WBC Disorders Flashcards
General classes of WBC disorders
Leukopenias
Proliferative: 1) Reactive, 2) Neoplastic
Most common cause of leukopenia (which cell type is low)
Low WBCs is usually caused by neutropenia
Lymphopenia is less common
What are the common causes of lymphopenia?
Lymphopenia is commonly caused by HIV, glucocorticoid treatment, autoimmune disorders, malnutrition, certain acute viral infections.
Why do viral infections sometimes cause lymphopenia?
Viral infections cause release of interferon type I => lymphocyte redistribution and sequestration.
T-Lymphocytes become activated and their surface receptors change so that they stay in lymph nodes and adhere to endothelial cells.
Neutropenia => inc risk of what?
What are some of the assoc. signs?
Bacterial and fungal infections
Candida and Aspergillus fungus
Often see ulcerating and necrotizing lesions in the mouth, but can also be present on the skin, vagina, anus, and GI
Deep infections can occur in the lungs, GU, and kidneys
Can also see bacterial colonies growing as if on agar plates
What is pancytopenia?
decreased RBC’s, WBC’s and platelets
Morphology of the bone marrow for neutropenia
Hypercellular: in cases where granulocytes are destroyed in periphery, or with ineffective granulopoiesis (megaloblastic anemia, myelodysplastic syndromes)
Hypocellular: in cases that dec or destroy granulocyte precursors
Clinical features of neutropenia
malaise, fever, chills, fatigue, weakness
infections can cause death in hours to days
4 mechanisms causing leukocytosis
Increased production in marrow: infection/inflammation, Paraneoplastic, Myeloproliferative disorders
Increased release from marrow: endotoxemia, infection, hypoxia
Decreased leukocyte margination: exercise, catecholamines
Decreased extravasation: glucocorticoids
How does infection => increased leukocytes in the blood?
Acute infection causes release of mature granulocytes from the marrow from TNF and IL-1.
With time, TNF and IL-1 cause macrophages, bone marrow stromal cells, and T-cells to release growth factors that will increase production of leukocytes for a prolonged period
Sepsis or severe inflammatory disorders => what morphologic changes in neutrophils?
Toxic granules: coarse, dark cytoplasmic granules
Dohle Bodies: Sky-blue cytoplasmic “puddles” that are dilated endoplasmic reticulum
Type of leukocytosis commonly assoc with myeloproliferative disease
Basophilia
Type of leukocytosis commonly seen with allergic disorders like asthma, hay fever, parasitic infections, as well as drug reactions and some malignancies?
Eosiniphilia
When would you see monocytosis?
Chronic infections like TB, bacterial endocarditis, rickettsiosis, malaria, autoimmune disorders like SLE, and IBD like ulcerative colitis
When would you see Neutrophilia?
Acute bacterial infections (escpecially pyogenic), sterile inflammation caused by infarction or burns
When would you see lymphocytosis?
With monocytosis in chronic immune stimulation, viral infections, Berdetella pertussis
Name stages of Neutrophil progression/development
blast => promyelocytes => myolocytes => metamyelocytes => bands => segs
Reference ranges for WBC, Neutrophils, Lymphocytes
WBC: 5,000-10,000
Neutrophils: 1,500-6,500
Lymphocytes: 1,200-3,400
Normal Myeloid to Erythroid cell ratio in the marrow
2:1 to 5:1
More myelo/granulocytic cells than erythroid
Causes of neutropenia and also pancytopenia
Myelophthisis Anemia: infiltrative process of the marrow like cancer, infection, leukemic or lymphoma infiltrate
Aplastic Anemia: Precursor cells fail, hypocellular marrow
Large Granular Lymphocytic Leukemia: CD8+ T cell Leukemia, pancytopenia from marrow suppression by neoplastic cell products
Ineffective Production:
-Defective DNA => intramedullary death, marrow is hypercellular, hypersegmented neutrophils, macrocytes and other WBC/RBC abnormal morphology; caused by Vit B12 and folate deficiency and Myelodysplastic syndromes
Neutropenia due to accelerated removal/destruction
Immunological-mediated injury: SLE, reaction to drugs
Increased peripheral use: overwhelming bacterial, fungal, rickettsia infections
Splenic sequestration: 2ndary to enlarged spleen, Felty Syndrome= RA, splenomegaly
Drug-induced neutropenia
Most common cause of neutropenia
Cancer chemotherapy
Immunologic reactions to drugs like sulfonamides, thiouracil
Alcohol toxicity
Differential diagnosis of Pancytopenia
Myelophthisis anemias including Leukemia Aplastic anemia Myelodysplatic syndromes Megaloblastic anemias Autoimmune like SLE Splenic sequestration Chemotherapy Total body rediation
Other causes of Neutrophil Dysfunction
Diabetes, Malignancy, Dialysis, Sepsis Myelodysplatic syndromes Chronic granulomatous disease Leukocyte adhesion deficiencies MPO deficiency Chediak-Higashi syndrome
What does a ‘left shift’ suggest?
Suggests a bacterial infection
What is a leukemoid reaction?
Leukemia-like reaction where the granulocyte counts are above and beyond the normal upper limits. Usually caused by severe infection or tumors
What is a leukoerythroblastic reaction?
Left shift in the presence of nucleated RBC’s
Implies a bone marrow space-occupying lesion
What signaling molecule will cause an increase in Eosinophils?
IL-5
Types of eosinophilic pneumonias
Coccidioidomycosis
Loeffler’s pneumonia
Chronic eosinophilic pneumonias
What is classic sign of eosinophilia?
Charcot-leyden chrystals left behind and in macrophages
Relationship between Neutrophils and Monocytes in terms of infection
Neutrophils show up first, but subside with time as monocyte numbers rise unless it is a pyogenic infection.
Causes of monocytosis
Chronic infection: TB Bacterial endocarditis Rickettsiosis Malaria IBD: ulcerative cholitis Autoimmune: RA, SLE
Causes of reactive lymphocytosis
Bordetella pertussis (whooping cough) Chronic infection (TB) Viral infection
Common viral causes of lymphocytosis and differences between them
Infectious mononucleosis (IM) caused by EBV: likely diagnosis if >20%reactive lymphs
CMV: IM-like but w/o cervical lymph node involvement
Toxoplasmosis: IM-like
Viral hepatitis
What do reactive or atypical lymphs look like?
These are CD8+ lymphs
Larger cells with large and abnormally shaped nuclei
If seen, first think leukemia, but if large cytoplasm present then think virus caused
What to think when see nucleated RBC’s in the peripheral blood
Rapidly evolving anemia=> increased release of RBC’s from the marrow
Post splenectomy
Bone marrow replacement–think myelophthisic process (space-occupying lesion in the bone)
Categories of Neoplastic Proliferations of White cells
1) Lymphoid
2) Myeloid
3) Histiocytosis, Langerhans cell type
Risk factors for leukemia
Inherited: defects in DNA repair–Bloom Syndrome, Ataxia Telangiectasia, Fanconi Anemia; Down Syndrome; Neurofibromatosis type I
Viruses, Radiation and Chemicals, Chemotherapy, Smoking, Benzene
Categories of Leukemia
Can be acute or chronic
Can be lymphocytic or myelocytic
ALL, AML, CLL, CML
All acute cause death within months if not treated
Chronic cause death within years, CML=>death earlier than CLL
Leukemia vs lymphoma
Leukemia is a lymphocytic neoplasm in the marrow
Lymphoma is a lymphocytic neoplasm in the lymph nodes or other place outside the marrow
WHO classification of lymphoid malignancies
Precursor B and T cells (lymphoblasts): in marrow or thymus
Peripheral lymphoid malignancies: in lymph nodes, spleen, blood
Pathogenesis of ALL
Accumulation of mutations (fewer than with solid tumors)
T-cell: NOTCH-1 gain of function in 70% of cases
B-Cell: Transcription factor PAX5, loss of development factors E2A, EBF; t(12;21) ETV6: RUNX in early precursors
Chromosomes often abnormal in number
General epidemiology for ALL
Most common childhood malignancy
Generally
Epidemiology of Pre-T neoplasms
Lymphomas 50-70% of the time Adolescent males Mediastinal mass of Thymus Respiratory symptoms Rapidly progresses to leukemic phase Worse prognosis than pre-B type
If there are circulating blasts, think:
Acute form of leukemia
Lab findings for ALL
Anemia always present
Thrombocytopenia almost always present
Peripheral WBC count can be high, normal, or low
Circulating Blasts
Bone marrow: hypercellular, blasts>20% of nucleated cells
Significance of TdT, CD10/19/7/34, PAX 5
TdT indicates a precursor cell and therefore an acute disease CD10/19 are markers for B-Cells CD7 is a marker for T-cells CD34 on pre-T & B PAX 5 with pre-B
Histological presentation of ALL cells
Large, relatively uniform nuclei
Increased N:C ratio
Delicate chromatin
Vague nucleoli
Symptoms of all Acute Leukemias
Think cytopenias:
Anemia=> fatigue
Neutropenia=> infections, fever
Thrombocytopenia=> bleeding, ecchymoses, epistaxis, gum bleeding, intracerebral bleeding
Think Infiltrate packing: Bone pain and tenderness Generalized lymphadenopathy Hepatosplenomegaly Mediastinal mass CNS infiltrates=> meningeal spread=> headache, vomiting, nerve palsies (more common in ALL than AML)
Treatment of ALL
Chemotherapy and prophylactic CNS treatment
95% reach complete remission
75-85% are cured
ALL prognostic factors
Best: 2-10 y/o, lots of chromosomes 50-60 pre-B Low WBC counts t(12;21) trisomy of some chromosomes
Worst:
Common features of Myeloid neoplasms
Involve hematopoietic progenitor cells
Involve the bone marrow
May also involve the spleen, liver, lymph nodes
Categories of Myeloid Neoplasia?
AML
Myelodysplastic syndromes
Myeloproliferative diseases
Peak age for AML
Peak age is 60, but can happen at all ages
Incidence rises through life
Pathophysiology of AML
Mutation in transcription factors
Blasts accumulate in bone marrow because failure to mature
Causes anemia, neutropenia, thrombocytopenia
WHO Classification of AML
Genetic Aberrations:
11q23 (MLL gene) -poor
t(8;21)-good
Myelodysplasia-like:
aberrations: 5q-, 7q-, 20q- all poor prognosis
Therapy-related: very poor prognosis
post alkylating agents; radiation > 2years
Follows topoisomerase II inhibitors by 1-3 yrs
Auer Rods are a sign of:
AML?
They are seen in Myeloblasts
CD34 vs 64 in myeloid cells
CD34 expressed by immature myeloid cells
CD64 expressed by mature myeloid cells
