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Aplastic anemia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aric Hall, M.D., Beth Israel Deaconess Medical Center, Boston, MA [2]

Overview

The primary diagnostic dilemma is differentiating aplastic anemia from a hypocellular myelodysplastic syndrome.

Differentiating Aplastic anemia from other Diseases

Aplastic anemia must be differentiated based on different laboratory findings including mean cell volume (MCV), reticulocytosis, and hemolysis.

To review the differential diagnosis of anemia, see below table.

To review the differential diagnosis of microcytic anemia, click here.

To review the differential diagnosis of normocytic anemia, click here.

To review the differential diagnosis of macrocytic anemia, click here.

To review the differential diagnosis of hypochromic anemia, click here.

To review the differential diagnosis of normochromic anemia, click here.

To review the differential diagnosis of anisochromic anemia, click here.

To review the differential diagnosis of hemolytic anemia, click here.

To review the differential diagnosis of anemia with intrinsic hemolysis, click here.

To review the differential diagnosis of anemia with extrinsic hemolysis, click here.

To review the differential diagnosis of anemia with low reticulocytosis, click here.

To review the differential diagnosis of anemia with normal reticulocytosis, click here.

To review the differential diagnosis of anemia with high reticulocytosis, click here.

Disease Genetics Clinical manifestation Lab findings
History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Iron studies Specific finding on blood smear
Serum iron Serum Tfr level Transferrin or TIBC Ferritin Transferrin saturation
Iron deficiency anemia[1] βˆ’ βˆ’ βˆ’ Hypochromic Microcytic ↑ Nl or ↓ Nl Nl ↓ ↑ ↑ ↓ ↓↓↓
Iron deficiency anemia (early phase)[2] βˆ’ βˆ’ βˆ’ Normochromic Normocytic ↑ ↓ Nl Nl ↓ ↑ ↑ ↓ ↓
Lead poisoning[3] βˆ’
  • House painted with chipped paint
βˆ’ βˆ’ Hypochromic Microcytic Nl Nl or ↓ Nl Nl Nl to ↓ Nl Nl Nl to ↓ βˆ’
  • RBCs retain aggregates of rRNA
  • Basophilic stippling
Sideroblastic anemia[4] βˆ’ βˆ’ Hypochromic Microcytic Nl Nl or ↓ Nl Nl ↑ Nl Nl to ↓ ↑ βˆ’
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Anemia of chronic disease[5] βˆ’ βˆ’ βˆ’ βˆ’ Hypochromic Microcytic Nl Nl or ↓ Nl ↑ ↓ Nl ↓ ↑ βˆ’ NA
Thalassemia[6] Ξ±-thalassemia
  • Ξ±– globin gene deletions
  • Cis deletions
  • Trans deletions

Ξ²-thalassemia

Ξ±-thalassemia

Ξ²-thalassemia

βˆ’ βˆ’ Hypochromic Microcytic Nl
  • Thalassemia trait: Nl or ↓
  • Thalassemia Syndromes: ↑
Nl Nl Nl to ↑ Nl Nl ↑ Nl to ↑
G6pd deficiency[7]
  • History of using
+ Intrinsic Normochromic Normocytic ↑ ↑ but usually causes resolution within 4-7 days ↓ ↓ Nl to ↑ Nl ↑ ↑ ↑
Pyruvate kinase deficiency[8] + Intrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↑ Nl Nl ↑ βˆ’
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Sickle cell anemia[9] + Intrinsic Normochromic Normocytic ↑ ↑ ↓ Nl or moderately ↑ Nl Nl Nl or moderately ↑ ↓ Nl
HbC disease[10]
  • Glutamic acid–to-lysine mutation in Ξ²-globin
+ Intrinsic Normochromic Normocytic ↑ ↑ ↓ Nl Nl Nl Nl ↓ βˆ’
Paroxysmal nocturnal hemoglobinuria[11][12] + Intrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↓ Nl ↑ ↓ βˆ’ NA
Hereditary spherocytosis[13] + Intrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↓ Nl ↑ Nl βˆ’
  • Small, round RBCs with less surface area and no central pallor
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Microangiopathic hemolytic anemia[14][15] βˆ’ Associated with + Extrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↓ Nl βˆ’ ↑ βˆ’
  • Helmet cells
Macroangiopathic hemolytic anemia[16] Associated with + Extrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↓ Nl βˆ’ βˆ’ βˆ’
Autoimmune hemolytic anemia[17] βˆ’ Associated with:
  • Painful, blue fingers and toes with cold weather
+ Extrinsic Normochromic Normocytic ↑ ↑ ↓ Nl ↓ Nl βˆ’ βˆ’ βˆ’
  • RBC agglutination
Aplastic anemia[18]
  • Symptoms based on underlying condition
βˆ’ βˆ’ Normochromic Normocytic ↑ ↓ Nl Nl ↓ ↓ Nl ↑ ↓
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Folate deficiency[19]
  • Impaired DNA synthesis
βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Vitamin B12 deficiency[20] βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Orotic aciduria[21]
  • Neurological manifestation
βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑ NA
Fanconi anemia[22]
  • Significant for bilateral short thumbs
βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Diamond-Blackfan anemia[23] Mutations in:
  • RPL5
  • RPL11
  • RPL35A
  • RPS7
  • RPS10
  • RPS17
  • RPS19
  • RPS24
  • RPS26
βˆ’ βˆ’ Anisochromic Macrocytic Nl ↓ Nl Nl ↑ ↑ ↓ ↑ ↑ NA
Infections[24] βˆ’ Associated with + Extrinsic Normochromic Normocytic ↑ ↑ ↓ Nl Nl Nl βˆ’ βˆ’ βˆ’
Chronic kidney disease[25] βˆ’ βˆ’ βˆ’ Normochromic Normocytic ↑ Nl/↑ Nl ↑ ↓ βˆ’ ↓ ↑ ↓ Nl
Liver disease[26] βˆ’
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↑ Nl Nl ↑ ↑ ↓ ↑ ↑
Alcoholism[27] βˆ’ βˆ’ βˆ’ Anisochromic Macrocytic ↑ ↑ Nl Nl ↑ ↑ ↓ ↑ ↑
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear

References

  1. ↑ Camaschella C (May 2015). “Iron-deficiency anemia”. N. Engl. J. Med. 372 (19): 1832–43. doi:10.1056/NEJMra1401038. PMIDΒ 25946282.
  2. ↑ De Andrade Cairo RC, Rodrigues Silva L, Carneiro Bustani N, Ferreira Marques CD (June 2014). “Iron deficiency anemia in adolescents; a literature review”. Nutr Hosp. 29 (6): 1240–9. doi:10.3305/nh.2014.29.6.7245. PMIDΒ 24972460.
  3. ↑ Bain BJ (December 2014). “Lead poisoning”. Am. J. Hematol. 89 (12): 1141. doi:10.1002/ajh.23852. PMIDΒ 25220013.
  4. ↑ Bottomley SS, Fleming MD (August 2014). “Sideroblastic anemia: diagnosis and management”. Hematol. Oncol. Clin. North Am. 28 (4): 653–70, v. doi:10.1016/j.hoc.2014.04.008. PMIDΒ 25064706.
  5. ↑ Roy CN (2010). “Anemia of inflammation”. Hematology Am Soc Hematol Educ Program. 2010: 276–80. doi:10.1182/asheducation-2010.1.276. PMIDΒ 21239806.
  6. ↑ Zainal NZ, Alauddin H, Ahmad S, Hussin NH (December 2014). “Ξ±-Thalassemia with Haemoglobin Adana mutation: prenatal diagnosis”. Malays J Pathol. 36 (3): 207–11. PMIDΒ 25500521.
  7. ↑ Luzzatto L, Seneca E (February 2014). “G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications”. Br. J. Haematol. 164 (4): 469–80. doi:10.1111/bjh.12665. PMCΒ 4153881. PMIDΒ 24372186.
  8. ↑ Grace RF, Zanella A, Neufeld EJ, Morton DH, Eber S, Yaish H, Glader B (September 2015). “Erythrocyte pyruvate kinase deficiency: 2015 status report”. Am. J. Hematol. 90 (9): 825–30. doi:10.1002/ajh.24088. PMCΒ 5053227. PMIDΒ 26087744.
  9. ↑ Singh PC, Ballas SK (March 2015). “Emerging drugs for sickle cell anemia”. Expert Opin Emerg Drugs. 20 (1): 47–61. doi:10.1517/14728214.2015.985587. PMIDΒ 25431087.
  10. ↑ Lemonne N, Billaud M, Waltz X, Romana M, Hierso R, Etienne-Julan M, Connes P (2016). “Rheology of red blood cells in patients with HbC disease”. Clin. Hemorheol. Microcirc. 61 (4): 571–7. doi:10.3233/CH-141906. PMIDΒ 25335812.
  11. ↑ Bunyaratvej A, Butthep P (January 1992). “Cytometric analysis of paroxysmal nocturnal hemoglobinuria erythrocytes”. J Med Assoc Thai. 75 Suppl 1: 237–42. PMIDΒ 1402472.
  12. ↑ Kahng J, Kim Y, Kim JO, Koh K, Lee JW, Han K (January 2015). “A novel marker for screening paroxysmal nocturnal hemoglobinuria using routine complete blood count and cell population data”. Ann Lab Med. 35 (1): 35–40. doi:10.3343/alm.2015.35.1.35. PMCΒ 4272963. PMIDΒ 25553278.
  13. ↑ Da Costa L, Galimand J, Fenneteau O, Mohandas N (July 2013). “Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders”. Blood Rev. 27 (4): 167–78. doi:10.1016/j.blre.2013.04.003. PMIDΒ 23664421.
  14. ↑ Morishita E (July 2015). “[Diagnosis and treatment of microangiopathic hemolytic anemia]”. Rinsho Ketsueki (in Japanese). 56 (7): 795–806. doi:10.11406/rinketsu.56.795. PMIDΒ 26251142.
  15. ↑ George JN, Charania RS (March 2013). “Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia”. Semin. Thromb. Hemost. 39 (2): 153–60. doi:10.1055/s-0032-1333538. PMIDΒ 23390027.
  16. ↑ Westphal RG, Azen EA (May 1971). “Macroangiopathic hemolytic anemia due to congenital cardiovascular anomalies”. JAMA. 216 (9): 1477–8. PMIDΒ 5108522.
  17. ↑ Hill QA (October 2015). “Autoimmune hemolytic anemia”. Hematology. 20 (9): 553–4. doi:10.1179/1024533215Z.000000000401. PMIDΒ 26447931.
  18. ↑ Dolberg OJ, Levy Y (2014). “Idiopathic aplastic anemia: diagnosis and classification”. Autoimmun Rev. 13 (4–5): 569–73. doi:10.1016/j.autrev.2014.01.014. PMIDΒ 24424170.
  19. ↑ Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M, Katsuno M, Doi H, Tanaka F, Sobue G (March 2015). “Clinicopathologic features of folate-deficiency neuropathy”. Neurology. 84 (10): 1026–33. doi:10.1212/WNL.0000000000001343. PMIDΒ 25663227.
  20. ↑ Hunt A, Harrington D, Robinson S (September 2014). “Vitamin B12 deficiency”. BMJ. 349: g5226. PMIDΒ 25189324.
  21. ↑ Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G (April 2015). “Hereditary orotic aciduria with epilepsy and without megaloblastic anemia”. Neuropediatrics. 46 (2): 123–5. doi:10.1055/s-0035-1547341. PMIDΒ 25757096.
  22. ↑ Alter BP (2014). “Fanconi anemia and the development of leukemia”. Best Pract Res Clin Haematol. 27 (3–4): 214–21. doi:10.1016/j.beha.2014.10.002. PMCΒ 4254647. PMIDΒ 25455269.
  23. ↑ Vlachos A, Blanc L, Lipton JM (June 2014). “Diamond Blackfan anemia: a model for the translational approach to understanding human disease”. Expert Rev Hematol. 7 (3): 359–72. doi:10.1586/17474086.2014.897923. PMIDΒ 24665981.
  24. ↑ Bustinduy AL, Parraga IM, Thomas CL, Mungai PL, Mutuku F, Muchiri EM, Kitron U, King CH (March 2013). “Impact of polyparasitic infections on anemia and undernutrition among Kenyan children living in a Schistosoma haematobium-endemic area”. Am. J. Trop. Med. Hyg. 88 (3): 433–40. doi:10.4269/ajtmh.12-0552. PMCΒ 3592521. PMIDΒ 23324217.
  25. ↑ Drawz P, Rahman M (June 2015). “Chronic kidney disease”. Ann. Intern. Med. 162 (11): ITC1–16. doi:10.7326/AITC201506020. PMIDΒ 26030647.
  26. ↑ Marks PW (July 2013). “Hematologic manifestations of liver disease”. Semin. Hematol. 50 (3): 216–21. doi:10.1053/j.seminhematol.2013.06.003. PMIDΒ 23953338.
  27. ↑ Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K (May 2014). “Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men”. Alcohol. Clin. Exp. Res. 38 (5): 1237–46. doi:10.1111/acer.12372. PMIDΒ 24588059.

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