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2000 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2001

Although Marino first showed that antiplatelet antibodies might against extracellular parasites. Th17 cells are involved in host defense
cause thrombocytopenia in animal studies in 1905, the Harrington- against extracellular bacteria and fungi. Treg cells (formerly known as
Hollingsworth experiment (1951) was an important milestone in the suppressor T cells) play an important role in self-tolerance by inhibit-
understanding of autoantibody-directed platelet destruction in the ing autoimmune responses. Abnormal T-cell responses drive the dif-
pathophysiology of ITP. In this pioneering work, normal volunteers ferentiation of autoreactive B-cell clones and autoantibody secretion.
(including Harrington himself, who received the highest dose) were In patients with ITP, both Th1 and Th17 cells have been found to be
infused with the plasma from patients with ITP, resulting in severe upregulated, whereas the number and the suppressor functions of the
thrombocytopenia in the recipients, and they postulated that ITP could Treg cells were found to be decreased. 113–115 This imbalance is believed
be caused by antiplatelet antibodies. 95,96 Subsequently, Shulman and to induce an autoimmune responses against the platelets. It is unclear
97
coworkers showed that the thrombocytopenic effect of ITP plasma whether these abnormalities are causative or represent an epiphenom-
was dose-dependent and associated with the globulin fraction. In the enon. 114,115 In addition, CD8+ cytotoxic T cells might be involved in the
1950s, glucocorticoids began to be used to treat ITP, and they became pathogenesis of ITP through cell-mediated destruction of platelets and
first-line therapy for adults. Shortly thereafter other immunosuppres- megakaryocytes and through suppression of megakaryocytes, impair-
sive agents were introduced for the treatment of chronic ITP. 92 ing platelet production. 115–117
In the early 1970s, two groups showed that platelets from chronic Antiplatelet autoantibodies may also activate platelet destruction
ITP patients had elevated levels of platelet-associated immunoglobu- by activating complement through the classical complement pathway.
lin G (PAIgG). 98,99 In 1982, the first platelet target was identified: auto- Increased platelet-associated C3, C4, and C9 have been demonstrated
antibodies from patients with ITP failed to bind platelets deficient on the platelets from patients with ITP. 118,119 In vitro studies show that,
in the integrin α β complex (i.e., from patients with Glanzmann in the presence of antiplatelet antibodies, C3 and C4 can bind plate-
IIb 3
100
thrombasthenia). In the late 1980s, two specific assays for the target lets, increase the phagocytosis of the platelets by macrophages, and
antigens were described: the immunobead assay and the monoclo- can cause their lysis by stimulating assembly of the membrane attack
101
nal antibody-specific immobilization of platelet antigens (MAIPA) complex. 120,121
102
assay. These assays showed that the majority of antiplatelet anti- Early studies demonstrated that platelet survival is shortened in
bodies in patients with ITP are directed against integrin α β ITP patients and returns to normal after splenectomy-induced remis-
IIβ 3(GPIIβ-IIIα)
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(approximately 80 percent), and the remainder are against the GPIb- sion. Platelet transfusion only transiently increases a patient’s plate-
IX-V complex and other platelet GPs such as GPIV and integrin α β let count, and the transfused platelets also have a shortened survival,
2 1
(GPIa-IIa). 103,104 Some sera contain antibodies that recognize several reflecting the fact that the major problem in ITP is platelet destruc-
antigens. Most antiplatelet autoantibodies are IgG; the remainder are tion. However, later studies showed that platelet life span was not short
IgM and IgA. Unfortunately, elevated levels of PAIgG later were found enough to account for the observed thrombocytopenia on the basis of
in patients with non-ITP. Therefore, PAIgG could not be used as a spe- destruction alone, again suggesting a concomitant defect in platelet
123
cific laboratory test for ITP in the same way that the direct antiglobulin production. Potential mechanisms for this observation were provided
test is used for the diagnosis of autoimmune hemolytic anemia. 105,106 To by later studies that autoantibodies against platelet surface GPs might
date there is still no specific laboratory test for ITP, the diagnosis of ITP interfere with the maturation of megakaryocytes, resulting in reduced
being based on exclusion of other causes. platelet production, contributing to the severity of thrombocytopenia
Antibody-coated platelets bind tissue macrophages through Fcγ in some ITP patients. Antibodies that target the GPIb–IX–V com-
124
receptors, leading to their destruction primarily in the spleen and, to a plex may induce thrombocytopenia by decreasing platelet production,
lesser extent, in the liver and marrow. 97,107,108 In 1981, Imbach reported as GPIb autoantibodies inhibit megakaryopoiesis in vitro, and GPIb
124
successful treatment of pediatric ITP with intravenous immunoglobu- monoclonal antibodies inhibit proplatelet formation in vitro. 125
lin (IVIG) and suggested that the mechanism could involve blockade of In 1958, a hematopoietic growth factor regulating platelet produc-
126
macrophage Fc receptors. IVIG became first-line therapy in children, tion was proposed and named TPO by Kelemen. Although interleu-
and now is also used in adults when a prompt increase is the platelet kin (IL)-3, IL-6, IL-11, granulocyte-macrophage colony-stimulating
count is desired. 109 factor, and c-KIT ligand increase megakaryocyte or platelet counts in
Early studies of PAIgG reported that the antibodies in ITP were vivo and in vitro, animal studies of these factors proved that they are
110
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polyclonal. However, later studies showed that at least some ITP not the main regulator of megakaryopoiesis. In 1994, TPO was first
patients had clonal B-cell proliferation, as determined by DNA anal- characterized by five independent groups. TPO binds to its receptor
ysis for immunoglobulin heavy- and light-chain rearrangements and MPL (formerly known as c-MPL), enhances megakaryocyte colony for-
by flow cytometry of B cells from blood and spleen for surface Ig light mation, and increases the size, number, and ploidy of megakaryocytes,
chains. 111,112 This led to the use in ITP of the chimeric anti-CD20 mono- and platelet production (Chap. 113). 128–130 TPO is synthesized in greatest
clonal antibody, rituximab, which was designed for the treatment of quantity in the liver but is found in other organs (kidney, muscle, and
CD20-positive B-cell lymphomas. The rapid elimination of B cells with marrow stromal cells). TPO is also required to maintain the viabil-
128
131
rituximab encouraged the use of this agent in the treatment of ITP. ity of hematopoietic stem cells. The regulation of TPO production is
Numerous abnormalities in cell-mediated immunity have been complex. Hepatic production of TPO is both constitutive (in the steady
described in patients with ITP, including abnormalities in antigen- state) and inducible (by inflammation), and the concentration of TPO
presenting cells, T lymphocytes, and cytokine release. Under normal to which megakaryocytes are exposed is also determined by the platelet
conditions, antigen-presenting cells recognize and process foreign concentration. Platelets, bearing TPO receptors, remove the hormone
antigens and express the antigens on their surface in association with from the circulation, at least partially accounting for the inverse rela-
major histocompatibility complex (MHC) molecules. MHC–antigen tionship between TPO and platelet levels. TPO levels are markedly
complexes activate resting (naïve) CD4+ T cells to differentiate into a elevated in patients with thrombocytopenia associated with megakary-
variety of phenotypes such as T-helper 1 (Th1) and T-helper 2 (Th2), ocytic hypoplasia, including disorders such as aplastic anemia or acute
Th17, and T-regulatory (Treg) cells. Th1 cells are involved in cell-medi- leukemia. In most reports, ITP patients have normal or slightly elevated
ated immunity and host defense against intracellular bacteria and pro- TPO levels whether measured in plasma or serum, but the levels are
tozoa. Th2 cells are involved in humoral immunity and host defense always lower than the concentrations found in thrombocytopenias

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