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Hypotensive reactions associated with platelet transfusions and angiotensin-converting enzyme inhibitors
CURRENT L I TERA TURE
TeANSFVS*ON MEmcxN REWWS
Sunny Dzik, Mindy Goldman, and Marion E. Reid, Abstract Editors
HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome. Sundaresan S, Mohanakumar T, Smith MA, et al. Transplantation 65:648-653, 1998. Bronchiolitis obliterans is a progressive immune-based destruction of small airways seen in patients after lung transplantation. It is a major cause of morbidity and mortality after lung transplantations, and its exact pathogenesis remains mysterious. Previous studies have suggested that bronchiolitis obliterans may be a clinical manifestation of posttransplantation cytomegalovirus disease or a specific pattern of graft rejection. This study draws attention to the role of human leukocyte antigen (HLA)matching in the development of this syndrome. The study was a retrospective analysis of 94 lung transplants. Patients who did not survive more than 3 months were excluded. The development of progressive bronchiolitis obliterans was correlated with a variety of dependent variables, including gender, age, single versus double lung transplant, indication, graft ischemia time, use of bypass, cytomegalovirus (CMV) status, degree of HLA matching, presence of HLA antibodies pretransplantation, presence of a positive cross-match, development of acute rejection, and development of HLA antibodies posttransplantation. Multivariant analysis found that only the degree of HLA-A locus mismatch and the development of anti-HLA antibodies posttransplantation correlated with the development of bronchiolitis obliterans. With data based on nearly 100 patients, this study provides reasonably strong support for the notion that recipient response to class I HLA is fundamental to the development of bronchiolitis obliterans and that HLA matching--particularly at class I loci may be a way to avoid this complication after lung transplantation. It would be of interest to review the findings in multicenter registries and to examine the relationship between obliterans and disparities at HLA-A locus private specificities versus disparities at HLA class I public antigens. Don't close your HLA lab just yet! (S.D.) r
Lack of clinically significant contact system activation during platelet concentrate filtration by leukocyte removal filters. Scott CF, Brandwein H, Whitbread J, et aL Blood 92:616-622, 1998. A growing body of clinical observation suggests that bedside leukofiltration can result in hypotensive reactions among some recipients who are taking medications (such as angiotensinconverting enzyme inhibitors) that inhibit the breakdown of bradykinin. This article provides in vitro laboratory evidence to the contrary. The work is a joint venture by investigators from a filter manufacturer and by a highly respected laboratory (RW Colman) known for studies of activation of the intrinsic coagulation cascade. Pall PXL8K and Asahi PLS-5A leukoreduction filters were used. Twenty batches of single-donor apheresis 68
platelets were collected, divided into two aliquots, and filtered through either the Pall or the Asahi filter. Samples were collected after the first 5 mL of filtration and again at the end of filtration. To assay for the release of bradykinin, the investigators used a particle concentration fluorescence immunoassay (PCFIA). The assay uses fluorescent-tagged antibodies to detect cleavage products of either high-molecular-weight kininogen or low-molecular-weight kininogen. Cleavage of these compounds occurs as a precursor to the development of bradykinin. The investigators determined a ratio of cleaved to uncleaved highmolecular-weight kininogen, expressed as a "cleaved kininogen index (CKI)." This study differs from others reported in the literature because it attempts to directly measure kininogen cleavage rather than measure the production of bradykinin. The results showed little evidence for activation of bradykinin as measured by the CKI or as measured by the changes in the concentration of high-molecular-weight or low-molecularweight kininogen. These results led the authors to conclude that the kallikrein-kinin system was not substantially activated by either filter as a result of filtration. This study does not support the notion that bradykinin is activated during leukofiltration. The authors speculate that another factor (such as serotonin) that is released during platelet storage may account for the clinical observation of hypotension in some patients after bedside leukofiltration of platelet concentrates. The authors note that their assay would have missed up to 5% activation of bradykinin from precursor kininogen. Whether this may account for the difference between their results and those of laboratories that have attempted to directly measure bradykinin levels after leukofiltration awaits more study. (S.D.)
Hypotensive reactions associated with platelet transfusions and angiotensin-converting enzyme inhibitors. Mair B, Lepar GF. Vox Sang 74:27-30, 1998. There have been several reports of unexplained hypotensive reactions associated with the transfusion of platelets through bedside leukoreduction filters. Features common to many of these reactions include the onset of marked hypotension during or shortly after transfusion, with fairly rapid resolution after cessation of transfusion. They have been associated with the use of negatively charged leukoreduction filters and are more frequent in patients receiving angiotensin-converting enzyme (ACE) inhibitors. The authors describe a series of 16 hypotensive transfusion reactions occurring in 14 patients in a 3-month period, after the introduction of negatively charged filters (PALL PL 100) in their hospital. All patients were undergoing coronary artery bypass graft surgery and taking ACE inhibitors. Patients experienced a mean drop in systolic and dyastolic blood pressure of 53 and 25 mg, respectively, abruptly in the minutes after the start of transfusion. In most cases, symptoms abated after cessation of the transfusion; however, some patients required pressor agents. One patient had recurrent hypotensive
Transfusion Medicine Reviews, Vo113, No 1 (January), 1999: pp 68-74
CURRENT LITERATURE
episodes on three separate transfusions. No similar reactions occurred in patients not on ACE inhibitors, or in patients transfused before May 1996 with positively charged leukoreduction filters. The authors hypothesized that bradykinin generated by contact with negatively charged surfaces may be responsible for hypotension in these patients; bradykinin clearance is reduced in patients receiving ACE inhibitors. Similar reactions have been noted in patients receiving ACE inhibitor therapy and undergoing therapeutic plasma exchange; withholding the medication appeared to eliminate most of these reactions. Few details are given about the investigations done into the potential causes of the reactions. Because only 179 patients received platelet transfusions in the hospital during this period, the reaction incidence was remarkably high. A questionnaire sent to all AABB institutional members regarding platelet transfusion reactions in 1993 only showed 17 hypotensive reactions, primarily in patients with hematologic disease or malignancy; two of these patients had received ACE inhibitors (Hume et al., Transfusion 36:904-909, 1996). Although it is difficult to draw conclusions on the frequency or causes of these reactions, transfusionists should be alert to them, particularly in patients on ACE inhibitors. (M. G.)
Detection of microchimerism after allogeneic blood transfusion using nested polymerase chain reaction amplification with sequence-specific primers (PCRSSP): A cautionary tale. Carter AS, Bunce IV~, Cerundolo L, et al. Blood 92:683-689, 1998. Because donor cell microchimerism may play an important role in the immunomodulatory effect of blood transfusion, several laboratories have been developing assays to track the persistence of donor cells after transfusion. The polymerase chain reaction (PCR) is a natural choice for such studies because of its ability to amplify small amounts of residual donor DNA. PCR primers specific for donor-type material are often used because general primers would amplify recipient DNA as well as donor DNA. Because of the large number of sequencespecific PCR primers for HLA sequences, HLA-based primers are a very appropriate choice. This was the basis for the studies presented in this report. Despite selecting a very appropriate research strategy, the authors encountered several difficulties with using HLA-based sequence-specific primers (SSP). First, they found great variation in the efficiency of amplification of different HLA-DR alleles. This is likely attributable to different binding efficiencies of different HLA-DR primers. Second, single-amplification PCR was inadequate to achieve the high degree of assay sensitivity necessary to detect microchimerism. Thus, the authors resorted to a nested PCR approach to detect donor DNA representing 0.001% of total DNA. Most importantly, the authors identified a problem with the specificity of the nested PCR assay. In the course of their investigations, falsepositive bands repeatedly appeared in the PCR product. To determine their nature, the bands were sequenced and analyzed. They were found to be highly homologous to known pseudogenes present in the HLA-DR region, including HLADRB7 0101. The chance of false-positive PCR reactions increases if the "hot start" reaction is not used. Unfortunately, the authors of this article do not comment in their methods on whether they used "hot start PCR." Some investigators have claimed to have found very long persistence of donor material after transfusion or transplantation. Whether false-positive PCR
69
results arising from amplification of pseudogenes has accounted for any of these findings is not known at this time. However, the authors note that one recent paper on the topic of microchimerism and transplant rejection would have been expected to show false-positive results in 17% of subjects tested. Thus, the current report does provide a useful cautionary note to those who are following the study of microchimerism after transfusion and emphasizes the need for multiple controls and attention to the specificity as well as the sensitivity of the assay. (S.D.)
Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. van Duijn CM, Delasnerie-Laupr#tre IV, Masullo C, et al, for the European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease. Lancet 351:1081-1085, 1998. This is the largest case-control study of risk factors for Creutzfeldt-Jakob disease (CJD) published to date, involving 405 patients with definite or probable CJD. Potential risk factors for CJD transmission evaluated included blood transfusion, neurosurgical procedures, meat consumption, and various occupations that include contact with blood, animals, or animal products. The patients were part of the European Union Collaborative Studies monitoring the incidence of CJD in Belgium, France, Germany, Italy, the Netherlands, and the United Kingdom and had been diagnosed between 1993 and 1995, using a standardized diagnostic protocol. The controls were matched according to age and sex and recruited from the hospital where the patients had been diagnosed. This study found evidence of familial aggregation of CJD with dementia due to other causes (relative risk, 2.26). There was no significant association with blood transfusion in general or transfusions 10 years before diagnosis, neurosurgical procedures, overall meat consumption, or occupational exposure to meat or blood. There were weak associations With consumption of raw meat and brain, frequent exposure to leather products, and exposure to fertilizer consisting of hoofs and horns (relative risks ranging from 1.63 to 2.32). These associations were not more pronounced in the United Kingdom compared with the other countries. Weaknesses of this study include its retrospective design, because relatives of patients with CJD who were questioned may have recall bias. The hospital controls that were used already have an increased risk of blood transfusion; therefore, in further studies, general population-based controls may be useful. The authors also point out that their study is limited to patients diagnosed at or before 1995 and therefore does not include any of the new variant CJD patients. The main strength of this study is its large size, permitting greater statistical power than previous case-control studies. (Mr.G.)
On the origins of BSE. Brown R Lancet 352:252-253, 1998. Since the previous issue of TMR, the United Kingdom has recommended that universal leukocyte depletion of blood components occur in an attempt to potentially have some impact on human-to-human transmission of new variant CreutzfeldJacob disease (nvCJD). Bovine spongiform encephalopathy (BSE) is considered to have been the source of prions resulting in nvCJD. The first cases of BSE occurred in the United Kingdom in 1985, and the epidemic peaked in 1993, when over 170,000 animals died of BSE. This short commentary in the
TeANSFVS*ON MEmcxN REWWS
Sunny Dzik, Mindy Goldman, and Marion E. Reid, Abstract Editors
HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome. Sundaresan S, Mohanakumar T, Smith MA, et al. Transplantation 65:648-653, 1998. Bronchiolitis obliterans is a progressive immune-based destruction of small airways seen in patients after lung transplantation. It is a major cause of morbidity and mortality after lung transplantations, and its exact pathogenesis remains mysterious. Previous studies have suggested that bronchiolitis obliterans may be a clinical manifestation of posttransplantation cytomegalovirus disease or a specific pattern of graft rejection. This study draws attention to the role of human leukocyte antigen (HLA)matching in the development of this syndrome. The study was a retrospective analysis of 94 lung transplants. Patients who did not survive more than 3 months were excluded. The development of progressive bronchiolitis obliterans was correlated with a variety of dependent variables, including gender, age, single versus double lung transplant, indication, graft ischemia time, use of bypass, cytomegalovirus (CMV) status, degree of HLA matching, presence of HLA antibodies pretransplantation, presence of a positive cross-match, development of acute rejection, and development of HLA antibodies posttransplantation. Multivariant analysis found that only the degree of HLA-A locus mismatch and the development of anti-HLA antibodies posttransplantation correlated with the development of bronchiolitis obliterans. With data based on nearly 100 patients, this study provides reasonably strong support for the notion that recipient response to class I HLA is fundamental to the development of bronchiolitis obliterans and that HLA matching--particularly at class I loci may be a way to avoid this complication after lung transplantation. It would be of interest to review the findings in multicenter registries and to examine the relationship between obliterans and disparities at HLA-A locus private specificities versus disparities at HLA class I public antigens. Don't close your HLA lab just yet! (S.D.) r
Lack of clinically significant contact system activation during platelet concentrate filtration by leukocyte removal filters. Scott CF, Brandwein H, Whitbread J, et aL Blood 92:616-622, 1998. A growing body of clinical observation suggests that bedside leukofiltration can result in hypotensive reactions among some recipients who are taking medications (such as angiotensinconverting enzyme inhibitors) that inhibit the breakdown of bradykinin. This article provides in vitro laboratory evidence to the contrary. The work is a joint venture by investigators from a filter manufacturer and by a highly respected laboratory (RW Colman) known for studies of activation of the intrinsic coagulation cascade. Pall PXL8K and Asahi PLS-5A leukoreduction filters were used. Twenty batches of single-donor apheresis 68
platelets were collected, divided into two aliquots, and filtered through either the Pall or the Asahi filter. Samples were collected after the first 5 mL of filtration and again at the end of filtration. To assay for the release of bradykinin, the investigators used a particle concentration fluorescence immunoassay (PCFIA). The assay uses fluorescent-tagged antibodies to detect cleavage products of either high-molecular-weight kininogen or low-molecular-weight kininogen. Cleavage of these compounds occurs as a precursor to the development of bradykinin. The investigators determined a ratio of cleaved to uncleaved highmolecular-weight kininogen, expressed as a "cleaved kininogen index (CKI)." This study differs from others reported in the literature because it attempts to directly measure kininogen cleavage rather than measure the production of bradykinin. The results showed little evidence for activation of bradykinin as measured by the CKI or as measured by the changes in the concentration of high-molecular-weight or low-molecularweight kininogen. These results led the authors to conclude that the kallikrein-kinin system was not substantially activated by either filter as a result of filtration. This study does not support the notion that bradykinin is activated during leukofiltration. The authors speculate that another factor (such as serotonin) that is released during platelet storage may account for the clinical observation of hypotension in some patients after bedside leukofiltration of platelet concentrates. The authors note that their assay would have missed up to 5% activation of bradykinin from precursor kininogen. Whether this may account for the difference between their results and those of laboratories that have attempted to directly measure bradykinin levels after leukofiltration awaits more study. (S.D.)
Hypotensive reactions associated with platelet transfusions and angiotensin-converting enzyme inhibitors. Mair B, Lepar GF. Vox Sang 74:27-30, 1998. There have been several reports of unexplained hypotensive reactions associated with the transfusion of platelets through bedside leukoreduction filters. Features common to many of these reactions include the onset of marked hypotension during or shortly after transfusion, with fairly rapid resolution after cessation of transfusion. They have been associated with the use of negatively charged leukoreduction filters and are more frequent in patients receiving angiotensin-converting enzyme (ACE) inhibitors. The authors describe a series of 16 hypotensive transfusion reactions occurring in 14 patients in a 3-month period, after the introduction of negatively charged filters (PALL PL 100) in their hospital. All patients were undergoing coronary artery bypass graft surgery and taking ACE inhibitors. Patients experienced a mean drop in systolic and dyastolic blood pressure of 53 and 25 mg, respectively, abruptly in the minutes after the start of transfusion. In most cases, symptoms abated after cessation of the transfusion; however, some patients required pressor agents. One patient had recurrent hypotensive
Transfusion Medicine Reviews, Vo113, No 1 (January), 1999: pp 68-74
CURRENT LITERATURE
episodes on three separate transfusions. No similar reactions occurred in patients not on ACE inhibitors, or in patients transfused before May 1996 with positively charged leukoreduction filters. The authors hypothesized that bradykinin generated by contact with negatively charged surfaces may be responsible for hypotension in these patients; bradykinin clearance is reduced in patients receiving ACE inhibitors. Similar reactions have been noted in patients receiving ACE inhibitor therapy and undergoing therapeutic plasma exchange; withholding the medication appeared to eliminate most of these reactions. Few details are given about the investigations done into the potential causes of the reactions. Because only 179 patients received platelet transfusions in the hospital during this period, the reaction incidence was remarkably high. A questionnaire sent to all AABB institutional members regarding platelet transfusion reactions in 1993 only showed 17 hypotensive reactions, primarily in patients with hematologic disease or malignancy; two of these patients had received ACE inhibitors (Hume et al., Transfusion 36:904-909, 1996). Although it is difficult to draw conclusions on the frequency or causes of these reactions, transfusionists should be alert to them, particularly in patients on ACE inhibitors. (M. G.)
Detection of microchimerism after allogeneic blood transfusion using nested polymerase chain reaction amplification with sequence-specific primers (PCRSSP): A cautionary tale. Carter AS, Bunce IV~, Cerundolo L, et al. Blood 92:683-689, 1998. Because donor cell microchimerism may play an important role in the immunomodulatory effect of blood transfusion, several laboratories have been developing assays to track the persistence of donor cells after transfusion. The polymerase chain reaction (PCR) is a natural choice for such studies because of its ability to amplify small amounts of residual donor DNA. PCR primers specific for donor-type material are often used because general primers would amplify recipient DNA as well as donor DNA. Because of the large number of sequencespecific PCR primers for HLA sequences, HLA-based primers are a very appropriate choice. This was the basis for the studies presented in this report. Despite selecting a very appropriate research strategy, the authors encountered several difficulties with using HLA-based sequence-specific primers (SSP). First, they found great variation in the efficiency of amplification of different HLA-DR alleles. This is likely attributable to different binding efficiencies of different HLA-DR primers. Second, single-amplification PCR was inadequate to achieve the high degree of assay sensitivity necessary to detect microchimerism. Thus, the authors resorted to a nested PCR approach to detect donor DNA representing 0.001% of total DNA. Most importantly, the authors identified a problem with the specificity of the nested PCR assay. In the course of their investigations, falsepositive bands repeatedly appeared in the PCR product. To determine their nature, the bands were sequenced and analyzed. They were found to be highly homologous to known pseudogenes present in the HLA-DR region, including HLADRB7 0101. The chance of false-positive PCR reactions increases if the "hot start" reaction is not used. Unfortunately, the authors of this article do not comment in their methods on whether they used "hot start PCR." Some investigators have claimed to have found very long persistence of donor material after transfusion or transplantation. Whether false-positive PCR
69
results arising from amplification of pseudogenes has accounted for any of these findings is not known at this time. However, the authors note that one recent paper on the topic of microchimerism and transplant rejection would have been expected to show false-positive results in 17% of subjects tested. Thus, the current report does provide a useful cautionary note to those who are following the study of microchimerism after transfusion and emphasizes the need for multiple controls and attention to the specificity as well as the sensitivity of the assay. (S.D.)
Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. van Duijn CM, Delasnerie-Laupr#tre IV, Masullo C, et al, for the European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease. Lancet 351:1081-1085, 1998. This is the largest case-control study of risk factors for Creutzfeldt-Jakob disease (CJD) published to date, involving 405 patients with definite or probable CJD. Potential risk factors for CJD transmission evaluated included blood transfusion, neurosurgical procedures, meat consumption, and various occupations that include contact with blood, animals, or animal products. The patients were part of the European Union Collaborative Studies monitoring the incidence of CJD in Belgium, France, Germany, Italy, the Netherlands, and the United Kingdom and had been diagnosed between 1993 and 1995, using a standardized diagnostic protocol. The controls were matched according to age and sex and recruited from the hospital where the patients had been diagnosed. This study found evidence of familial aggregation of CJD with dementia due to other causes (relative risk, 2.26). There was no significant association with blood transfusion in general or transfusions 10 years before diagnosis, neurosurgical procedures, overall meat consumption, or occupational exposure to meat or blood. There were weak associations With consumption of raw meat and brain, frequent exposure to leather products, and exposure to fertilizer consisting of hoofs and horns (relative risks ranging from 1.63 to 2.32). These associations were not more pronounced in the United Kingdom compared with the other countries. Weaknesses of this study include its retrospective design, because relatives of patients with CJD who were questioned may have recall bias. The hospital controls that were used already have an increased risk of blood transfusion; therefore, in further studies, general population-based controls may be useful. The authors also point out that their study is limited to patients diagnosed at or before 1995 and therefore does not include any of the new variant CJD patients. The main strength of this study is its large size, permitting greater statistical power than previous case-control studies. (Mr.G.)
On the origins of BSE. Brown R Lancet 352:252-253, 1998. Since the previous issue of TMR, the United Kingdom has recommended that universal leukocyte depletion of blood components occur in an attempt to potentially have some impact on human-to-human transmission of new variant CreutzfeldJacob disease (nvCJD). Bovine spongiform encephalopathy (BSE) is considered to have been the source of prions resulting in nvCJD. The first cases of BSE occurred in the United Kingdom in 1985, and the epidemic peaked in 1993, when over 170,000 animals died of BSE. This short commentary in the