Page 520 - Hematology_ Basic Principles and Practice ( PDFDrive )

440 Part IV Disorders of Hematopoietic Cell Development

5

Phagocytosis Inflammatory 4
of bacilli TPO
Macrophage Platelet mass turnover (′10 6 fl/µl/day) 3

Steady state 2
TPO
TNF-α 1
Stromal cell
TPO 0
0 4 8 12 16 20 24 28
Megakaryocyte cytoplasmic mass
Fibroblast (×10 fl/kg body weight)
11
Fig. 32.11 INEFFECTIVE PLATELET PRODUCTION. In thrombocy-
topenia, the relationship between marrow megakaryocyte cytoplasmic mass
IL-6
and the turnover of platelet mass in the peripheral blood is usually direct.
Kidney Platelet mass turnover represents the product of the mean megakaryocyte
cytoplasmic volume multiplied by the total number of marrow megakaryo-
cytes. The results in normal patients are indicated by the arrow, and the
Liver stippled area represents 95% of confidence limits in thrombocytopenic
patients with effective production. Ineffective thrombocytopoiesis is identi-
fied as a disparity between available marrow substrate (megakaryocyte cyto-
plasmic mass) and delivery of platelet mass to the peripheral blood (platelet
mass turnover). Results in patients with autosomal dominant thrombocyto-
penia (open circles), Wiskott-Aldrich syndrome (open triangles), megaloblastic
anemia (open squares), and preleukemia (closed triangles) are characterized by
ineffective platelet production. (Data from Thompson A, Harker L: Quantitative
platelet disorders. In Manual of hemostasis and thrombosis, Philadelphia, 1983, FA
Davis, p 65.)

Thrombocytosis Thrombocytopenia
smear is the first step in the initial assessment of patients who present
with thrombocytopenia. The presence of platelet clumps, indicative
of pseudothrombocytopenia, or abnormally large, or small, platelets
Bone marrow can be very useful in generating a differential diagnosis, as can the
presence of inclusion bodies in neutrophils. Nevertheless, the current
Megakaryocyte gold standard for diagnosing thrombocytopenia caused by ineffective
platelet production is a bone marrow aspirate and biopsy. At the
moment, direct visualization of the marrow and its cellular contents is
the only way to judge the quantity and quality of the megakaryocyte
population (Fig. 32.12). However, noninvasive methods for making
a diagnosis of ineffective platelet production are being developed.
Reduced Enhanced For example, the concentration of serum glycocalicin, the soluble
thrombopoiesis thrombopoiesis fragment of glycoprotein Ib, has been shown to be significantly
Fig. 32.10 THE REGULATION OF THROMBOPOIETIN LEVELS. A diminished in patients with platelet production abnormalities when
225
steady-state amount of hepatic thrombopoietin (TPO) is regulated by platelet compared with normal control patients. Reticulated platelets, like
c-Mpl receptor–mediated uptake and destruction of the hormone. Hepatic RBC reticulocytes, contain ribonucleic acid (RNA). It has been sug-
production of the hormone is depicted. Upon binding to platelet c-Mpl gested that as is true for RBC reticulocytes, the presence of residual
receptors, the hormone is removed from the circulation and destroyed, which RNA in platelets indicates that they have been newly formed. Thus,
reduces blood levels. In the presence of inflammation, interleukin-6 (IL-6) is they may be useful for assessing the dynamics of platelet production
released from macrophages and, through tumor necrosis factor-α (TNF-α) under baseline conditions and after marrow insults such as chemo-
stimulation, from fibroblasts and circulates to the liver to enhance TPO therapy or irradiation. Platelet RNA can be detected by staining
production. Thrombocytopenia also leads to enhanced marrow stromal cell with dyes such as thiazole orange, and it has been suggested that
production of TPO, although the molecular mediator(s) of this effect is not assessing the mean thiazole orange staining can be used to construct
yet completely understood. (Modified from Kaushansky K: The molecular mecha- a reticulated platelet maturation index. Another approach to assessing
nisms that control thrombopoiesis. J Clin Invest 115:3339, 2005.) platelet production is the measurement of serum thrombopoietin
levels. Thrombopoietin is synthesized constitutively in the liver and
then binds to its receptor c-Mpl on megakaryocytes and platelets.
Accordingly, in patients with disorders in which megakaryocytes are
lead to ineffective thrombopoiesis. The relative effectiveness of reduced in the marrow, thrombopoietin levels rise. However, the
platelet production can be calculated by measuring platelet mass wide variation in “normal” thrombopoietin concentrations in serum
turnover, which is defined as the product of the mean megakaryo- make this determination somewhat problematic as well. Some of this
cyte cytoplasmic volume multiplied by the total number of marrow variability may be attributed to the fact that thrombopoietin synthesis
megakaryocytes. A disparity between cytoplasmic mass and platelet is inducible in marrow stromal cells, perhaps by platelet α-granule
delivery to blood (platelet count divided by platelet survival, cor- proteins. Reports attesting to the increased reliability and precision
rected for splenic pooling) is the hallmark of ineffective platelet of measuring several of these parameters at once have appeared, but
production (Fig. 32.11). An examination of the peripheral blood it remains unclear whether the expense and time involved will prove