Potential for transfusion-associated graft-versus-host disease due to apheresis platelets matched for HLA class I antigens

Transfusion-associated graft-versus-host disease (TA-GVHD) has been reported in immunocompetent recipients of nonirradiated cellular blood components from donors who are homozygous for an HLA haplotype shared with the patient. In these cases, donor lymphocytes have no antigens foreign to the recipient, and this similarity in HLA antigens appears important for the development of TA-GVHD. Experience with 65 patients receiving apheresis platelets matched for class I HLA antigens was reviewed to determine the incidence of such a transfusion among HLA- matched, unrelated donor-recipient pairs. In 5 percent of transfusions (31/673), the patient received lymphocytes from a donor exhibiting no antigens foreign to the recipient, but the patient had additional HLA-A or -B antigens not present on donor lymphocytes. Twenty-three percent (n = 15) of patients received at least one such transfusion. In addition, most patients were immunosuppressed as a result of their underlying disease or therapy, which may decrease the degree of antigen matching required to initiate TA-GVHD. Until the pathogenesis of this disease is better understood, it is recommended that the transfusion of an HLA-matched cellular blood component be considered a risk factor for the development of TA-GVHD regardless of the patient's immune status, and that all such blood components be irradiated.     

Diagnosis of transfusion-associated graft-versus-host disease by genetic fingerprinting and polymerase chain reaction

A patient with Hodgkin's disease (clinical stage IIIB) received chemotherapy and total nodal irradiation. After the transfusion of filtered packed red cells, this patient developed transfusion-associated graft-versus-host disease (TA-GVHD). The genetic fingerprint of the patient's peripheral blood lymphocytes (PBLs) differed completely from that of her other body tissues. Normally, after transfusion, only the patient's own genetic fingerprints are observed in the PBLs, as exemplified in more than 10 control cases in which the transfused blood had not been filtered before transfusion. No signal bands corresponding to those of the blood donor could be demonstrated in samples of the patient's tissue DNA. Moreover, chimerism was detected in the hybridization pattern of the patient's PBLs on the ninth day after the onset of symptoms. Polymorphic simple repeats in the HLA-DRB gene after amplification by polymerase chain reaction were also investigated, which confirmed the fingerprinting results. The advantages of these methods for the diagnosis of TA-GVHD include the rapid and unequivocal diagnosis as well as the fact that there is no need for the relatives to be HLA typed.     

Transfusion-associated graft-versus-host disease in immunocompetent patients: report of a fatal case associated with transfusion of blood from a second-degree relative, and a survey of predisposing factors

A patient without evident immune deficiency who received a transfusion of blood from a second-degree family member developed fatal transfusion- associated graft-versus-host disease (TA-GVHD). The donor was homozygous for an HLA haplotype for which the recipient was heterozygous (one-way HLA match). All 39 reported cases of TA-GVHD in immunocompetent patients were reviewed to ascertain the predisposing factors and to define the indications for irradiating blood for this population. HLA typing was described in 15 cases; in 13, including seven related and six unrelated donors, a one-way HLA match was present. Thirty-one (79%) of the 39 cases were reported from Japan (and 196 other cases are cited in the Japanese literature), but a one-way HLA match among unrelated donors at HLA-A, -B, -DR loci is only approximately two to four times more likely in Japanese persons than in whites. Fresh blood (< 96 hours old) was used in 29 (94%) of the 31 cases reported from Japan and in 33 (87%) of 38 cases overall (in one case, the age of the blood used was not reported). Thus, factors that appear to predispose to TA-GVHD in immunocompetent patients are a one- way HLA match, fresh blood, and, possibly, Japanese ancestry. Irradiating cellular blood components from all blood relatives of transfusion recipients will not completely eliminate the risk of TA- GVHD.     

Transfusion-associated graft-versus-host disease: do transfusions from second-degree relatives pose a greater risk than those from first- degree relatives?

When a patient receives blood from a closely related donor, there is the potential for transfusion-associated graft-versus-host disease (TA-GVHD). With a mathematical model, the potential risk of TA-GVHD was derived for six classes of related donors. This risk was considered to be present when an HLA-heterozygous patient received blood from a donor who was homozygous for one of the patient's haplotypes. Calculations showed that second-degree related donors present a greater risk of TA-GVHD than some (siblings) but not all (parents, children) first-degree related donors. Moreover, there is, in general, no sharp cutoff of risk among the various classes of donors. These results should be considered in the determination of a policy for the irradiation of directed-donor units.     

Fatal graft-versus-host disease associated with transfusions of HLA- matched, HLA-homozygous platelets from unrelated donors

BACKGROUND : Transfusion-associated graft-versus-host disease (TA-GVHD) due to blood from HLA-homozygous related and unrelated blood donors has been described. CASE REPORT: Fatal TA-GVHD due to the transfusion of HLA-matched platelets from an unrelated HLA-homozygous donor is reported. A 61-year-old man with a history of diabetes mellitus and myelodysplastic syndrome was diagnosed with acute myelogenous leukemia in November 1991. Induction chemotherapy resulted in aplasia, which was followed by a normocellular marrow with mild dysplasia and continued karyotypic abnormalities. High-dose chemotherapy was given in a second attempt to achieve complete remission. HLA-matched platelets were ordered when platelet refractoriness developed. The patient was HLA- heterozygous for HLA-A and -B antigens (A2, 29; B37, 44). Over the next 7 days, four unirradiated HLA-matched plateletpheresis units were transfused; one was probably homozygous for both HLA-A and -B antigens (A2, -; B44, -) and was transfused first, and three were probably homozygous for an HLA-B antigen (A2, 29; B44, -) and were white cell reduced. No blood relatives served as donors. Seven days after the first HLA-matched platelet transfusion, fever, chills, and diarrhea developed; 2 days later, a rash was present. Liver enzymes increased markedly. Renal and respiratory failure ensured. A skin biopsy was consistent with GVHD. Despite immunosuppressive therapy, the patient died 19 days after the first HLA-matched platelet transfusion. CONCLUSION : TA-GVHD has been recognized in immunocompromised, HLA- heterozygous patients receiving blood from blood relatives who are HLA- homozygous. patients receiving blood from either blood relatives or non- blood relatives who are HLA-homozygous. This HLA-heterozygous patient received transfusions of unirradiated, class I HLA-homozygous platelets, which were specifically ordered as HLA-matched, and his death was attributed to TA-GVHD. Consideration should always be given to providing irradiated blood for immunosuppressed patients, especially when HLA-matched platelets are used, to prevent TA-GVHD.     

Transfusion-associated graft-versus-host disease in immunocompetent patients: case series and review of the literature

BACKGROUND: Transfusion-associated graft-versus-host disease (TA-GVHD) is a fatal complication of transfusion of blood products that usually affects immunocompromised patients. Articles reporting this condition in immunocompetent recipients are usually from countries that still have problems in irradiation of blood products. CASE REPORTS: This report presents fatal TA-GVHD in four immunocompetent patients referred from rural areas where blood irradiation is still not the routine procedure to our tertiary-care center between July 2004 and July 2005. A similar history and chronological order of events were observed: fresh whole-blood transfusion from relatives, fever, rash, liver dysfunction, diarrhea, and pancytopenia. Skin biopsies demonstrated Grade II to III GVHD involvement. Marrow biopsies showed hypoplasia. In two cases, HLA typing studies were performed. Donors were homozygous for a shared HLA haplotype in the patients. All cases were admitted to the intensive care unit within 3 weeks after transfusions with the diagnosis of sepsis, which rapidly progressed to septic shock and multiorgan failure. Another common observation was Candida albicans growth in blood cultures. Unfortunately, all died despite prompt and appropriate sepsis treatment, along with immunomodulatory therapy. CONCLUSION: TA-GVHD is probably more prevalent than reported in the literature. It must be considered in the differential diagnosis, if the patient with a recent transfusion history admits with fever, skin rash, abnormal liver function tests, and pancytopenia associated with hypoplastic marrow. In rural areas where gamma irradiation is not possible, the overall policy of transfusion (e.g., restriction of transfusion indications and alternative methods for pathogen inactivation) should be reassessed.     

Guest Editorial: Two hits and four factors affecting the development of,or resistance to,transfusion-associated graft-versus-host disease

Transfusion-associated graft-versus-host disease (TA-GVHD), a rare but usually fatal adverse effect of transfusion, is hypothesized here as a two-hit phenomenon: 1) predisposing “cytokine weather” irrespective of immunocompetence, plus 2) consequence of a (partial or total) one-way (donor to recipient) HLA match of viable donor T lymphocytes with proliferation potential. Since the introduction of irradiation, universal leukoreduction with third or later generation filters, and avoidance of transfusion from blood relatives, TA-GVHD has been successfully prevented in developed countries. However, potassium release from stored red blood cells is accelerated after irradiation, increasing the likelihood of hyperkalemia-associated mortality during rapid, and/or high-volume RBC transfusions, including exchange transfusions and extracorporeal circuit priming. Pathogen inactivation technologies may effectively prevent T lymphocyte replication, but have not yet been perfected for whole blood or red cell components. Protection against organ transplantation-associated GVHD (mainly from liver transplants) would likewise be improved by knowing and avoiding HLA one-way matched organ donors.     

Early diagnosis and successful treatment of a patient with transfusion-associated GVHD with autologous peripheral blood progenitor cell transplantation

BACKGROUND: Transfusion-associated GVHD (TA-GVHD) is an uncommon complication of blood transfusion. Diagnosis of TA-GVHD is difficult, and it is usually rapidly fatal. There are few documented sur- vivors of TA-GVHD. CASE REPORT: A 61-year-old woman with chronic lymphocytic leukemia (CLL) was treated with fludarabine followed by combination chemotherapy and high-dose radioimmunotherapy and peripheral blood progenitor cell (PBPC) rescue. She was transfused with nonirradiated blood components at an outside hospital and presented 10 days later with rash, elevated liver enzymes, and progressive pancytopenia. Skin biopsy was consistent with GVHD, and HLA typing of lymphocytes from the patient demonstrated mixed chimerism. The patient was treated with solumedrol and cyclosporin A, followed by high-dose cyclophosphamide and antithymocyte globulin and autologous PBPC infusion. She had rapid engraftment, resolution of skin rash, and normalization of liver function abnormalities. She is in good health with normal blood counts and no evidence of CLL 34 months after transplantation. CONCLUSION: TA-GVHD occurs in the setting of an immunocompromised recipient receiving nonirradiated blood components. A typical presentation includes skin rash, liver function abnormalities, and pancytopenia. Demonstration of mixed chimerism by HLA typing facilitated diagnosis in this patient. High-dose immunosuppression, facilitated by the availability of autologous PBPCs, resulted in a successful outcome.     

Universal or selective irradiation: a comparison of approaches

Pathological mechanisms proposed for transfusion-associated graft-versus-host diseases (TA-GVHD) include HLA homozygosity in donor cells of the transfusion unit that is shared by the recipient (one-way HLA match) and immunosuppression in the transfusion recipient. Which of these factors is indispensable or to what degree each factor contributes to the development of TA-GVHD has been the issue of debate. In countries like Japan with higher HLA homogeneity, TA-GVHD occurrence was thought to be primarily dependent on the one-way HLA match mechanism regardless of immunosuppression. Accordingly, universal irradiation of blood components has been conducted with no further TA-GVHD cases. In other developed countries, in contrast, TA-GVHD was thought to be a sort of extrapolation of GVHD observed among heavily immunosuppressed patients. Guidelines with the detailed list of diseases with the indication for irradiated components have been established in those countries. Although TA-GVHD occurrence decreased markedly after the introduction of universal leukoreduction, a considerable number of TA-GVHD cases have occurred among immunocompetent patients mostly by the one-way HLA match mechanism. Because one-way HLA matching with donor homozygosity is thought to be a ubiquitous and independent mechanism for TA-GVHD, it could occur in any transfusion setting regardless of immunosuppression. It would be thoughtful to select an area-specific strategy considering the drawbacks of irradiation and the frequency of TA-GVHD in that area. However, if complete abolition of TA-GVHD is required from the perspective of the high fatality of the disorder, universal irradiation of cellular components will be necessary.     

A model to determine required pool size for HLA-typed community donor apheresis programs

Community donor plateletpheresis programs must have adequate numbers of HLA-typed donors to support the transfusion needs of alloimmunized patients, and donor pool size calculations should reflect the fact that each patient needs more than one donor to provide his or her support. The average number of donors needed to provide a patient's support was estimated as a function of donor usage and commitment. A model was developed for determining an appropriate size of the donor pool for a community donor plateletpheresis program that would incorporate the average number of donors needed per patient, the level of HLA compatibility to be maintained between patient and donor, and the frequencies of patient and donor HLA phenotypes. A database of 4338 plateletpheresis transfusions given to 591 patients from a pool of up to 870 community donors over a 3-year period was analyzed retrospectively to validate the estimates of the average number of donors needed to support a patient, which ranged from 4 to 33 donors. This database was also used to illustrate the application of the pool size determination model. Model results suggest that plateletpheresis donor pools of 1000 to 3000 donors are capable of meeting the transfusion needs of most patients at an HLA-match grade of B2 or better.     

A case of transfusion-associated graft-versus-host disease not prevented by white cell-reduction filters

A case of transfusion-associated graft-versus-host disease (TA-GVHD) in a patient with non-Hodgkin's lymphoma is reported. The patient, a 67-year-old woman, was diagnosed as having diffuse, mixed type non-Hodgkin's lymphoma, at clinical stage IIIA. She was treated with combination chemotherapy and received multiple blood transfusions for anemia and thrombocytopenia. Although white cells (WBCs) were reduced in the transfused components by WBC-reduction filters, the patient developed TA-GVHD that was confirmed by skin biopsy. It is suggested that the WBC reduction attained with these filters does not prevent TA-GVHD in immunocompromised patients. It is recommended that all blood components should be irradiated before transfusion to such patients.     

Recurrent transfusion-related acute lung injury after a two-year interval

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of blood transfusion. The epidemiology and pathogenesis of TRALI are not well established. A Medline literature search shows only rare reports of recurrent TRALI, all occurring soon after the first episodes. We report a case of recurrent TRALI after a 2-year interval. A patient developed TRALI after transfusion of 4 units of fresh frozen plasma for gastrointestinal bleeding due to oesophageal varices in September 2002. The patient required mechanical ventilation but recovered completely. Two years later, in October 2004, the patient experienced a second episode of TRALI during liver transplantation for hepatitis C virus /alcoholic cirrhosis. Again, the patient recovered after ventilator support. Laboratory investigation of the first TRALI episode (2002) showed antibodies against class II human leukocyte antigens (HLA) in three female donors. Laboratory investigation of the second episode (2004) showed anti-DR52 (HLA class II) antibodies in one female donor matching the DR-52 HLA class II antigen in the recipient. TRALI can rarely recur. Consideration of future blood needs for patients experiencing recurrent TRALI should include preventive measures against further TRALI reactions, such as blood from male donors or blood less than 14 days old.     

Fatal transfusion-associated graft-versus-host disease with concomitant immune hemolysis in a group A combat trauma patient resuscitated with group O fresh whole blood

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but well-established fatal complication of blood transfusion. It can occur in immunocompetent patients when they receive transfusions from human leukocyte antigen-haploidentical donors who have lymphocytes with antigens that are not recognized as foreign by the host, but that recognize the host's tissues as foreign. It is generally viewed as a T-cell-mediated process. Graft-induced immune hemolysis or passenger lymphocyte syndrome is a well-described complication of marrow or solid organ transplantation in which immune competent donor B cells produce alloantibodies to recipient red blood cell (RBC) antigens and cause hemolysis of the recipient's RBCs. It is generally considered as a separate process from GVHD, although it could be considered a type of GVHD. Despite the theoretical possibility of both a B-cell and T-cell component to TA-GVHD, detection of a humoral antibody in cases of acute TA-GVHD has not been described. We describe the clinical course and laboratory evaluation of a group A combat trauma patient who was acutely resuscitated with group O fresh whole blood and RBCs and group AB fresh-frozen plasma who experienced the onset of the clinical symptoms of TA-GVHD as well as the onset of hemolysis due to donor-derived anti-A in his plasma 11 days after transfusion.     

Transfusion-associated GVHD: 10 years' experience at the American University of Beirut-Medical Center

BACKGROUND: Although rare, transfusion-associated GVHD (TA-GVHD) is a fatal complication of blood transfusion in which active lymphocytes from the donor attack and destroy recipient organs and tissues. STUDY DESIGN AND METHODS: A search of patient records was carried out at the American University of Beirut-Medical Center, looking for patients who developed TA-GVHD over a 10-year period extending from 1991 to 2001. Relevant information was collected and analyzed. RESULTS: A total of 10 records were found as a result of this search. All were immunocompetent and received fresh nonleukoreduced, nonirradiated blood. The majority received the transfusion at outside periphery hospitals. They received different treatment modalities. The mortality rate was 100 percent. CONCLUSION: TA-GVHD is a serious complication with very high mortality. Effective prevention guidelines should be established in Lebanon including irradiation and the creation of a central blood bank.     

潍坊地区无偿献血者HLA抗体和HNA抗体检测情况分析

目的:通过随机抽样检测潍坊地区无偿献血者血清HLA抗体及HNA抗体阳性率,评估在潍坊献血人群中开展HLA及HNA抗体筛查的必要性.方法:随机选取有输血、妊娠、移植等免疫史的无偿献血者208例作为实验组,选取无上述免疫史的无偿献血者168例作为对照组,运用流式荧光微珠法对两组标本进行HLA抗体和HNA抗体检测,运用统计分...     

How is transfusion-associated graft-versus-host disease similar to,yet different from,organ transplantation-associated graft-versus-host disease?

Graft-versus-host disease (GVHD) is a rare, usually fatal complication following blood transfusion or organ transplantation, namely transfusion-associated GVHD (TA-GVHD) and organ transplantation-associated GVHD (OA-GVHD). The dominant mechanism of GVHD is exposure to viable donor lymphocytes that are not recognized as foreign by, but able to respond to, the recipient. The clinical features and relative risk factors of either TA-GVHD or OA-GVHD are yet to be fully understood. The current review article aims to discuss and summarize the similarities and differences between TA-GVHD and OA-GVHD to gain a deeper understanding of the pathogenesis.It is evident that the shared human leukocyte antigens (HLA) between donor and recipient and immunocompromised status of the recipient are the two main risk factors for the development of both TA-GVHD and OA-GVHD. In particular, the homozygous donor with donor-dominant one-way matching at the three loci HLA-A, -B, and -DR has a high risk of developing GVHD following liver transplantation, and such donors should be excluded to prevent it. However, the development of GVHD is thought to be related to a combination of several risk factors, and the contribution of each risk factor remains unknown. Further studies are warranted to determine the important contributing factors that lead to an accurate prediction of GVHD development.     

Transfusion-associated GVHD after fludarabine therapy in a patient with systemic lupus erythematosus

BACKGROUND: Fludarabine, a purine antimetabolite with potent immunosuppressive properties, has previously been associated with the development of transfusion-associated GVHD (TA-GVHD) in patients with hematologic malignancies. Its role as a risk factor for TA-GVHD in patients without underlying leukemia or lymphoma is uncertain. STUDY DESIGN AND METHODS: A 42-year-old female with refractory lupus nephritis received three monthly cycles of fludarabine (30 mg/m2/day on Days 1-3) and cyclophosphamide (500 mg/m2 on Day 1). Three months after the last dose of fludarabine, she received 2 units of packed RBCs and 6 units of pooled random platelets, none of which were irradiated. Two weeks later, fever, rash, aminotransferase elevations, hyperbilirubinemia, and pancytopenia developed. RESULTS: Marrow biopsy showed severe aplasia and skin biopsy was consistent with GVHD. Allele-level HLA typing on circulating lymphocytes revealed extra HLA alleles not present in her pretreatment sample, but identical to the HLA haplotypes of an unrelated platelet donor. Treatment with antithymocyte globulin, cyclosporine, and prednisone was followed by preparatory conditioning for a PBPC transplant from an HLA-identical sibling, but the patient died of disseminated candidiasis before transplant. CONCLUSIONS: Fludarabine and other purine analogs are increasingly used in the treatment of disorders other than hematologic malignancy, such as autoimmune disease. The occurence of TA-GVHD after fludarabine therapy in a patient with lupus strongly suggests that this drug is sufficiently immunoablative to be an independent risk factor for TA-GVHD. Irradiation of blood components should be considered in all patients who receive fludarabine therapy.     

Diagnosis of transfusion-associated graft-vs.-host disease: the importance of short tandem repeat analysis

Transfusion-associated graft-vs.-host disease (TA-GvHD) can occur following transfusion of blood products containing immunocompetent lymphocytes, usually from HLA homozygous donors, into immunocompromised patients sharing one HLA haplotype with the donor. The diagnosis of TA-GvHD may be delayed due to the initial nonspecific clinical features involved. Investigations to detect the presence of donor-derived cells in the blood and/or affected tissues of the recipient are essential to confirm the diagnosis. We report the investigation of suspected TA-GvHD using short tandem repeat (STR) analysis, to detect the presence of donor cells (chimerism), in an immunocompetent patient admitted for coronary artery bypass surgery. Peripheral blood and skin biopsies (from affected and nonaffected sites) from the patient and peripheral blood samples from the implicated donors were taken for HLA typing and STR analysis. STR analysis revealed the presence of donor material in the patient's peripheral blood sample and in DNA extracted from the affected skin biopsy but not the unaffected biopsy, suggesting lymphocytes from this donor were responsible for the development of TA-GvHD. Furthermore, HLA typing results supported the diagnosis of TA-GvHD. These data demonstrate the use of STR and HLA analysis as effective tools in the diagnosis of TA-GvHD.     

Transfusion-related acute lung injury caused by an NB2 granulocyte- specific antibody in a patient with thrombotic thrombocytopenic purpura

HLA and granulocyte-specific antibodies have been implicated in the production of transfusion-related acute lung injury (TRALI). Reported here is a case that suggests that the patient's preexisting condition may play an important role in determining whether TRALI develops upon transfusion of blood products containing anti-white cell (WBC) antibodies. A 29-year-old woman with thrombotic thrombocytopenic purpura (TTP) underwent an uneventful 1.5-volume plasma exchange, which was followed by the transfusion of 2 red cell (RBC) units. At the end of the second RBC transfusion, the patient developed clinical signs and symptoms of noncardiogenic pulmonary edema. Serologic studies demonstrated that the serum from the second RBC donor had no HLA antibodies but did have a granulocyte-specific antibody (anti-NB2) that caused the agglutination of the recipient's granulocytes, which were NB2 positive. Serum from the donor of the first RBC unit and serum from the donors of units used in the exchange had no HLA or granulocyte-specific antibodies that reacted with the recipient's WBCs. Because the donor implicated in this reaction had a history of 21 blood donations, none of which had been associated with a transfusion reaction, we suggest that the patient's preexisting condition played a significant role in this episode of TRALI, owing to the granulocyte-specific antibody.     

The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy

BACKGROUND: Antibodies to human leukocyte antigens (HLA) in donated blood have been implicated as a cause of transfusion-related acute lung injury (TRALI). A potential measure to reduce the risk of TRALI includes screening plateletpheresis donors for HLA antibodies. The prevalence of HLA antibodies and their relationship to previous transfusion or pregnancy in blood donors was determined.
STUDY DESIGN AND METHODS: A total of 8171 volunteer blood donors were prospectively recruited by six US blood centers from December 2006 to May 2007. Donors provided a detailed history of pregnancy and transfusion and a sample for HLA Class I and II antibody testing by multiantigen bead flow analysis.
RESULTS: A total of 8171 donors were enrolled; 7920 (96.9%) had valid HLA antibody test results and 7841 (99%) of those had complete pregnancy and transfusion information. The prevalence of any HLA antibody was similar in nontransfused (n = 1138) and transfused (n = 895) men, 1.0% versus 1.7% (p = 0.16). HLA antibodies were detected in 17.3% of all female donors (n = 5834) and in 24.4% of those with a history of previous pregnancy (n = 3992). The prevalence of HLA antibodies increased in women with greater numbers of pregnancy: 1.7% (zero), 11.2% (one), 22.5% (two), 27.5% (three), and 32.2% (four or more pregnancies; p < 0.0001).
CONCLUSION: HLA Class I and Class II antibodies are detectable at low prevalence in male donors regardless of transfusion and in female donors without known immunizing events. The prevalence of HLA antibodies increases significantly with more pregnancies. These data will allow blood centers to estimate the impact of HLA antibody testing as a potential TRALI risk reduction measure.