Hematology

Hereditary elliptocytosis and hereditary pyropoikilocytosis

Hereditary elliptocytosis and hereditary pyropoikilocytosis

What every physician needs to know about hereditary elliptocytosis and hereditary pyropoikilocytosis:

Hereditary elliptocytosis (HE) is characterized by the presence of elliptical or oval erythrocytes on the blood films of affected individuals.

The worldwide incidence of HE is estimated to be between one in 2,000 and one in 4,000 individuals. The true incidence of HE is unknown because its clinical severity is heterogenous and many patients are asymptomatic. It is common in individuals of African and Mediterranean descent, presumably because elliptocytes confer some resistance to malaria.

Hereditary pyropoikilocytosis (HPP) is a rare cause of anemia, with erythrocyte morphology similar to that seen in patients with thermal burns. HPP patients experience marked hemolysis and anemia in infancy that gradually improves, evolving to typical hemolytic HE later in life. However, the blood smear remains striking. A strong relationship exists between HE and HPP. Up to a third of family members of HPP patients have typical HE, and many of these family members share identical mutations in erythrocyte spectrin. In addition, many patients with HPP proceed to develop typical mild to moderate HE.

What features of the presentation will guide me toward possible causes and next treatment steps:

The clinical presentation of HE is heterogenous, ranging from asymptomatic carriers to patients with severe, life-threatening anemia. Of note, the overwhelming majority of HE patients are asymptomatic. Diagnosis is made incidentally while testing for unrelated disorders.

Asymptomatic carriers who possess the same molecular defect as an affected HE relative, but who have normal or near normal blood films have been identified. The erythrocyte life span is normal, and the patients are not anemic. Asymptomatic HE patients may experience hemolysis in association with infections, hypersplenism, vitamin B12 deficiency, or microangiopathic hemolysis, such as disseminated intravascular coagulation or thrombotic thrombocytopenic purpura. In the latter two conditions, worsening hemolysis may result from microcirculatory damage superimposed on the underlying mechanical instability of red cells.

HE patients with chronic hemolysis experience moderate to severe hemolytic anemia with elliptocytes and poikilocytes on blood film. Red cell life span is decreased, and patients may develop complications of chronic hemolysis, such as gallbladder disease. The blood films of the most severe HE patients with chronic hemolysis exhibit elliptocytes, poikilocytes, and very small microspherocytes. Thus, their clinical presentation is indistinguishable from HPP.

HPP represents a subtype of common HE, as evidenced by the coexistence of HE and HPP in the same family, and the presence of the same molecular defect of spectrin. Unlike HE, subjects carrying the spectrin mutation, red cells of HPP subjects are partially deficient in spectrin.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Peripheral blood smear

The diagnosis of hereditary elliptocytosis is made by examination of the peripheral blood smear. The sine qua non of HE, is the presence of "cigar-shaped" elliptical erythrocytes on peripheral blood smear. Elliptocytes number from a few to many, even up to 100% of red blood cells. In hemolytic HE or HPP, spherocytes, stomatocytes, and fragmented cells may be seen. HPP erythrocytes may be bizarrely shaped with fragmentation or budding; poikilocytosis, fragmented cells, and microspherocytosis are common. Pyknocytes are prominent on blood films of neonates with HPP.

Complete blood count

The blood count is normal in typical HE. In hemolytic HE and HPP, varying degrees of anemia are present. HE elliptocytes are normochromic and normocytic. In HPP, the presence of microspherocytosis contributes to a markedly decreased mean corpuscular volume. The reticulocyte count generally is less than 5%, but may be higher when hemolysis is severe.

Osmotic fragility

Osmotic fragility is normal in typical HE, but abnormal in severe HE and in HPP.

Other laboratory findings

Other laboratory findings in hemolytic HE and HPP are similar to those of other hemolytic anemias, and are nonspecific markers of increased erythrocyte production and destruction.

What conditions can underlie hereditary elliptocytosis and hereditary pyropoikilocytosis:

What conditions can underlie hereditary elliptocytosis?

There is usually little confusion in the diagnosis of hereditary elliptocytosis. The patient is typically asymptomatic when elliptocytes are incidentally seen on peripheral blood smear.

The differential diagnosis of elliptocytes on peripheral blood smear include:

  • Megaloblastic anemias

  • Hypochromic microcytic anemias (iron deficiency anemia and thalassemia)

  • Myelodysplastic syndromes

  • Myelofibrosis

In these conditions, elliptocytosis is acquired and generally represents less than one fourth of red cells seen on blood film. History and additional laboratory testing usually clarify the diagnosis of these disorders.

When do you need to get more aggressive tests:

Beyond a complete blood count (CBC) and peripheral blood smear, additional testing is not necessary. Bone marrow examination is typically non-diagnostic.

What imaging studies (if any) will be helpful?

Imaging studies are not beneficial in the diagnosis of HE or HPP. In cases of hemolytic HE and HPP, imaging, such as abdominal ultrasonography, is helpful in diagnosing complications of chronic hemolysis such as cholelithiasis and its complications.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Therapy is rarely needed in patients with HE.

In rare cases, occasional red blood cell transfusions may be required.

What other therapies are helpful for reducing complications?

In cases of severe HE and HPP, splenectomy has been palliative, as the spleen is the site of erythrocyte sequestration and destruction. The same indications for splenectomy in HS can be applied to patients with symptomatic HE or HPP. Post-splenectomy, patients with HE or HPP exhibit increased hematocrit, decreased reticulocyte counts, and improved clinical symptoms.

Patients should be followed for signs of decompensation during acute illnesses.

Interval ultrasonography to detect gallstones should be performed. In some cases, cholecystectomy may be required.

Patients with significant hemolysis should receive daily folate supplementation to prevent megaloblastic disease.

Counseling of family members should be provided.

What should you tell the patient and the family about prognosis?

HE is an asymptomatic disease in most cases. Prognosis is excellent, as most patients do not develop any disease-related complications.

In cases of hemolytic HE and HPP, the degree of anemia and hemolysis should be assessed. Complications of anemia and hemolysis, pallor, fatigue, dyspnea on exertion, jaundice, et cetera, may occur. In most cases, no therapy is necessary. In acute hemolytic episodes, red blood cell transfusion is indicated to improve cardiovascular status. When splenectomy is performed, the hemolytic anemia is ameliorated in almost all patients. The risk of gallstones decreases to baseline. Mortality due to HE is very uncommon.

“What if” scenarios.

N/A

Pathophysiology

The principal defect in HE and HPP erythrocytes is mechanical weakness of the erythrocyte membrane skeleton leading to increased membrane fragility. Studies of membrane proteins have identified abnormalities of various proteins, including α and ß spectrin, protein 4.1R, and glycophorin C. Most defects occur in spectrin, the principal structural protein of the membrane skeleton. Most spectrin defects impair the ability of spectrin dimers to self-associate into tetramers and oligomers, the primary structural component of the membrane skeleton. Defects of protein 4.1R lead to disruption of the spectrin-actin attachment to the membrane via GPC, causing changes in cell shape and membrane stability similar to those found in abnormalities of spectrin. The mechanical instability in GPC variants appears to result from secondary protein 4.1 deficiency. In all of these defects, disruption of the membrane skeleton leads to mechanical instability sufficient to cause red cell fragmentation with hemolytic anemia under conditions of normal circulatory shear stress.

What other clinical manifestations may help me to diagnose hereditary elliptocytosis and hereditary pyropoikilocytosis?

What other clinical manifestations may help me to diagnose hereditary elliptocytosis?

Elliptocytes may be seen in association with several disorders, including megaloblastic anemias, hypochromic microcytic anemias (iron deficiency anemia and thalassemia), myelodysplastic syndromes, and myelofibrosis. In these conditions, elliptocytosis is acquired and generally represents less than one fourth of red cells seen on blood film. History and additional laboratory testing usually clarify the diagnosis of these disorders.

Pseudoelliptocytosis is an artifact of blood film preparation. Pseudoelliptocytes are found only in certain areas of the film, usually near its tail. The long axes of pseudoelliptocytes are parallel, whereas the axes of true elliptocytes are distributed randomly.

Except in cases of hemolytic HE or HPP, physical examination is unremarkable. In hemolytic HE and HPP, pallor, jaundice, and splenomegaly may be found on physical examination.

What other additional laboratory studies may be ordered?

Specialized testing has been used in difficult cases or cases requiring a molecular diagnosis. Specialized tests include analysis of membrane proteins by one-dimensional gel electrophoresis, limited tryptic digestion of membrane spectrin followed by one- or two- dimensional gel electrophoresis, spectrin dimer self-association assays, ektacytometry, and cDNA (complementary DNA) and genomic DNA analyses.

What’s the evidence?

Gallagher, PG. " Hereditary elliptocytosis: spectrin and protein 4. 1R". Semin Hematol. vol. 41. 2004. pp. 142-164.

[This is a comprehensive overview of the hereditary elliptocytosis and pyropoikilocytosis syndrome.]

Bennett, V, Healy, J. " Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin". Trends Mol Med. vol. 14. 2008. pp. 28-36.

[This reference provides a detailed review of the structure and function of cell membranes in health and disease.]

Dhermy, D, Schrevel, J, Lecomte, MC. " Spectrin-based skeleton in red blood cells and malaria". Curr Opin Hematol. vol. 14. 2007. pp. 198-202.

[This report provides an overview of the role of the erythrocyte membrane in malaria invasion.]

Ipsaro, JJ, Harper, SL, Messick, TE. " Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex". Blood. vol. 115. 2010. pp. 4843-4852.

[This report provides the molecular insight into the pathogenesis of disease associated with abnormalities of spectrin self-association.]
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