Clinical Aspects of Hematopoiesis

Robert Wise, M.D.

I. Overview of Hematopoietic Cell Growth and Differentiation

•
Pluripotential stem cells

•
Progenitor cells committed to specific cell lineages

•
Precursor cells recognizable in the bone marrow

Circulating RBCs, WBCs, platelets

II. The Important Hematopoietic Factors and Their Biologic Functions

A. General

Several growth factors act cooperatively at each of the different stages of hematopoietic cell
development. Some growth factors (eg, stem cell factor (SCF) and IL-3), tend to act at
earlier stages and on multiple cell lineages; others, like erythropoietin and thrombopoietin,
act on later, more differentiated progenitor and precursor cells that are committed a single
lineage.

B. Specific factors and their loci of action

Table 1. Major Hematopoietic Growth Factors

Factor Early/Late* Major Target Cells*

Stem cell factor Primarily very early Early stem and progenitor cells
Interleukin-3 Primarily early Progenitor cells of multiple lineages (RBCs,
WBCs, platelets)
GM-CSF Early and late Progenitor cells of multiple lineages
(granulocytes, monocytes, RBCs)
Interleukin-6 Early and late B-lymphocytes, hematopoietic cells of
multiple lineages
G-CSF Primarily late Neutrophil progenitor and precursor cells
G-CSF Primarily late Neutrophil progenitor and precursor cells
 M-CSF Primarily late Monocyte-macrophage progenitor and precursor
cells
Erythropoietin Late Erythroid progenitor and precursor cells
Thrombopoietin Late Platelet (megakaryocyte) progenitor and precursor
cells

* These are generalization since many of these factors act at different phases of hematopoiesis
and on multiple cell lineages.

III. Diseases of Hematopoietic Stem Cells and Progenitor Cells

A. Common Features:

Involvement of multiple cell lines (RBCs, neutrophils, platelets, sometimes lymphocytes)

Associations/transformations among the several diseases

Possible termination in myelodysplasia or acute myelogenous leukemia

Potential cure by allogeneic bone marrow transplantation

B. Diseases:

Aplastic anemia

Acquired pure red cell aplasia (only erythroid line involved)

Paroxysmal nocturnal hemoglobinuria

Myeloproliferative disorders: polycythemia vera, CML, essential thrombocythemia,

agnogenic myeloid metaplasia with myelofibrosis

Myelodysplastic ("preleukemic") syndromes

Acute myelogenous leukemia (AML) in its several forms

IV. Bone marrow transplantation (BMT):

A. Allogeneic BMT: replace abnormal marrow, stem cells (defective, as in aplastic

anemia, or malignant, as in AML) with normal stem cells from a histocompatible
donor. Also permits high dose therapy (which might otherwise be lethal) of the
malignant disease before the marrow is transplanted.
 B. Autologous BMT: permits use of very high doses of chemotherapy, often with
total body irradiation, in treatment of malignant diseases, with reinfusion of the
patient's own marrow stem cells to prevent aplastic anemia from ensuing. The
marrow cells are harvested and cryopreserved before the high dose therapy is
given, usually when the patient is in clinical remission. Stem cells from the
peripheral blood instead of marrow cells are being used with increasing frequency.
Problem: reinfusion of residual malignant cells in the marrow infusate could re-
seed the malignant process in the patient; various "purging" techniques using
antibodies or cytotoxic drugs are used to try to eliminate residual malignant cells,
but their value is not fully proven.

V. Clinical uses of hematopoietic growth factors (a field of rapid, ongoing clinical

experimentation)

A. Erythropoietin - effective in anemia due to renal failure, chronic disease, malignancy,

chemotherapy.

B. G-CSF, GM-CSF

1. Hasten WBC recovering after chemotherapy

2. Hasten WBC regeneration after BMT

3. Increase harvest of stem/progenitor cells in peripheral blood for use of instead of

marrow in BMT

4. Increase WBC and combat infections in various congenital and acquired causes
of neutropenia, including aplastic anemia, myelodysplasia, drug-induced
agranulocytosis.

5. Used in attempts to treat disorders of stem cell differentiation, eg,

myelodysplasia.

C. IL-3, usually in combination with another growth factor such as C- or GM-CSF. Not
in wide clinical use. Has been tried in several of the situations outlined for G-, GM-
CSF, hoping for multi-lineage (WBC, RBC, and platelet) response. Only partly
successful to date.
D. IL-6, IL-11. In trials to determine whether they will hasten platelet recovery after
chemotherapy, BMT.

E. Thrombopoietin. Recently identified. Good prospects of increasing platelet

regeneration, perhaps if combined with IL-3, -6, or -11.

APLASTIC ANEMIA
Etiology: Idiopathic

Drug-induced (chloramphenicol, benzene, etc)

Radiation-induced

Vital (hepatitis, EBV)

Pathogenesis: Autoimmune attack on hematopoietic stem cells

Treatment: Transfusion, antibiotic support

Allogeneic marrow transplantation
Anti-thymocyte globulin, cyclosporine, combined therapy
Androgens of limited value
G-CSF to stimulate neutrophil response

Complications: Development of PNH defect, myelodysplasia, AML

PURE RED CELL APLASIA

Congenital (Blackfan-Diamond syndrome) vs. acquired

Association with thymoma (may respond to tumor excision), lymphoproliferative

disorders

Autoimmune pathogenesis in many cases: antibodies to early erythroid cells; response

to steroids, cyclophosphamide, cyclosporine

Vital etiology (parvovirus-19) in rare cases of chronic PRCA (may respond to (-

globulin)

Paroxysmal Nocturnal Hemoglobinuria

Defect in Pig-a gene (phosphatidyl inositol glycan-anchor, type A defect).

Lack of anchoring protein - decreased membrane proteins including delay accelerating factor
(DAF), causing increased sensitivity to 1ysis by complement.

Prototypic clinical manifestation consists of intravascular hemolysis (hemoglobinuria,

hemosiderinuria), especially at night. May lead to iron deficiency.

Frequently pancytopenia (Pig-a and DAF defect present in RBCs, neutrophils, platelets,
lymphocytes, endothelial cells).
Thrombotic complications

Renal abnormalities

Diagnosis: sugar water (sucrose hemolysis) test, acid hemolysis (Ham) test, tests for deficiency of
DAF and other anchored proteins

Associations: PNH defect may be seen in other disorders with damaged stem cells (aplastic
anemia, MPD, MDS, AML); PNH patients may develop AML

Myelodysplastic Syndrome

Defective differentiation of marrow cells (ineffective hematopoiesis)

Peripheral blood cytopenias with usually hypercellular bone marrow

"Dyspoietic" marrow cells, giving rise to "dysplastic" peripheral blood cells (ringed sideroblasts,
Pelger cells, etc.)

Often an "excess of blasts" in marrow, peripheral blood

Chromosomal abnormalities, often involving chromosome 5 or 7

Clinical course: anemia, infection, bleeding, transformation to AML

Treatment: EPO for anemia, G-CSF for neutropenia. Allogeneic bone marrow transplantation
may be curative

Acute Myelogenous Leukemia: Update

Acute promyelocytic leukemia: All-trans retinoic acid leads to improved survival, causes
promyelocytes to differentiate into mature neutrophils

Adult AML: Consolidation therapy with high dose cytosine arabinoside, after remission induction,
improves survival

MPD vs. MDS vs. AML

Myeloproliferative disorder: excessive proliferation of marrow cells with differentiation to mature

cells virtually normal (increased peripheral blood counts)

Myelodysplastic syndrome: defective differentiation of marrow cells (hypercellular marrow with

decreased peripheral blood counts; marrow and peripheral blood cells may appear dysmorphic)

Acute myelogenous leukemia: differentiation blocked at or near the level of the myeloblast
(marrow filled with blasts, with few normal precursor cells; normal peripheral blood cells
decreased with variable numbers of blasts)

Bone Marrow Transplantation (BMT)

I. Allogeneic: replace abnormal stem cells by normal stem cells from histocompatible marrow
donor. Also permits high dose chemotherapy, XRT before marrow is transplanted.

Aplastic anemia

Acute leukemia and other marrow malignancies (e.g., multiple myeloma)

II. Autologous: Permits high dose chemotherapy, XRT, before patient's own cryopreserved
marrow cells are reinfused.

Acute leukemia, other malignancies that are in remission or do not involve the marrow

III. Trend toward use of peripheral blood rather than BM stem cells

References

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