Chapter 13.1--Disorders of White blood cells--leukopenia

Question 1

Myeloid tissues

Answer 1

bone marrow and cells derived from it (red cells, platelets, granulocytes, monocytes)

Question 2

Lymphoid tissues

Answer 2

thymus, lymph nodes, spleen

Question 3

Not possible to draw neat lines bw diseases of myeloid vs. lymphoid tissues. Examples?

Answer 3

• bone marrow has few lymphocytes but is the source of all lymphoid progenitors and home of long lived plasma cells and memory lymphocytes
• neoplastic disorders of myeloid origebutirs cells (myeloid leukemias) originate in the bone marrow but secondarily involve spleen and lymphoid to lesser degree

Question 4

Blood cell progenitors first appear when?

Answer 4

• third week of embryonic development in yolk sac
• cells from yolk sac are source of tissue macrophages like microglial cells in the brain and Kupffer cells
• but contribution from yolk sac is only TRANSIENT; definitive hematopoietic stem cells arise several weeks later in the mesoderm of intraembryonic aorta/gonal/mesonephros region

Question 5

3rd month of embryogenesis

Answer 5

• HSCs migrate to the liver which becomes the chief site of blood cell formation until shortly before birth
• HSCs also take up residence in fetal placenta–HSCs harvested at birth from umbilical cord used for HSC transplant

Question 6

4th month of development

Answer 6

• HSCs migrate to bone marrow
• by birth marrow throughout skeleton is hematopoetically active and hepatic hematopoiesis decreases, persisting only in widely scattered foci that become inactive soon after birth

Question 7

Before vs. after puberty–hematopoesis

Answer 7

• until puberty active marrow found throughout skeleton but after puberty it becomes restricted to axial skeleton
• in normal adults only half of marrow space is hematopoetically active

Question 8

The formed elements of blood–red cells, granulocytes, monocytes, platelets, and lymphocytes have a common origin from

Answer 8

-HSCs, pluripotent cells that sit at apex of a hierarchy of bone marrow progenitors

Question 9

HSCs ultimately differentiate into what two group of cells

Answer 9

• HSCs give rise to early progenitor cells which have restricted differentiation to either myloid cells or lymphoid cells
• some cells are called colony forming units bc they produce colonies made of specific kinds of mature cells when grown in culture
• from progenitors–form precursors like myeloblasts, proerythroblasts and megakaryoblasts which are immediate progenitors of mature granulocytes, red cells and platelets

Question 10

Two essential properties that are required for the maintenance of hematopoeisis

Answer 10

-pluripotency and the capacity for self renewal!

Question 11

Pluripotency

Answer 11

• ability of a single HSC to generate all mature blood cells
• When an HSC divides, at least one daughter cell must self-renew to avoid stem cell depletion
• self-renewing divisions occur within a specialized marrow nice, in which stromal cells and secreted factors nurture and protect the HSCs

Question 12

stress conditions and HSCs

Answer 12

• HSCs are NOT sessile; in stress conditions like anemia or inflammmation, HScs are mobilized from bone marrow and appear in peripheral blood
• HSCs used in transplantation are now mainly collected from peripheral blood of donors treated with GCSF–one of the factors that can mobilize a fraction of marrow HSCs from their stem cell niches

Question 13

The marrow response to short-term physiologic needs is regulated by

Answer 13

• hematopoetic growth factors through effects on the committed progenitors
• since mature blood elements are terminally differentiated cells with finite lifespans, their numbers must be constantly replenished

Question 14

Multipotent progenitors

Answer 14

• more proliferative than HSCs but lesser capacity for self renewal
• Division of multipotent progenitors gives rise to at least one daughter cell that leaves the stem cell pool and begins to differentiate
• Once past this threshold, the newly committed cells lose capacity for self renewal and commence an inexorable journey down a road that leads to terminal differentiation and death but as these progenitors differentiate, they also begin to proliferate more rapidly in response to growth factors, expanding their numbers

Question 15

stem cell factor aka KIT ligand and FLT3-ligand act through?

Answer 15

-receptors that are expressed on very early committed progenitors

Question 16

erythropoetin, GM-CSF, G-CSF and thrombopoetin act through

Answer 16

-receptors that are only expressed committed progenitors with more restricted differentiation potentials

Question 17

What tunes the marrow output allowing numbers of formed blood elements (red cells, white cells and platelets) to be maintained within appropriate ranges?

Answer 17

-Feedback loops involving lineage-specific growth factors

Question 18

Many diseases do what to blood cells?

Answer 18

• alter the production of blood cells
• marrow is ultimate source of most cells of innate and adaptive immune system and responds to infectious or inflammatory challenges by increasing its output of granulocytes under direction of specific growth factors and cytokines
• In contrast, many other disorders are associated with defects in hematopoeisis that lead to deficiencies of one or more types of blood cells

Question 19

Diseases that interfere with production of blood cells by the marrow

Answer 19

• primary tumors of hematopoetic cells–most important

- also–genetic diseases, chronic inflammation

Question 20

Tumors of hematopoetic origin are often associated with mutations that

Answer 20

• block progenitor cell maturation or abrogate their growth factor dependence
• net effect is–unregulated clonal expansion of hematopoetic elements which replace normal marrow progenitors and spread to other hematopoeietic tissues
• sometimes these tumors originate from transformed HSC that retain ability to differentation into multiple lineages whereas other times origin is more differentiated progenitor that has acquired an abnormal capacity for self renewal

Question 21

Morphology of bone barrow–structure

Answer 21

• network of thin-walled sinusoids lined by single layer of endothelial cells with discontinuous BM and adventitial cells
• its interstitium has clusters of hematopoetic cells and fat cells
• differentiated blood cells enter circulation by transcellular migration through endothelial cells

Question 22

Morphology–Normal marrow orgnization

Answer 22

-megakaryocytes lie next to sinusoids and extend cytoplasmic processes that bud off into bloodstream to produce platelets while red cell precursors surround macrophages (nurse cells) that provide iron needed for synthesis of hemoglobin

Question 23

Leukoerythroblastosis

Answer 23

-the abnormal release of immature precursors into peripheral blood caused by processes that distort the marrow architecture like from deposits of metastatic cancer or granulomatous disorders

Question 24

What provides the best assessment of the morphology of hematopoetic cells?

Answer 24

• Marrow aspirate smears
• most mature marrow precursors can be identified based on their morphology alone; immature precursors (blast forms) of different types are morphologically similar and must be identified definitively using lineage-specific antibodies and histochemical markers
• Biopsy used to estimate marrow activity

Question 25

normal ratio of fat cells to hematopoetic elements is?

Answer 25

• 1:1
• in hypoplastic states (aplastic anemia), proportion of fat cells is increased; coversely, fat cells often disappear when marrow is involved by hematopoetic tumors and diseases characterized by compensatory hyperplasias (hemolytic anemias) and neoplastic proliferations like leukemias
• other disorders (metastatic cancers and granulomatous diseases) include local marrow fibrosis; such lesions are usually inaspirable and best seen in biopsies

Question 26

Disorders of white blood cells can be classifed into what two broad categories?

Answer 26

• proliferative disorders where there is an expansion of leukocytes and
• leukopenias–deficiency of leukocytes

Question 27

Reactive vs. neoplastic proliferations occur when?

Answer 27

• Reactive prolif–infections or inflammatory processes when leukocytes needed for host response
• Neoplastic prolif–less frequent but more important clinically

Question 28

Leukopenia

Answer 28

-usually results from reduced numbers of neutrophils (neutropenia, granulocytopenia)

Question 29

Lymphopenia

Answer 29

• less common than leukopenia
• seen in congenital immunodeficiency states and most commonly seen in advanced HIV infection following therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition and certain acute viral infections–>lymphopenia occurs from lymphocyte redistribution rather than a decrease in number of lymphocytes in body!!

Question 30

Acute viral infections and lymphopenia

Answer 30

• Acute viral infections induce production of type I IFN which activate T lymphocytes and change the expression of surface proteins that regulate T cell migration
• this results in sequestration of activated T cells in lymph nodes and increased adherence to endothelial cells both of which contribute to lymphopenia

Question 31

Granulocytopenia

Answer 31

-more common than lymphopenia and often associated with diminished granulocyte function

Question 32

Neutropenia

Answer 32

-reduction in the number of neutrophils in blood

Question 33

Agranulocytosis

Answer 33

-clinically significant reduction in neutrophils–makes individuals susceptible to bacterial and fungal infections

Question 34

Pathogenesis of neutropenia–neutropenia can be caused by?

Answer 34

• 1) inadequate or ineffective granulopoeisis OR

- 2) increased destruction or sequestration of neutrophils in the periphery

Question 35

Inadequate or ineffective granulopoesis is seen when?

Answer 35

• Suppression of hematopoetic stem cell
• Suppression of committed granulocytic precursors
• Diseases associated with ineffective hematopoesis
• Rare congenital conditions

Question 36

Inadequate or ineffective granulopoesis–Suppression of hematopoetic stem cells:

Answer 36

-aplastic anemia and infiltrative marrow disorders (tumors, granulomatous disease); here granulocytopenia is accompanied by anemia and thrombocytopenia

Question 37

Inadequate or ineffective granulopoesis–Suppression of committed granulocytic precursors:

Answer 37

by exposure to certain drugs

Question 38

Inadequate or ineffective granulopoesis–Diseases associated with ineffective hematopoesis

Answer 38

-megaloblastic anemias and myelodysplastic syndromes in which defective precursors die in the marrow

Question 39

Inadequate or ineffective granulopoesis–rare congenital conditions

Answer 39

-like Kostmann syndrome where inherited defects in specific genes impair granulocytic differentiation

Question 40

Accelerated destruction or sequestration of neutrophils occurs with

Answer 40

• Immunologically mediated injury to neutrophils–idiopathic or assciated with immuno disorder (SLE) or drug exposure
• Splenomegaly–enlarged spleen leads to sequestration of neutrohils with anemia and thrombocytopenia
• increased peripheral utilization–bacterial, fungal, ricketsial infxns

Question 41

Most common cause of agranulocytosis is

Answer 41

• Drug toxicity–certain drugs like alkylating agents and antimetabolites used in cancer tx produce agranulocytosis in a predictable, dose related fashion
• since sunch drugs cause a generalized suppression of hematopoesis, production of red cells and platelets is also affected

Question 42

implicated drugs that can cause agranulocytosis

Answer 42

-aminopyrine, chloramphenicol, sulfonamies, chlorpromazine, thiouracil and phenylbutazone

Question 43

Neutropenia induced by chlorpromazine and related phenothiazines results from

Answer 43

-a toxic effect on granuocytic precursors in the bone marrow

Question 44

Neutropenia (agranulocytosis) induced by administration of other drugs like sulfonamides stems from

Answer 44

-antibody mediated destruction of mature neutrophils through mechanisms similar to those involved in drug-induced immunohemolytic anemias

Question 45

acquired idiopathic neutropenia

Answer 45

• autoantibodies directed against neutrophil specific Ags detected in some
• severe neutropenia can also occur in association with monoclonal proliferations of large granular lymphocytes (LGL leukemia); mechanism of this neutropenia not clear; suppression of granulocytic progenitors by products of neoplastic cell (usually CD8+ T cell) is most likely

Question 46

Morphology–excessive destruction of neutrophils in periphery

Answer 46

• marrow is usually hypercellular due to compensatory increase in granulocytic precursors
• hypercellularity also seen with neutropenias caused by ineffective granulopoesis as occurs in megaloblastic anemias and myelodysplastic syndromes
• Agranulocytosis caused by agents that suppress or destroy granulocytic precursors is associated with marrow hypercellularity

Question 47

Common consquence of agranulocytosis and its morphology

Answer 47

• Infections
• Ulcerating necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or elsewhere in the oral cavity (agranulocytic angina) are characterisitic
• typically deep, undermined and covered by gray to green-black necrotic membranes from which numerous bacteria or fungi can be isolated
• less frequently ulcerative lesions occur in skin, vagina, anus, or GI tract
• severe life threatening bacterial or fungal infections may occur in lungs, urinary tract, and kidneys

Question 48

The neutropenic patient is at particularly high risk for deep fungal infections caused by

Answer 48

• Candida and Aspergillus
• sites of infection show massive growth of organisms with little leukocytic response; in most dramatic instances, bacteria grow in colonies (botryomycosis) resembling those seen on agar plates

Question 49

Clinical features of neutropenia

Answer 49

• S/S are related to infection and include malaise, chills, and fever often followed by marked weakness and fatigability
• With agranulocytosis, infections are often overwhelming and may cause death within hours or days

Question 50

Serious infections are most likely when neutrophil count falls below what value? Treatment?

Answer 50

• 500 per mm^3
• Infections are often fulminant so broad spectrum antibiotics must be given expeditiously whenever signs or symptoms appear
• sometimes, like after myelosuppressive chemotherapy, neutropenia is treated with G-CSF, a growth factor that stimulates production of granulocytes from marrow precursors