Massive hemothorax due to intrathoracic extramedullary hematopoiesis in a patient with hereditary spherocytosis

 Extramedullary hematopoiesis (EMH) is a rare disorder, characterized by the appearance of hematopoietic elements outside of the bone marrow, which occurs in patients with chronic myeloproliferative disorders or congenital hemolytic anemias. We report on a 64-year-old man with hereditary spherocytosis, who presented with anemia, jaundice, intrathoracic EMH, and massive hemothorax. The diagnosis of EMH was established after computer tomography (CT)-guided punctuation of the paravertebral mass. The patient underwent splenectomy and thoracic drainage. After 1 year, the patient is in good health, with normal hemoglobin values, and hemothorax has not recurred. Received: 23 December 1999 / Accepted: 31 May 2000     

Hereditary spherocytosis,elliptocytosis, and other red cell membrane disorders

Hereditary spherocytosis and elliptocytosis are the two most common inherited red cell membrane disorders resulting from mutations in genes encoding various red cell membrane and skeletal proteins. Red cell membrane, a composite structure composed of lipid bilayer linked to spectrin-based membrane skeleton is responsible for the unique features of flexibility and mechanical stability of the cell. Defects in various proteins involved in linking the lipid bilayer to membrane skeleton result in loss in membrane cohesion leading to surface area loss and hereditary spherocytosis while defects in proteins involved in lateral interactions of the spectrin-based skeleton lead to decreased mechanical stability, membrane fragmentation and hereditary elliptocytosis. The disease severity is primarily dependent on the extent of membrane surface area loss. Both these diseases can be readily diagnosed by various laboratory approaches that include red blood cell cytology, flow cytometry, ektacytometry, electrophoresis of the red cell membrane proteins, and mutational analysis of gene encoding red cell membrane proteins.     

Gilbert's syndrome co-existing with and masking hereditary spherocytosis

 An unusual case of co-existing Gilbert's syndrome and hereditary spherocytosis is reported. Diagnostic strategies are presented, and the literature is reviewed for simultaneous presence of these disorders. Received: 6 January 1997 / Accepted: 14 March 1997     

Hereditary Spherocytosis in Greece: Collective Data on a Large Number of Patients

This paper summarizes data from a haematological, biochemical, and clinical study carried out in 73 patients of Greek origin (38 non-splenectomized children and 35 adults; 17 splenectomized) with Hereditary Spherocytosis (HS). Mean haemoglobin levels in the non-splenectomized patients were significantly lower (122 ± 15 g/L) than those of the splenectomized group (144 ± 15 g/L). In all patients with HS (non-splenectomized and splenectomized adults, and children) the MCHC values (355 ± 22, 358 ± 16 and 356 ± 16 respectively) were significantly increased compared to a control group, while the percentage of microcytic and hyperchromic red cell subpopulations was significantly increased in the former group of adults. SDS-PAGE demonstrated that 29 patients (39.7%) had isolated spectrin deficiency, 22 patients (30.1%) had combined spectrin and ankyrin deficiency, 17 patients (23.3%) had band 3 deficiency and 1 patient had protein 4.2 deficiency. No quantitative biochemical defects were detected in 4 patients (5.5%). The biochemical findings did not correlate with the haematological and clinical phenotype of the disease.     

Abnormal binding of spectrin to the membrane of erythrocytes in some cases of hereditary spherocytosis

Summary In two cases of hereditary spherocytosis that we have examined, spectrin was bound abnormally tightly to the erythrocyte membrane, and could not be released by low ionic strength dialysis. This type of behaviour occurs in normal red cells only after heating above 50 C. It appears that some cases of spherocytosis may be due to the presence of a protein which is abnormally temperature sensitive.This work was supported by an Australian Government Research Grant     

Hereditary spherocytosis: identification of several HS families with ankyrin and band 3 deficiency in a population of southwestern Poland

Red blood cells of 17 patients out of seven families diagnosed with HS from the southwest of Poland were studied. In six families a deficiency of ankyrin was detected, and in one family a band 3 (anion-exchanger protein) deficiency was detected. Patients from six families with the ankyrin deficiency had a 19–51% decrease in ankyrin 2.1, while the family with the band 3 deficiency showed a 33% decrease in this protein content. All changes were statistically significant, as analysed by the Student t test (P<0.05). Analysis of haemolysis kinetics gives a reliable indication of altered osmotic properties of the spherocytic cells.Portions of these results have been previously presented in an abstract form at the VIII Polish Conference on Cell Biology, Wrocaw, 2002 [1]     

Thrombocytosis secondary to chronic lead poisoning

We report a case of total hyperpigmentation of the skin, severe itching, muscle weakness and thrombocytosis. Laboratory investigation showed white blood cell (WBC) 8.2 × 10⁶/L, Hb 125 g/L, platelets 1221 × 10⁶/L and urinary lead after DMSA mobilization test 2684 mcg/g creatinine (normal <5). Chelation therapy with DMSA resulted in complete recovery of the hyperpigmentation, itching and thrombocytosis. Lead poisoning should be considered in the differential diagnosis of obscured thrombocytosis.     

Haemolysis in Athletes due to Hereditary Spherocytosis

Three athletes, one cross-country skier and two middle distance runners, experiencing poor response to intensified training and decline in performance during prolonged periods of frequent competitions, associated with a tendency to develop anaemia, were found to have spherocytosis and increased osmotic fragility of the red blood cells. All had family members with the same blood abnormality, but without symptoms. The observations suggest that the frequency of hereditary spherocytosis is higher than indicated by overtly affected cases and that mild cases are easily overlooked. Hereditary spherocytosis should be looked for in athletes with a tendency to decline in blood haemoglobin concentration during periods of intensive training and competition.     

Hereditary spherocytosis and elliptocytosis associated with prosthetic heart valve replacement: rheological study of erythrocyte modifications

The implantation of a prosthetic heart valve (HVP) in patients with hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) is rare, and the changes in the structure and deformability of erythrocytes that follow implantation in these patients have been poorly described. In the present study, the erythrocytes in HS and HE patients with mechanical HVP were compared to the erythrocytes in patients with only congenital membrane defects, in terms of biochemical modifications and rheological behaviour. Integral and cytoskeletal erythrocyte membrane proteins were studied, and blood viscosity (shear rate/shear stress ratio), aggregation ratio [η(1 s⁻¹)/η(200 s⁻¹)], and red cell visco-elasticity were determined. Valve replacement with a mechanical prosthesis worsened anaemia and resulted in a change in haemolysis, from sub-clinical to evident. The rheological investigation of erythrocytes from HS patients confirmed the characteristic increased viscosity and aggregation ratio and the decreased deformability. The rheological behaviour of erythrocytes from patients with HVP showed a decrease in viscosity and an increase in elastic modulus. In these patients, the prosthesis seems to have induced traumatic damage to the erythrocyte membrane, leading to fragmentation and lysis, which in turn modified rheological parameters. The biochemical and rheological investigation allowed us to understand the clinical and haematological pictures of the patients and to describe the role played by different factors in haemolytic anaemia.     

Ankyrin gene mutations in japanese patients with hereditary spherocytosis

We studied mutations of the ankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance, and 30 patients had non-autosomal-dominant HS. Fifteen mutations of the ANK-1 gene pathognomonic for HS were identified: 4 nonsense mutations, 7 frameshift mutations, and 4 abnormal splicing mutations. These 15 mutations have not been previously reported. The frameshift mutations were found from exon 1 to exon 26, corresponding particularly to the band 3-binding domain of ankyrin. The nonsense mutations, on the contrary, were present mostly at the 3'-terminal side, especially in the spectrin-binding domain and the regulatory domain. The patients with ankyrin gene mutations tended to be more anemic with a higher level of reticulocytosis than those without these mutations. Fifteen silent mutations of the ANK-1 gene, most of which have previously been detected in HS patients in Western populations, were also found. The allele frequency of these silent mutations in the HS patients was nearly identical to that in normal subjects. There was no difference between the Japanese and Western populations in the allele frequency of these gene polymorphisms in healthy subjects or HS patients.     

Splenic Infarction after Epstein-Barr Virus Infection in a Patient with Hereditary Spherocytosis

We describe the first patient with hereditary spherocytosis (HS) known to have developed splenic infarction following infectious mononucleosis (IM). An 18-year-old Japanese man was referred to our hospital in November 2004 because of continuous fever and icterus. He had undergone cholecystectomy at the age of 14 years. On patient admission in November 2004, a physical examination showed marked hepatosplenomegaly, icterus, and jaundice. He had a white blood cell count of 14.9 x 10(9)/L with 9.5% atypical lymphocytes, a red blood cell count of 2.93 x 10(12)/L, and a hemoglobin concentration of 7.8 g/dL. Microspherocytes were observed in the patient's peripheral blood smear, and immunoglobulin M antibody to Epstein-Barr virus (EBV) viral capsid antigen was detected. The patient's diagnosis was HS with IM. On day 4 of admission, the patient complained of severe abdominal pain. Abdominal computed tomography scanning revealed findings of splenic infarction. Two months after the occurrence of splenic infarction, a splenectomy was performed. A pathohistologic examination of the resected spleen revealed no evidence of thrombosis or arterial occlusion. We assume that the cause of splenic infarction was insufficient blood flow to oxygenate the entire spleen during the acute enlargement of the spleen.     

Hereditary spherocytosis in an elderly woman with periodic attacks of jaundice

Hereditary spherocytosis is a disease with chronic hemolytic anemia found mostly in childhood. We encountered a rare case of sporadic hereditary spherocytosis in a 68-year-old woman who developed periodic jaundice caused by hemolytic crises. Since the hemolytic crises were caused by cholelithiasis-related biliary inflammation, administration of ursodeoxycholic acid was useful for the prevention of the hemolytic crises. In the differential diagnosis of periodic increases in indirect bilirubin, the possibility of hemolytic diseases, including hereditary ones, should be considered, even if the patients are elderly.     

The GEN.S: a fortuitous finding of a routine screening test for hereditary spherocytosis

As part of the evaluation of the GEN.S (Coulter®), we compared the Mean Corpuscular Volume (MCV) to the Mean Spherized Corpuscular Volume (MSCV) assessed during the reticulocyte count procedure under hypo-osmotic conditions. A sub-group of patients with hereditary spherocytosis (HS) was singled out in all of them, the MSCV became smaller than the MCV. As the cell volume normally increases in red cells derived from other patients in the same conditions, we decided to further study the reason for this particular behaviour of HS red cells. Whereas normal red cells are able to undergo an osmotic expansion, the spherocytes reach a critical osmotic volume leading to cell fragmentation consistent with the decrease of MSCV. This fortuitous finding is likely to be a reliable improvement for the routine screening of HS.     

Red cell membrane protein deficiencies in Mexican patients with hereditary spherocytosis

Twenty-seven families and four individual patients with hereditary spherocytosis (HS) from the northwestern region of Mexico were studied. An autosomal dominant inheritance pattern was identified in 59% of 22 families. Densitometric analysis of erythrocyte membrane proteins revealed individual protein deficiencies in 39% of the patients studied, in whom the principal altered proteins were the alpha spectrins (13%), band 3 protein (10%), ankyrin (6%), 4.2 protein (6%), and the beta spectrins (3%). A predominant deficiency of spectrins has also been observed in other Latin American and Mediterranean countries. However, it is well known that deficiencies in these proteins are heterogeneous across different ethnic groups. A combined protein deficiency was observed in 52% of patients, most frequently involving the spectrins, band 3 protein, 4.2 protein, and 4.1 protein. In three subjects, no abnormalities were detected (10%). We conclude that, despite the observed heterogeneity, the principal affected proteins are essentially similar to those observed in other ethnic groups.     

Uncommon sources and some unsual manifestations of lead poisoning in a tropical developing country

Lead-containing cooking utensils, sometimes used in South Indian homes, and indigenous medications, widely used in India and increasingly in developed countries, may be responsible for lead intoxication in adults. We report chronic lead poisoning in five adult patients. Not all patients had abdominal colic, while dramatic weight loss, depression and encephalopathy were seen. Once recognized, lead poisoning is treatable and sometimes preventable. Response to chelation therapy with agents such as calcium ethylenediaminetetraacetate (CaEDTA) is impressive, although several courses of therapy may be necessary.     

Absence of phosphorylation-induced gelation of erythrocyte membrane skeletons: A diagnostic tool for hereditary spherocytosis

Summary As yet there is no single test specific for the diagnosis of hereditary spherocytosis. In the search for a specific test, a method described by Pinder et al. [14] using a cAMP-independent protein kinase extracted from normal erythrocyte membranes was used. Membrane skeletons were prepared from erythrocyte ghosts by extraction with a non-ionic detergent, i.e., Triton X-100. Upon phosphorylation with c-AMP-independent protein kinase the suspension of normal membrane skeletons set to a gelatinous mass. Membrane skeletons from patients with spherocytosis failed to show this phenomenon. In order to clarify whether this phenomenological difference can be used as a diagnostic tool for hereditary spherocytosis, a semiquantitative method of observing the gelation process was used under definite shear stress conditions. We investigated 33 patients with different hemolytic anemias (spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, homozygous -thalassemia and enzymopenic hemolytic anemias). With the exception of spherocytosis, all preparations of membrane skeletons showed gelation after 30–50 min. Spherocytosis membrane skeletons did not show a significant gelation even after 12 h of incubation. Thus, the failing gelation is specific for the diagnosis of hereditary spherocytosis. The gelation assay might be a valuable method for defining patients with hemolytic anemias due to erythrocyte membrane defects. Its molecular basis and the possible importance for the pathogenesis of spherocytosis require further investigations.Supported by Grant Eb 99/1-1 from theDeutsche Forschungsgemeinschaft     

Hereditary spherocytosis is associated with decreased pyruvate kinase activity due to impaired structural integrity of the red blood cell membrane

Hereditary spherocytosis (HS) is characterised by increased osmotic fragility and enhanced membrane loss of red blood cells (RBC) due to defective membrane protein complexes. In our diagnostic laboratory, we observed that pyruvate kinase (PK) activity in HS was merely slightly elevated with respect to the amount of reticulocytosis. In order to evaluate whether impaired PK activity is a feature of HS, we retrospectively analysed laboratory data sets from 172 unrelated patients with HS, hereditary elliptocytosis (HE), glucose-6-phosphate dehydrogenase (G6PD) or PK deficiency, sickle cell or haemoglobin C disease, or β-thalassaemia minor. Results from linear regression analysis provided proof that PK activity decreases with rising reticulocyte counts in HS (R² = 0·15; slope = 9·09) and, less significantly, in HE (R² = 0·021; slope = 8·92) when compared with other haemolytic disorders (R² ≥ 0·65; slopes ≥ 78·6). Reticulocyte-adjusted erythrocyte PK activity levels were significantly lower in HS and even declined with increasing reticulocytes (R² = 0·48; slope = −9·74). In this report, we describe a novel association between HS and decreased PK activity that is apparently caused by loss of membrane-bound PK due to impaired structural integrity of the RBC membrane and may aggravate severity of haemolysis in HS.     

Hereditary spherocytosis associated with protein band 3 defect in a Swiss kindred

A kindred with hereditary spherocytosis, in which 10 individuals were affected, was investigated. Gel electrophoresis of membrane proteins revealed a protein band 3 defect (densitometric reduction 14·4±7·0%). The erythrocyte morphology of unsplenectomized patients showed so-called pincered erythrocytes (about 1%), which were not present in the five splenectomized patients. Splenectomy also reduced anisocytosis and all parameters of haemolysis, while haemoglobin increased. The osmotic resistance was reduced in patients with protein band 3 deficiency. Erythrocyte filterability through 3 μm pores was decreased. A significant correlation was found between osmotic resistance and filterability. The membrane elastic modulus of erythrocytes was not affected. These results on structural and functional properties of protein band 3 deficient erythrocytes may contribute to a better understanding of this newly discovered form of hereditary spherocytosis.     

The effect of splenectomy in hereditary spherocytosis by dual angle laser light cytometry

Summary We have applied dual angle laser scattering cytometry (DALC), which provides objective assessment of spherocytosis, to study the changes of hereditary spherocytosis (HS) red cell populations after splenectomy. Eighty unsplenectomized HS patients (32 mild, 37 moderate and 11 severe cases), 26 splenectomized HS patients (SHS, formerly 21 moderate and five severe cases) and 140 controls were studied. SHS were similar to unsplenectomized mild HS cases, with homogeneous red cell volume distribution and spherocytosis. Spherocytosis in SHS was significantly higher when compared with controls (P < 0.001) but less when compared with unsplenectomized HS patients (P < 0.01).     

SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant

BackgroundHereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in βI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency.ObjectiveSeven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients.MethodsClinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease.ResultsAmong the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G>C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients.ConclusionsThe co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD.