Hemolytic Episodes Research Articles

Increased erythrocyte deformability in fetal erythropoiesis and in erythrocytes deficient in glucose-6-phosphate dehydrogenase and other glycolytic enzymes.

Erythrocyte deformability was determined in more than 500 clinical samples, and was found to be elevated in conditions in which fetal-like red cells are produced: aplastic anemia (3/3 cases), myelodysplastic syndromes, polycythemias, sickle cell anemia during treatment with hydroxyurea, paroxysmal nocturnal hemoglobinuria, and recovery from B12 deficiency. Elevated deformability was observed in neonatal erythrocytes, and during recovery from transient erythroblastopenia of childhood, when fetal-like red cells are known to be produced. Increased deformability appears to be a feature of fetal and fetal-like red cells. Forty-eight cases of enzymatically verified glucose-6-phosphate (G-6-PD) deficiency were also examined. Thirty out of 32 G-6-PD(A-) individuals, including both heterozygotes and hemizygotes, exhibited increased deformability during the steady state. In contrast, G-6-PD(Med) hemizygotes had normal deformability. Increased deformability was also found in G-6-PD(Huron) (n=3), G-6-PD(Wayne) (n=4), triose phosphate isomerase deficiency (n=2), and pyruvate kinase deficiency (n=2). An elevated osmoscan was found in more than 90% of female G-6-PD heterozygotes, affording a simple screening test for heterozygotes. Deformability remained high during hemolytic episodes, when older enzyme deficient cells are removed from the circulation. In four cases of G-6-PD deficiency with normal deformability, evidence for co-existing hereditary spherocytosis was found. The combination of conditions with opposing effects on deformability resulted in nearly normal deformability. Because increased red cell deformability is a feature of fetal erythrocytes, these results suggest that the red cells in many cases of glycolytic enzyme deficiency are fetal-like.

Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia.

A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL). Data on 24 patients who developed HA related to fludarabine therapy were collected from the Spontaneous Reporting System of the Food and Drug Administration (FDA) and the Walter Reed Army Medical Center (Washington, DC). Seventeen (71%) patients developed HA after either the first, second, or third cycle of this drug. The longest duration of fludarabine therapy before HA occurred was six cycles. The median decline in hematocrit from baseline during the hemolytic episode was 14.1 (range, 8.0 to 28.9) for the 18 patients for whom this information was available. For the 11 patients for whom transfusion requirements were known, the number of transfusions administered ranged between three and 36. Seven (29%) patients died of medical complications associated with the HA. Seven of eight patients who were re-challenged with fludarabine after an episode of HA developed recurrent HA, and three of these patients died. HA associated with fludarabine therapy appears to be uncommon, but it can be severe and fatal, especially if a patient is re-treated with this drug after a previous episode of HA. The mechanism of this toxicity is unknown, but it may be caused by the release of a suppressed auto-antibody to a native red cell antigen.

Molecular characterization of G6PD deficiency in Southern Italy: heterogeneity, correlation genotype-phenotype and description of a new variant (G6PD Neapolis).

We report on the molecular basis of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Southern Italy (Campania region). Thirty-one unrelated G6PD-deficient males were analysed at DNA level for the presence of G6PD gene mutations. Nine different G6PD variants were identified, eight of which have already been described (Mediterranean, Seattle, two different A-, Santamaria, Cassano, Union and Cosenza). G6PD Mediterranean, Santamaria, A- and Union were associated with haemolytic episodes. G6PD Seattle, which is polymorphic in several populations, Cassano and Cosenza appeared to be asymptomatic. A new variant (G6PD Neapolis) is reported here. The 467(Pro-->Arg) substitution responsible for G6PD Neapolis is discussed in the light of the current 3D model of human G6PD and in comparison with other natural mutations which occur in the proximity of residue 467.

Sitosterolemia.

It is more than 21 years since the first report on sitosterolemia appeared (Bhattacharyya and Connor, 1974). Two sisters with tendon xanthomatosis and normal plasma cholesterol levels were found to have elevated plant sterol concentrations in the plasma. A high percentage of dietary sitosterol was absorbed from the intestine as measured by the sterol balance technique, and was believed to account for the plant sterol accumulation. Since the original report, 30 patients from 19 families have been detected (Bhattacharyya and Connor, 1974; Shulman et al., 1976; Khachadurian and Salen, 1980; Miettinen, 1980; Whitington et al., 1980; Kwiterovich et al., 1981; Wang et al., 1981; Lin et al., 1983; Salen et al., 1983; Beaty et al., 1986; Björkhem and Skrede, 1989; Belamarich et al., 1990; Hidaka et al., 1990; Skrede et al., 1985; Lutjohan et al., 1995). The clinical presentation includes tendon xanthomas, aortic stenosis with accelerated atherosclerosis (particularly affecting males at a young age), hemolytic episodes, and arthritis and arthralgias. The risk of atherosclerosis was observed in several young male subjects who died prematurely because of acute myocardial infarctions associated with extensive coronary and aortic arteriosclerosis.KeywordsBile AcidCholesterol SynthesisPlant SterolCholesterol BiosynthesisBile Acid SynthesisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Common G6PD Variant from Saudi Population and its Prevalence

Biochemical characterization of erythrocyte glucose-6-phosphate-dehydrogenase from 18 unrelated deficient Saudi Subjects from Al-Hassa and Al-Qatif areas of the Eastern Province was carried out according to WHO procedures. This had led to the identification of one genetically determined common variant, "G6PD Mediterranean". The overall prevalence rate of this deficiency in these areas was determined to be in excess of 42%. None of the subjects studied displayed any sign of favism, a condition usually associated with G6PD Mediterranean, which is characterized by a very low intracellular enzyme activity.

Sarcoïdose avec atteinte hématologique et hypogammaglobulinémie

Hematological changes are uncommon in childhood sarcoidosis. Case 1. This patient developed severe hemolytic anemia associated with splenomegaly at the age of 11 months. A second episode of hemolysis was seen at the age of 6 years; it was associated with thrombocytopenia and hypogammaglobulinemia. A partial splenectomy permitted histological diagnosis of sarcoidosis that was confirmed by elevated angiotensin-converting enzyme level, and subsequently developement of pulmonary involvement. Case 2. This boy suffered from autoimmune hemolytic anemia and thrombocytopenia associated with splenomegaly at the age of 3 years. At the age of 7 years, he had splenomegaly, enlarged cervical and lomboaortic lymph nodes and hypogammaglobulinemia. Diagnosis of sarcoidosis was made from lymph nodes and spleen biopsies after splenectomy; the patient had increased angiotensin-converting enzyme concentration, and subsequently developed specific renal involvement. Association of hemolytic anemia, thrombocytopenia, hypogammaglobulinemia and splenomegaly should suggest the diagnosis of sarcoidosis and could be considered as part of the disease spectrum.

Glucose-6-Phosphate Dehydrogenase Deficiency and Other Enzyme Defects

When the metabolic processes of erythrocytes do not function properly, problems may occur in a number of reactions in a metabolic pathway. Enzyme defects have been associated with each of the major erythrocyte metabolic processes, although not all enzymopathies are associated with hematologic problems inpatients. The defect in one of these enzymes, glucose-6-phosphate dehydrogenase (G6PD), exposes the red blood cell to the harmful effect of accumulated oxidants, especially those that convert hemoglobin to methemoglobin. Individuals deficient in G6PD are unaware of their disorder until some stress taxes the system, resulting in a hemolytic event. Diagnosis of the deficiency depends on the clinical features and laboratory findings during the hemolytic episode. Clinically significant deficiencies of other enzymes involved in glutathione metabolism are rare.

Priapism following splenectomy in an unstable hemoglobin: Hemoglobin Olmsted β141 (H19) Leu→Arg

We report a case of severe priapism occurring in a patient with an unstable hemoglobin, Hb Olmsted (β141 Leu→Arg). This is a rare hemoglobin variant, which until now has been reported only once. The clinical course of the 12-year-old boy was characterized by severe hemolytic anemia leading to splenectomy and cholecystectomy at the age of 3.5 years. The priapism occurred 8 years after splenectomy, during a hemolytic febrile episode and required aspiration of the corpora cavernosa. This report raises the question of the benefit of splenectomy in patients suffering from a chronic hemolytic anemia such as that due to an unstable hemoglobin. This treatment lowers the frequency and the severity of acute hemolytic attacks, but several cases of vascular complications have been reported after splenectomy. © 1996 Wiley-Liss, Inc.

Priapism following splenectomy in an unstable hemoglobin: Hemoglobin Olmsted β141 (H19) Leu→Arg

We report a case of severe priapism occurring in a patient with an unstable hemoglobin, Hb Olmsted (beta 141 Leu-->Arg) This is a rare hemoglobin variant, which until now has been reported only once. The clinical course of the 12-year-old boy was characterized by severe hemolytic anemia leading to splenectomy and cholecystectomy at the of 3.5 years. The priapism occurred 8 years after splenectomy, during a hemolytic febrile episode and required aspiration of the corpora cavernosa. This report raises the question of the benefit of splenectomy in patients suffering from a chronic hemolytic anemia such as that due to an unstable hemoglobin. This treatment lowers the frequency and the severity of acute hemolytic attacks, but several cases of vascular complications have been reported after splenectomy.

Oxidative Stress in Erythrocytes

Many compounds have the potential to cause oxidative stress in erythrocytes and are potentially harmful in susceptible individuals. Increased risk of adverse reactions is generally due to a genetic defect in one or more erythrocytic enzymes and/or haemoglobin. Administration of such drugs to enzymatically compromised individuals can cause serious haemolytic episodes with a resultant anaemia. The mechanism of haemolysis is a consequence of the system used to induce the stress, and in many cases, it is not well defined. This paper reviews the pathways which protect against oxidative damage, the effects of oxidative stress in the erythrocyte and the mechanisms for some compounds capable of causing such stress.

Molecular Abnormality of a Phosphoglycerate Kinase Variant (PGK-Alabama)

The molecular abnormality of a phosphoglycerate kinase variant associated with severe red cell enzyme deficiency (about 4% of normal) and episodes of hemolysis with jaundice was examined. The Michaelis constants for the substrates and co-enzymes (1,3-diphosphoglycerate, 3-phosphoglycerate, ATP and ADP) were not grossly different from that of normal. However, the variant enzyme was very labile in vitro. Nucleotide sequence analysis of the variant cDNA revealed a deletion of codon AAG in exon 7. The codon deletion should result in the deletion of one of the tandem lysine residues existing at amino acid 190-191 of the enzyme protein. Based on the three dimensional structure of the protein, molecular instability could be induced by the deletion of a lysine residue.

Tolerability of Fluoroquinolone Antibiotics Past, Present and Future

New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance. The main elements of their adverse reaction profile were predictable from human experience with precursor naphthyridines and quinolones, and from toxicological studies in animals. Thus gastrointestinal reactions (1 to 5%), skin disturbances (less than 2.5%) and central nervous system (CNS) effects (usually around 1 to 2%) were anticipated. Individual group members exhibit particular properties in relation to their chemical structures, for example the phototoxicity associated with 8-halogenation of the nucleus and found to be a particular problem with lomefloxacin and sparfloxacin. Other members, for example ofloxacin, are linked to a higher than usual incidence of CNS reactions and psychological disturbance. However, despite increasing usage, none of the present group have been implicated in joint damage in children, which had been a major concern following reports of this effect in juvenile animals in chronic toxicity studies. Furthermore, intravenous formulations appear to have no associated increase in toxicity. Crystalluria with associated renal damage, originally thought likely to limit intravenous dosage, has not proved to be a problem in humans. Clinically significant interactions may occur but, as with those involving various NSAIDs and potentially leading to convulsions, they have been defined and are thus avoidable. Postmarketing surveillance studies and prescription event monitoring have largely confirmed the limited adverse reaction profile defined during clinical trials. However, some unexpected reactions have appeared after launch, most notably the episodes of haemolysis, renal failure and hypoglycaemia which led to the withdrawal of temafloxacin. These effects have not been observed with other fluoroquinolones. However, severe tendinitis appears to be a group effect, albeit rare, and anaphylactoid reactions have been reported with several of the fluoroquinolone group, often in AIDS patients. The new fluoroquinolones are essentially a well tolerated group of antibacterials, the benefits of which clearly outweigh their disadvantages in a wide range of indications. Clinical efficacy has been a larger determinant of which members have succeeded in the marketplace than potential toxicity. However, the lesser potential for adverse effects of some of the class, e.g. norfloxacin, ofloxacin and ciprofloxacin, has undoubtedly led to their more widespread use. For others, e.g. enoxacin, limited clinical utility and a perception of increased toxicity have resulted in sidelining. There remains the potential for development of safer and yet more active fluoroquinolones via chemical manipulation both of the nucleus and the side chain substituents.

Myelodysplasia. The clinical spectrum of 51 patients.

Over a 15 year period, the authors followed 51 male patients with myelodysplastic syndromes whose clinical findings, laboratory data, and evolution demonstrated a wide spectrum of disease. The following characteristics were assessed: age at diagnosis, risk factors, clinical presentation, laboratory features, category of myelodysplasia, leukemic conversion, and overall survival. The clinical manifestations included hemolytic episodes in two patients, antibody-mediated thrombopenia in one, marked marrow fibrosis in two; thrombocytosis in three, and simultaneous lymphoproliferative disorders in two. There were 21 patients whose marrow was either normo- or hypocellular. Six patients presented with single cytopenia but not anemia. There were six instances of overlapping of the French-American-British classification. Eighteen patients progressed to acute leukemia and 1 to chronic myelomonocytic leukemia. These observations indicate that patients with myelodysplastic syndromes may have single cytopenia without anemia that progresses to acute leukemia and may, rarely, evolve into chronic myelomonocytic leukemia. The clinical aspects of these syndromes may include autoimmune phenomena and myeloproliferative features.

Transient Hemolysis during Growth Hormone Therapy

Two boys with idiopathic growth hormone (GH) deficiency developed hemolysis at 2 months and 4 months, respectively, after the start of GH replacement therapy. The hemolysis was subclinical and was noticed on routine laboratory tests. Although there was no direct evidence for a causal relationship between the incident and GH therapy, no other couse was found in these 2 patients. There were no family histories suggesting hemolysis, although we did not perform tests among the family members of either patient. Despite the continuation of GH administration, the hemolysis was transient and no other adverse effects were observed during the subsequent 4 years. Such hemolytic episodes could easily be overlooked even on routine laboratory tests during GH treatment.

Screening for glucose-6-phosphate dehydrogenase deficiency prior to dapsone therapy

Dapsone is widely used in dermatological practice. The case of a Greek female patient is reported who had a severe, acute, haemolytic episode shortly after commencing dapsone therapy, despite a normal glucose-6-phosphate dehydrogenase (G6PD) screening test. A subsequent quantitative assay revealed reduced levels of G6PD consistent with the heterozygous state. This illustrates that routine screening tests may fail to detect the decreased levels of (G6PD) which occur in female heterozygotes. Since these patients are at risk of severe dapsone-induced haemolysis, the need for quantitative G6PD assays in females from susceptible racial groups is emphasized.

Erythropoietin in the treatment of delayed immune hemolysis of a major ABO‐incompatible bone marrow transplant

Delayed immune hemolysis can be observed after major ABO-incompatible bone marrow transplants (BMT). The management of these hemolytic episodes includes transfusion of group O red blood cells and increases of immunosuppression. Here we report the case of a 25-year-old patient who developed overt immune hemolysis on day +50 after a HLA-identical ABO-incompatible BMT. To avoid added immunosuppression, erythropoietin was started: an increase in reticulocytes sufficient to maintain hemoglobin despite persistent hemolysis was observed. We conclude that erythropoietin may have a role in the management of delayed-onset hemolysis of major ABO-incompatible BMT, especially when added immunosuppression is undesirable.

Hypophosphatemia and hemolytic anemia associated with diabetes mellitus and hepatic lipidosis in cats.

Hypophosphatemia associated with hemolytic anemia was diagnosed in five cats with diabetes mellitus and in one cat with idiopathic hepatic lipidosis. The hematocrit began decreasing within 24 to 48 hours after documented hypophosphatemia in each case. The anemia resolved in all five surviving cats. Because of the temporal relationship and lack of other detectable causes, hemolytic anemia was presumed to be caused by hypophosphatemia. There were increased Heinz bodies in three of six hypophosphatemic cats during episodes of hemolysis. Intravenous potassium phosphate administration corrected the hypophosphatemia in four of five cats. The effective dosages of intravenous phosphate ranged from 0.011 to 0.017 mmol of phosphate/kg/h for 6 to 12 hours. Hypocalcemia (5.4 to 8.7 mg/dL) occurred in four of five cats treated with intravenous phosphate; however, only one cat developed clinical signs attributable to hypocalcemia. Based on this retrospective study, we recommend monitoring serum phosphorus concentration every 6 to 12 hours in cats likely to become hypophosphatemic. Treatment of hypophosphatemia in cats is warranted because of the apparent increased susceptibility of cats to hypophosphatemia-induced hemolysis. Cats with severe hypophosphatemia (< or = 1.5 mg/dL) should be given oral or parenteral phosphate if contraindications do not exist.

An outbreak of Heinz body positive hemolytic anemia in chronic hemodialysis patients.

During the four month period, from December 1988 to March 1989, there was an outbreak of Heinz body positive hemolytic anemia in 34 patients undergoing hemodialysis in a 500-bed hospital, Seoul, Korea. The episodes of hemolysis were not reduced by changing the charcoal column and reverse osmosis system, or by adding ascorbic acid to the dialysate. The concentrations of nitrate, copper, aluminum and zinc in the treated water were all within the standards for hemodialysis. The chloramine concentration of the treated water was over 0.6 mg/L, markedly exceeding the allowable level of 0.1 mg/L. This high level of chloramine was proved to be due to the contamination of the water source by raw sewage. After we changed the source of water supply to another, no more episodes of hemolytic anemia occurred. It is concluded that chloramine is one of the major contaminants causing dialysis-induced hemolytic anemia and regular determinations are necessary, especially during winter and dry seasons.

Loxoscelism threatening pregnancy: Five cases

Envenomation by the spider Loxosceles reclusa in five pregnant women proved to have no sustained adverse effects on mother or baby when managed conservatively only with low-dose prednisone. A striking toxic erythema of the skin, common with the bite of the spider, caused the greatest discomfort and concern for the patients but proved to be entirely tractable. No episodes of hemolysis, disorders of coagulation, or renal damage were discovered. There is no clinical evidence of any special risk during pregnancy in the event of loxoscelism.

Loxoscelism threatening pregnancy: Five cases

Envenomation by the spider Loxosceles reclusa in five pregnant women proved to have no sustained adverse effects on mother or baby when managed conservatively only with low-dose prednisone. A striking toxic erythema of the skin, common with the bite of the spider, caused the greatest discomfort and concern for the patients but proved to be entirely tractable. No episodes of hemolysis, disorders of coagulation, or renal damage were discovered. There is no clinical evidence of any special risk during pregnancy in the event of loxoscelism. Envenomation by the spider Loxosceles reclusa in five pregnant women proved to have no sustained adverse effects on mother or baby when managed conservatively only with low-dose prednisone. A striking toxic erythema of the skin, common with the bite of the spider, caused the greatest discomfort and concern for the patients but proved to be entirely tractable. No episodes of hemolysis, disorders of coagulation, or renal damage were discovered. There is no clinical evidence of any special risk during pregnancy in the event of loxoscelism.