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Autoimmunity to platelets was looked for by complement fixation, antiglobulin consumption, transformation and migration-inhibition techniques. Only the migration-inhibition method gave consistently positive results. The test was positive in nine out of 14 patients with idiopathic thrombocytopenic purpura and all five patients with glandular fever.
Serial prospective studies of coagulation status have been undertaken on 73 babies with a positive Coombs test. No abnormalities were detected in the babies with mild haemolytic disease, but seven of the 36 babies with severe haemolytic disease (cord Hb less than 11 g/dl or cord bilirubin greater than 85 mumol/1) showed evidence of transient defibrination 1 d after birth and another six had evidence of coagulation failure at birth with a platelet count of less than 150 x 10(9)/1 and a severe deficiency of multiple coagulation factors. The level of factor II and factor X was less than a fifth of the normal cord blood level in these six babies and the level of I, VII and IX was severely reduced; the factor VIII level was normal or high. Exchange transfusion started within 1 h of birth corrected the immediate factor deficiency in these six babies, but evidence of defibrination then became apparent with afibrinogenaemia, a marked fall in factors II and V, less constant falls in factors VII, IX and X, and a raised fibrin:fibrinogen degradation product level. One of these six babies died with severe pulmonary hypoplasia within an hour of birth; the other five died from haemorrhage into the lung or brain 1 1/2--6 d after birth. The very low vitamin-K dependent factor levels in the cord blood of the babies who died are presumably the result of liver damage in utero, but the subsequent changes are those of a comsumption coagulopathy. Simple screening tests at birth served to indicate which babies were at risk and it is concluded that death due to haemorrhage might be reduced by more intensive factor replacement before there is overt evidence of haemorrhage in these babies.
Three techniques, based on the antiglobulin principle, used for the detection of autoantibodies against platelets, were compared; the antiglobulin consumption assay (QACA), the platelet radioactive antiglobulin test (PRAT) and the platelet suspension immunofluorescence test (PSIFT). Upon incubation of normal donor platelets with purified IgG, in concentrations higher than that in serum, an increased amount of platelet-associated IgG was demonstrated only in the QACA. Upon incubation with aggregated IgG, all three tests became positive, but the PSIFT only with high concentrations of aggregates. Binding of soluble C1q-binding immune complexes (IC), which consisted of tetanus toxoid and IgG antitetanus antibodies (TaT) to normal donor platelets, was only detectable in the QACA. However, a positive result was obtained in all three tests with platelets incubated with soluble DNA-IgG-antiDNA antibodies (DaD) IC. Fixation of the platelets with paraformaldehyde prevented the binding and the detection of the DaD-IC, but not of IgG, aggregated IgG or TaT-IC. Eluates from platelets incubated with aggregated IgG, TaT- or DaD-IC did not react with normal donor platelets in the three techniques, in contrast to eluates from platelets sensitized with platelet antibodies.
Castleman's disease (CD) is a rare disease of unknown aetiology and pathogenesis. We present an unusual case of abdominal CD in whom the first manifestation was an autoimmune haemolytic anaemia presenting 9 years before the diagnosis. The Coombs test became negative 2 months after surgical resection of the mass, suggesting that the mass was the source of the autoantibody. CD may be present in autoimmune haemolytic anaemia in patients with no evidence of any other disease.
Minor reactions to streptokinase are not uncommon, although the etiology is unknown. It is widely presumed, however, that these, like the more serious immune reactions, are antibody-mediated. We measured specific anti-streptokinase IgG, subclasses IgG1, IgG2, IgG3, IgG4 and IgE by ELISAs, haemagglutination, indirect Coombs' test and immunoblotting in six patients who developed reactions to streptokinase. Evidence of complement activation by streptokinase was sought by a haemolytic complement assay and by measurement of C3, C4 and C3d. The patients who reacted to streptokinase presented with low titres of anti-streptokinase IgG (median = 5; range 0-32) and IgG1 (median = 3; range 0-14). No evidence of any other IgG subclass was found, nor of specific anti-streptokinase IgE. Anti-streptokinase IgG1 was found to fix complement; patients who reacted to streptokinase were found to have low levels of total complement 1 year post reaction. Probable aggregates and fragments of human albumin (added stabilizer) were found in the streptokinase preparation and proved to be antigenic in some patients, but were not found to be related to the development of reactions. The findings suggest that patients who develop reactions to streptokinase cannot be predicted on the basis of antibody titres at presentation. Minor reactions to streptokinase would not appear to be antibody-mediated, although complement activation may be involved.
Twenty-three courses of i.v. anti-D (Rho) immunoglobulin were administered to 13 Rh D-positive patients with chronic idiopathic thrombocytopenia (ITP). Clinically significant responses were seen in a proportion of patients treated with 500-2500 i.u. anti-D, but all those treated with 12,500 i.u. (180 i.u./kg) responded. Patients refractory to other forms of treatment responded well to anti-D, and previous splenectomy did not influence the clinical response. No adverse reactions were observed. The anti-D response was preceded by a lag period of 3-16 days and was maintained for 14-145 days. Platelet-associated IgG was increased after treatment, due to improved survival of immunosensitized platelets or platelet Fc receptor binding of high molecular weight IgG in the therapeutic material. There was no clinical or biochemical evidence of haemolysis. The erythrocyte direct Coombs' test remained positive for 3-45 days, and histological examination of splenic material showed no erythrophagocytosis. We conclude that anti-D (Rho) immunoglobulin is a safe and effective treatment for chronic ITP and that the therapeutic dose is now established in standardized units. The mechanism of action appears to be complex and is probably not due to macrophage Fc receptor blockade with immunosensitized red cells.
Immune-mediated haemolytic anaemia (IMHA) is the commonest immune-mediated disease of the dog, representing a major health concern to this species. The aim of this investigation was to determine whether genetic susceptibility to IMHA is associated with genes of the canine major histocompatibility complex (MHC; dog leucocyte antigen system, DLA). Samples were collected from 108 dogs with primary idiopathic, Coombs' positive IMHA. This diseased population was subdivided on the basis of Coombs' test results into two groups: 1) dogs with dominant warm-reactive immunoglobulin (Ig) G haemagglutinins and (2) dogs with an additional or dominant cold-reactive IgM haemagglutinin. The DLA class II alleles and haplotypes of the diseased population were characterised, and these data were compared with those derived from a breed-matched control cohort and a much larger group of DLA-typed dogs. Two haplotypes were increased in the patient group: DLA-DRB1*00601/DQA1*005011/DQB1*00701 (in the group with warm-reactive IgG haemagglutinins only) and DLA-DRB1*015/DQA1*00601/DQB1*00301 (in both groups, but more so in the group with cold-reactive IgM haemagglutinins). One haplotype, DLA-DRB1*001/DQA1*00101/DQB1*00201, was decreased in the total patient group, but this decrease was limited to the warm-reactive IgG haemagglutinins group, and it was actually increased in the cold-reactive IgM haemagglutinins group. A second haplotype, DLA-DRB1*015/DQA1*00601/DQB1*02301, was also decreased in the total patient group, and this decrease was found in both subgroups. In addition, all haplotypes carrying DLA-DRB1*001 were significantly increased in the cold-reactive IgM haemagglutinins group. When the overall patient group was divided on the basis of individual breeds with more than six animals represented, each of the haplotypes could be shown to be implicated in one of the breeds. Thus, it was apparent that different breeds had different MHC associations with canine IMHA, which is similar to the observation that different human ethnic groups can have different HLA associations with the same immune-mediated disease.
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Histiocytic necrotizing lymphadenitis is rare outside Japan, including Brazil, despite the many Japanese immigrants and descendants who live there. The authors describe the case of a 32 year old white female, who presented with cervical lymph node enlargement and severe anemia. Histological findings of the lymph node were typical for Kikuchi's disease. Bone marrow showed hyperplasia of normoblasts, suggesting hemolysis, but a Coombs' test was negative. The patient had a spontaneous resolution of all symptoms and has remained asymptomatic for 3 years. Especially where this disease is rarely reported, it is important to recognize it, in order to avoid a misdiagnosis of malignant lymphoma.
A 12-year-old girl with transverse myelopathy, massive pleural effusion and ascites as the presenting features of systemic lupus erythematosus (SLE), is described. All these features developed within a week, but other manifestations of SLE such as malar rash and arthritis were not seen during the illness. Investigations revealed positive direct Coombs' test, high titer of antinuclear antibodies, elevation of serum anti-DNA antibodies, depressed complement activity, thrombocytopenia and proteinuria, indicating that she had SLE. A week after starting treatment with prednisolone 35 mg/day, the thrombocytopenia improved, and following an increase in dosage to 60 mg/day the pleural effusion and ascites diminished after two weeks, and the serological abnormalities improved after two months. The neurological disturbances were unchanged in spite of injections of methylprednisolone 1 g/day for three days from the 89th day of her illness. Review of other cases reported to be improved neurologically, suggested that the earlier initiation of corticosteroids in higher dosage might be beneficial in transverse myelopathy in SLE.
To assess hemolysis in hyperbilirubinemic infants with ABO isoimmunization, we measured the carboxyhemoglobin (HbCO) concentrations in full-term infants with ABO isoimmunization during the first week of life. Two groups of infants, ABO compatible (n = 34) and ABO incompatible (n = 30), were further divided into two groups with and without hyperbilirubinemia. All the infants from ABO incompatible pregnancies showed a positive indirect Coombs' test. The groups with hyperbilirubinemia included infants with maximum serum total bilirubin levels about 15 mg/dL and infants treated by phototherapy or exchange transfusion. In the ABO incompatible infants, the HbCO levels in those with hyperbilirubinemia were significantly higher than in infants without hyperbilirubinemia during the first week after birth (p less than 0.01 at 24, 72, 120 hours after birth, respectively). The levels of HbCO in the ABO incompatible infants with hyperbilirubinemia were significantly higher compared with the levels in the ABO compatible infants with hyperbilirubinemia (p less than 0.05 at 24 hours, p less than 0.01 at 72 and 120 hours after birth, respectively). HbCO measurement may facilitate the early diagnosis of hemolytic disease and the prediction of jaundice caused by ABO isoimmunization.
A 12 year old boy was found to be deficient in immunoglobulins (Ig) A, G2 and G4, and common variable immunodeficiency was diagnosed. He also had cyclic thrombocytopenia at intervals of approximately 28-30 days. His bone marrow revealed normocellular with slightly decreased megakaryocytes. In vitro colony assays showed markedly imparied megakaryocytopoiesis, erythropoiesis and granulopoiesis. Platelet-associated IgG was elevated at his thrombocytopenic phase. Direct Coombs' test was repeatedly positive. Although not defined at present, we suggest the autoimmune nature of the disease.
We describe a 27-month-old boy who was first admitted to our hospital on 7 January 1995 with nasal bleeding. From 6 months of age he has had lymphadenopathy, low levels of serum uric acid, increased levels of serum lactate dehydrogenase and hyper gamma-globulinemia. From the age of 18 months he has had persistent Epstein-Barr virus (EBV) infection (target cells; B cells), recurrent episodes of thrombocytopenia, anemia and hepatosplenomegaly. Dysmobility of the left leg and arm from a central nervous system complication during a relapse with pancytopenia on March 1995, was also observed. Relapses of thrombocytopenia with increases of platelet-associated immunoglobulin G and hepatosplenomegaly have been observed approximately every 2 months, and two relapses of pancytopenia were accompanied with weak positivity of Coombs test and low level of haptoglobin. These recurrent episodes were improved with prednisolone. However, now in June 1997 we have not been able to diagnose what underlies the above clinical symptoms, except that the patient has a persistent EBV infection.
A 54-year-old man of Persian origin presented to our department with a 1-year history of ulcers on the right leg that had been unresponsive to numerous topical treatments, accompanied by lymphedema of the right leg. Medical history included hypergonadotropic hypogonadism, which had not been further investigated. He was treated for 20 years with testosterone IM once monthly, which he stopped a year before the current hospitalization for unclear reasons. The patient reported no congenital lymphedema. Physical examination revealed two deep skin ulcers (Figure 1) on the right leg measuring 10 cm in diameter with raised irregular inflammatory borders and a boggy, necrotic base discharging a purulent hemorrhagic exudate. Bilateral leg pitting edema and right lymphangitis with lymphadenitis were noted. He had low head hair implantment, sparse hair on the body and head, hyperpigmentation on both legs, onychodystrophia of the toenails (mainly the large toe and less prominent on the other toes), which was atrophic lichen-planus-like in appearance and needed no trimming (Figure 2), normal hand nails, oral thrush, and angular cheilitis. Other physical findings were gynecomastia, pectus excavatum, small and firm testicles, long extremities, asymmetrical goiter, systolic murmur 2/6 in left sternal border, and slow and inappropriate behavior. The patient's temperature on admission was 39 degrees C. Blood cultures were negative for bacterial growth. Results of laboratory investigations included hemoglobin (11.2 g/dL), hematocrit (26.8%), normal mean corpuscular volume and mean corpuscular hemoglobin volume, and red blood cell distribution width (16%). Blood smear showed spherocytes, slight hypochromia, anisocytosis, macrocytosis, and microcytosis. Blood chemistry values were taken for iron (4 micro g/dL [normal range 40-150 micro g/dL]), transferrin (193 mg/dL [normal range 220-400 mg/dL]), ferritin (1128 ng/mL [normal range 14-160 ng/mL]), transferrin saturation (1.5% [normal range 20%-55%]), serum folate (within normal limits), and vitamin B12 (within normal limits). Direct Coombs' test equaled positive 2 + IgG. All these values indicated anemia of chronic diseases combined with hemolytic anemia. Further blood work-up tested antinuclear antibody (positive <1:80 homogeneous pattern), rheumatoid factors (143 IU/mL [positive >8.5 IU/mL]), C-reactive protein (286 mg/L [normal range 0-5 mg/L]), anticardiolipin IgM antibody (9.0 monophosphoryl lipid U/mL [normal range 0-7.00 MPL U/mL]) and antithrombin III activity (135% [normal range 74%-114%]). Results of other blood tests were within normal limits or negative, including lupus anticoagulant, beta2 glycoprotein, anticardiolipin IgG Ab, anti-ss DNA Ab, C3, C4, anti-RO, anti-LA, anti-SC-70, anti-SM Ab, P-ANCA, C-ANCA, TSH, FT4, anti-T microsomal, antithyroglobulin, protein C activity, protein S free, cryoglobulins, serum immunoelectrophoresis, VDRL, hepatitis C antibodies, hepatitis B antigen, and human immunodeficiency virus. Endocrinological work-up examined luteinizing hormone (22.9 mIU/mL [normal range for adult men 0.8-6 mIU/mL]), follicle stimulating hormone (49.7 mIU/mL [normal range for adult men 1-11 mIU/mL]), testosterone (0.24 ng/mL [normal range for adult men 2.5-8.0 ng/mL]), bioavailable testosterone (0.02 ng/mL [normal range for adult men >0.6 ng/mL]), and percent bioavailable test (8.1% [normal value >20%]). These results indicate hypergonadotropic hypogonadism. Plasminogen activator inhibitor 1 was 6 U (normal value 5-20 U/mL). Karyotyping performed by G-banding technique revealed a 47 XXY karyotype, which is diagnostic of Klinefelter's syndrome. Doppler ultrasound of the leg ulcers disclosed partial thrombus in the distal right femoral vein. X-rays and bone scan displayed osteomyelitis along the right tibia. Histological examination of a 4-mm punch biopsy from the ulcer border revealed hyperkeratosis, acanthosis, hypergranulosis, and mixed inflammatory infiltrate containing eosinophils compatible with chronic ulcer. Multiple vessels were seen, compatible with a healing process. Direct immunofluorescence of the biopsy revealed granular IgM in the dermo-epidermal junction. Indirect immunofluorescence was negative. Thyroid function tests showed normal thyroid stimulating hormone and free throxine4. Multinodular goiter was seen on thyroid scan and ultrasound. Thyroid fine needle aspiration was compatible with multinodular goiter (normal follicular cells, free colloid, macrophages with pigment). IV treatment with amoxicillin-clavulanic acid 1 g t.i.d. was administered for 2 weeks, with a decrease in temperature and normalization of the leukocyte level. Oral antibiotic treatment with amoxicillin-clavulanic acid was continued for 10 more days, followed by 25 days of ciprofloxacin for the osteomyelitis. Local treatment included saline soakings followed by application of Promogran (Johnson & Johnson, New Brunswick, NJ) and Kaltostat (ConvaTec Ltd., a Bristol-Myers Squibb Company, New York, NY) with slight improvement. At the same time, the patient was treated with warfarin sodium due to deep vein thrombosis under international normalized ratio 2-3. The patient was treated with IM testosterone once monthly for 1 year, which resulted in a reduction in the diameter and depth of the leg ulcers (Figure 3). Blood tests were not performed for follow-up of the immune state.
An unclassified case of haemolytic anaemia with voluminous splenomegaly is reported. This anaemia was normocytic without any specific morphologic aspect of red blood cells (RBC); Coombs test was negative; the osmotic fragility was normal; the increased autohaemolysis was not affected by the presence of glucose; Hb studies were normal; no RBC enzyme deficiency was found; RBC lipids and membrane proteins were normal; there was a marked reduction in RBC survival with exclusive splenic uptake of erythrocytes. Before splenectomy, RBC cations and water content were abnormal: 1) the RBC water was decreased moderately; 2) the RBC sodium was about twice the normal mean with an increased 22Na turn-over; 3) the RBC potassium was markedly reduced and 42K influx was twice the normal mean; 4) the RBC calcium content was increased. Splenectomy was followed by rapid disappearance of haemolysis and RBC water and cation disturbances. Because of this extremely rapid disappearance after splenectomy the authors suggest this case of haemolytic anaemia could be a primary disease of the spleen.