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 ß-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.

Rheology of red blood cells in patients with HbC disease.

Patients with hemoglobin C disease (CC) usually do not develop severe complications in comparison with individuals with sickle cell anemia (SS) or with sickle cell hemoglobin C disease (SC). The present study compared the hematological, biochemical, hemorheological and clinical characteristics of CC patients to those of SS, SC and healthy individuals (AA). Blood viscosity was measured at 225 s(-1) with a cone plate viscometer. The hematocrit-to-blood viscosity ratio (HVR), i.e. an index of red blood cell (RBC) oxygen transport effectiveness, was calculated. RBC deformability was determined at 30 Pa by ektacytometry, and RBC aggregation properties by syllectometry. CC and SC had higher blood viscosity and lower HVR than AA. Nevertheless, HVR was higher in CC compared to SS and tended to be higher than in SC. The CC group exhibited very rigid hyperchromic RBC compared to the three other groups. RBC aggregation abnormalities were observed in CC: low RBC aggregation index and high RBC aggregates strength. Despite these hemorheological abnormalities, CC never had hospitalized painful vaso-occlusive crisis or acute chest syndrome. In contrast, all of them had splenomegaly. Of note, 2 out of 7 CC developed retinopathy or otologic disorders. Whether the blood hyperviscosity and decreased RBC deformability are responsible for these complications is unknown. The higher oxygen transport effectiveness (i.e., HVR) of CC compared to SS is probably at the origin of the very low risk of medical complication in this population.

Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease.

The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 µm. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P ≥ 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P ≤ 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P ≥ 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions.

Blood transfusions leading to apparent hemoglobin C, S, and O-Arab hemoglobinopathies.

CONTEXT: Apparent hemoglobinopathies caused by blood transfusions rarely have been reported in the scientific literature. OBJECTIVE: To interpret the abnormal hemoglobins appearing as small peaks on hemoglobin chromatograms or electrophoresis membranes. DESIGN: In the clinical laboratories of a university hospital and a metropolitan hospital affiliated with a medical school, we interpreted hemoglobin chromatograms and electrophoresis membranes; correlated them with patients' medical, laboratory, and transfusion records; and when possible, identified the abnormal hemoglobin in the donors' transfusion segments. RESULTS: We detected 52 incidences of apparent hemoglobinopathies in 32 recipients caused by blood transfusion, of which 46 were hemoglobin C, 4 were hemoglobin S, and 2 were hemoglobin O-Arab. When first detected, the abnormal hemoglobins in recipients ranged from 0.8% to 14% (median, 5.6%). Multiple transfusions with abnormal hemoglobins occurred in 11 patients with 2 patients receiving hemoglobin C blood 5 separate times. One patient received hemoglobin C and later S, and another patient received C and later O-Arab. CONCLUSIONS: Apparent hemoglobinopathies caused by blood transfusions are far more common than previously reported and represent diagnostic challenges. Misdiagnosis could lead to unnecessary testing, treatment, and counseling. If a hemoglobinopathy from a unit of transfused blood is identified in a recipient, we recommend notifying the donor of that abnormality.

Intrathoracic extramedullary hematopoietic tumor in hemoglobin C disease.

A case of intrathoracic extramedullary hematopoietic tumor associated with hemoglobin C disease is reported in a 27-year-old Bangladeshi man. The patient's initial complaints were generalized weakness, weight loss, and left upper abdominal pain. Hospital workup revealed a solitary intrathoracic mass in the posterior mediastinum, which was suspected to be a lymphoma based on fine-needle aspiration. The mass was excised and proved to be an extramedullary hematopoietic tumor. The problem of differential diagnosis is discussed.

Ultrastructural abnormalities and arrest of protein biosynthesis in some erythroblasts from homozygotes for haemoglobin C and double heterozygotes for haemoglobin C and beta-thalassaemia.

Various ultrastructural abnormalities were found in the erythroblasts of three homozygotes for haemoglobin C (HbC), one patient with HbC/beta(+)-thalassaemia and one patient with HbC/beta (0) thalassaemia. These included a coarsely granular or reticular appearance and altered electron-density of the heterochromatin, loss of parts of the nuclear membrane, and oozing of nuclear material into the cytoplasm. In addition, the two patients with HbC/beta-thalassaemia, but not the others, showed precipitated intracytoplasmic alpha-chains in a few profiles of polychromatic erythroblasts and marrow reticulocytes. Electron microscope autoradiographic studies of bone marrow cells from two of the patients with HbC disease and the patient with HbC/beta (0)-thalassaemia showed a marked depression or failure of incorporation of 3H-leucine into protein in some of the ultrastructurally abnormal erythroblasts. This impairment of protein synthesis may lead to alterations in the erythroblast membrane that are involved in the recognition and phagocytosis of the abnormal erythroblasts by macrophages.

Dyserythropoiesis in homozygous haemoglobin C disease.

Electron microscope studies of the bone marrow of three patients with homozygous haemoglobin C (HbC) disease have shown marked ultrastructural abnormalities in several of the polychromatic erythroblasts and marrow reticulocytes and the presence of phagocytosed erythroblasts within the macrophages. Such abnormalities were not found in the bone marrow of three patients with sickle cell anaemia indicating that the abnormalities represented a feature of HbC disease rather than a disturbance secondary to peripheral haemolysis. The characteristic ultrastructural finding in the polychromatic erythroblasts in HbC disease was the presence of grossly-disorganized nuclei showing multiple intranuclear clefts, the loss of parts of the nuclear membrane, oozing of nuclear material into the cytoplasm and an alteration of the structure and stainability of the nuclear chromatin. It is proposed that both the dyserythropoiesis and ineffective erythropoiesis in HbC disease may have resulted from the formation in vivo of very small aggregates of HbC within erythropoietic cells.

Retinal and choroidal neovascularization in sickle cell disease.

Small vessel obstruction characterizes sickle cell disease and, when occurring in the peripheral retinal vessels, initiates a sequence of vascular events which may culminate in the development of proliferative sickle retinopathy (PSR). Repeated examinations of the retinal vasculature of patients with different genotypes of sickle cell disease over the last 10 years (Condon and Serjeant, 1972a, b, c; 1975; 1980a) have allowed observations on the natural history of PSR and on factors related to its development. Choroidal neovascularization has been a common complication of a trial of xenon arc photo-coagulation in PSR. Observations on the aetiology and natural history of both retinal and choroidal neovascularization are presented in this report.

Retinal and choroidal neovascularization in sickle cell disease.

Small vessel obstruction characterizes sickle cell disease and when occurring in the peripheral retinal vessels, initiates a sequence of vascular events which may culminate in the development of proliferative sickle retinopathy (PSR). Repeated examinations of the retinal vasculature of patients with different genotypes of sickle cell disease over the last 10 years (Condon and Serjeant,1972a,b,c; 1975; 1980a) have allowed observations on the natural history of PSR and on factors related to its development. Choroidal neovascularization has been a common complication of a trial of xenon arc photo-coagulation in PSR. Observations on the aetiology and natural history of both retinal and choroidal neovascularization are presented in this report. (AU)

Fluorescein angiography in sickle-cell retinopathy and von Hippel-Lindau disease.

Fundus involvement in sickle-cell-hemoglobin C disease and von Hippel-Lindau disease was ascertained by clinical observation with the benefit of indirect ophthalmoscopy. Fluorescein angiography, however, has added new dimensions to our understanding of early lesions in these entities, the morphology of full-blown lesions, and the evaluation of therapeutic efforts to obliterate them. Like so many adjunct studies available to us today in medicine, it does not replace clinical acumen, but enhances evaluation.

Macular and perimacular vascular remodelling sickling haemoglobinopathies.

The posterior pole vasculature of 100 patients with different sickling haemoglobinopathies was studied prospectively over a period of three years. Various abnormalities of the posterior pole vasculature were seen in 29 per cent of the patients. Continuous remodelling of the macular and perimacular vasculature occurred. Visual acuity was variably affected and sometimes remained intact.

Migratory white-without-pressure retinal lesions.

Nine patients had white-without-pressure retinal lesions. These lesions were seen in areas of vitreoretinal adhesions. The configuration and location of these lesions changed over variable periods of time. The cause of this pecular migration is unknown, but may be related to separation and re-creation of vitreoretinal adhesions. The migratory nature of white-without-pressure areas has not, to our knowledge, previously been reported in the literature.

Spontaneous remodeling of the peripheral retinal vasculature in sickling disorders.

Periodic photographic and angiographic surveys of patients with the earliest stages of sickle retinopathy showed a number of fundus findings. In seven cases (sickle cell anemia, four; sickle cell hemoglobin C, three), these findings included: (1) a variety of vascular abnormalities in the equatorial and post-equatorial retina such as segmented dilations of the vessel walls, hairpin-shaped vascular loops, hypertrophic, tortuous A-V anastomoses, intraluminal plugs, closure and loss of capillary bed, and terminal budding of capillaries; and (2) a continuous, spontaneous remodeling of the peripheral retinal vasculature due to successive closures and reopenings of equatorial retinal vessels. A centripetal recession of the peripheral retinal vasculature usually resulted. No correlation between the ophthalmoscopic and the systemic condition of the patients could be made.