Hereditary haemolytic anaemia due to red cell pyrimidine 5‘-nucleotidase deficiency in two Irish families with a note on the benefit of splenectomy

Summary Hereditary haemolytic anaemia with basophilic stippling caused by pyrimidine 5′-nucleotidase deficiency is described in three members of two unrelated Irish families. In one family, the disease was moderately severe and the patient's condition was improved by splenectomy. In the other family the haemolytic anaemia was well compensated. In neither family was there a marked elevation of reduced glutathione. The implications are that pyrimidine 5′-nucleotidase deficiency is a heterogeneous disorder, both clinically and biochemically. In more severe forms splenectomy may be beneficial.     

A Case of Gamma Heavy Chain Disease Associated with Autoimmune Haemolytic Anaemia: Clinical,Haematological, Immunological and Pathological Details

A 76-year-old Japanese man, presented with a case of gamma heavy chain disease associated with autoimmune haemolytic anaemia. The clinical course progressed rapidly, accompanied by fever, lymphadenopathy, erythematous palate and hepatosplenomegaly. As the disease progressed, haemoglobin level gradually reduced, and jaundice occurred. A complication of autoimmune haemolytic anaemia was deduced from the laboratory data obtained at this time. The patient's serum and urine contained an M-component with electrophoretic and antigenic properties resembling those of the Fc-fragment of G₁ globulin. Microscopic and electron microscopic findings on the tumor cells infiltrating in lymphnodes indicated all types of transitional forms from small lymphocytes to large lymphoplasmoblastic cells.     

Haemolytic anaemia in a multi-ethnic cohort of lupus patients: a clinical and serological perspective

Systemic lupus erythematosus is a chronic autoimmune disease that can be associated with a variety of haematological manifestations. We identified 76 patients with haemolytic anaemia in a cohort of 1251 unrelated female lupus patients enrolled in our studies. The presence of the various American College of Rheumatology clinical criteria for lupus and serological specificities were determined in lupus patients with haemolytic anaemia and compared with a group of race-matched control lupus patients without haemolytic anaemia. Clinical data were obtained from medical records, and serological specificities were determined in our clinical immunology laboratory at OMRF. The presence of haemolytic anaemia in lupus patients was associated with a higher frequency of proteinuria (OR = 2.70, P = 0.000031), urinary cellular casts (OR = 2.83, P = 0.000062), seizures (OR = 2.96, P = 0.00024), pericarditis (OR = 2.21, P = 0.0019), pleuritis (OR = 1.72, P = 0.028) and lymphopenia (OR = 1.79, P = 0.015). These findings were independent of the presence of thrombocytopenia, which was approximately five times more common in lupus patients with haemolytic anaemia. Lupus patients with haemolytic anaemia were about 8 years younger than lupus patients without haemolytic anaemia at the time of disease onset (P = 0.000001). In the absence of thrombocytopenia, lupus patients with haemolytic anaemia were approximately two times more likely to have anti-dsDNA antibodies (P = 0.024). The presence of haemolytic anaemia is associated with a subset of lupus characterized by a younger age of disease onset, and a more severe disease with a higher likelihood of renal involvement, seizures, serositis and other cytopenias.     

Dermatomyositis-scleroderma overlap syndrome presenting as autoimmune haemolytic anaemia

SIR, We report a case of dermatomyositis–scleroderma overlapsyndrome presenting with autoimmune haemolytic anaemia. A 41-yr-oldCaucasian woman was refer red to the Department of Haematologyin January 1998 from her general practitioner with a haemoglobinof 6 g/dl (normal range 11.5–16.5) and a 6-month historyof lethargy, night sweats and recurrent oral ulceration. Inaddition, she had experienced arthralgia for the last 6 yr,which had responded dramatically to NSAID, and also describedRaynaud's phenomenon and dysphagia of solids. She was foundto have Coombs-positive autoimmune     

Induction of Remission with Intravenous Immunoglobulin and Cyclophosphamide in Steroid-Resistant Evans’ Syndrome Associated with Dermatomyositis

Evans’ syndrome is characterised by the simultaneous or sequential occurrence of Coombs’-positive haemolytic anaemia (AIHA) and immune thrombocytopenia without underlying aetiology. It has been found to be associated with collagen vascular diseases, especially systemic lupus erythematosus (SLE) and scleroderma. However, Evans’ syndrome with dermatomyositis is very rare. A 59-year-old woman, who had been taking high-dose prednisolone for a month and cyclosporin for 10 days for dermatomyositis, developed purpura on the left popliteal fossa. The platelet and haemoglobin levels decreased to 77.000/mm³ and 9.8 g/dl, respectively. Antiplatelet antibody was positive. Thrombocytopenia responded to intravenous immunoglobulin (IVIG) for a short time, but further decreased in a week. Her blood film showed features of haemolytic anaemia. Laboratory findings showed reticulocytosis and a positive direct Coombs’ test. Bone marrow examination showed a mild hyperplasia of erythroid precursors and megakaryocytes. The patient was successfully treated with cyclophosphamide in addition to oral prednisolone. AIHA in connective tissue disease may develop gradually and show a benign clinical course in most patients. Therefore, we suggest that patients with dermatomyositis and anaemia should always be checked for haemolysis if there is no other explanation. Received: 22 December 1999 / Accepted: 7 July 2000     

Decreased red cell enolase activity in a 40-year-old woman with compensated haemolysis

A 40-year-old woman splenectomized 17 years previously for hereditary haemolytic anaemia was investigated in our laboratory because of persistent conjunctival subic-terus associated with compensated haemolysis. The results of the autohaemolysis and osmotic fragility tests were similar to those usually observed in hereditary spherocytosis. Red cell enzyme assays indicated a decreased amount of kinetically normal enolase. The genetic transmission of this defect could not be established since the only other affected member of the family was the proposita's father who died several years ago after splenectomy for an undefined haemolytic disorder.     

Pel-Ebstein Fever Coinciding with Cyclical Haemolytic Anaemia and Splenomegaly in a Patient with Hodgkin's Disease

A 46-year-old man with an aortic valve replacement was investigated for recurrent episodes of fever associated with splenomegaly and haemolytic anaemia. Initially bacterial endocarditis was suspected. At laparotomy he proved to have mixed cellularity Hadgkin's disease confined to the spleen. The undefined mechanism underlying Pel-Ebstein fever in this patient may also have been the cause of simultaneous haemolysis and splenomegaly.     

The utility of the autohaemolysis test for children with congenital haemolytic anaemia

Autohaemolysis testing can assist the evaluation of haemolytic anaemia, but involves a cumbersome assay that is difficult to perform accurately. Because this test persists in clinical practice without clear indications or guidelines, we retrospectively reviewed our experience with autohaemolysis testing for children with suspected congenital haemolytic anaemia. Over 12 years, autohaemolysis without glucose was elevated for 38 of 39 children with congenital spherocytosis, while glucose corrected or reduced autohaemolysis in 33 of these patients. Autohaemolysis was elevated only once among seven other cases (four with congenital nonspherocytic haemolytic anaemia and three normal siblings). In three cases of congenital spherocytosis with equivocal osmotic fragility, autohaemolysis was abnormal and corrected with glucose in two. In our experience, autohaemolysis testing was helpful diagnostically in only two of 54 cases, so has only limited utility as a routine test for children with suspected congenital haemolytic anaemia.     

Immune Complex-Mediated Haemolytic Anaemia and Evans Syndrome Induced by Diclofenac

Background and objectives: Sodium diclofenac is one of the most widely used nonsteroidal anti-inflammatory drugs. Cases of acute haemolytic anaemia have been ascribed to the drug. We describe such a case, mediated by immune complexes. Materials and methods: Standard serologic tests were carried out for blood grouping and the detection and identification of red cell allo- and autoantibodies. Drug-anti-drug complexes were detected with an ex-vivo method. Results: Warm IgG drug-independent red cell and platelet autoantibodies were detected in the serum. At first, the patient was diagnosed as having the Evans syndrome, and corticosteroids were administered. Later, because of the severity of the anaemia, the possibility of an immune complex mechanism was considered. This was confirmed by the detection of diclofenac-dependent antibodies that reacted with RBC only in the presence of urine from a volunteer receiving diclofenac as a source of ex-vivo antigen. The antibodies neither reacted with an in-vitro solution of the drug nor with the volunteer's serum. Diclofenac and corticosteroids were stopped, and the clinical condition of the patient completely normalised within 15 days. Conclusions: We describe a patient with acute haemolytic anaemia caused by diclofenac through an immune complex mechanism.     

Treatment of refractory fludarabine induced autoimmune haemolytic with the anti‐cd20 monoclonal antibody rituximab

A patient with cold‐type autoimmune haemolytic anaemia for 8 years developed progressive B cell chronic lymphocytic leukaemia (CLL). Despite the risk of fludarabine induced exacerbation of haemolysis, he was given aggressive anti‐CLL therapy with six courses of FCR (fludarabine 25 mg/m² D1–3, cyclophosphamide 250 mg/m² D2–4 and rituximab 375 mg/m² D1) every 4 weeks. This resulted in a marked acute increase in haemolysis shortly after completing each course of fludarabine. However, haemolysis had settled to its baseline level by the time of subsequent courses of FCR. FCR resulted in complete clinical remission of CLL but residual haemolysis persisted. The patient was then given four weekly infusions of single agent rituximab, resulting in ongoing remission of haemolysis. In this patient, rituximab appears to have controlled fludarabine induced exacerbation of autoimmune haemolysis. In addition, subsequent single agent rituximab therapy resulted in prolonged remission of cold‐type autioimmune haemolytic anaemia. It remains to be seen if the addition of rituximab will allow other patients with a positive direct Coomb's test and/or autoimmune haemolysis to receive fludarabine containing chemotherapy without undue risk of life‐threatening haemolytic anaemia.     

Analysis of erythrocyte membrane proteins in patients with hereditary spherocytosis and other types of haemolytic anaemia

ABSTRACT

Objectives: In order to investigate the pathophysiology of erythrocyte membrane proteins, 10 patients (6 pre- and 4 post-splenectomy) with hereditary spherocytosis (HS) and other patients with haemolytic anaemia were examined.

Methods: The membrane proteins were analysed by biochemical and mass spectrometry.

Results: Reductions in the extracellular membrane of band 3 protein by eosin-5'-maleimide (EMA) binding test were greater in patients with pre-splenectomy HS than in patients with post-splenectomy HS, other types of haemolytic anaemia, and controls. Compared to patients with haemolytic anaemia and healthy controls, the band 3 protein of patients with HS pre- or post-splenectomy was more easily decomposed with N-glycosidase F and by mass spectrometry interactions with degraded low-molecular-weight spectrin and ankyrin. The resulting fragments were observed more frequently in pre-splenectomy than post-splenectomy HS. Haemoglobin-derived peptides were present in patients with haemoglobinopathy (Hb Evans, Hb Sabine) but not in those with haemolytic anaemia and healthy controls.

Conclusion: Haemolysis in patients with HS occurred because the fragile proteins in erythrocytes (band 3, spectrin, and ankyrin) collapsed due to compression during blood circulation in the spleen. Further, haemolysis in patients with haemoglobinopathy occurred owing to membrane damage due to combined spectrin, band 3 with denatured haemoglobin in the vessel during blood circulation.     

Prevalence,patterns of disease and outcome in patients with systemic lupus erythematosus who develop severe haematological problems

OBJECTIVE: To evaluate the prevalence of major haemolytic disease-severe autoimmune haemolytic anaemia and severe thrombocytopenia-and to assess when these features develop. We also sought to analyse the clinical and serological outcomes of patients with haemolytic anaemia and thrombocytopenia with systemic lupus erythematosus (SLE) as compared with patients without these cytopenias. METHODS: We reviewed retrospectively all the available case notes from our lupus cohort of 305 patients followed up between 1978 and 2000 (mean follow-up 7 yr). We identified 30 patients with SLE (9.8%), of whom 20 (6.6%) had severe haemolytic anaemia and 10 (3.3%) had severe thrombocytopenia. Each patient was matched for age, sex and ethnicity with two control patients. RESULTS: We recorded a total of 42 episodes of severe haematological events: four patients had a second haemolytic episode and eight patients had a second thrombocytopenic episode. Five patients had both thrombocytopenia and haemolytic anaemia. One per cent of patients had severe haemolytic anaemia prior to the diagnosis of SLE and 2.5% of patients presented with these haematological disorders. Haemolytic anaemia and thrombocytopenia were associated with renal involvement (0.01>P>0.001) and anticardiolipin antibodies (ACL) (0.01>P>0.001), but not anti-dsDNA antibodies. Calculation of the BILAG index at the time of severe haematological crisis demonstrated that renal, central nervous system involvement and general symptoms are more frequently present. Forty-one per cent of patients were already on either prednisolone (<10 mg) or an immunosuppressive agent at the onset of the event. CONCLUSION: Our data demonstrate that both haemolytic anaemia and thrombocytopenia are associated with ACL but not anti-dsDNA antibodies. When faced with a patient with a severe haematological manifestation of lupus, active disease in other organs is likely to be present.     

Erythropoietin response to anaemia in children with sickle cell disease and Fanconi's hypoproliferative anaemia

The erythropoietin response to anaemia was compared in 30 children with haemolytic anaemia and in 5 children with Fanconi's hypoproliferative anaemia. Serum erythropoietin was measured by radioimmunoassay. In children with haemolytic anaemia the serum erythropoietin concentration increased exponentially with decreasing haematocrit values (r = 0.74; p less than 0.001). Serum erythropoietin levels also correlated with reticulocyte counts (r = 0.62; p less than 0.001). Children with Fanconi's hypoproliferative anaemia had considerably higher serum erythropoietin levels than children with haemolysis for the same degree of anaemia. These data indicate that erythropoietin production in Fanconi's anaemia may be dependent on other factors in addition to the degree of anaemia and relative hypoxaemia.     

Chronic haemolytic anaemia in hypertrophic cardiomyopathy.

A patient with hypertrophic cardiomyopathy was found to have a chronic intravascular haemolytic anaemia. After investigation this was attributed to the abnormal haemodynamics of the cardiac disease. Treatment with propranolol was associated with an improvement in the anaemia. No further cases of haemolytic anaemia were found in 37 other patients with hypertrophic cardiomyopathy. It is concluded that haemolytic anaemia is a very rare feature of the condition.     

Haemolysis in a G6PD-deficient child induced by eating unripe peaches

A child suffering from G6PD deficiency developed a severe haemolytic crisis without an apparent trigger. The possible pathogenetic role of the ingestion of unripe peaches was studied biochemically in this anaemia. We show that an extract from the unripe peach exerts an oxidative challenge on normal as well as on asymptomatic G6PD-deficient erythrocytes. This effect is analogous to that of the favism-inducing agents. The effect of the extract on the patient's red blood cells was more pronounced than on other asymptomatic G6PD-deficient erythrocytes, particularly during his haemolytic crisis. The chemical nature of the deleterious component was not identified. It is suggested that unripe peaches be added to the list of hazards for G6PD-deficient subjects in combination with other factors.     

Severe reversible autoimmune haemolytic anaemia and thrombocytopenia associated with diclofenac therapy

Severe immune haemolytic anaemia and thrombocytopenia developed in a 71-year-old female within 10 d of starting diclofenac (Voltarol) therapy. These complications resolved within 3 weeks of discontinuation of the drug and corticosteroid therapy. A warm autoantibody of the IgG type together with C3 was found in the direct antiglobulin test of the patient's RBC. The patient's serum and RBC eluate contained a warm autoantibody which reacted with all commercial panel cells without the addition of diclofenac, and gave a negative reaction with Rh null and -D- RBC. This pattern of interactions is similar to haemolysis associated with alpha-methyldopa, indicating the presence of autoantibodies directed against structural components common to all Rh antigens. The coexistence of immune thrombocytopenia and immune haemolytic anaemia is suggestive of an autoimmune disease caused by modified T-cell regulation. Although immune haemolytic anaemia is a rare complication of diclofenac therapy, our observations illustrate the severity of haemolytic anaemia in the occasional patient and stress the need for increased awareness of such a development.     

Fibrinogen Catabolism in Microangiopathic Haemolytic Anaemia

S ummary . Fibrinogen catabolism has been studied in six patients with microangiopathic haemolytic anaemia, three patients with fragmentary haemolytic anaemia following the insertion of valve prostheses into the heart and ten control patients. Increased rates of catabolism of ¹³¹ I-fibrinogen were found in the patients with microangiopathic haemolytic anaemia. Evidence of enhanced fibrinolysis was not present.
This finding suggests that intravascular coagulation is a feature of some cases of microangiopathic haemolytic anaemia and supports the hypothesis that the interaction of red cells with fibrin may result in the characteristic morphological appearances in these cases.     

Autoimmune haemolytic anaemia triggered by Bartonella henselae infection: a case report

Bartonella henselae is a hitherto unidentified cause of autoimmune haemolytic anaemia. Here we report a case of Coombs-negative autoimmune haemolytic anaemia. The episode was preceded by exposure to a cat and a non-specific infectious syndrome. Concomitant serum titres of B. henselae antibodies were indicative of a recent infection. The case report suggests that B. henselae infection can trigger secondary autoimmune haemolytic anaemia.     

Evans syndrome and primary biliary cirrhosis

Primary biliary cirrhosis associated with autoimmune haemolytic anaemia and thrombocytopaenia has rarely been reported in adults. We are presenting an 83-year-old woman with primary biliary cirrhosis who was also diagnosed with autoimmune haemolytic anaemia and idiopathic thrombocytopaenic purpura.     

Hereditary non-spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain: clinical and molecular studies

In four unrelated patients with chronic haemolysis and markedly reduced red blood cell (RBC) glutathione (49.5%, 12.6%, 11.5% and 15% of the normal concentration respectively), a severe glutathione synthetase (GSH-S, EC 6.3.2.3) deficiency was found. One case exhibited a neonatal haemolytic anaemia associated with oxoprolinuria, but without neurological manifestations. The family study revealed GSH-S activity in both parents to be around half the normal level, a finding consistent with the presumed autosomal recessive mode of inheritance of this enzymopathy. Two cases exhibited a well-compensated haemolytic syndrome without anaemia or splenomegaly at steady state. One of these cases was diagnosed after an episode of acute haemolytic anaemia after fava bean ingestion. The remaining patient suffered from moderate to severe chronic non-spherocytic haemolytic anaemia and splenomegaly, and required occasional blood transfusion for a haemolytic crisis associated with drug ingestion. In this patient, the anaemia was corrected by splenectomy. In addition to GSH-S, a panel of 16 other RBC enzyme activities was also studied in all the patients. Hexokinase, aldolase, glucose-6-phosphate dehydrogenase and pyruvate kinase activities all increased; these increases were to be expected, given the rise in the number of circulating reticulocytes. In two patients, the incubation of RBCs with hydrogen peroxide revealed an enhanced production of malonyldialdehyde. DNA analysis showed a homozygous state for 656 A-->G mutation in patients 2 and 3. The GSH-S gene of patient 1, studied elsewhere, revealed an 808 T-->C. The GSH-S gene of patient 4 was not available for study. The present study demonstrates that GSH-S deficiency is also present in Spain and further supports the molecular and clinical heterogeneity of this enzymopathy