White Cell Disorders

Myeloid cells:

• Granulocytes (neutrophils, eosinophils, basophils)

  • Neutrophils maturation in BM: 7-10 days, circulates in blood: 1 day, duration in tissue: 2-3 days

• Monocytes

• Macrophages

  • Gaucher’s Disease: 

    • Autosomal recessive lysosomal storage disorder

    • Caused by a deficiency of the enzyme glucocerebrosidase (GBA gene)

    • Cells accumulate in the liver, spleen, and bone marrow

    • Classic “crumpled tissue paper” appearance (Buzz word)

• Dendritic cells

• Mast cells

Lymphocytes:

• B cells

• T cells

• NK cells

Leukocytosis

• Mechanism:

  • Demargination (acute)- Changes in production or release from storage (long term)

• Causes:

  • Infection

  • Stress

  • Drug induced (steroids, beta agonists, lithium)

  • Chronic inflammation

  • Post-splenectomy

  • Non-hematologic malignancy

  • Marrow stimulation

  • Primary hematologic disease

    • CML (BCR/ABL)

    • Hereditary neutrophilia

    • Down’s syndrome

    • Leukocyte adhesion deficiency

      • Defective integrin receptor (LAD1)

      • Loss of expression of LFA1, Mac-1, gp150;95

      • Inability to ingest and kill microbes opsonized by C3bi

      • Elevated WBC, recurrent infections (cutaneous abscesses), delayed umbilical cord separation

      • Treated with HSCT

        
        

Neutropenia

Mechanism:

• Defect in WBC production, increased margination, peripheral destruction

• Drug induced agranulocytosis:

  • Methimazole, Propothiouricil, Cephalosporins, Penicillins, Sulfa drugs, Chloramphenicol, Carbamazapine, Valproic Acid

  • Significant morbidity and mortality

  • Remove offending agent

Causes:

• Benign neutropenia (Duffy null associated neutropenia):

  • Constitutional neutropenia

  • Usually a story of non-white individual with mildly decreased WBC without any problematic symptoms

• Severe congenital neutropenia (SCN):

  • Severe infections, survival improved with GCSF

  • High incidence of AML

  • ELANE mutation

  • Kostmann’s Syndrome:

    • Autosomal recessive

    • HAX1 mutation→ disrupts mitochondrial function→ defective neutrophil differentiation

• Cyclic neutropenia:

  • Usually benign, “cyclic” every 15-35 days

    • Myelocyte arrest on BMBx

  • May require GSCF in certain circumstances

  • Mutation in ELA2 

  • Not associated with AML

• Autoimmune Neutropenia:

  • Primary (more common in children)

    • Moderate to severe neutropenia, caused by anti neutrophil antibodies

    • Spontaneous remission over 2 years: 95%

    • Treated with ppx abx, GCSF with severe/recurrent infection

  • Secondary (more common in adults)

    • Large granular lymphocytic leukemia (LGL)

      • Treated with MTX

    • Autoimmune diseases

      • Neutropenia can be a marker of disease activity

      • Felty Syndrome:

        • Rheumatoid arthritis, neutropenia, splenomegaly

        • Treated with steroids, IVIG

• Chediak-Higashi Syndrome:

  • Autosomal recessive

  • Lysosomal trafficking regulator protein 

  • Increased bacterial infections, albinism and neuropathy

  • Blood smear: giant cytoplasmic granules in the leukocytes and platelets

  • Consider HSCT

• Chronic granulomatous disease:

  • Defects in NADPH oxidase → Cells are unable to produce reactive oxygen compounds

  • Prone to develop infections with catalase producing bacteria

    • Staphylococcus aureus, Serratia, E. Coli, Klebsiella, Nocardia, Burkholderia cepacia, Aspergillus

  • Diagnosis: Nitroblue tetrazolium or dihydrorhodamine 123 (DHR)

  • Treatment: Lifelong antifungal and antibacterial prophylaxis with or without immunomodulatory (interferon gamma) therapy

Hemophagocytic Lymphohistiocytosis (HLH)

• Life threatening syndrome characterized by excessive immune activation and hyperinflammation

  • Primary:

    • More common in children, rare in adults

  • Secondary:

    • Due to infection (frequently EBV), malignancy, autoimmune disease

    • Macrophage activation syndrome (MAS) is a subtype of secondary HLH, triggered by rheumatic or autoimmune diseases.

  • Diagnostic criteria:

    • Fever 

    • Splenomegaly 

    • Bicytopenia 

    • Hypertriglyceridemia or hypofibrinogenemia

    • Hemophagocytosis 

    • Ferritin >500

    • Low/absent NK cell activity 

    • Soluble CD25 elevation

  • Treatment:

    • HLH-94 protocol: Etoposide + Dexamethasone (taper)

    • Treat underlying cause