Blood and blood products

J.R.B. Williams

35

Blood and blood products

Interest and anxiety about the side effects of blood products have been concerned particularly with the acquired immune deficiency syndrome, which is included in SEDA for the first time. Attention is drawn to reviews detailing the precautions advisable in laboratories and clinical units but which avoid excessive restrictions on clinical management. This Annual also discusses the complications of granulocyte infusions and their prevention at some length, and draws further attention to the occurrence of graft-versushost disease as a complication of blood product infusion. It is possible that this diagnosis is missed in clinical units not engaged in a transplant program, especially in the early stage of the disease when it may still be amenable to treatment. SEDA-7 is also updated with regard to hemolytic transfusion reactions and hemolytic disease of the newborn. REACTIONS TO WHOLE BLOOD AND RED CELL TRANSFUSIONS An antibody reacting with the high frequency antigen Cromer was found in a Japanese man who probably had a null phenotype in the Cromer blood group complex (1 c). Previous examples of anti-Cra antibody have been found in negroes, and it appears that races of other than African origin may produce it. The antibody reacts by antigiobulin and enzyme methods and would be detected readily by routine crossmatching methods. A new variety of anti-V, which reacts in saline at room temperature, has been reported. It occurred in a multitransfused Caucasian woman in conjunction with antiglobulin-reactive anti-CD (2c).

Side Effects o f Drugs Annual 8 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 $0.80 per article per page (transactional system) $0.20 per article per page (licensing system)

Multiple transfusions in a woman also resulted in the second example of antibody to the low-incidence antigen Hil. It was not possible to determine whether the antibody had been stimulated by previous transfusion or pregnancy, although the original anti-Hil was associated with hemolytic disease of the newborn (3c). The distribution of the Kidd locus phenotypes varies appreciably between different ethnic groups. The Jk(a-b-) phenotype is relatively frequent in Polynesians and was present in 0.9% of this race living in New Zealand (4c). In this study over a period of 13 years, 9 examples of the associated antibody, anti-Jk3, were detected. One of these produced a delayed transfusion reaction and some others caused mild hemolytic disease of the newborn. A strange example of antiJk a reacting only in the presence of methyl esters of para- and ortho-hydroxybenzoic acid was found in an individual with Jk(a+) red cells. The patient was receiving topical treatment with methyl salicylate at the time the antibody was identified, and it appears likely that immune complexes between the antibody and the chemical antigen crossreacted with the Jk a antigen and bound complement (5C). This example of anti-Jka was found by the indirect antiglobulin test using low-ionic-strength-solution (LISS) suspended red cells containing the preservative methyl paraben. The use of LISS also allowed the detection of an auto-anti-P which was causing hemolytic anemia. The anti-P and anti-P1 were IgM in nature and the DonathLandsteiner reaction was negative (6c). Problems with polyagglutination associated with T-activation and severe bacterial infections have been reported again (SEDA7, 329). Polyagglutination with features of Th and Tk activation with an acquired B antigen occurred in a 47-year-old woman with peritonitis and respiratory tract infection of mixed bacterial type. The problem was noticed by the discrepancy between the red cell and serum ABO grouping and at

304 that stage the presence of an acquired B antigen was considered (7c). Fatal intravascular hemolysis associated with T-polyagglutination also occurred in a Korean man with liver abscess containing Escherichia cell, Aspergillus niger and probably Clostridium perfringens (Be). The authors comment on the need to consider microbial infection, especially clostridial sepsis, in patients with sudden massive hemolysis, and the development of an acquired ABO antigen or polyagglutination of red cells may also ifidicate severe bacterial infection requiring rapid treatment. Difficulties in cross-matching blood may also arise in patients who have been treated with equine antilymphocyte serum (9e). Both direct and indirect antiglobulin tests with reactive eluates may occur in patients treated with this immunosuppressive agent and are specific to anti-IgG1. The reverse problem of reduced or absent laboratory evidence o f red cell incompatibility may be due to genetic factors affecting the red cell antigen or choice of the crossmatching techniques. An inherited depression of red cell antigens may affect a wide range of blood group series including H, I, i, Diego and others (10c). Some antibodies, however, may react only by techniques which are not in routine use for crossmatching in most hospital transfusion laboratories. Investigation of 17 patients with hemolytic transfusion reactions, associated with antibodies not detected by routine procedures, included anti-C demonstrated by ficin-capillary and Polybrene, and anti-E and anti-Jk a shown only by Polybrene (11C). Pretransfusion antibody screening may allow a reduction of cross-matching to an immediate spin and room temperature incubation if blood is unlikely to be used in cold surgery. If these methods are used when transfusion is certain or probable, then occasional incompatibilities will be missed, usually due to the lack of certain specificities in the red cell screening panel (12c). The inclusion of a LISS technique and an antiglobulin method for both screening and cross-matching is important (13c). Red cell survival studies using SlCr may confirm that a hemolytic reaction was due to red cell incompatibility during transfusion. Subsequent testing with patient's serum concentrated to one-fourth its volume may allow demonstration of the incompatibility and identification of the specificity (14e). What-

J.R.B. Williams ever techniques are chosen, it may be impossible to prove the incompatibility in vitro, and repeated SlCr studies may be necessary. F o r example, after 4 such tests, it seemed likely that a blood group O R2R2 patient destroyed E negative cells in spite of compatible serological testing (15c). Rare or unknown antibodies occasionally cause severe transfusion reactions, and incompatible cross-matches must always be taken seriously. A group O Rhesus positive man was found to carry anti-E and anti-c with an additional antibody shown to be anti-Co b . He was inadvertently transfused with red cells containing this antigen which appeared to be responsible for the hemolytic reaction which followed (16c). A severe transfusion reaction due to anti-EnaTS occurred in a woman with an unusual pattern of red cell sialoglycoproteins who received three units of red cells compatible by the antiglobulin test, but incompatible by direct agglutination at 37 ~ (17e). Interpretation of unusual or discrepant cross-matching tests can be difficult, as the infusion of Xg a positive red cells into a Japanese man with anti-Xg a caused an urticarial and febrile reaction without evidence of hemolysis (18c). Delayed transfusion reactions are infrequent, a recent study recording only one in every 10,688 transfusion units (19c). The specificities included the usual Kidd and Rhesus antigens/antibodies and anti-S. Delayed reactions to the Kell system antigens have been reported involving anti-Js a 23 days after transfusion (20 c) and anti-Js b after 15 days (21c). Anti-Fy b caused a delayed reaction 2 weeks after transfusion of compatible A Rh positive cells in a woman who had been transfused twice and pregnant 4 times. The patient was transfused for excision of a ruptured spleen, and the authors suggest that this may have reduced the severity of the hemolytic reaction (22r Anti-Co a has also been reported as a cause of a delayed transfusion reaction (23e). In sickle cell patients, delayed transfusion reactions may be misdiagnosed as sickle cell crises. This particularly occurs in patients with U-variants. In a 22-year-old woman with anti-U in her serum, transfusion with C positive and one U T M unit caused a delayed transfusion reaction 13 days later. Since delayed transfusion reactions are severe in sickle cell patients, only units confirmed as U-negative by adsorption elution should

Blood and blood products be administered to anti-U carriers (24e). A primary immune response is an unusual cause for a delayed transfusion reaction but may occur with anti-C 2 months after transfusion. Serial testing for the antibody is necessary as it may not be demonstrable for a further 4 weeks (25c). The problems o f massive transfusion were reviewed in SED-9 and little new has appeared recently. A retrospective study of case records of 24 patients with severe trauma showed that red cell transfusions decreased the platelet count 2.5 times more than colloid infusions (26c). The authors provide equations which give the platelet requirements according to the amount of blood transfused and stress the need for fresh frozen plasma at the ratio of 2 units to 1 unit of red cells in the admission room. A review of defects in hemostasis caused by blood transfusion also comments on thrombocytopenia, which in the present author's experience is a more frequent clinical problem than abnormalities of coagulation (27c). HEMOLYTIC DISEASE O F THE NEWBORN/ANTI-D PROPHYLAXIS Since the introduction of anti-D prophylaxis, the occurrence of hemolytic disease of the newborn (HDN) from other red cell antigens has assumed proportionately greater significance. Low frequency red cell antigens may provoke HDN, and a new antigen 'Pollio' has been identified this way (28c). Severe HDN may occur with these antigens, especially those of the Miltenberger series such as anti-Verweyst (Vw). In puzzling cases of HDN, red cell panels in routine use may not carry the antigen involved and cross-checking the father's red cells with maternal serum at an early stage may help, together with collaboration among laboratories in different centers (29c). High frequency antigens may also cause HDN, although a recent report of sensitization to Lu b with an IgG antibody was of a low level detectable by elution, but with a negative antiglobulin reaction and no clinical effects (30c). It is important to tailor red cell screening panels of antenatal patients to the population: HDN due to anti-Dia occurred in an infant born to Japanese parents in Brazil, highlighting the problems of increasing mixed populations throughout the world ( 3 1C ) . A major historical review of Rh e sus

305 hemolytic disease of the newborn provides an account of the development of understanding of the disease and its treatment and prophylaxis (32R). In spite of prophylaxis, Rhesus HDN is still a problem. The outcome of an affected pregnancy is related to the maternal anti-D concentration. In a study using the British working standard, it was found that when serial anti-D concentrations remained below 4 IU/ml, only 3 babies in 78 were significantly affected, whereas above this level, 79 babies in 106 required exchange transfusions (33c). Determination of the right dose of anti-D for prophylaxis is more difficult than routine practice takes into account. The standard United States dose of 330 pg anti-D should suppress the immunogenicity of 30 ml fetal blood in the maternal circulation. Two recent studies show that enzyme-linked antiglobulin tests and a rosetting technique are sensitive and allow quantitation of a fetal/maternal bleed and adjustment of anti-D dose (34 C, 35c). This may be even more important in countries using lower doses of anti-D as a routine. The formation of anti-D in male volunteers may be facilitated by the simultaneous injection of 1 btg anti-D. The degree of immunization was n o t augmented, but it is probable that a higher proportion of subjects was sensitized (36c).

REACTIONS TO WHITE CELLS The survival of neutropenic patients with gram-negative sepsis is related to the compatibility of the granulocytes as shown by the granulocyte indirect immunofluorescence tests. This test is a measure of granulocytespecific antibodies. There is no relation between patient outcome and a lymphocytotoxicity assay, showing that HLA compatibility is less important in this respect than specific anti-leucocyte antibody (37c). A study of granulocyte cytotoxins in multitransfused patients and multiparous identified 3 granulocyte specificities (38 c ) which may well relate to the incompatibility responsible for the failure o f leucocyte infusion therapy in cytotoxic-induced neutropenia. Combined prophylactic granulocyte and platelet infusions in 23 patients with acute myelogenous leukemia resulted in frequent transfusion reactions in 10 of them. Recovery of granulocytes in all these 10 was less than

306 5% on at least one occasion, probably due to rapid alloimmunization (39c). The accompanying diminished platelet recovery was also probably due to alloimmunization and although an 'innocent bystander' effect from antiqeucocyte reaction was not excluded. In this study, at least, granuloeyte infusion appeared to be effective for only 2 to 3 weeks. This raises problems in the management of induction therapy in acute leukemia of all types and with the effect of induction cytotoxic protocols on immunesuppression. Further doubt on the value of prophylactic granulocyte transfusions was cast by a prospective randomized trial, also o n patients with acute myelogenous leukemia, in which there was no difference in deaths or frequency of infection, or in the frequency or duration o f fever (40c). In another trial, no effect on response rate or survival was found, but data on infection rate and the incidence of septicemia are not yet complete (41c). Comparison between the groups is difficult to make because of the many clinical variables, including the nature and site of infection and choice of antibiotics (42c). The immune response to leucocyte antigens appears to be genetically determined. In highly transfused thalassemia patients, an increased incidence of antileucocyte antibodies occurred in HLA-DR2 carriers and a reduced incidence in Bw35 and DR7 individuals. (43c). It seems likely that immunosuppressive factors related to tfiese HLA groups play a role in the reduced immune response. The preparation, indications, use and side effects of granulocyte ~nfusions have been reviewed, the author commenting on the incidence and nature of the adult respiratory distress syndrome and its relation to anti-leucocyte antigen-antibody reaction (44r). Whether microaggregatesofleucocytes in banked blood can cause respiratory failure is still uncertain, and the evidence largely suggests that they do not do so to a significant degree (45r). In massive transfusions, the extent of trauma, shock and pulmonary involvement are probably more important. In a prospective study of pulmonary function in patients having elective coronary bypass surgery, there was no difference between patients receiving blood through a 20-micron filter or a 170-micron one (46r Some of the patients studied had some degree of pulmonary dysfunction before transfusion and even in these there

J.R.B. Williams

was no evidence that the use of microaggregate filters provides clinical benefit. Microaggregate blood filtration may, however, reduce the incidence of febrile transfusion reactions by 77% and units centrifuged before filtration rarely caused reactions (reduction of 98%). The study also showed that febrile reactions are less frequent in units within 2 weeks of their shelf life due to the reduced granulocyte content (47c). At present, it seems that microaggregate filtration is most useful in patients who are likely to be transfused repeatedly, to reduce the onset and frequency of febrile reactions (48r). The removal of microaggregates from granulocyte concentrates is best done by screen filters, as depth filters remove a substantial proportion (20-60%) of neutrophils (49c). The best filters for the removal of leucocytes from whole blood appear to be the Imugard IG500 and Erypur, which can be relied on to reduce the absolute numbers by 98% (50c), although other methods such as freezing-and-thawing or centrifugation will remove appreciable numbers (51R). The authors of this detailed review suggest that most nonhemolytic febrile transfusion reactions will be abolished by microaggregate filtration at the bedside and should be tried before more complicated and expensive methods of leucocyte depletion are initiated. The collection of granulocytes from donors is a fairly safe procedure, analysis of data from 190 establishments showing that adverse reactions occurred 54.9 times per 1000 procedures and that 94 per cent were mild. Moderate reactions occurred in 5.9% and severe ones in 0.4% (52r Leucocyte infusions may induce consumption coagulation changes. Fibrin degradation products may increase in association with a reduction in factor VIII and antithrombin levels (53e). The clinical significance of these changes is not clear.

REACTIONS TO PLATELETS In spite of previous reports, posttransfusion purpura may respond to high-dose steroid treatment, hydrocortisone 500 mg intravenously 6-hourly producing a sharp rise in the platelet count on the 5th day after the onset of purpura (54c). An unusual case of posttransfusion purpura concerned a female patient with platelets negative for

Blood and blood products group P1A1 (Zw a) with antibody to this antigen who was treated with methylprednisolone 2 mg/kg/day. The platelet count rose 2 days later, and she was then treated by plasma exchange. Immunological studies showed that the patient's platelets did not react with the circulating antibody in vitro, but platelet survival was reduced and turnover increased. In addition to the unusual platelet antigen/antibody reaction, the patient had a delayed transfusion reaction in association with anti-E and anti-c and developed lymphocytotoxic antibodies of wide specificity (55 C). Further transfusions after the development of lymphocytotoxic antibodies may be possible for a time, using leucocyte poor blood and platelet concentrates, but ultimately only HLA-compatible blood may be tolerate d (56c). REACTIONS TO HUMAN ALBUMIN PREPARATIONS Properly prepared human albumin should n o t elicit any adverse reaction, and when, from time to time, such reactions are reported, they may be attributable to impurities in a particular batch. From outside Europe, reports of such reactions do occasionally appear, and one is bound to question the conditions under which the preparations have been stored and handled when this happens. Two cases reported from Kuwait (110 c) provide an example. A 48-yeas-old man was given 100 ml of human albumin 25% (Behringwerke) for mieronodular liver cirrhosis. Simultaneously, the patient was taking furosemide, spironolactone and vitamin B complex. He developed rigors, pyrexia and dyspnea on two occasions after the albumin had be~n administered intravenously. A boy aged 15 received the same human albumin preparation for hypoalbuminemia, as well as receiving digoxin, furosemide and ampiciUin for cardiac disease and chest infection. The patient experienced the same reaction.

In both patients, symptoms subsided on withdrawal of the infusion. REACTIONS TO PLASMA PROTEIN FRACTIONS Developments in the use of immunoglobulin preparations for specific therapeutic

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purposes require comment in this Annual. A review of their uses describes the common side effects, mentioning the possible etiology from IgA antibody reactions or the effect of contaminating proteins such as prekallikrein activator (57r). The new intravenous preparations cause minor side effects in some patients, but severe symptoms or anaphylaxis are only likely in known susceptible individuals. Preparations containing maltose seem to be less toxic than those in glycine alone (58 c, 59r). The use of anti-thymocyte globulin is usually associated with adverse reactions, fever, rigor and skin rashes being frequent (60 c, 61c). The major dose-limiting toxicity is thrombocytopenia, especially if the bone marrow reserve is already reduced by disease and previous cytotoxic treatment. Specific antibodies of animal origin are well known to be toxic, but an unusual effect of tetanus antitoxin is reported from India and is probably misdiagnosed even in countries where tetanus neonatorum is common. 14 children between the ages of 3.5 and 13 years were treated surgically for fibrosis of the quadriceps muscles. This had been noticed as painless limitation of knee flexion following repeated intramuscular injections of antitoxin in this site. The authors advise that every available intramuscular injection site is used and that consideration is given to the use of oral and intravenous routes (62e). Murine monoclonal antibody T101 has been used in 2 patients with chronic lymphocytic leukemia. The first patient received 2 doses without complications but developed an anaphylactoid reaction 20 min after completing the third. The other patient became hypotensive and dyspneic 15 min after the first dose and then experienced rigors and fever (63c). Rabbit-derived anti-human ovarian tumor serum has been used in women with stage-III or stage-IV epithelial ovarian cancer in addition to standard combination chemotherapy. Out of 9 patients, 3 developed low-grade fever and 2 skin rash. There was no increase in bone marrow toxicity (64C). A further attempt at immunotherapy in cancer patients has been the administration of autologous lymphocytes stimulated by previous incubation with phytohemagglutinln and human AB serum. All 8 patients treated developed fever and some complained of headache, nausea and vomiting. There was

J.R.B. ~r

308 also a temporary reduction in pulmonary diffusion capacity (65e). Animal protein fractions other than immunoglobulin preparations may produce side effects presumably related to their antigenicity. Bovine fibrin used during ear, nose and throat operations may induce delayed hypersensitivity with cutaneous erythema and edema (66c). Highly purified animal material such as porcine factor VIII may also cause severe allergic reactions, but its lack of crossreaction with factor VIII inhibitors in hemophiliac patients makes it a valuable agent for treatment ( 6 7 c ) . Severe reactions may also occur with human material as shown by the death in status asthmaticus of a hemophiliac who developed epileptiform fits after self-administration of factor VIII concentrate (68c). Treatment of hemophilia with activated prothrombin complex is known to cause thrombotic episodes sometimes, and there are 2 further reports of myocardial infarction induced by this agent (69 e, 70c). Whole plasma preparations only occasionally cause side effects (SEDA-7,331) and a recent review of adverse reactions to plasma substitutes shows that plasma protein fraction and human serum albumin have a lower incidence than any other studied except dextran 40 (71r).

TRANSMISSION O F DISEASE BY BLOOD PRODUCTS

Hepatitis The transmission of hepatitis A by blood transfusion was reviewed last year (SEDA-7, 332), and another case has been reported. 2 weeks after blood donation, the donor became ill with symptoms of hepatitis, and hepatitis-A-specific IgM was demonstrated in her serum. The blood, meanwhile, had been transfused and the recipient developed serologically confirmed hepatitis A 3 weeks later (72e). The exclusion of hepatitis B antigen carriers from donating blood requires a sensitive test such as a radioimmunoassay system. The usual systems detect hepatitis B surface antigen (HBsAg). Testing for e antigen and its related antibody (HBeAg and anti-HBe) may help selection of those donors who carry hepatitis B antigen but who are already producing an immune response not detectable by routine tests

and whose clinical management with possible treatment with hepatitis B immune serum may be modified (73c). Unfortunately, the commercial radioimmunoassay kits for HBsAg are not entirely specific and give a 4 per cent nonspecific reaction when tested by neutralization with pooled surface antigen (74c). The incidence of markers of hepatitis B in volunteer donors is 6.3% in the United States (0.2% HBsAg), providing that they have not been transfused previously or been jaundiced (75c). In spite of this relatively high incidence before exclusion of antigen carrying donors in a small survey of 164 recipients receiving 689 units of blood products, there were no cases of posttransfusion hepatitis. The donor population in this instance were US A r m y personnel in training who appear to be a safe source of blood for transfusion (76e). The risk attached to plasma products can be reduced by manufacturing techniques or by the addition of antihepatitis B antibody (77R). Albumin a n t ' p l a s m a protein fraction are heated to 60vC for 10 hours and are low-risk. A reduction in risk of antihemophilic factor, factor IX as well as antithrombin III, a-l-antitrypsin, fibronectin, C-1 inactivator and factor XIII may be obtained by a combination of chemical stabilization and heating, or by the addition of anti-HB immunoglobulin. A recent analysis of treatment of hemophilia in the United Kingdom based on the annual reports of the directors of hemophilia centers includes data for 1980 (78c). The incidence of hepatitis is given in Table 1. The annual clinical attack rate has dropped since 1974 when it was 5.2% and has remained about 3% since. This rate is relatively low, but includes all cases treated in the centers including mild ones only requiring occasional treatment. Higher infection rates as determined by serological testing for HBsAg, anti-HBs and anti-HBc were Table 1 Coagulation defect

No. of patients treated

Cases of hepatitis No. %

Hemophilia A Hemophilia B Von Willebrand's disease Total

2107 355 235

52 2 9

2.5 0.6 3.8

2697

63

2.3

Blood and blood products found in Edinburgh being 7% and 9.5% for the two periods 1971-1975 and 1975-1979. Of the 16 patients who showed seroconversion only one developed clinically evident hepatitis (79C). The patients were treated predominantly with cryopreeipitate, but large-pool factor VIII concentrate was also used. Commercial factor VIII preparations now carry the same hepatitis risk as products prepared from voluntary donors (80c), but it still appears that the safest source of factor VIII supplements for new and mild hemophiliacs is cryoprecipitate (81 e). Pooled preparations of prothrombin complex still carry a high risk of hepatitis: 56% of patients undergoing cardiac surgery and receiving this material developed non-A, non-B hepatitis. In this study, only 5% of patients receiving blood transfusion without prothrombin complex developed hepatitis (82e), and it is evident that the use of pooled clotting factor concentrates should be avoided if at all possible. Cardiac surgery also carries a high risk of posttransfusion hepatitis in Spain, where 40 of 230 patients developed clinical or laboratory evidence of it. Of these, a quarter were due to hepatitis B, in one patient to CMV infection and the rest to non A, non B (83C). In the United States, a history of viral hepatitis excludes a person from blood donation, but this regulation was reduced in 1975 in the United Kingdom to a history of 12 months hepatitis or jaundice. With the m o d e m sensitive tests, the majority of carriers of hepatitis B are identified, and in spite of the occasional occurrence of posttransfusion hepatitis B with volunteer donors, this practice seems reasonable (840. A history of previous transfusion or contact with patients with hepatitis has no influence on the incidence of anti-HBc in the absence of other HBV markers strongly suggesting that these 2 factors may be ignored in the selection of donors. The value of testing donors for abnormal serum alanine aminotransferase (ALT) is still unknown but a Special Report from the United States advises against the routine adoption of the procedure (85R). There is a need for more information on the significance of raised ALT levels with regard to the transmission of non-A, non-B hepatitis and the development of chronic hepatitis. The incidence of chronic hepatitis following acute non-A, non-B infection is not known, but in Italy, of 21 patients developing the

309 acute illness, 13 progressed with histologicaUy confirmed changes. Chronic persistent hepatitis occurred in one, chronic lobular hepatitis in 2, and chronic active hepatitis in 10. 5 of these progressed to cirrhosis and one died ( 8 6 c ) . Other infections. Post-transfusion hepatitis rarely occurs as a result of cytomegalovirus (CMV) infection, Epstein-Barr virus infection and extremely rarely from toxoplasma infection (87R). CMV infection without jaundice as a side effect of transfusion is frequent, especially so in neonates and neutropenic or immunologically suppressed adults. Glandular fever following transfusion of blood donated during the incubation period in the donor tends to be severe, but of the 2 seen by the present author, only one was jaundiced. A review from Papua, New Guinea, includes discussion of the need for treating all patients with anti-malarials in endemic areas. Syphilis is still prevalent in some areas of New Guinea and as serological testing is not a complete safeguard, it is advisable to store blood for 72 hours when possible (88r). Recent unusual infections transmitted by transfusion include Babesiosis surviving in frozen-thawed blood given to a splenectomised woman with thalassemia major. Treatment with pentamidine was successful (89c). Yersinia enterocolitica cbntaminating blood packs was responsible for 2 severe infections, one fatal. This organism multiplies rapidly in whole blood or red cells at 4 - 8 ~ and appears to be widely distributed among the negro population in South Africa (90c).

Acquired immune deficiency syndrome (AIDS) A I D S is a relatively new clinical entity, which is poorly understood. It is not, so far as is known, an adverse reaction, but it almost certainly can be transmitted via blood products. The clinical picture o f malaise, fever, weight loss, lymphadenopathy and diarrhea should raise suspicion, supported further by lymph node histology o f nonspecific reactive hyperplasia and the development o f Kaposi's sarcoma in some cases. There is lymphopenia, defective cellular immune response with reversion o f

310 T-helper cell/T-suppressor cell ratio but increased immunoglobulin levels. Most cases have occurred in promiscuous male homosexuals, intravenous drug abusers and Haitian immigrants, but some have occurred in hemophiliacs, presumably in relation to the blood products they have received. The distribution o f the disease is predominantly in North America and the Caribbean, but it is also present in Europe. A report from the United Kingdom lists 14 cases o f either Kaposi's sarcoma and/or A I D S between August 1982 and March 1983, and surveillance is continuing (91c). In hemophiliacs, the disease may be symptom-free but associated with painless lymphadenopathy and not necessarily progressive (92c). Infection with microorganisms associated with reduced immunity states may occur, and Pneumocystis cariniL Candida albicans and Herpes virus are the best known but others, including mixed infections with the preceding and Mycobacterium avium intracellulare, have been reported [93 c, 94R). The abnormal T-cell and increased B-cell response may be associated with clinically and hematologically typical immune thrombocytopenia occurring as a complication o f severe hemophilia with high-dose factor 11111 supplements, but the clinical e x t e n t o[ A I D S involvement varies and may be minimal (95C). The etiology is at present unknown, but the disease-affected patients often have serological evidence o f previous infection with hepatitis B, Epstein-Barr virus and CMV, and the altered T-cell function may perhaps be related to the complex antigen load and immune response to these combined infections (94R). It is also possible that human T-cell leukemia virus is involved in the pathogenesis and laboratory methods f o r determination for markers o f this agent are becoming available (96c). The precautions that seem advisable in the handling o f whole blood and blood products are largely those usual in the handling o f material known or suspected to be infected with hepatitis B antigen. They should provide safe conditions f o r work by clinical, laboratory and nursing s t a f f and are given with some general advice on the problem in the following references (97 C, 98 R, 99 R, l OOr).

J.R.B. Williams

HOST-vs-GRAFT, AND GRAFT-vs-HOST INTERACTIONS Cytotoxic antibodies developed in 33 (14.6%) of 226 patients awaiting renal transplantation. This frequency was no different whether the transfusions were random or deliberate in timing, but the production of the cytotoxic antibodies and their anamnestic response showed that it is important to preserve all reactive patients' sera for cross-matching against possible donors later (101c). Alloimmunization following cardiopulmonary bypass surgery with its associated transfusions occurred in 33.6% of males and 64.3% of females, these presumably sensitized by previous pregnancies ( 102c). This alloimmunization carries implications for future transfusions and pregnancies. The inddence of graft-versus-host disease following bone marrow transplantation is falling and depends on the careful use and timing of immunosuppressive drugs, especially methotrexate, antithymocyte globulin and prednisone (103R). The use of cyclosporin A instead of methotrexate may help in the prevention of graft-versus-host disease with less bone marrow suppression, but toxic effects, especially renal, may limit dosage (104 C, 105 c). Granulocyte infusions may provoke graftversus-host disease. A S-year-old boy with Hodgkin's disease developed it after receiving nonirradiated granulocytes from his mother, and clinical and histological evidence of it followed fresh buffy coat infusions in a 59-year-old woman (106r Similar clinical and pathological changes followed syngeneic engraftment with cryopreserved buffy coat in chronic granulocytic leukemia. In the 2 cases reported, there was no reduction in suppressor T-cell numbers, and it seems possible that there was in fact an allograft derived from blood products causing the graft-versus-host disease (107c). This complication of cellular blood product infusion is now well recognized as occurring in immunosuppressed adults and in neonates, and requires the administration of at least 107 lymphocytes/kg. The simplest precaution to take is irradiation with a commercially available cesium source at a dose of at least 15 Gy (I08 R, 109R).

Blood and blood products

311

REFERENCES 1. Danlels GL, Tohyama H, Uchikawa M (1982) A possible null phenotype in the Cromer blood group complex. Transfusion, 22, 362. 2. Cheng MS (1982) Saline-reactive anti-V. Transfusion, 22, 401. 3. Ellisor SS, Zelski D, Sugasawara E et al (1982) A second example of anti-HiL Transfusion, 22, 402. 4. Woodfield DG, Douglas R, Smith J e t al (1982) The Jk(a-b-) phenotype in New Zealand Polynesians Transfusion, 22, 276. 5. Halima D, Garratty G, Bueno R (1982) An apparent anti-Jka reacting only in the presence of methylesters of hydroxybenzoic acid. Transfusion, 22, 521. 6. Cohen DW, Nelson L (1983) Auto-anti-P reacting only by low-ionic-strength-solutions in a patient with hemolysis. Transfusion, 23, 79. 7. Klarkowski DB, Ford DS (1983) A case of polyagglutination with features of Th and Tk activation associated with an acquired B antigen. Transfusion, 2.3, 59. 8. Judd WJ, Oberman HA, Flynn S (1982) Fatal intravascular hemolysis associated with T-polyagglutination. Transfusion, 22, 345. 9. Draper EK, Dignam CM, Yang S, Ballas SK (1982) Anti-lymphocyte globulin - a transfusion problem. Transfusion, 22, 345. 10. Bixo V, Garratty G, Johnson CL, Marsh WL (1983) Depressed blood group antigens on red cells from a Mexican donor. Transfusion, 23, 65. 11. Garratty G, Vengelen-Tyler V, Postoway N et al (1982) Hemolytic transfusion reactions (HTR) associated with antibodies not detectable by routine methods. Transfusion, 22, 429. 12. Mintz PD, Haines AL, Sullivan MF (1982) Incompatible crossmatch following nonreactive antibody test. Transfusion, 22, 107. 13. Oberm'arl HA, Barnes BA, Steiner EA (1982) Role of the crossmatch in testing for serologic incompatibility. Transfusion, 22, 12. 14. Whitsett CF, Dafffm LE, Heffner LT et al (1982) slCr studies verify anti-P P1 pk not detectable by in vitro crossmatch as cause of immediate hemolytic transfusion reaction. Transfusion, 22, 407. 15. Baldwin ML Barrasso C, Ness PM, Garratty G (1983) A clinically significant erythrocyte antibody detectable only by SlCr mrvival studies Transfusion, 23, 40. 16. Lee EL, Bennett C (1982) Anti-Cob causing acute hemolytic transfusion reaction. Transfusion, 22, 159. 17. Postoway N, Anstee D, Wortman M e t al (1982) A severe transfusion reaction due to anti-EnaTS in a patient with an unusual pattern of red cell sialoglycoproteins (SGP). Transfusion, 22, 412. 18. Azar PM, Saji H, Yamanaka R, Hosoi T (1982) Anti-Xga suspected of causing a trams-

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