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Pancytopenia including MDS

Topics Covered in This Page
  • Pancytopenia
  • MDS

Approach to Pancytopenia:
2 Bottom Line Points 
Etiology: Primary BM disease vs Systemic Disease
Narrowing DDx: Based on BM biopsy findings along with other clinical features 

  • Due to Primary Bone Marrow Disease
    • Myelophthistic Anemia:  Myelofibrosis, myeloid metaplasia, ineffective erythropoiesis
    • MDS, PNH, BM Lymbhoma, Aleukemic Leukemia etc
  • Due to Systemic Disease: Infection (TB, Leishmaniasis, Brucellosis); Metobolic (B12, Folic Acid, Alcohol); Immune Mediated (SLE, Sarcoidosis); Hypersplenism
Narrowing DDx
    • Due to Hypocelluar BM (5 Groups):
      • Congential Aplastic Anemia
        • Fanconi Anemia
        • Dyskeratosis Congenita
        • Shwachman-Diamond Syndrome
        • Amegakaryocytic thrombocytopenia
        • Reticular Dysgenesis
      • Acquired Aplastic Anemia
        • Chemicals/Drugs
        • Benzene
          Glue vapors
          Anticonvulsants: carbamazepine, hydantoins, phenacemide
          Antibiotics: sulfonamides, chloramphenicol
          Non steroidal anti-inflammatory drugs (NSAIDs): phenylbutazone, indomethacin
          Anti-thyroid medications: methimazole, propylthiouracil
        • Cytotoxic Drugs or Radiation
        • Viral Infections (EBV, HIV, Seronegative Hepatitis ) 
        • Immune Disorders
        • Eosinophilic fasciitis
          Systemic lupus erythematosus (can also cause hyper cellular marrow)
          Graft versus host disease
        • Idiopathic
        • Thymoma
          Anorexia nervosa
      • PNH
      • Hypoplastic MDS
      • Large Granular Lyphocytic Lymphoma
    • Despite Cellular BM: Primary BM Disease vs. Secondary to Systemic Disease (Table 107-1)
      •  Primary BM Disease Secondary to systemic ds
         MDS Hypersplenism
         PNH B12 / Folate deficiency
         Myelofirbosis SLE
         Myelopthisis  Overwhelming Infection
         BM Lymphoma Alcohol
         Aleukemic Leukemia Brucellosis
         Hairy Cell Leukemia Sarcoidosis 
      • References
        • Table 107–1 Differential Diagnosis of Pancytopenia Harrison's Textbook of Internal Medicine 

Clinical Questions

23 y/o M is seen for petechial lesions. No Fever, or Chills. These are non-palpable petehice. Hgb is 7.2, WBC 1.2 (N: 34 %, L 63 %), ANC 400, Platelet 18000. What is the next step to do . USG abdomen is done. Liver and Spleen are of normal size. 

HIV, B12, Folate. All were normal or non-reactive. 

Next step is. BM biopsy. 
Findings include. 

Erythroid: 21 %
Meta / myelocyte: 5 %
Lymphocytes: 41 %
Neutrophil: 29 %
Monocyte: 2 %
Plasma Cell 1 %
Blasts: 0 %
Eosinophils: 1 %

Markedly Hypocellular
Iron stain: Markedly reduced
Myeloid: Normal Morphology seen
Megakaryocytes: Not seen

What is the diagnosis: 
Aplastic Anemia: 
Aplastic anemia is typically a disease of a young. 

How severe is the aplastic anemia.
Severe: ANC 200-500, Platelet < 20000, Absoulte reticulocyte count < 40,000. 
Very severe: ANC < 200

With a Hypocellular Bone Marrow, What is the DDx. 

Congential Disorders  Acquired Disorders
  • Often present with abrupt onset of low blood counts in a healthy individual
  • Seronegative hepatitis or medical drug use often precede this 
Fanconi Anemia
  • DNA repair defect 
  • Can present as a marrow failure in a normal-appearing adults 
 Chemical Drugs No use of chemical drugs, but need to ask about NSAIDS
Dyskeratosis Congenita  
  • Can present as a marrow failure in a normal-appearing adults 
 Cytotoxic Drugs or Radiation No such use of cytotoxic drugs or radiation 
Shwachman-Diamond Syndrome
  Viral / other Infections
  • HIV
  • EBV (IM)
  • Seronegative Hepatitis
  • Miliary TB  
  • HIV is negative
  • Hepatitis in the previous 1-2 months is seen in 5 % of such case series 
  • Rarely follows Infectious Mononucleosis 
  • Tests for EBV or seronegative Hepatitis should be done
Amegakaryocytic thrombocytopenia
  • Typically presents early in the age 
  • Acquired form may present later
  • Typically, present with only thrombocytopenia 
 Immune Disorders
  • SLE
  • Eiosinophilic Fascitis 
  • GVHD 
  •  None were present in this patient 
Reticular Dysgenesis
  •  Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. 
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558504/
Idiopathic Causes (Thymoma, Pregnancy, Anorexia Nervosa)
  •  Needs to be assessed for Thymoma 
  Other Acquired Causes:
  • PNH
  • Hypoplastic MDS
  • Large Granular Lympocytic Lymphoma
  • PNH in younger individual may later develop frank aplastic anemia years later. Similraly, patient with aplastic anemia upfront may develop hemolytic anemia years later. So, either of the presentation can occur. Hence, PNH is still a possibility. 
  •  Hypoplastic MDS is favored by morphologically abnormalities. This is especially in Megakaryocytes, and Myeloid precursor cells, and cytogentic testings. 
  • No Lymphoma were seen 

Next step: 
  • Diepoxybutaine or Mitomycin C induced chromosomal breakdown test in peripheral blood to test for Fanconi Anemia. Very short telomere telomerase is often seen. 
  • Chromosome studies of BM cells are often reveling in MDS 
  • Flow cytometry offers a sensitive diagnostic tests for PNH 
  • Serological Studies for EBV, and HIV should be done if not done
  • Review the concern for Miliary TB 
What determines the prognosis

Cell counts

Absoulte retic count > 25K/uL, and Lymphocytes >1K/uL confers better prognosis in the era of effective immunosupressive therapies 

  • Pancytopenia Harrison's Textbook of Internal Medicine 

MDS (Myelodysplastic Syndrome): 

TYPE (Table 2 of WHO Classification) - IPSS Score - IPSS Risk Group - Performance Status 
Asymptomatic / Symptomatic - Immuziation status 
  • Anemia:
  • Thrombocytopenia:
  • Neutropenia with recurrent Infection:
MDS Classification

MDS Prognosis

Immunization Status:
The 2008 revision of the WHO classification of myeloid neoplasms and acute leukemia Blood 2009
IPSS MDS Up-To-Date    (IPSS Calculator: Up-To-Date)
IPSS-R MDS Up-To-Date (IPSS R Calculator Up-To-Date)
Eastern Cooperative Oncology Group (ECOG, Zubrod, WHO) performance scale Up-To-Date 
Karnofsky performance status scale Up-to-Date
Overview of the treatment of myelodysplastic syndromes Up-To-Date
MDS references
Myelodysplastic syndromes Lancet 2014

How I treat patients with myelodysplastic syndromes Blood 2009
How we treat lower-risk myelodysplastic syndromes. Blood 2013
How we treat higher-risk myelodysplastic syndromes Blood 2014