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Publications and source records attributed to T S Kickler.
Neonatal alloimmune thrombocytopenia is caused by the transplacental passage of maternal antibodies directed against platelet-specific antigens. Because complications from bleeding may result, prompt institution of therapy may be necessary. Accurate diagnosis by serologic techniques permits appropriate therapy to be administered both prenatally and postnatally.
Immune hemolytic anemia due to minor ABO incompatibility between recipient and donor is a well-recognized occurrence in kidney and liver transplantation. In some cases, the responsible antibodies have been shown to be derived from the donor passenger lymphocytes using Gm allotyping. We report a case of acute, transient hemolysis following heart-lung transplantation in which serologic and Gm allotype studies confirmed the etiology of hemolysis.
BACKGROUND AND METHODS: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A treatment protocol was introduced in 1979 for patients admitted to Johns Hopkins Hospital with the diagnosis of TTP-HUS. Treatment regimens included 200 mg of prednisone a day, for patients with minimal symptoms and no central nervous system symptoms, and prednisone plus plasma exchange, for patients with rapid clinical deterioration who did not improve after 48 hours of prednisone alone and for patients presenting with central nervous system symptoms and rapidly declining hematocrit values and platelet counts. RESULTS: A total of 108 patients were treated, and 91 percent survived. Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (two relapses and two deaths). Plasma exchange plus prednisone was given to 78 patients with complicated TTP-HUS, resulting in 67 relapses and 8 deaths. Relapses occurred in 22 of 36 patients given maintenance plasma infusions. Neither splenectomy nor treatment with aspirin and dipyridamole was effective in those with a poor response to plasma exchange. None of the 71 patients tested had positive cultures for O157:H7 Escherichia coli. Nine percent of the patients were pregnant, and none gave birth to infants with TTP-HUS. CONCLUSIONS: Effective treatment with 91 percent survival is available for patients with TTP-HUS.
We describe the obstetric complications and management of a patient with Bernard-Soulier syndrome. Severe bleeding at the time of delivery and delayed postpartum hemorrhage were prominent features of her pregnancies. Further complicating this woman's pregnancies was the development of antibodies to platelet glycoprotein IB/IX, leading to neonatal alloimmune thrombocytopenia.
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This report illustrates the importance of serologic techniques for defining the etiology of neonatal thrombocytopenia. In Case 1 the maternal count was low normal to normal during the first postpartum week. Several weeks later the appearance of persistent maternal thrombocytopenia led to the demonstration of anti-GP IIb-IIIa in stored and freshly obtained maternal sera, suggesting that the mother had an autoimmune type of thrombocytopenia. The mother of Case 2 had systemic lupus erythematosus. However, serologic testing revealed that the infant's thrombocytopenia was not related to the mother's lupus but was secondary to alloimmunization with the PlA1 antigen. An algorithm for defining etiologic mechanisms in infants with antibody-mediated forms of thrombocytopenia is presented.
We investigated whether the platelet-membrane surface carries IgG allotypic antigens and whether these determinants may be important in platelet transfusion therapy. Using a hemagglutination inhibition assay, we showed that the G1m IgG allotypes (a, x, f) and K1m and K3m light-chain allotypes are expressed on the surface of platelets, whereas G3m allotype antigenic determinants were not detectable. In 146 multitransfused thrombocytopenic patients, 35 (24%) patients were found to have antiallotypic antibodies. To study the effect of antiallotypic antibodies on platelet transfusion outcome, patients received platelet transfusions from donors, either positive or negative for the IgG allotype to which patients were immunized. Of the 19 antigen-positive and 19 antigen-negative platelet transfusions given, respectively, the mean platelet count increments at 1 hour were 8,402 +/- 6,402 +/- 6,721 (1 SD) and 9,799 +/- 5,559 (1 SD) P less than .2. Transfusion reactions were not more common when antigen-positive platelet transfusions were given. Despite the presence of IgG allotypic determinants on platelets, allotypic antibodies do not decrease platelet transfusion recovery. Furthermore, passive administration of plasma containing IgG allotypes to patients with antiallotypic antibodies does not lead to innocent bystander-mediated platelet destruction.
The limiting factor in platelet transfusion therapy is the development of alloimmunization. Although using HLA matched platelets may be effective in reducing the problem of alloimmune platelet transfusion refractoriness, relying solely upon HLA matching has its shortcomings. The selection of compatible platelet transfusions can be improved by compatibility testing. Despite these maneuvers, compatible platelets may not be found for some patients. When faced with these difficult patients there are few effective alternatives. The preventive measures of leukocyte depletion or ultraviolet irradiation of platelets promise to reduce or prevent alloimmunization.
Removal of white cells (WBCs) from platelets may reduce alloimmunization to WBC antigens, prevent febrile reactions, and improve platelet increments in multiply transfused patients receiving HLA-matched platelets. A new surface-modified fibrous polyester filter was evaluated; it requires no special processing of pooled platelet concentrates and can be used at the patient's bedside. The studies were designed to measure WBC removal, platelet function, in vitro platelet recovery, and in vivo platelet survival. WBC mean removal was 99.8 percent +/- 0.56 (n = 37) when a pool similar in volume to 6 platelet concentrates was tested. The mean number of residual WBCs after filtration was 5.6 x 10(5). In vitro mean platelet recovery was 86.9 percent for a pool size of 6 units (n = 37). Clot retraction and platelet aggregation were unaffected by filtration. Survival studies of 111Indium-labeled platelets done with filtered autologous platelets showed no reduction in the normally expected survival. These studies indicated that the filter efficiently removes WBCs without substantially decreasing platelet number, survival, or function. This device offers the potential of considerably improving platelet transfusion therapy.
Th activation of red cells is characterized by agglutination with the peanut lectin from Arachis hypogaea and is diminished by treatment with proteolytic enzymes. The first cases of Th activation were associated with bacterial infections. More recently, a high incidence of Th activation in congenital hypoplastic anemia has been reported, along with the finding that 13.5 percent of cord bloods are Th activated. The incidence of Th reactivity in newborn infants was confirmed by studying 200 paired samples of maternal and cord blood. Twenty-two (11%) of the cord samples and 13 (6.5%) of the maternal samples were Th activated. In 6 paired samples (6/22), both the mother and child had Th activation, a finding that demonstrates a high degree of concordance. Additionally, 3 (6%) of 50 pregnant women were Th positive. These findings indicate that Th activation is another of the red cell antigen alterations related to pregnancy.
We characterized neutrophil autoantigens using an immunoblotting technique with antibodies obtained from patients with autoimmune neutropenia. These results were correlated with serologic characterization of the antibodies, using indirect immunofluorescence and leukoagglutination. Of the 17 sera immunoblotted, 16 showed discrete bands in the molecular weight range of 30 to 112. Three patients with Felty's syndrome reacted with an antigenic target of 80 to 84 Kd molecular mass, a finding not seen in any of the other patients studied. By serologic testing, none of the autoimmune sera showed serologic specificity for any known neutrophil-specific alloantigen. Using an anti-NA-1 serum, we identified antigenic targets at 40, 50, and 101 Kd in both NA-1-positive and NA-1-negative neutrophils. Ten of 17 autoimmune sera showed reactivity in this corresponding range. These studies demonstrate that immunoblotting may be used to identify antigenic targets in autoimmune neutropenia and may suggest a specificity of these antibodies not definable by serologic techniques. Correlation of immunoblot reactivity with disease states associated with immune neutropenia may be useful in the study of the pathogenesis of the different forms of autoimmune neutropenia.
The effect of repeated phlebotomy on serum immunoreactive erythropoietin levels was studied prospectively in 69 autologous blood donors. At the time of the initial phlebotomy, 11 men (33%) and two women (6%) were anemic; during the course of blood donations, anemia (defined as a hematocrit less than 0.41 for men and less than 0.36 for women) developed in an additional 17 men (71%) and 14 women (45%). Although there was an increase in the level of serum immunoreactive erythropoietin with successive phlebotomies, the increase was not substantially out of the normal range. The lack of an erythropoietic response to repeated phlebotomies in association with the small increment in the serum erythropoietin level was not due to iron deficiency, since the level of red-cell free protoporphyrin did not increase in these patients. We conclude that within the hematocrit range permissible for autologous blood donation, the degree of anemia experienced is insufficient to initiate an adequate increase in erythropoietin production; as a consequence, mild anemia develops in a majority of donors, and the volume of blood donated is inadequate to meet their operative needs.
To further define the molecules that may mediate spontaneous abortion due to maternal-fetal blood group incompatibility within the P blood group system, we have examined the fine specificities of maternal antibodies and the glycolipid antigens from the placenta of a P infant born to a Pk1 mother. Maternal antibodies obtained during therapeutic plasmapheresis were analyzed to determine their reactivities with placental glycolipid extracts on thin-layer plates. Second antibodies specific for IgM, IgG, and IgA revealed immunoglobulins of all of these classes strongly reactive with one major placental glycolipid that comigrates with globoside. GC/MS analysis confirmed that the major P-active pentaglycosylceramide of placenta has the same structure as that previously shown for the P antigen of red blood cells: GalNAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc-Cer. Serum antibodies partially purified by affinity chromatography on globoside-octyl-Sepharose specifically recognize glycolipids that contain terminal GalNAc beta 1-3Gal . . . residues and also recognize the same sequence as an internal determinant in some, but not all, glycolipids with extended globoside core regions. Thus, in the blood group P incompatible fetus, the major P antigen present in placenta has the same carbohydrate structure as the P antigen present in fetal and adult erythrocytes and might be a target for the maternal immune system.
A 70-year-old man developed severe immune intravascular hemolysis and renal failure following ingestion of fenoprofen, a nonsteroidal, anti-inflammatory drug. The patient's red blood cells were sensitized with both IgG and C3d. The serum reacted with normal red blood cells in the presence and absence of the drug. Addition of albumin to the serum inhibited the reactivity with both neat and drug-treated serum. These atypical serologic findings for drug-related immune hemolytic anemia were explained by (1) the measurement of fenoprofen by high performance liquid chromatography (HPLC) in the neat serum; and (2) solid-phase adsorption studies showing that albumin can bind drug, leading to the disappearance of agglutination when albumin is added. This case demonstrates the utility of drug levels and adsorption techniques to confirm the diagnosis of drug-induced immune hemolytic anemia despite the anomalous serologic results which obscured the diagnosis and management of the patient.
Selection of platelets for alloimmunized, thrombocytopenic patients has traditionally been based on HLA matching. This approach is indirect and may not adequately recognize incompatibility between the recipient and the platelet donor. The authors evaluated the usefulness of directly showing donor-recipient compatibility by crossmatching the patient's serum with prospective platelet donors who were not preselected on the basis of their HLA type. Eleven alloimmunized patients were chosen for study, and crossmatching was done by a radiolabeled antiglobulin test. These patients had high levels of HLA alloantibody, and their unusual HLA types made the provision of HLA-matched platelets difficult. When the crossmatch was compatible, the mean one-hour corrected count increment was 18,379 +/- 4,670 (1 standard deviation), n = 22, and at 18-24 hours, 7,318 +/- 3,317. If the crossmatch was positive, the mean one-hour corrected increment was 2,536 +/- 3,057, and at 18-24 hours, 227 +/- 657, n = 16. There were two false negative crossmatches and one false positive crossmatch. One hundred forty-eight crossmatches were done to find 48 potential donors, who, by conventional selection using HLA matching, would not have been considered appropriate donors. These results show that successful platelet transfusions for alloimmunized thrombocytopenic patients can be prospectively selected by platelet crossmatching without the need of doing expensive HLA typing of a large population of platelet donors. Although it may be difficult to find compatible platelets for some patients with broadly reactive HLA antibodies, platelet crossmatching may detect compatible donors who are ordinarily excluded on the basis of their HLA phenotype.
Baka is a platelet alloantigen whose putative allele, Bakb, has not been identified previously. By using a serum, "Har," obtained from a patient with posttransfusion purpura, we describe the platelet alloantigen Bakb. The Har serum reacted with an NP-40-extractable platelet membrane protein of 142 kd with mobility similar to platelet glycoprotein IIb alpha. We found that the antigen recognized by the Har serum is inherited in an autosomal dominant mode with an apparent gene frequency of .39. Chi-square analysis of observed and expected phenotype frequencies indicated that serum Har recognizes Bakb, the anticipated allele of Baka. Our findings provide new evidence for polymorphism of glycoprotein IIb and for the association of posttransfusion purpura with alloimmunization to determinants on this glycoprotein.
The peanut agglutinin from Arachis hypogea is a lectin that reacts with red blood cells expressing the Th antigen. The Th antigen has been said to be qualitatively similar to the T antigen, a well-defined antigen due to desialylation of glycophorin A and B that also reacts with the peanut agglutinin. We examined Th activated red blood cells from two patients with Fanconi's anaemia using 125I radiolabelled peanut agglutinin as a probe in Western blotting of red blood cell membrane proteins. We also probed the surface of intact Th activated red blood cells for structures related to the T antigen using [3H]sialic acid and a purified sialyltransferase. Neither of these techniques found antigens on the Th activated red blood cells that were similar to the antigen found on T activated red blood cells. These results show that the Th antigen in Fanconi's anaemia is qualitatively different to the antigen found in T activation.
Autoimmune hemolytic anemia (AIHA) caused by warm-reacting IgM autoantibodies is rare. We report a fatal case of primary AIHA with a warm-reacting IgM autoantibody. Recurrent episodes of intravascular hemolysis, unresponsive to all therapy and progressive hepatic dysfunction characterized the patient's clinical course. Despite corticosteroid therapy, splenectomy and multiple blood transfusions, the patient died from liver failure. The IgM autoantibody caused autoagglutination of the patient's red cells at 37 degrees C. Eluates prepared from the patient's red cells agglutinated saline-suspended test cells without the addition of antiglobulin reagent. We propose that warm-reacting IgM antibodies may lead to in vivo autoagglutination and may be associated with hepatic failure.