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A seven-year-old male with circulating red blood cells showing a thermal injury-like morphology.


A seven-year-old African-American male presented with a history of hematuria, proteinuria, jaundice, and anemia occasionally treated with transfusions since early childhood. The family history included a father and sister with similar symptoms of anemia, both of which had been diagnosed with hereditary pyropoikilocytosis. Due to the patient's family history and symptoms indicating a possible hematologic problem, a blood draw was performed. Laboratory studies showed an elevated alkaline phosphatase and bilirubin, and hemolytic anemia with unusual erythrocyte indices (Table 1). The patient's vital signs and abdominal ultrasound were normal, and he had no known allergies. Examination of the patient's peripheral blood smear revealed extreme erythrocyte poikilocytosis with bizarre forms resembling the erythrocyte morphology sometimes seen in individuals with severe thermal burns (Figure 1). (2, 3)


A diagnosis of hereditary pyropoikilocytosis (HPP) was rendered based on laboratory studies, family history, erythrocyte osmotic fragility testing, and erythrocyte morphology. Molecular diagnostics were not performed.

HPP is characterized by erythrocyte poikilocytosis and fragmentation, erythrocyte budding, spherocytes, triangulocytes, micropoikilocytosis, microspherocytosis, and occasional elliptocytes, which together result in a pattern reminiscent of thermal injury. (2-4) The red cell distribution width is characteristically greater than 40 fL and erythrocyte fragmentation can result in hematology analyzers counting the fragments as platelets, leading to over-estimation of the actual platelet count, as seen in this case (Table 1). (4) HPP was first identified in 1975 by Zarkowsky et al. (5) who found this unusual erythrocyte morphology in three children with congenital hemolytic anaemia. Interestingly, HPP erythrocytes fragment after 17 hours at 37[degrees]C, partially explaining their in vivo instability, and fragment after 15 minutes at 45[degrees]C, while normal erythrocytes fragment after 15 minutes at 49[degrees]C. (5) They also show unusual osmotic fragility, which together with the thermal instability, can result in an MCV as low as 25 to 75 fL. (4-6)

Initial work-up revealed that a spectrin protein abnormality was the likely cause of the unusual erythrocyte thermal sensitivity and HPP erythrocytes are often deficient in this protein. (7-9) Molecular genetic studies have revealed that mutations of the erythrocyte cytoskeletal protein-encoding genes [alpha]--and [beta]-spectrin cause all, or most HPP cases. (4, 5 7-10) [alpha]--and [beta]-spectrin self-associate into tetramers that play a central role in maintaining the shape, flexibility, and strength of the erythrocyte membrane. (11) The pathology of HPP is poorly understood, it was considered to be a recessive disease owing to the fact that both the parents are sometimes asymptomatic. The genetic pathogenesis mainly involves three different gene alterations; they can be homozygotes, compound heterozygotes or double heterozygotes. Homozygotes and compound heterozygotes have a structural variant of self-association sites, while as in double heterozygotes, one spectrin allele caries a structural defect and the second defect located trans to the structural variant produces a thalassemia like defect resulting in low erythrocyte spectrin. (4, 5, 7-11)

Originally HPP was thought to be a different disease than hereditary elliptocytosis (HE). However molecular genetic analyses have shown that HPP is a severe form of HE and many HE cases carry a- and p-spectrin mutations and the two diseases show significant molecular and clinical overlap. (4, 5, 7-11) Interestingly, for many individuals with HPP one parent or sibling often has HE or HPP. In the case presented here, the father and sister of the individual both had HPP. (4) HPP is diagnosed by a variety of methods including erythrocyte osmotic fragility testing, eison-5'-maleimide-binding (where increased fluorescence is seen), molecular a- and b-spectrin mutation diagnostic testing, with erythrocyte indices and peripheral blood smear examination. (4,11,12) Individuals with HPP are usually of African descent, and HPP has been hypothesized to increase malarial parasite resistance. (4, 11) Clinically, HPP often manifests as neonatal hyperbilirubinemia and early childhood anemia that often improves over time. (4, 11) Splenomegaly and symptoms indicating severe anemia/hemolysis may be present, including early gallbladder disease, frontal bossing, and growth retardation. (4-6, 11) The severity of HPP symptoms seen in specific individuals likely relates to the degree of erythrocyte membrane instability conferred by different spectrin mutations. (11-13) If the anemia in HPP is very severe, it can be treated with blood transfusions, particularly in the neonatal period. As the spleen is the main site for erythrocyte sequestration and destruction, splenectomy often raises the hemoglobin level up to 10 to 14 g/dL range and usually resolves the anemia. (9) If hemolysis persists after splenectomy, daily folate administration can be useful. (9)

The case presented here is typical of HPP. The individual had a family history of HPP in his father and sister, and anemia and jaundice stemming from early childhood. Laboratory studies (Table 1), osmotic fragility testing, and erythrocyte morphology were typical of HHP and the patient was diagnosed based on these observations. The patient's anemia was successfully treated with transfusions and supportive care. A splenectomy was not performed, as transfusions were sufficient to maintain adequate patient hemoglobin levels. The patient is now doing well and as is common in HHP, no longer needs frequent transfusion to maintain an adequate hemoglobin level. (4-11)


(1.) Doi = RANGES.pdf

(2.) HAM TH, SHEN SC, et al. Studies on the destruction of red blood cells; thermal injury; action of heat in causing increased spheroidicity, osmotic and mechanical fragilities and hemolysis of erythrocytes; observations on the mechanisms of destruction of such erythrocytes in dogs and in a patient with a fatal thermal burn. Blood. 1948; 3:373-403.

(3.) Baar S, Arrowsmith DJ. Thermal damage to red cells. J Clin Pathol. 1970; 23:572-576.

(4.) Da Costa L, Galimand J, Fenneteau O, Mohandas N. Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders. Blood Rev. 2013; 27:167-178.

(5.) Zarkowsky HS, Mohandas N, Speaker CB, Shohet SB. A congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. Br J Haematol. 1975; 29:537-543.

(6.) Wiley JS, Gill FM. Red cell calcium leak in congenital hemolytic anemia with extreme microcytosis. Blood. 1976; 47:197-210.

(7.) Chang K, Williamson JR, Zarkowsky HS. Effect of heat on the circular dichroism of spectrin in hereditary pyropoikilocytosis. J Clin Invest. 1979; 64:326-328.

(8.) Coetzer T, Lawler J, Prchal JT, Palek J. Molecular determinants of clinical expression of hereditary elliptocytosis and pyropoikilocytosis. Blood. 1987; 70:766-772.

(9.) Tolpinrud W, Maksimova YD, Forget BG, Gallagher PG. Nonsense mutations of the alpha-spectrin gene in hereditary pyropoikilocytosis. Haematologica. 2008; 93:1752-1754.

(10.) Hanspal M, Hanspal JS, Sahr KE, Fibach E, Nachman J, Palek J. Molecular basis of spectrin deficiency in hereditary pyropoikilocytosis. Blood. 1993; 82:1652-1660.

(11.) Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. 2004; 41:142-164.

(12.) King MJ, Zanella A. Hereditary red cell membrane disorders and laboratory diagnostic testing. Int J Lab Hematol. 2013; 35:237-243.

(13.) Johnson CP, Gaetani M, Ortiz V, Bhasin N, Harper S, Gallagher PG, Speicher DW, Discher DE. Pathogenic proline mutation in the linker between spectrin repeats: disease caused by spectrin unfolding. Blood 2007; 109:3538-3543.

Drs. Shackelford, Veillon and Cotelingam are associated with the Department of Pathology, and Dr. Jeroudi is associated with Department of Pediatrics, Section of Hematology/Oncology at the Louisiana State University Health Sciences Center, Shreveport, LA; Dr. Ansari is affililated with the Feist Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA; Mr. Jusino is associated with Clinical Molecular Pathology Consultative Services, LSU Health Shreveport, Shreveport, LA.

Table 1: The patient's red blood cell indices. Normal values are from
reference 1.

Index                         Patient's Value   Normal Value
                                                Range 6-8yrs

Hemoglobin (Hbg)              8.4 gm/dL         11.5-14.5 g/ dL
Hematocrit (Hct)              28%               35-42%
Mean cell Volume (MCV)        51.4 fL           77-95 fL
Mean Corpuscular hemoglobin   30%               31-37%
Concentration (MCHC)
Red Cell Distribution         >40               <15.0
Width (RDW)
Platelets                     703 x 103/mL      250-550 x 103/ mL
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Author:Shackelford, R.; Ansari, J.; Veillon, D.; Ong, M.; Jusino, T.; Jeroudi, M.; Cotelingam, J.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Clinical report
Date:Jan 1, 2016
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