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Concept: Spherocytosis

51

Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the “physical fitness test” to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria.

Concepts: Immune system, Blood, Malaria, Plasmodium falciparum, Red blood cell, Thalassemia, Hematology, Spherocytosis

32

A method that can rapidly quantify variations in the morphology of single red blood cells (RBCs) using light and sound is presented. When irradiated with a laser pulse, an RBC absorbs the optical energy and emits an ultrasonic pressure wave called a photoacoustic wave. The power spectrum of the resulting photoacoustic wave contains distinctive features that can be used to identify the RBC size and morphology. When particles 5-10 μm in diameter (such as RBCs) are probed with high-frequency photoacoustics, unique periodically varying minima and maxima occur throughout the photoacoustic signal power spectrum at frequencies >100 MHz. The location and distance between spectral minima scale with the size and morphology of the RBC; these shifts can be used to quantify small changes in the morphology of RBCs. Morphological deviations from the normal biconcave RBC shape are commonly associated with disease or infection. Using a single wide-bandwidth transducer sensitive to frequencies between 100 and 500 MHz, we were able to differentiate healthy RBCs from irregularly shaped RBCs (such as echinocytes, spherocytes, and swollen RBCs) with high confidence using a sample size of just 21 RBCs. As each measurement takes only seconds, these methods could eventually be translated to an automated device for rapid characterization of RBC morphology and deployed in a clinical setting to help diagnose RBC pathology.

Concepts: Cell nucleus, Blood, Red blood cell, Blood type, Bone marrow, Blood cells, Blood cell, Spherocytosis

22

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.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology, Hereditary spherocytosis, Spherocytosis

9

A 50-year-old man with a history of warm-antibody autoimmune hemolytic anemia and splenomegaly presented with fatigue of 2 weeks' duration and recent onset of jaundice. Physical examination revealed scleral icterus, conjunctival pallor, and splenomegaly.

Concepts: Hemoglobin, Anemia, Hemolytic anemia, Hematology, Bilirubin, Gallstone, Leptospirosis, Spherocytosis

2

Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon. Ank-1((MRI61689/+)) mice exhibit an HS-like phenotype including reduction in mean corpuscular volume (MCV), increased osmotic fragility and reduced RBC deformability. They were also found to be resistant to rodent malaria Plasmodium chabaudi infection. Parasites in Ank-1((MRI61689/+)) erythrocytes grew normally, but red cells showed resistance to merozoite invasion. Uninfected Ank-1((MRI61689/+)) erythrocytes were also more likely to be cleared from circulation during infection; the “bystander effect”. This increased clearance is a novel resistance mechanism which was not observed in previous ankyrin mouse models. We propose that this bystander effect is due to reduced deformability of Ank-1((MRI61689/+)) erythrocytes. This paper highlights the complex roles ankyrin plays in mediating malaria resistance.

Concepts: Evolution, Blood, Malaria, Cell membrane, Red blood cell, Sickle-cell disease, Hereditary spherocytosis, Spherocytosis

0

Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia with heterogeneous clinico-laboratory manifestations. We evaluated the flow-cytometric tests: eosin-5'-maleimide (EMA) and flow-cytometric osmotic fragility test (FOFT) and the conventional osmotic fragility tests (OFT) for the diagnosis of hereditary spherocytosis (HS).

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology, Hereditary spherocytosis, Spherocytosis

0

The case of a 16-year-old boy with an intrapancreatic accessory spleen presenting as a rapidly growing pancreatic mass after splenectomy for splenomegaly due to hereditary spherocytosis is reported herein. When he was 15 years old, the patient visited at a hospital due to jaundice and radiological examinations showed a huge spleen with a 2-cm mass near or in the pancreatic tail. Sonazoid-enhanced ultrasonography showed hypervascularity in the mass located near the pancreatic tail, which was suspicious for an accessory spleen. During splenectomy by laparotomy, the mass could not be found by inspection or intraoperative ultrasonography. One year after the splenectomy, the mass grew rapidly to 4 cm. Laparoscopic surgery was performed to aid in the differential diagnosis of the mass, and a laparoscopic ultrasonogram revealed that the mass was located in the pancreatic tail. The patient underwent laparoscopic distal pancreatectomy and was discharged uneventfully on the 11th postoperative day.

Concepts: Medical terms, Surgery, Pancreatic cancer, Differential diagnosis, Splenomegaly, Splenectomy, Asplenia, Spherocytosis

0

Patients with combined hereditary spherocytosis (HS) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) deficiency have been reported sporadically. A discrepancy between the level of elevated serum bilirubin concentration and the degree of anemia may suggest the possibility of a coexistence of these conditions. In the present case report, a 20‑year‑old female presented with congenital jaundice and anemia, but did not present with the discrepancy between hyperbilirubinemia and anemia in the patient’s childhood, and was not previously diagnosed with either HS or UGT1A1 deficiency. During a follow‑up of >10 years, the patient’s hyperbilirubinemia accumulated progressively, whereas the patient’s anemia became relatively mild. Upon further genetic analysis, it was determined that the patient had HS combined with UGT1A1 partial deficiency. Next generation sequencing combined with direct sequencing was used to identify a novel heterozygous mutation (c.G828T; p.Y276X) in the spectrin β gene, which is causative for HS. Sequence analysis of the patients' UGT1A1 gene revealed a compound heterozygote with c.G211A (p.G71R) and T3279G mutations, which reduced UGT1A1 activity to 30‑60% of the normal level. Genetic analysis was crucial for determining the diagnosis and pathogenesis of this unusual case.

Concepts: Genetics, Mutation, Red blood cell, Bilirubin, Jaundice, Gilbert's syndrome, Hereditary spherocytosis, Spherocytosis

0

Hereditary spherocytosis is the most frequent congenital hemolytic anemia and is characterized with variable degree of anemia, jaundice, and splenomegaly. In the case of severe hyperbilirubinemia out of proportion with hemolysis, other causes of hyperbilirubinemia must be considered. Gilbert syndrome (GS) is an autosomal dominant disorder characterized with intermittent hyperbilirubinemia without any other sign and symptom of liver disease as a result of reduced activity of uridine diphosphate-glucuronyl transferase 1A1. The calculated rate of coexistence of these 2 diseases is 15 to 35/million births. Here we present a 21-month-old girl with hereditary spherocytosis diagnosed at the age of 40 days with hyperbilirubinemia out of proportion of hemolysis which led to diagnosis of GS. Thereby, the diagnosis of GS should be considered in unexplained unconjugated hyperbilirubinemia in different age groups, including infants and toddlers.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hepatology, Bilirubin, Jaundice, Spherocytosis

0

During hypothermic storage, a substantial fraction of red blood cells (RBCs) transforms from flexible discocytes to rigid sphero-echinocytes and spherocytes. Infusion of these irreversibly-damaged cells into the recipient during transfusion serves no therapeutic purpose and may contribute to adverse outcomes in some patients. In this proof-of-concept study we describe the use of hypotonic washing for selective removal of the irreversibly-damaged cells from stored blood.

Concepts: Cell nucleus, Blood, Red blood cell, Blood type, Bone marrow, Blood transfusion, Hereditary spherocytosis, Spherocytosis