Page 1840 - Williams Hematology ( PDFDrive )

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CHAPTER 111 recovers by day 7. In most physiologic and pathologic states, the platelet
2
count is inversely related to plasma thrombopoietin levels. For example,
MEGAKARYOPOIESIS AND liver failure is associated with moderate thrombocytopenia as a result of
splenomegaly and thrombopoietin deficiency. Within the first week fol-
THROMBOPOIESIS lowing orthotopic liver transplantation, the platelet count rises substan-
tially, with kinetics matching those of thrombopoietin infusion. These
3,4
findings indicate expansion of the megakaryocyte mass takes from 3 to
4 days following a thrombopoietin stimulus in humans and, coupled
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Kenneth Kaushansky with the approximate 12 hours required for platelet release, results in a
relatively brisk response to thrombocytopenia.
SUMMARY CELLULAR PHYSIOLOGY
OF THROMBOPOIESIS
Each day the adult human produces approximately 1 × 10 platelets, a level of
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production that can increase 10- to 20-fold in times of increased demand and Platelets form by fragmentation of megakaryocyte membrane exten-
an additional five- to 10-fold under the stimulation of exogenous thrombopoi- sions termed proplatelets, in a process that consumes nearly the entire
etin mimetic drugs. Production of platelets depends on the proliferation and cytoplasmic complement of membranes, organelles, granules, and solu-
differentiation of hematopoietic stem and progenitor cells to cells committed ble macromolecules. Although at first controversial, as the process was
initially observed only in vitro, in situ microscopic studies have identi-
to the megakaryocyte lineage, their maturation to large, polyploid megakary- fied proplatelet formation and fragmentation in living animals. Each
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ocytes, and their final fragmentation into platelets. The external influences megakaryocyte is estimated to give rise to 1000 to 3000 platelets before
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that impact megakaryopoiesis and thrombopoiesis are a supportive marrow the residual nuclear material is engulfed and eliminated by marrow
stroma consisting of endothelial and other cells, matrix glycosaminoglycans, macrophages. This process has been extensively reviewed. The con-
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and a family of protein hormones and cytokines, including thrombopoietin, tinuum of megakaryocyte development is arbitrarily divided into four
stem cell factor, and stromal cell-derived factor-1. The role of the cytokines stages. The major criteria differentiating these stages are the quality of
essential for these processes has been defined, the transcription factors crit- the cytoplasm and the size, lobulation, and chromatin pattern of the
ical for megakaryocyte development identified, the molecular mechanisms nucleus (Table 111–1).
that underlie the two most unusual aspects of thrombopoiesis—endomitosis
and proplatelet formation—have been studied, and reagents to specifically MEGAKARYOBLAST
modify platelet production have been generated. This chapter focuses on the Stage I megakaryocytes, also termed megakaryoblasts, account for
development of megakaryocytes, their precursors and their progeny, and the approximately 20 percent of all cells destined to form platelets. These
hematopoietic growth factors and transcriptionally active molecules that cells in human marrow are 8 to 24 μm in spherical diameter (i.e., the
control the survival, proliferation, and differentiation of these cells. actual size in vivo, as opposed to the apparent size of a cell on a flattened
marrow smear), contain a relatively large, minimally indented nucleus
with loosely organized chromatin and multiple nucleoli, and scant
basophilic cytoplasm containing a small Golgi complex, a few mito-
KINETICS OF THROMBOPOIESIS chondria and α granules, and abundant free ribosomes (Fig. 111–1).
The circulatory life span of a platelet is approximately 10 days in humans Surface Adhesion Molecule Expression
with normal platelet counts, but somewhat shorter in patients with Although elegant experiments clearly demonstrated that the gene for
moderate (7 days) to severe (5 days) thrombocytopenia, as a higher pro- integrin α is expressed as early as the erythroid-megakaryocytic pro-
IIb
portion of the total-body platelet mass is consumed in the day-to-day genitor stage and possibly in the common myeloid progenitor, the cell-
9
function of maintaining vascular integrity. Based on a “normal” level of surface protein becomes demonstrable and functionally important only
1
200,000 platelets/μL, a blood volume of 5 L, and a half-life of 10 days, at the early stages of megakaryocyte development. Integrin α β is an
IIb 3
1 × 10 platelets per day are produced. If 1 megakaryocyte produces integral transmembrane protein of two subunits, but only the α sub-
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approximately 1000 platelets, approximately 1 × 10 megakaryocytes are unit is megakaryocyte-lineage specific. Absence of integrin α β leads
8
IIb 3
generated in the marrow each day. to Glanzmann thrombasthenia resulting from failure of the defective
Several independent lines of evidence indicate the transit time platelets to engage fibrinogen and other adhesive ligands during hemo-
from megakaryocyte progenitor cell to release of platelets into the circu- stasis (Chap. 120). Megakaryocytes and platelets contain in their cyto-
lation ranges from 4 to 7 days. For example, following platelet apheresis, plasmic membranes approximately twice the amount of integrin α β
IIb 3
the platelet count falls, recovers substantially by day 4, and completely as is present on the cell surface. The granule compartment serves as a
mobilizable pool that is exteriorized upon platelet activation. During
the early and midstages of megakaryocyte development, the granule
content of integrin rises. Moreover, as developing megakaryocytes do
Acronyms and Abbreviations: CAMT, congenital amegakaryocytic thrombocy- not synthesize but contain fibrinogen in their α-granules and cells from
topenia; FGF, fibroblast growth factor; GP, glycoprotein; HPS, Hermansky-Pudlak patients with Glanzmann thrombasthenia do not, integrin α β clearly
IIb 3
syndrome; IFN, interferon; IL, interleukin; ITP, immune thrombocytopenic purpura; begins to function, at least at the level of fibrinogen binding and uptake,
MAPK, mitogen-activated protein kinase; P4P, polyphosphate-4-phosphatase; PI3K, long before platelet formation.
phosphoinositol 3′-kinase; SDF, stromal cell-derived factor; TGF, transforming growth The glycoprotein (GP) Ib-IX complex is expressed only slightly
factor. after the appearance of integrin α β . Although endothelial cells
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IIb 3
reportedly express GPIb, its levels are very low; otherwise, GPIb is the
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