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2 . . Dyserythropoiesis, Refractory f . .- RE? osmw DOE-FORRESTAL MARKEY FILES COLLECTI~ Box No. e;*..,+- .._?.,:'2.. Dyserythropoiesis, Refractory 'Anenlia, and "Preleuliernia :" L. .: . ..,I. .',.., ~:*.!.:, Metabolic Features of the Erythrocytes ,,...... ';r ';r t . ' By William N. Valentine, Patricia-. N. Konrad, and Donald E. Paglia j-?- * Twenty-one enzymatic activities and red relatively or absolutely low and somelimes cell glutathione contentr..ar.c ,compared .in , , drarnaticalJy,so. El\ryme ratios were grossly cord blood, dyserythropoietic disorders, aberrant. Capricious. very high individual normal subjects. and subjects with hemo- aclivities occurred in some instances. The lytic syndromes and reticulocytosis ap- heterogeneous nalure of case material, proximating that of the, newborn. The including both hereditary and acquired syn- dysery!hropoietic states are heterogeneous dromes, renders it difficult to interpret and include several hereditary disorders, similarities often seen from case lo case "prgewse-Eic- a@ overt .!e~kemL?: refrac- and somelimes to cord blood patterns on tory anemia with and without marrow the basis of the reversion to fetal erylhro- ringed sideroblasts. and folate deficiency. poiesis as a common denominator. Ralher. Many activities exceeded those of cord the cyto- and karyokirletic abnormalities erythrocytes and "high reticulocyte" con- characterizing dyserythropoiesis of diverse trols by one or even several ;standard etiologies may result in exaggerations and deviations. 'The low phosphoglycerate ki- distortions of a normal asynchronism in ..:-'... nase and glulalhione peroxidase and rela; loss of functional genetic material govern- ..' tively low ribosophosphate pyrophospho- ing enzyme synthesis as the nucleus de- ' .: kinase and adenine-phosphoribodyl trans- generates and cytoplasmic organelles are : ferase of cord erythrocytes were mimicked lost. Uncommonly. Pyruvate kinase was often ,. ..,. HE DYSERYTHROPOIETIC ANEMIAS are clinically, hematologically, .."' Tand metabolically heterogeneous. They may be congenital or acquired, responsive' or unresponsive2.3. to pyrodoxine and androgens, and may or may not evolve into overt myeloblastic leukemia.z*' Ringed sideroblasts may be abundant,2*3*5-' inconspiwous, or absent in the bone marrow. The marrow morphology in some instances has special characteristics, such as erythroid ,. m~ltinuclearity,~-~5megaloblastqid features, or othe; evidence of dysplasia.' The peripheral blood frequently contains a variably numerous population O€ h~pochrornicerythrocyte; together with well-hemoglobinated cek6 Oval macrocytes are prominent in some cases; in others, shape changes of the .. - From the Depnrfrnents of Medicine, Pedinfrics, and Pufhology, University of California, Center for the Health Science, and CVadsworfh General Ifospital, Vefernns Administrafion Cenfcr, Los Angcles, Calif. 90524. ...... 5I ..... ..:. ., 2 ....... I. L.: , .- Sicbnritted Sepfember 27, 1972; revised October 26, 1972; accepted October 27, 1972. ................ -?.'.< Supporfed by NIH Grant HL 12944 and by fhe Lerckernia Research Forcndation of Los Angeles. William N. Valentine, M.D.: Professor of Medicine; Deparfrnenf of Mcdicine, Utriuersify Of California, Ccrtter for the Health Sciences, Los Angelcs, Calif. 90024. Patricia N. Konrad, M.D.: Assistant Professor of Pediatrics, Departrnenf of Pediatrics, Uniuersify of California, Centtr for the Health Sciences, Los Arigcles, Cnlif. 90024. Donald E. Paglia, M.D.: Assisfant Professor of Pathology, Departnlcnt of Pathology, Universify of Culifornin, Center for the Henlfh Sciences, Los Angelcs, Calif. 90024. @ 1973 by Gritrte & Strotton, fnc. I Dlood, Vol. 41. No. G (June), 1973 857 .... 1010833 I 858 . VALENTINE. KONRAD, AND PAGLIA :i .t ery~lirocytesare incons'picuous. In still other cases, bizarre morphology and marked poikilo- and anisocytosis characterize the stained blood film. i The dyseryt1iropo;etic states share certain features, !-$owever. In most st;ltcs . there is marrow erythroid hy~~crplasia,and crythropoicsis is inektive 2.3.6 i , ___- -- : The ineffective erythropoiesis is characterized-by evidence of intraniedul]ary ccll death and abnormally large 6ile pigment excretion not attributable to . destruction of circulating red cells. The reticulocyte 'count is often inappro- f priately low in relation to the degree of anemia and marrow hyperplasia. i Ferrokinetic studies most frequently show increased plasma iron turnover with defective utilization of iron.2 Red cell lifespan may approach normal, or ic variably severe hemolysis may complicate defective erythrocyte production. Leukocytes and platelets may -or may not be involved in the disturbed f . henlatopdiesis. I~~?e--~:but.b.y_,no-m-eans._ all--jn.stances, chromq~omalabnor- 1 . malities- have-been.n~ted.~-"-"~- These hematologic aberrations have .metabolic counterpaKts. There is often evidence of defective svnthesis of hemei2*7*'3*24Hb F is sometime's modestly (or occasionally markedly) increased. 25-29 There are other reseinblan'ces to fetal erythropoiesis. These include a glycine y-chajdalanine y-chain ratio like that in ~ord~blood,3~*~~an increase in the i antigen,9*".3147 a pattern of lactate ' dehydrogenase (LDH) isozyme distribution similar to that of cord blood,3840 I- *: :t: and alterations in red cell enzyme activities sometimes resembling those of ,; the rtc~born.~~~~*~~*~'A decrease or absence of antigens AI, 13, and B is ?. r- sometimes noted.26.32-3437*42In addition, low red cell pyruvafe kinase activity !- has frequently been 0bserved,33-~~-~~"'although this is not invariable. Several .: 1 separate clones of cells have been identified in the erythrocyte population of some s~bjects.'~~~'*~~~~~ Extensive investigations, particularly in France,2s*263'-37 have emphasized the diverse nature of enzymatic and serologic abnormalities in idiopathic refractory anemias and in the dyserythropoiesis associated with some leuke- . .. mias., While recognizing that embryonal characteristics are varied and i:. inconstant and that features of adult erythropoiesis are also present, Rochant ;., et al. have suggested that reactivation_____------ of normall~~.~~e~r~sse~~~~e~a~~ge~~~~ could ::, possibly be related'.- ---I -- to ...-_ the etiology.- . ... .. and to the malignant-.!rapsformations :: sometimes seen in the dyserythropoietic states?' The production of enibryonai :. A-AT .-~ .-__-_.-.-.> -.--.._. - __ ..____---.- proteins in certain leukemic and other malignant states is well doc- t: 1.. -. -. ____ . ~ e. umented.2'-29*?4-!6 .. .. '. -1- :. The present report presents a comparison of the erythrocyte glutathione ': (GSH) content and 21 enzymatic activities in 28 dyserythropoietic disorders of diverse etiology with those of erythrocytes of normal subjects, with those of cord blood, and with those of selected subjects with hemolytic anemia and reticulocytosis approximating that normally present in the newborn. -1, .: CASE REPORTS .. The case material can be arbitrarily divided into four groups: (A) helcrogeneous group of congenital dyserythropoietic states; (B) cases ccnsidered as probably "preleukcmic" or who have developed overt leukemia; (C) acquired idiopathic refraciory anemias with and without ringed sideroblasts in the marrow; (D) a single case of severe megaloblastic : ., .. 859 . to folate deficiency. SinW the case material is voluminous (28 subjects), ta of necessity are limited. Certain pertinent information is summarized in I I. No subject had a positive antiglobulin test, an abnormal hemoglobin, or ce of paroxysmal nocturnal hemoglobinuria. Congenifnl or Probably Congenifal Dyserythropdietic Disorders s 1 and i, A.P. and R.P., are brothers, the offspring OF a first cousin marriage, have been, ancmic since birth. The disorder has been characterized by Hb.values in ge OE 9~10g/iOo .ml, mild neutropenia, nb.rrhht'*~tclets;.iirrd*rctbdcqtosissof . The peripheral blood film shows marked poikilo- and 'anisocytosis, elliptocytes, fl' e'*' Ils, teardrop forms, and schistocytes. The bone marrow aspirate rsajs intense v+ p% with about 5% binucleate erythroblasts. The nuclei of the latter vary in size and depth of staining, and in some, karyolysis and <- karyorrhexis are prominent. Internuclear chromatin bridges are rare but present. The ,I $; $; ;anemia conforms to that described by Wendt and Heimpel13.14 as congenital dyserythro- 8: pictic anemia (CDA) Type I. Both parents have normal hernograms and enzymologic .. .. ..!. Cases 3, 4, and ha-& hereditary erythroblastic multinclclearity associated with a positive acidified-serum test (HEiMPA5.9 CDA Type IIIO). They have previously been reported -in detail (cases 1, 4, and 5;9 cases M.F., L.F., and C.L.,47). The disorder is characterized 'by erythrob!astic multinuclearity, ineffective erythropoiesis, a positive acidified-'serum test erent characteristics from the Ham test, and by unusual susceptibility of the s to agglutination with anti-i and lysis by anti-i and anti3.9 Cases 6, 7, 8, and 9 have many similarities, but identity is not proved. Cases, 6 and 7, V., are sisters, and have been ancmic since birth. While Hb values have often /le -,;L. ! the range of 5-7 g/100 ml, transfusions have been rare. Erythrocyte morphology 5' I se,to any form of hematinics. The hemogram of both parents is normal, a5 are atic activities OC their erythrocytes. No consanguinity is known in the kindred. I Case 8, K.Y., a female of Japanese descent, has had recognized anemia since her early g .( 8;' kens. The anemia probably is congenital, although four siblings are said
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