- Email: [email protected]
The role of the plasma from platelet concentrates in transfusion reactions
CURRENT LITERATURE
AECA reactivity. By immunoblotting techniques, it was shown that, among V regions of AECAs, IVIG selectively recognized certain idiotypes expressed by the autoantibodies of a given individual. The ability of IVIG to retain AECAs varied between donors and also AECA IgG of a single donor, depending on the autoantibody species. These results provide direct evidence that IV1G interacts idiotypically with V regions of autoantibodies and may be relevant for the understanding of the mechanisms that control the expression of natural autoantibody activity in serum as well as for that of the difference in immunomodulatory response to IVIG therapy seen between patients with antoimmune disease.
Residue at Position 331 in the IgG1 and IgG4 CH2 Domains Contributes to Their Differential Ability to Bind and Activate Complement. Xu Y, Oomen R, Klein MH. J Biol Chem 269:3469-3474, 1994. IgG is the major immunoglobulin in normal human serum and is divided into four subclasses termed lgGl, IgG2, IgG3, and IgG4. Whereas the sequence differences between these subclasses is minimal, they do differ markedly in their ability to activate the classical pathway of complement. IgG 1 and lgG 3 are the most effective at binding and activating C1 component of complement, whereas IgG 2 is much less active, and IgG 4 is inactive. Although IgG 1 and IgGg differ mostly in the hinge region, it has been clearly shown that the hinge region is not a factor determining complement binding and activation. In addition, both IgGl and IgG4 possess the " E K K " putative Clq binding motif in their CH2 domains. To investigate what might constitute an underlying feature determining complement activation by IgG molecules, the authors focused on a single amino acid (proline331 in IgG1) in the CH2 domain, conserved in complement-fixing IgGs but not found in IgG~; the latter possess a serine at this location. A pair of anti-dinitrophenol (DNP) chimeric IgG~ and IgG4 antibodies were genetically engineered, with reciprocal amino acid substitutions at position 331 (Pro Ala for IgG1 and Ala Pro for IgG4), and these were tested for ability to fix complement by examining hemolysis of DNPderivitized red blood ceils. The results showed that the Pro Ala switch abolished the ability of IgG 1 to hemolyze red blood cells, whereas the Ala Pro switch conferred partial complement-fixing activity to the IgG4 molecule. Molecular modelling by the authors suggests that the conformation of the Clq binding motifs are essentially unchanged between the wild-type IgG~ and the variant. The suggestion is offered that the serine in IgG4 may preclude contact with a complementary surface on Clq, and that the Pro TM in IgG~, IgG2, and IgG 3 molecules contributes in a major way to the ability of these IgG subclasses to fix complement, possibly by facilitating Clq docking with IgG.
The Role of the Plasma From Platelet Concentrates in Transfusion Reactions. Hedd/e NM, K/area L, Singer ,1, et a/. N Engl J Med 331:625-628, 1994. The widespread use of leukocyte depletion has spurred renewed interest and experimentation into the pathogenesis of febrile nonhemolytic (FNH) transfusion reactions. Clinical experience has repeatedly shown that although leukodepletion is nearly always effective for the prevention of FNH reactions to red cell concentrates, the success at preventing FNH reactions
179
to platelet concentrates (PLTs) has been less impressive. This landmark report provides clinical evidence to address this issue. Previous studies had shown that inflammatory cytokines accumulate in PLTs containing residual donor leukocytes during storage. Passive transfer of these cytokines at the time of transfusion was speculated to cause FNH reactions. The authors directly addressed this question as follows: platelets prepared from whole blood and pooled in groups of five units were used. Whenever possible, four- or five-day-old PLTs were used to increase the likelihood of using plasma with high levels of cytokines. The pooled PLT concentrate was centrifuged at 2,000g for 10 minutes, and then 150 to 180 mL of the plasma superuatant was removed to a sterile transfer bag. The plasma supernatant contained low residual numbers of platelets and leukocytes. The platelet pellet was then resuspended in 150 to 180 mL of FFP previously donated by one of the platelet donors. The superuatant from the pool and the resuspended platelets were then transfused to the patient in random order with 2-hour intervals between transfusions. A total of 64 pairs of components were transfused. In 20 instances the patient reacted to the plasma only; whereas in only 6 instances did the patient react to the resuspended ceils only. In 8 instances the patient reacted to both and in 30 instances reacted to neither. The severity of the reactions to the plasma supernatant correlated with the level of interleukin (IL)-l13 and IL-6 present in the plasma. Although 34 transfusion pairs were associated with reactions, it is important to note that only 7 actually involved a fever >I~ Unfortunately, the patients were all administered premedication with both intravenous diphenhydramine hydrochloride (Benadryl; Parke-Davis, Scarborough, Canada) and acetaminophen. This outdated practice of routine premedication may have obscured the clinical picture. Nevertheless, this study provides the best clinical evidence to date that passive transfer of inflammatory cytokines from 4-day and 5-day-old PLTs represents one mechanism of FNH reactions to PLTs.
Mucosa-Associated Lymphoid Tissue Lymphoma of the Lung With Cold-Reacting Autoantibody-Mediated Hemolytic Anemia. Liaw Y-S, Yang P-C, Su l-J, et al. Chest 105:288-290, 1994. Primary mucosa-associated lymphoid tissue lymphoma (MALToma) of the lung is a rare low-grade B-cell lymphoma. This is the first report of the association of MALToma of the lung and cold-reacting autoantibody-mediated hemolytic anemia. The tumor lymphoid cells were positive for the CD19 and CD20 B-cell markers, showing IgMh restriction. Serum immunofixation electrophoresis also showed IgMh monoclonal gammopathy. The Coombs'-positive hemolytic anemia (hemoglobin 86 g/L, reticulocytes 13%, lactic dehydrogenase 1,150 U/L, and bilirubin 2.1 mg/dL) was presumably caused by a cold agglutinin with a titer > 1:1,024 at 4~ but not reactive at 37~ Whereas the patient's MALToma and hemolytic anemia both responded to chemotherapy, the cold agglutinin titer remained unchanged. Unfortunately, no further details of cold agglutinin characterization are provided and this case serves to remind that when attempting to claim a new observation in particular, it is essential to investigate critically and characterize as fully as possible and to provide the data. In this case the authors have failed to do this and, given the low titer and apparent low thermal amplitude of the autoantibody, it is difficult to support their contention.
AECA reactivity. By immunoblotting techniques, it was shown that, among V regions of AECAs, IVIG selectively recognized certain idiotypes expressed by the autoantibodies of a given individual. The ability of IVIG to retain AECAs varied between donors and also AECA IgG of a single donor, depending on the autoantibody species. These results provide direct evidence that IV1G interacts idiotypically with V regions of autoantibodies and may be relevant for the understanding of the mechanisms that control the expression of natural autoantibody activity in serum as well as for that of the difference in immunomodulatory response to IVIG therapy seen between patients with antoimmune disease.
Residue at Position 331 in the IgG1 and IgG4 CH2 Domains Contributes to Their Differential Ability to Bind and Activate Complement. Xu Y, Oomen R, Klein MH. J Biol Chem 269:3469-3474, 1994. IgG is the major immunoglobulin in normal human serum and is divided into four subclasses termed lgGl, IgG2, IgG3, and IgG4. Whereas the sequence differences between these subclasses is minimal, they do differ markedly in their ability to activate the classical pathway of complement. IgG 1 and lgG 3 are the most effective at binding and activating C1 component of complement, whereas IgG 2 is much less active, and IgG 4 is inactive. Although IgG 1 and IgGg differ mostly in the hinge region, it has been clearly shown that the hinge region is not a factor determining complement binding and activation. In addition, both IgGl and IgG4 possess the " E K K " putative Clq binding motif in their CH2 domains. To investigate what might constitute an underlying feature determining complement activation by IgG molecules, the authors focused on a single amino acid (proline331 in IgG1) in the CH2 domain, conserved in complement-fixing IgGs but not found in IgG~; the latter possess a serine at this location. A pair of anti-dinitrophenol (DNP) chimeric IgG~ and IgG4 antibodies were genetically engineered, with reciprocal amino acid substitutions at position 331 (Pro Ala for IgG1 and Ala Pro for IgG4), and these were tested for ability to fix complement by examining hemolysis of DNPderivitized red blood ceils. The results showed that the Pro Ala switch abolished the ability of IgG 1 to hemolyze red blood cells, whereas the Ala Pro switch conferred partial complement-fixing activity to the IgG4 molecule. Molecular modelling by the authors suggests that the conformation of the Clq binding motifs are essentially unchanged between the wild-type IgG~ and the variant. The suggestion is offered that the serine in IgG4 may preclude contact with a complementary surface on Clq, and that the Pro TM in IgG~, IgG2, and IgG 3 molecules contributes in a major way to the ability of these IgG subclasses to fix complement, possibly by facilitating Clq docking with IgG.
The Role of the Plasma From Platelet Concentrates in Transfusion Reactions. Hedd/e NM, K/area L, Singer ,1, et a/. N Engl J Med 331:625-628, 1994. The widespread use of leukocyte depletion has spurred renewed interest and experimentation into the pathogenesis of febrile nonhemolytic (FNH) transfusion reactions. Clinical experience has repeatedly shown that although leukodepletion is nearly always effective for the prevention of FNH reactions to red cell concentrates, the success at preventing FNH reactions
179
to platelet concentrates (PLTs) has been less impressive. This landmark report provides clinical evidence to address this issue. Previous studies had shown that inflammatory cytokines accumulate in PLTs containing residual donor leukocytes during storage. Passive transfer of these cytokines at the time of transfusion was speculated to cause FNH reactions. The authors directly addressed this question as follows: platelets prepared from whole blood and pooled in groups of five units were used. Whenever possible, four- or five-day-old PLTs were used to increase the likelihood of using plasma with high levels of cytokines. The pooled PLT concentrate was centrifuged at 2,000g for 10 minutes, and then 150 to 180 mL of the plasma superuatant was removed to a sterile transfer bag. The plasma supernatant contained low residual numbers of platelets and leukocytes. The platelet pellet was then resuspended in 150 to 180 mL of FFP previously donated by one of the platelet donors. The superuatant from the pool and the resuspended platelets were then transfused to the patient in random order with 2-hour intervals between transfusions. A total of 64 pairs of components were transfused. In 20 instances the patient reacted to the plasma only; whereas in only 6 instances did the patient react to the resuspended ceils only. In 8 instances the patient reacted to both and in 30 instances reacted to neither. The severity of the reactions to the plasma supernatant correlated with the level of interleukin (IL)-l13 and IL-6 present in the plasma. Although 34 transfusion pairs were associated with reactions, it is important to note that only 7 actually involved a fever >I~ Unfortunately, the patients were all administered premedication with both intravenous diphenhydramine hydrochloride (Benadryl; Parke-Davis, Scarborough, Canada) and acetaminophen. This outdated practice of routine premedication may have obscured the clinical picture. Nevertheless, this study provides the best clinical evidence to date that passive transfer of inflammatory cytokines from 4-day and 5-day-old PLTs represents one mechanism of FNH reactions to PLTs.
Mucosa-Associated Lymphoid Tissue Lymphoma of the Lung With Cold-Reacting Autoantibody-Mediated Hemolytic Anemia. Liaw Y-S, Yang P-C, Su l-J, et al. Chest 105:288-290, 1994. Primary mucosa-associated lymphoid tissue lymphoma (MALToma) of the lung is a rare low-grade B-cell lymphoma. This is the first report of the association of MALToma of the lung and cold-reacting autoantibody-mediated hemolytic anemia. The tumor lymphoid cells were positive for the CD19 and CD20 B-cell markers, showing IgMh restriction. Serum immunofixation electrophoresis also showed IgMh monoclonal gammopathy. The Coombs'-positive hemolytic anemia (hemoglobin 86 g/L, reticulocytes 13%, lactic dehydrogenase 1,150 U/L, and bilirubin 2.1 mg/dL) was presumably caused by a cold agglutinin with a titer > 1:1,024 at 4~ but not reactive at 37~ Whereas the patient's MALToma and hemolytic anemia both responded to chemotherapy, the cold agglutinin titer remained unchanged. Unfortunately, no further details of cold agglutinin characterization are provided and this case serves to remind that when attempting to claim a new observation in particular, it is essential to investigate critically and characterize as fully as possible and to provide the data. In this case the authors have failed to do this and, given the low titer and apparent low thermal amplitude of the autoantibody, it is difficult to support their contention.