Cytopenias / BM Failure

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    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:
      • AnemiaFatigue, 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:
      • 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)

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