to be seen. Finally, informed consent is difficult to manage because the donor’s role has been inflated in an attempt to motivate him. M r . R o g e r Dworkin of t h e Indiana University School of Law discussed the informed consent doctrine, a tool by which the law a t t e m p t s after-the-fact regulation of technological development. In the medical treatment context, the current legal standard is that the patient must be given all infor-
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mation that is material ( i . e . ,all that a responsible person would use to make a reasoned rather than emotional decision). In the experimental setting, requirements for informed consent must be met before a research proposal is approved. There must be fair explanation of procedures, risks, benefits, and alternative procedures, an offer to answer questions, and a stipulation that consent may be freely withdrawn. Whether platelet donation is characterized as experimental or nonexperimental, information on the purpose of HL-A typing, the potential physical, psychological, and social risks, and the probable benefits to the recipient must be given at the time of initial donation. Consenting to a procedure means only that the donor has agreed to having it competently done. Thus, if negligence occurs, the donor can recover a damage award. A signed consent form does not obligate the donor to continue in the program, even if termination injures the recipient. Mr. Michael Shapiro of the University of Southern California Law Center reviewed donor motivation and consent emphasizing the principle of personal autonomy. H e criticized the practice of paternalism in donor selection: potential d o n o r s a r e screened using unscientific judgments of motives or emotional stability. Instead, there should be a presumption of competence and a commitment to personal autonomy. This does not mean that donor selection is casual; rather, it necessitates the most rigid requirements of informed consent so that decisions are based on full and complete information. In the context of platelet donation, disclosure must be made at initial contact that blood will be HL-A typed and that the donor might be called repeatedly to undergo plateletpheresis. Since a matched platelet donor program requires computerized banks of information on donor locations and HL-A types, security measures must be carefully planned to guarantee that only authorized persons have
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access to the data. It is not enough to rely upon the honesty and good intentions of existing scientists and blood bank personnel.
Planning an Ideal Platelet Donor Program After the individual presentations, participants engaged in an open discussion of the following aspects of an ideal matched platelet donor program: 1 ) appropriate recruitment techniques; 2) a reliable donor education/information system; 3) mechanisms for informed consent; and 4) effective physician education. General consensus was apparent in several areas. First, while the development of effective educational programs for donor recruitment and consent is essential, the complexity of the information requires some staggering of delivery according to the level of commitment of the donor. However, if a follow-up request is plainly anticipated, the donor must be told. As computerized data sharing, plateletpheresis, and m a t c h e d platelet donor programs are developed, potential donors should receive much more detailed descriptions and explanations of the programs and signify their understanding by signing an informed consent document. I n this regard, a number of consent forms should be developed, including forms for HLA typing, information sharing and computer storage, plateletpheresis, matched platelet donor programs, and transplantation. Such forms should be circulated among participating scientists as well as to public and government agencies to insure maximum agreement and uniformity. At the same time, educational materials should be shared and evaluated by participating scientists t o develop ‘the most effective donor education possible. Finally, a plan for management of computer data is essential. Procedures for maintaining the confidentiality of donor typing information, names, and locations should continue to be discussed until a uniform policy is established.
