WBC Disorders

Bone Marrow

red marrow→myeloid tissue

primary site of residence for stem cells

hematopoietic stem cells (HSCs)
-progenitors of all blood cells
-regulated by cytokines+growth factors

mesenchymal stem cells
-maintain HSCs

differentiate into:
-osteoblasts
-adipocytes
-chondrocytes

Niches

microenvironments in marrow

stem cells stored+maintained+self renewal

provide coordinated signaling network
-differentiation
-growth
-maintenance of hematopoietic stem cells (HSCs)

Differentiation Process

pluripotent stem cell→multipotent stem cell→hematopoietic stem cells (HSCs)→committed progenitor cell→precursor cells

Colony-Stimulating Factors (CSFs)

glycoproteins

initiate cell maturation events

produced by:
-endothelial cells
-fibroblasts
-lymphocytes

Pluripotent Stem Cells

starting cell of differentiation

present by day 5 after fertilization

grow into:
-blood
-nerves
-heart
-bone
-etc.

Bone Marrow Pools

hematopoiesis pools:

stem cell pool
maintains pluripotent stem cells
maintains partially committed progenitor cells

bone marrow pool
maintains+stores proliferating+maturing cells
prepare cells for release into bloodstream

storage pools:

circulation pool

marginating storage pool
contains neutrophils on endothelium
moves to mucosa+tissues when needed

Myelopoiesis

development of granulocytes+monocytes from myeloid precursors→stored in bone marrow→released into bloodstream

myeloid precursors: common myeloid progenitors

Lymphopoiesis

development of lymphocytes from lymphocyte precursors→stored in bone marrow→mature in secondary lymphoid organs (spleen/lymph nodes/tonsils/peyer patches)

lymphocyte precursors: common lymphoid progenitors

WBC Bone Marrow Lineages

myeloid line

• monocytes

• macrophages

• neutrophils

• basophils

• eosinophils

• megakaryocytes (platelets)

• erythrocytes (RBCs)

lymphoid line

• t lymphocytes (t cells)

• b lymphocytes (b cells)

• NK cells

Thymus Gland

primary lymphoid organ

major role in t lymphocyte growth

development+maturation+exportation→different steps in thymus

develops adaptive immunity

“education center” for T cells

Spleen

secondary lymphoid organ

contains

• macrophages

• t lymphocytes

• b lymphocytes

• phagocytes

function

• filters blood-borne antigens

• phagocytes→cleans blood

• starts bacteria immune response

• destroys old RBCs

• produces antibodies

• separates+obtains formed blood products

Splenectomy+Secondary Effects

spleen not necessary for circulatory system→removal of spleen

secondary effects

• leukocytosis→over production risk of leukocyte stem cells in bone marrow

• decreased iron in bloodstream

• decreased bacteria immune response→increased infxn risk

• thrombocytosis

• thrombosis

Lymph Nodes

secondary lymphoid organ

contains

• b lymphocytes

• t lymphocytes

• macrophages

function

• primary site for 1st encounter between antigens and lymphocytes

• filters debris

• removes foreign substances

• removes microorganisms

Tonsils

contains

• lymphocytes

• monocytes

function

• 1st line of defense

• pathogens
  -inhaled
  -ingested

Peyer Patches

location:

• distal jejunum→mucous membrane

• small intestine→ileum

contains

• macrophages

• b lymphocytes

• t lymphocytes

function: immune response of GI tract

Cell Lifespans

mature RBCs→120 days

mature WBCs→2-3 days

platelets→8-12 days

CBC+Diff Readings

WBC→4k-10k

specific WBCs→CBC+diff

pluripotent stem cells→WBCs

• neutrophils (immature WBCs→±bands/segs)

• lymphocytes

• monocytes

• eosinophils

• basophils

acronym→NL-MEB

Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils

Absolute Neutrophil Count (ANC)

measure of neutrophils in entire bloodstream

WBCs x % of neutrophils+bands=ANC
(10,000 × 0.50=5,000 ANC)

under 1,000→bad→immunocompromised risk

Leukocyte Classification

structure

granulocytes

• neutrophils

• basophils

• eosinophils

round cells
multiple lobed nucleus+granules in cytoplasm

agranulocytes

• monocytes

• lymphocytes

function

phagocytes→WBCs engulf+digest other cells

• neutrophils

• basophils

• eosinophils

• monocytes

immunocytes→WBC recognize/destroy antigens

• lymphocytes

Granules+Granulocytes

granules:
enzymes+biochemical mediators
pathogen invasion→cells accumulate→attack+digest pathogens

granulocytes (neutrophils):
found in large #s in bone marrow
50%→circulation
50%→marginating pool in capillary wall

Polymorphonuclear Neutrophils/Neutrophils (PMN)

57-67% of WBC

highly mobile

first to appear

maintain normal host defenses against bx

2 wk development→circulate x hours
lifespan→1-2 days

chief phagocytes of early inflammation

• stimulated to move into tissues by microbes/endotoxins

• enzymes
  -maintain normal host defenses
  -mediate inflammation

• release neutrophil extracellular traps (NETs)
  -DNA deposits
  -attach to pathogens→control pathogen proliferation

• lysis of dead neutrophils→digestive enzymes→dissolve cellular debris→prepare site for healing

Eosinophils+Granules

1-4% of WBC

similar fxn to Polymorphonuclear Neutrophils (PMN)

accumulate at site 2-3 hrs after neutrophils

process antigens→release leukotrienes/prostaglandins/other cytokines/etc.

seen in
-allergic rxn
-parasite rxn
-chronic rxn

granules:
toxic chemicals
destroy parasites+viruses
contain enzymes→control inflammatory process

Basophils

0.01-0.3% of WBCs

phagocytic
mostly in IgE-mediated responses

involved in
allergic+stress responses
ectoparasites

release
heparin
histamine
cytokins

Mast Cells

0.01-0.3% of WBCs

highly similar to basophils
-come from different precursors

reside in vascular connective tissues
-GI tract
-respiratory tract

affect many cells involved in inflammation+healing
-endothelial cells circulating platelets/nerves
-contribute to increased permeability of blood vessels

Monocytes

3-8% of WBCs

monocytes

• in circulation

• macrophages in tissues

macrophages

• in tissues

histiocytes

• connective tissue

microglial cells

• in CNS

kupffer cells

• liver

• alveolar macrophages in lungs

lifespan

• circulation→1-3 days

• months-years in tissues

phagocytes

• engulf larger+more foreign material than neutrophils

• engulf non-digestable material→cause granulomatous inflammation

• activate lymphocytes

• present antigens to T cells in immune response

Lymphocytes

25-33% of WBCs

b cell

• humoral-mediated immunity (antibody mediated immunity)

• mediate recognizing of antigens

• maturation→plasma cells→produce antibodies to attack antigens

• origin→bone marrow

t cell

• cell-mediated immunity

• monocytes present antigen to it

• produce cytokines→activate macrophages

• chronic inflammation

• migration between
  -blood
  -lymph nodes
  -spleen

• stored for hours/years

• immune-mediated inflammation
  -infectious agents
  -cell injury
  -death

-Cytosis

increase

ex: leukocytosis→increase of WBCs

-Penia

decrease

ex: leukopenia→decrease of WBC production

Bandemia

infection→presence of slightly immature WBCs (bands) in circulation

“shift to left”/“left shift”

Blasts

presence of very immature+abnormal WBCs in circulation

E: leukemic states

Leukocytosis

PP: leukocyte count greater than 10,000

E:
normal
infection
strenuous exercise
emotional changes
temperature
anesthesia
surgery
pregnancy
mxs
hormones
toxins

pathologic
malignancy
lymphoma
leukemia

Leukopenia

PP: leukocyte greater less than 4,000
abnormal

E: radiation
anaphylactic shock
autoimmune dx
immune deficiency
chemotherapy

Neutrophilia

PP: WBC count greater than 7,500

E: infection
inflammation
exercise
trauma
MI
corticosteroids

Neutropenia

PP: absolute neutrophil count (ANC) under 1,500 cells/µl

E: defective production
leukemia
hypoplasia
vitamin B12 deficiency
anorexia
cytotoxins

Agranulocytosis

PP: absolute neutrophil count (ANC) under 200 cells/µl
a type of granulocytopenia
only affects neutrophils

E: defective production
leukemia
hypoplasia
aplastic anemia
cytotoxins

Plasma Cells

fully differentiated WBCs from B lymphocytes

pathogens stick to b cell/t cell receptors (antigenic stimulation)→secrete immunoglobulin antibodies
-bx
-fungi
-viruses
-toxins
-chemicals
-mxs

locations

• bone marrow

• spleen

• lymph nodes

do not use DXs

• CBC

• peripheral blood

lifespan→2-3 days

Neutropenia

PP: abnormally low neutrophil count
mild→1,000-1,5000
moderate→500-1,000
severe→under 500
agranulocytosis→under 200-absent

E:
acquired

• bone marrow suppressing mxs

• infection

• neoplastic cells in bone marrow

• felty syndrome

inherited

• inherited cyclic neutropenia

• kostmann syndrome

P: depends on severity

increased risk
-bx infxn
-respiratory protozoa infxn
-skin protozoa infxn
-mouth protozoa infxn
-vagina protozoa infxn
-GI tract protozoa infxn

prolonged/severe→fatal

Leukemia (General)

one WBC type suppresses the rest
-lymphoid
-myeloid

differentiated by predominant cells found in bone marrow
-cells replace bone marrow with immature neoplastic cells (blasts)
-disseminated neoplasm from the onset

infiltration→enlarged organs→cancer cells crowd out/suppress normal cell proliferation
-liver
-spleen
-lymph nodes

types

• acute/chronic

• lymphocytic/myelogenous (myelocytic)

Acute Myeloid Leukemia (AML)

PP: gene mutation→precursor cells can’t differentiate→uncontrolled division of immature WBCs (blast cells)→build up in blood→decreased development of WBCs+RBCs+platelets→leukopenia+anemia+thrombocytopenia

RF: old
radiation

E: translocation→disrupts retinoic acid receptor gene→disrupted cell production
-15+17
myelodysplastic syndrome
down syndrome (trisomy 21 mutation)

CM:
anemia→fatigue
thrombocytopenia→easier bleeding
leukopenia→increased infxns
pain+tenderness in bones
swollen gums

DX:
peripheral blood smear→myeloblasts
bone marrow biopsy→increased blast cells
stained smear→large cells+aurer rods (AML→Adults Mostly/Mega Leukemia)
immunophenotyping

TX: chemotherapy
biological tx
stem cell transplant
bone marrow transplant
acute promyelocytic→all-trans retinoic acid (ATRA)

Acute Lymphocytic Leukemia (ALL)

PP: gene mutation→precursor cells can’t differentiate→uncontrolled division of immature WBCs (blast cells)→build up in blood→decreased development of WBCs+RBCs+platelets→leukopenia+anemia+thrombocytopenia

RF: children
radiation
alkylating chemotherapy

E: mutated precursor t/b cells
affect blood cell development regulation genes
gene translocation→abnormal proteins
-12+21
-9+22 (philadelphia chromosome)
down syndrome (trisomy 21 mutation)

CM:
anemia→fatigue
thrombocytopenia→easier bleeding
leukopenia→increased infxns
pain+tenderness in bones
hepatosplenomegaly abdominal fullness
lymphadenopathy→lymph node pain
thymus enlargement→mass/growth in mediastinum

DX:
peripheral smear→lymphoblasts
bone marrow biopsy→increased blast cells
stained smear→small cells (ALL→ A Little Leukemia)
immunophenotyping

TX: chemotherapy
biological tx
stem cell transplant
bone marrow transplant

Chronic Myelogenic Leukemia

PP: chromosomal translocation→partial maturation of granulocytes (neutro/baso/eosinophils)→excess cell multiplication→too many premature cells/blasts→crowd out other cells in bloodstream→cytopenia/anemia/thrombocytopenia

E: philadelphia chromosome translocation (9+22)

CM: hepatosplenomegaly→abdominal tenderness/pain
fatigue
easier bleeding
frequent infxn

DX:
blood smear
increased granulocytes
increased monocytes

confirmation→genetic testing

TX: tyrosine kinase inhibitors (effective)
chemotherapy
stem cell transplant
bone marrow transplant

P: chromosome 8 trisomy→acute leukemia/blast crisis

Chronic Lymphocytic Leukemia

PP: chromosomal mutations→partial maturation of lymphocytes (b cells)→cells don’t die→too many premature cells/blasts→crowd out other cells in bloodstream→cytopenia/anemia/thrombocytopenia/leukopenia

E: unknown

CM: lymphadenopathy→lymph node pain
fatigue
easier bleeding
frequent infxn

DX: blood smear→smudge cells

confirmation→genetic testing

TX: tyrosine kinase inhibitors (not effective)
chemotherapy
stem cell transplant
bone marrow transplant

P: lymphoma→richter transformation
autoimmune hemo=lytic anemia
hypogammaglobulinemia

Multiple Myeloma

PP: deletion/translocation/duplication in plasma cells→uncontrolled production of paraprotein-secreting plasma cells (m-protein)

pre b cell activation in another area→sends signals to plasma cells→response

E: chronic+abnormal response to unknown antigen stimulation

DX: fluorescence in-situ hybridization (FISH)
bence-jones proteins (50-80%)
IL-6 production
myeloma cells

TX: depends on severity

P: decreased humoral immune response

Monoclonal Gammopathy of Undetermined Significance (MGUS)

excess production of premalignant plasma cells

causes plasma cell cytogenic abnormalities

causes antigenic response

precursor to multiple myeloma

Splenomegaly Etiology

inflammation/infection

• viral
  -hepatitis
  -CMV
  -mono

• parasitic

• autoimmune
  -SLE
  -RA

congestive

• heart failure

• cirrhosis

• portal vein thrombosis

tumors+cysts

Duffy-Null Associated Neutrophil Count

PP: genetic variation→creates more neutrophils in tissues instead of blood circulation
completely normal+healthy

E: malaria-endemic areas
sub saharan africa
southwest asia

DX: simple serum test
CBC→anemia→can’t read WBCs in tissues