Cytopenias / BM Failure

Approach to Pancytopenia

• A - Aplasia
• I - Infiltration
  • Malignant
    • Primary - Malignancy
    • Secondary - Metastasis
  • Non-Malignant
    • TB
• D - Dysplastic
  • Primary - MDS
  • Secondary - Alcohol, HIV
• S - Substrate
  • B12, folate, low calorie intake
• S - Spleen

Aplastic Anemia

• Pathobiology:
  • Abnormal suppressor T-cell line that suppresses bone marrow.
  • Suppresses all 3 cell lines.
  • Treatments target suppressor T-cells
• Classification:
  • ANC (Absolute Neutrophil Count = [% of Neutrophils+ % Bands] * WBC)
    • Normal ANC 4000

  • Severity	ANC
    Very Severe	<200
    Severe	200-500 (Plts + Retics Low)
    Moderate	500-1000

• Causes:
  • Congenital
  • Must rule out secondary causes:
    • Infectious: HIV, Hepatitis ABC
    • Nutritional: Vitamin B12, Folate
    • Drugs: Chloramphenicol, Sulfa Drugs, Gold
    • Others: Toxins, Radiation Exposure
    • Congenital: 20% inherited, most common Fanconi (see below)
    • Idiopathic (Majority)
  • Fanconi Anemia:
    • Autosomal recessive (X-linked disorder) characterized by skin defects,  short stature, hypogonadism, microcephaly, urogenital abnormalities, and marrow suppression.
    • Many mutations/abnormalities in DNA... bone marrow failure.
    • Diagnosed by chromosomal breakpoint analysis (fragile DNA)
• Presentation:
  • Anemia: Fatigue, dyspnea, worsening angina
  • Thrombocytopenia: Bleeding, Bruising
  • Neutropenia: infection (sx rare)
• Diagnosis/Workup:
  • Suspect in pts with pancytopenia without a particular cause.
  • **Bone Marrow Biopsy** (essential)
    • Note: Cellularity = 100-Age  (i.e. 5yo has 95% cellularity)
    • Acellular with increased fat space.
  • **Bone Marrow Aspirate** (essential)
    • Lack of stem cells and immature cells.
  • Cytogenetics
    • Further define the disorder (chromosomal abnormalities: MDS)
  • Flow Cytometry (FLAER)
    • To exclude PNH (aplasia predates hemolysis)
• Treatment:
  • <40yo and healthy with HLA matched sibling
    • Allogenetic hematopoietic stem cell transplant (Definitive Treatment)
    • As get older, GVH disease risk increases (BM transplant less likely to work)
    • Still 5-10% risk of MDS or AML
  • If cannot transplant:
    • Cyclosporine + Antithymocyte Globulin (equine or rabbit, horse one works better)
      • Can result in long-term remission (50%), relapses occur during tapering of cyclosporin, may need chronic low-dose cyclosporine to maintain counts. 
  • Supportive Care:
    • Prophylactic abx, antivirals (herpes), antifungals
    • Need transfusions or RBC and platlets (<10,000 if not bleeding)
      • Must minimize alloimmunization by leukodepletion (at collection and leukoreduction filter) (also decreases tfsn-associated fever).
      • Give CMV negative products if CMV status unknown.
      • Irradiated blood products (T-cells in blood can cause GVH disease)
  • Annual screening for PNH clone is recommended.  (aplasia predates classic hemolytic presentation of PNH)
  • NOTE: Growth factor therapy are ineffective b/c don't have growth factor stem cells. 
• Source:
  • MKSAP Lecture Series (audio)

Paroxysmal Noctural Hemoglobinuria

• Acquired Stem Cell Disorder due to dysfunction of the GPI linker protein.
• Pathophysiology:
  • Mutations in PIG-A gene lead to reduction or absence of glycosylphosphatidylinositol (GPI) (erythrocyte anchoring protein).
    • Lose GPI linker, as well as GPI-linked proteins
    • Unable to anchor CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis)
      • Absense of them on RBC surface leads to sensitivity to complement --> complement mediated destruction.
  • Eventually PNH clone can infiltrate bone marrow.
• Characterized by triad:
  • 1. Chronic hemolytic anemia (acquired)
    • Iron deficiency (Urinary loss of Hb)
  • 2. Venous Thrombosis
    • unusual places: i.e. mesenteric and cerebral circulation.
    • Unclear why (unclear why, perhaps through GPI-linked urokinase receptor or platelet activation from ADP released from hemolyzed cells)
  • 3. Pancytopenia (predates hemolysis) 
    • GPI linker proteins on all cells
• Must exclude this in patients with marrow aplasia
• Diagnosis:
  • Flow cytometry: look for CD55, CD59 (absent due to absence of linker protein)
    • FLAER:
      • Fluorescent linkled GPI linked molecule
    • This typically detects a "PNH clone"
• Treatment
  • In absence of hemolysis, typically not treated.
  • Anticoagulation w/ warfarin:
    • Indications:
      • Active clot
      • if >50% are CD55 and CD59 negative, addition of warfarin markedly decreases thrombosis. (Prophylaxis)
      • (Source: MKSAP16, http://www.onlinecjc.ca/article/S082...10)00031-0/pdf)
  • Eculizumab
    • NEW! (2006-2014) RCT of eculizumab (humanized monoclonal ab against C5 terminal complement).
      • Decreased transfusion requirements, improved QOL, decrease thrombosis.
    • Higher risk of neisserial infection (MUST VACCINATE for meningococcus) due to complement inhibition.
    • If Severe! (refractory hemolysis, or bone marrow failure)
      • Treat similar to aplastic anemia (immunosuppressives or allogeneic BM transplant).
  • Corticosteroids:
    • Reduce complement activation, improves Hb.
  • Survival: 10-15y Median, often death from thrombosis

Pure Red Cell Aplasia

• Symptoms of anemia.
• Isolated normocytic anemia, only red cell lineage affected.
• Causes:
  • Primary (Idiopathic)
  • Secondary:
    • Infection:
      • Parvovirus B19 (rare, need concurrent hemolytic anemia, sickle cell,  b/c red cells last >120 days), HIV
    • Malignancy:
      • Thymomas
      • Lymphoproliferative Disorders (i.e. CLL)
      • Large Granular Lymphocytosis (Granular lymphocytes, ++cytoplasm, blueish granules on smear), often few of these cells, if overproduced => LGL
        • CD57 positive, and clonal if rearrangement studies, big spleen, rheumatoid condition (i.e. arthritis)
    • Collagen Vascular and Autoimmune Disease
    • Drugs (Phenytoin, Chloramphenicol)
    • Pregnancy
    • ABO incompatible transfusion
    • Previous EPO treatment (anti-EPO antibodies)
• Evaluation:
  • Virus testing (serologic, Parvovirus B19, HIV, Hepatitis)
  • Chest Xray for thymoma.
• Management:
  • Treat Cause (drugs, anti-infectives, chemotherapy, surgical resection to thymoma.)
  • Prednisone, Anti-Thymocyte Globulin, Cyclosporine
    • Can also use cyclophosphamide.
  • (Historically keep transfusing until patient passes away).
  • IVIG if Parvovirus B19 - but most often resolves by itself.
  • Many resolve without therapy
• REF: MKSAP audio

Neutropenia

• Infection risk increases greatly when absolute neutrophil count if ANC < 500, and greatest in ANC < 200.
• Causes:
  • Mild chronic congenital asymptomatic neutropenia (ANC 1000-1500) -> no risk of infection.
  • Severe Congenital Neutropenia (varied inheritance/pathogenesis).  Present early in life.
  • Acquired:
    • Drugs (MOST COMMON!, always ask old/new drugs)
      • Chemotherapy (Antimetabolites, alkylating therapies - often given GCSF)
      • Anticonvulsants: (Carbamazepine, Phenytoin)
      • Antibiotics (cefalosporins, septra)
      • Antiarrhythmics (Procainamide, Amiodarone)
      • Antiinflammatories (NSAIDs, Gold salts)
    • Vitamin Deficiencies: B12, Folic Acid
    • Autoimmune Disorders (SLE, often mild neutropenia)
    • Viral Syndromes (HIV, EBV, CMV, ricketsial infections, sepsis with S. pneumoniae, M. meningitidis)
    • Malignancies (I.e. LGL)
  • Cyclic neutropenia
    • Abnormality in gene for neutrophil elastase.
    • Fall in 21-day cycle (Collie dogs also have short-cycle neutropenias)
    • Dampening problem (i.e. such as drunk person walk.. overcompensate both ways)
  • Non-autoimmune Chronic Neutropenia
    • Dx of exclusion
• NOTE: "Felty Syndrome"
  • Rheumatoid Arthritis, Splenomegaly, Neutropenia
  • Easy to remember "Feel the spleen".
• Workup
  • If severe, new onset, excluded drugs
    • Bone Marrow Evaluation
    • Cytogenetic workup to ensure no myelodysplasia
• Treatments:
  • Often self-limited, stop drugs (may take some time to resolve), replace vitamins.
  • GCSF
    • Effective in increasing neutrophil counts, decreasing infectious risks, improve aphthous ulcers.
    • High risk for myelodysplasia, and AML.
    • Effective in nadirs of cyclic neutropenia.
• Ref: MKSAP audio

Thrombocytopenia

• Isolated thrombocytopenia is not due to bone marrow syndromes!
• Causes
  • Vitamin B12, Folate deficiencies (often causes pancytopenia)

PLATELETS --> See Platelet Disorders Section (Click here)