Page 1849 - Williams Hematology ( PDFDrive )

1824 Part XII: Hemostasis and Thrombosis Chapter 111: Megakaryopoiesis and Thrombopoiesis 1825

interactions will occur. A particularly important interaction for than proliferation. 189,190 The preclinical effects of IL-11 were evaluated in
177
thrombopoiesis is between the marrow sinusoidal endothelial cell and mice, rats, and subhuman primates and revealed moderate activity in
the mature megakaryocyte. Studies using in situ videomicroscopy indi- normal animals and following cytoreductive therapy. 98,191,192
cate that proplatelet processes extend through the sinusoids into the The first clinical trials of IL-11 were reported in abstract form in
vascular lumen, where the shear stress of flowing blood liberates sin- 1993 and 1994. 193,194 Randomized clinical trials were reported a few
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gle platelets. Marrow stromal cells influence hematopoiesis in a num- years later. 195–197 Most studies reported IL-11 ameliorated drug-induced
ber of other ways, perhaps the most prominent through production thrombocytopenia. For example, IL-11 administered to patients with
of several cytokines that positively or negatively affect megakaryocyte advanced stages of breast cancer undergoing multiple courses of anthra-
growth. 145,178–180 Stromal cells are the origin of a number of extracellu- cycline-based chemotherapy significantly reduced the need for platelet
lar matrix proteins and glycomucins that either directly affect hemato- transfusions by 27 percent. However, use of the drug in patients under-
poietic cells or indirectly affect hematopoietic cells by binding growth going autologous stem cell transplantation did not enhance platelet
factors and presenting them in a functional context. 181,182 Stromal cells recovery or other indices of hematopoiesis. Although chemical evidence
also bear ligands for Notch proteins, cell-surface receptors that are crit- of an acute-phase response was noted in many of the patients treated in
183
ical mediators of cell fate decisions. Notch and its ligands Delta and these studies, the drug was generally well tolerated, even though fluid
Jagged play important roles as regulators of hematopoietic progenitor retention has been a significant side effect, often necessitating concomi-
184
cell proliferation and play a potential role in influencing the lineage tant use of diuretics. IL-11 (oprelvekin, Neumega) was approved by the
fate choice between erythropoiesis and megakaryopoiesis. Cell–cell Food and Drug Administration in 1998 for use in patients undergoing
185
interactions mediated by integrins present on hematopoietic cells and chemotherapy who have evidence of previous drug-induced thrombo-
counterreceptors on stromal cells are very important for megakaryo- cytopenia (Chap. 119).
186
poiesis, both by bringing hematopoietic cells into close proximity
to stromal cells producing soluble or cell-bound cytokines and more INTERFERON-α
directly by triggering or augmenting intracellular signaling, promoting
entry into the cell cycle, and preventing programmed cell death. As noted in “Hormones and Cytokines” above, IFN suppresses hemato-
poiesis and thrombopoiesis by multiple mechanisms. As a consequence,
IFN-α has been used to reduce platelet counts in patients with many
THERAPEUTIC MANIPULATION OF forms of myeloproliferative disease. The first reported clinical trial was
performed in patients with a mixture of these disorders. The trial found
THROMBOPOIESIS BY NATURALLY the mean platelet count decreased significantly from 1050 × 10 /L to
9
198
OCCURRING CYTOKINES 340 × 10 /L. Long-term therapy with IFN also was shown to be effec-
9
tive and safe. From these and other studies, IFN (2 to 5 million units
199
Thrombocytopenia is a major clinical problem with multiple origins 3 times per week) clearly effectively reduces the platelet count toward
(Chap. 117). Primary marrow diseases, certain infections, and solid normal in most patients with myeloproliferative disease. More aggres-
tumors with a high propensity for marrow metastases directly affect sive regimens (2 to 6 million units daily) result in complete hematologic
platelet production. Nearly all leukemias, advanced lymphomas, and remissions but with no evidence that the clonal disorder responsible
myelomas ultimately cause thrombocytopenia by this mechanism. has been affected. Not surprisingly, reduced energy level, weight loss,
200
Hypersplenism and thrombopoietin deficiency contribute to platelet myalgia, and depression have been consistently reported, forcing dis-
sequestration and reduced platelet production in patients with hepatic continuation of the drug in approximately one-third of patients taking
failure. Consumptive coagulopathies, initiated by infection, tumors, or low to moderate doses of various forms of IFN-α. Of some concern
201
severe injury, can be responsible for severe thrombocytopenia. In other and possibly related to its effects on the immune system, a significant
patients, autoimmune thrombocytopenia arises during the course of number of patients treated with IFN for thrombocytosis have devel-
disease or is a primary disease. However, the most common cause of oped antibodies to the administered drug, with subsequent reduced
significant thrombocytopenia is iatrogenic: the use of potentially cura- efficacy. 202
tive or palliative chemotherapy or radiation therapy in patients with
malignancy. An estimated 300,000+ persons yearly worldwide undergo THROMBOPOIETIN
courses of chemotherapy adequate to produce clinically significant Clinically, the most important activity of thrombopoietin likely is its
thrombocytopenia. Recovery from the marrow suppressive effects of effects on megakaryopoiesis, potentially ameliorating the thrombocy-
most chemotherapeutic agents occurs within 1 to 3 weeks following dis- topenia that occurs in natural and iatrogenic states of marrow failure.
continuation of therapy. However, some agents, including mitomycin C In this regard, a number of promising results in preclinical trials of the
or nitrosoureas, can produce prolonged periods of marrow suppression. cytokine were reported. 126,128,129,203 In general, in rodent, dog, and non-
Moreover, the widespread use of IFN-α for chronic hepatitis C infec- human primates, almost every model of myelosuppression or immune-
tion adds large numbers of patients who experience thrombocytopenia mediated platelet destruction has responded favorably to parenteral
as a dose-limiting toxicity. Tumor- or treatment-related thrombocy- administration of thrombopoietin. In addition to the favorable effects
topenia often delays much needed additional therapy, may necessitate on platelet recovery, many of these studies also reported enhanced
potentially complicated platelet transfusions (Chap. 139), and causes recovery or hematopoietic progenitors of all lineages, accelerated recov-
significant morbidity and occasional mortality. Given the increased ery of erythrocytes or leukocytes, or both. The only exception to these
understanding of the humoral basis for megakaryopoiesis and throm- generally favorable results has been reported in animal models of stem
bopoiesis, numerous attempts have been made to manipulate these pro- cell transplantation, where negligible to minimal acceleration of blood
cesses for therapeutic benefit.
cell recovery was found, unless the stem cell donor was treated with the
hormone. 204,205
INTERLEUKIN-11 A number of clinical trials in patients with cancer undergo-
IL-11 augments the growth of megakaryocytic progenitors in the pres- ing cytotoxic therapy have been conducted. Results were varied, with
ence of IL-3 187,188 and acts to promote megakaryocyte maturation rather the hormone helpful in many patients, 206–208 but not in all clinical

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