Immune thrombocytopenic purpura

Immune pathophysiology of primary

immune thrombocytopenia

R. Stasi
Department of Haematology,
St George’s Hospital, London,
United Kingdom
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2011;5:173-178
A B S T R A C T
Primary immune thrombocytopenia (ITP) is characterized by antibody mediated destruction of
platelets and suppression of megakaryocyte and platelet development. The underlying defect leading
to autoantibody production is unknown, and it is likely that both genetic and environmental factors
are involved. Platelet-specific autoantibodies are often directed against a restricted number of “dom-
inant” epitopes of GPIIbIIIa, or less frequently of GPIbIX or other platelet glycoproteins.
The T cell compartment is now known to play a crucial role in ITP. Cytotoxic T cells may be involved
in platelet destruction and suppression of megakaryopoiesis. Many models of autoimmune disease
have a Th1 bias, which is also seen in ITP, and which is reversed upon treatment. Furthermore, a reduc-
tion in suppressor T-regulatory cells may predispose to the emergence of autoantibodies in response
to exogenous antigens.
Finally, an ITP-like presentation occurs in the setting of chronic infections, such as HIV, HCV, and
Helicobacter pylori. Antibodies that cross-react with platelets have been identified in patients who
develop thrombocytopenia in association with these infections, suggesting that molecular mimicry
and epitope spread may be a common pathway to antiplatelet antibody development in patients with
ITP as well.

autoantibodies are not detectable in up to

Introduction
Primary immune thrombocytopenia (ITP)
is an acquired autoimmune disorder charac-
terized by isolated thrombocytopenia in the
absence of conditions known to cause
thrombocytopenia, such as infections, other
autoimmune disorders, drugs, and so on.1
In this review, we shall discuss the current
understanding of the pathophysiology of ITP.
Abnormalities of B and T cells
Harrington’s seminal experiment provided
the first evidence that thrombocytopenia in
ITP is caused by a plasma-derived factor,2
later identified as antiplatelet antibodies.3,4
The most commonly identified antigenic tar-
get of these autoantibodies is platelet glyco-
proteins (GP). Autoantibodies are often
directed against a restricted number of
“dominant” epitopes of GPIIbIIIa, or less fre-
quently of GPIbIX or other platelet glycopro-
teins.5 A number of ITP patients have anti-
bodies directed to multiple platelet antigens.6
Antibodies against GP IIb/IIIa show clonal
restriction in light-chain use,7 and antibodies
derived from phage-display libraries show
selective usage of a single Ig heavy-chain
variable region gene (VH3-30).8 Sequencing of
the antigen-combining regions of these anti-
bodies suggests that they originate from a
limited number of B-cell clones by antigen-
driven affinity selection and somatic muta-
tion.8 It should be noted, however, that
50% of ITP patients,6,9 and that remission in
ITP can occur despite the continued presence
of platelet autoantibodies.10 Reasons for
these findings may include technical factors
(current monoclonal-based assays only
detect antibodies with known specificity,
typically GPIIb-IIIa and GPIb-IX; variable
sensitivity of the assays), removal of autoan-
tibodies by megakaryocytes, and the pres-
ence of alternative mechanisms of the
thrombocytopenia.
As a matter of fact, several lines of evi-
dence also link T cells to the pathogenic
process in ITP. Platelet-reactive T cells have
been found in the blood of patients with this
disorder, with the major target antigen being
GP IIb/IIIa.11 In these patients, T cells stimu-
late the synthesis of antibody after exposure
to fragments of GP IIb/IIIa but not after
exposure to native proteins.12 The derivation
of these cryptic epitopes in vivo and the rea-
son for sustained T-cell activation are
unknown. It has been hypothesized that
cryptic epitopes, normally not exposed in a
self-antigen, may become exposed and rec-
ognized by the immune system under cer-
tain circumstances, for example, an infec-
tion.13
The cytokine profile in the peripheral
blood of patients with ITP is consistent with
a Th1 (proinflammatory) response,14 a pat-
tern seen in most organ-specific autoim-
mune diseases. These results were support-
ed by flow cytometry studies, showing an

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 173 |
16th Congress of the European Hematology Association
increased Th1/Th2 ratio in ITP patients compared with
controls.15 In keeping with these findings, investigation
of whole blood gene expression profile using DNA
microarrays identified an ITP-specific signature, which
also included interferon (IFN)-induced genes, such as
GBP2 and IFIT2.16 Pathway analysis demonstrated that
IFN signaling, death receptor, and protein ubiquitination
pathways were associated with ITP.
Other studies have shown that patients with chronic
ITP often exhibit expansion of oligoclonal T-cells15,17 and
the presence of cytotoxic T cells against autologous
platelets.18 In fact, T cells from patients with ITP show
increased expression of cytotoxic genes, such as tumor
necrosis factor- alpha, perforin, and granzyme A and
granzyme B.18,19 Interestingly, several members of the
killer cell immunoglobulin-like receptor (KIR) family
were upregulated in patients with active disease, and
CD3+ lymphocytes expressing KIRs were greater in
number in ITP patients in remission than in patients
with active ITP or normal controls patients.18 Since KIRs
downregulate cytotoxic T-lymphocyte (CTL) and natu-
ral killer cell responses by binding to MHC class I mol-
ecules, thereby preventing lysis of target cells, it may be
speculated that cytotoxic T cells play a part in at least
some patients with ITP.
The emergence of antiplatelet autoantibodies and
antiplatelet cytotoxic T cells is a consequence of a loss
of the immunological tolerance for self antigens. Filion
et al. have shown that autoreactive T cells directed
against GPIIb/IIIa are present in the peripheral blood of
all healthy individuals,20 implying that peripheral toler-
ance mechanisms are crucial to prevent autoreactive T
cells from becoming activated. Several other T cell
abnormalities have emerged from the investigation of
immune regulation in ITP patients. Among these,
CD4+CD25+ regulatory T cells have an impaired sup-
pressive activity when compared with healthy sub-
jects.21 Also, CD3+ T lymphocytes from patients with
active ITP present an altered expression of genes associ-
ated with apoptosis and are significantly more resistant
to dexamethasone-induced suppression compared with
normal lymphocytes.18,22
As far as B cells are concerned, the expansion of
autoreactive clones is suppressed in the bone marrow. If
some B cells escape this suppression or deletion, periph-
eral mechanisms, most importantly the functional bal-
ance between activating and inhibitory Fc receptors
(FcR), may also be launched to maintain tolerance.23
Antigen-presenting cells in ITP
Like all immunoglobulin (Ig) isotype-switched IgG
antibody responses, autoreactive IgG against a protein
antigen is initiated by activated T helper cells that rec-
ognize specific peptide sequences on major histocom-
patibility complex class II-positive antigen-presenting
cells (APCs). The role of APCs for the loss of tolerance
in ITP remains unclear, but dendritic cells from patients
with ITP have upregulated costimulatory molecules
enhancing autoreactive T- and B-cell responses against
platelets.24 A model has been advanced in which APCs
are crucial in generating a number of new or cryptic epi-
topes from platelet glycoproteins.25 In this model, APCs
expressing these novel peptides, and along with co-
stimulatory molecules, induce the activation of T cells
| 174 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
that recognize these additional platelet antigens. Thus,
this acquired recognition of new self-determinants, or
epitope spreading, may play an important role in the ini-
tiation and perpetuation of ITP. T-cell clones that react
with cryptic epitopes may escape the negative selection
in the thymus when self-determinants are present at a
sub-threshold concentration.
Infection-associated ITP and the role of molecular mimicry
Thrombocytopenia may accompany or follow a vari-
ety of infections from which ITP must be differentiated.
In adults, the most prevalent infections associated with
thrombocytopenia are those from hepatitis C virus
(HCV), human immunodeficiency virus (HIV), and
Helicobacter pylori (H. pylori).26 In typical cases, the throm-
bocytopenia presents with an insidious onset, has no
tendency to remit spontaneously (although its severity
may parallel the stage of the infectious disease), and
may closely mimic chronic ITP. Response to infection
may generate antibodies that cross-react with platelet
antigens, most notably GP IIb-IIIa or immune complex-
es that bind to platelet Fc receptors.27–30
Many patients with HIV-associated thrombocytope-
nia have autoantibodies that recognize a restricted pep-
tide sequence (GPIIIa49-66) in platelet membrane
GPIIIa, and can be recovered from patient plasma in the
form of immune complexes consisting of autoantibody
and platelet fragments.27,28 Recently, Zhang et al. found
that sera from patients coinfected with HCV and HIV
reacted with four peptides present in nonconserved
regions of the HCV core envelope 1 protein.29 Antibodies
raised against one of these peptides (PHC09) caused
severe thrombocytopenia when injected into wild-type
mice whose GPIIIa is more than 80% identical to that of
humans. Immunization of wild-type mice with HCV
core envelope protein 1 had no effect on platelet count.
However, NZB/W F1 mice, a strain in which immune
surveillance is defective, produced antibodies specific
for PHC09 and became thrombocytopenic. The titer of
PHC09-specific antibody in patients coinfected with
HCV, and HIV correlated with both the incidence of
thrombocytopenia and its severity. The authors con-
clude that humans and immunodeficient mice immu-
nized with HCV core envelope protein 1 often produce
antibodies that recognize GPIIIa49-66 through molecu-
lar mimicry and are capable of causing clinically signifi-
cant thrombocytopenia.
With regards to ITP and H. pylori infection, platelet-
cross-reactivity has been shown between platelet-asso-
ciated immunoglobulins and bacterial components, in
particular cytotoxin-associated gene (Cag) A protein30
and urease B.31
In support of the molecular mimicry theory, microbial
reduction/eradication leads to remission in a substantial
fraction of infected patients. In the case of H. pylori,
questions remain regarding why there appears to be
marked variation in response rates among patients from
different geographic areas.32
Genetic factors
Little is known of the genetic factors that may con-
tribute to the predisposition to develop ITP or influence
the natural history of ITP and response to treatment. A
pilot study in 37 children with chronic ITP investigated

common variants in the regulatory regions of cytokines
(TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6, and IL10) and
structural variants of the low affinity Fcg receptors
(FCGR2A, FCGR3A, and FCGR3B).33 Two combinations
of genotypes (TNF and FCGR3A; P = 0.0003, and LTA
and FCGR3B; P = 0.011) were significantly associated
with ITP compared with healthy controls. The
NA1/NA1 genotype of the FCGR3B locus was observed
in 30% of patients compared with 10% of controls and
may be particularly relevant to ITP, as NA1 has a higher
affinity than NA2 to IgG. The heterozygous V/F geno-
type of the FCGR3A locus was also more frequent in
patients than in controls (62% vs. 41%). These results
suggest that immune complex handling may play a role
in the pathophysiology of ITP, and that variant FcgR
genes with decreased activity may provide partial pro-
tection against ITP.
With regards to cytokines, the transcriptionally more
active allele of TNF (allele 2 of −308) and the closely
linked LTA allele 1 were both less common in children
with ITP than in healthy controls. No clear hypotheses
to account for these findings have been advanced.
In an earlier study, deletions of Humhv3005, a devel-
opmentally regulated Ig variable (V) gene, and/or highly
homologous VH genes were found more frequently in
ITP patients (14 of 44, 31.8%) than in healthy controls
(7/88, 8%, p = 0.002).34
Finally, associations with HLA-DRw235 and HLA-
DRB1*041036 have been reported, although the role
played by these MHC molecules remains obscure.
Mechanisms leading to thrombocytopenia
Ex vivo studies have shown that the spleen is the pri-
mary site of antibody production,37,38 whereas platelet
kinetic studies have shown that the spleen is also the
dominant organ for the clearance of IgG-coated
platelets.39,40 In a minority of patients, hepatic clearance
predominates.
Human macrophages express several Fc receptors that
bind IgG specifically.41 Functionally, there are two differ-
ent classes of Fc receptors: the activation and the
inhibitory receptors, which transmit their signals via
immunoreceptor tyrosine-based activation (ITAM) or
inhibitory motifs (ITIM), respectively. Clinical data,
along with information gained from animal models,
suggest that the FcgRI, the high affinity receptor, does
not play a relevant role in ITP.42,43 On the other hand, evi-
dence has accumulated to indicate that the low-affinity
receptors FcgRIIA and FcgRIIIA are primarily responsible
for removal of opsonized platelets.44 Engagement of
FcgRIIA on the surface of human macrophages by anti-
GPIIb/IIIa-coated platelets triggers intracellular signaling
through the tyrosine kinase Syk that leads to engulf-
ment of the opsonized platelets.
The presence of antibodies against GP Ib/IX has been
associated with resistance to intravenous immunoglob-
ulin therapy both in a mouse model45 and in retrospec-
tive series of ITP patients.46 These findings suggest the
possibility of direct cytotoxicity or complement fixation
as a mechanism of platelet destruction rather than anti-
body-dependent, Fc receptor-mediated phagocytosis by
macrophages.
Interestingly, platelet kinetic studies using indium-111
(111In)-labeled autologous platelets have shown consider-
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 175 |
London, United Kingdom, June 9-12, 2011
able heterogeneity in platelet turnover in patients with
chronic ITP.39,40,47,48 While the platelet lifespan is often
markedly decreased in most patients, in some it is only
mildly reduced; furthermore, platelet turnover (a meas-
ure of platelet production) is frequently subnormal.
Overall, approximately 40% of patients with ITP were
found to have a reduced platelet turnover.39,40
If platelet destruction were the only mechanism to
cause thrombocytopenia, then platelet production
would be expected to increase and offset low platelet
counts. It, therefore, was proposed that thrombocy-
topenia may result not only from platelet destruction,
but also from antibody-mediated damage to megakary-
ocytes. Evidence to support this hypothesis has accu-
mulated over time.
McMillan et al. reported that IgG produced by cells
(grown in vitro) from the spleens of patients with ITP
would bind to megakaryocytes, whereas IgG produced
by cells from the spleens of healthy controls did not
bind to megakaryocytes.49 A few years later, other inves-
tigators demonstrated that antibodies against platelet
antigens would bind to megakaryocytes as well.50,51
More recent in vitro experiments have further defined
the role of autoantibodies in patients with ITP. Two
studies in particular, by Chang et al.52 and McMillan et
al.53 support the view that autoantibodies in ITP sup-
press megakaryocyte production and maturation and
platelet release.
Electron microscopy studies have clarified some
aspects of the autoantibody-induced damage in bone
marrow megakaryocytes from patients with ITP.
Extensive megakaryocytic abnormalities were consis-
tently present in a significant percentage of all stages of
ITP megakaryocyte.54,55 In the most recent of these stud-
ies, Houwerzijl et al. described the features characteris-
tic of nonclassic apoptosis, including mitochondrial
swelling with cytoplasmic vacuolization, distention of
demarcation membranes, and condensation of nuclear
chromatin.55 Para-apoptotic changes could be induced in
megakaryocytes derived from CD34+ cells grown in
ITP plasma, suggesting that autoantibodies may initiate
the cascade of programmed cell death. In addition,
megakaryocytes may be surrounded by neutrophils and
macrophages, suggesting an inflammatory response
against these cells.
A role for direct T cell–mediated cytotoxicity against
platelets has been demonstrated in vitro.18 Whether this
effect occurs in vivo and its relative importance in deter-
mining platelet destruction has not been elucidated.
There is also evidence that ITP is associated with accu-
mulation and activation of T cells in the bone marrow
that occurs through increased VLA-4 and CX3CR1
expression.56 It has been advanced that these activated T
cells may mediate the destruction of platelets in the
bone marrow.56
Thrombocytopenia associated with infectious dis-
eases is characterized by antibody-mediated platelet
destruction. However, platelet production may be
impaired by infection of megakaryocytes (HCV and
HIV), decreased production of thrombopoietin (HCV),
and splenic sequestration of platelets secondary to por-
tal hypertension (HCV).26
A unique feature of antibodies specific for GP49-66,
frequently found in patients with HIV and HCV infec-
16th Congress of the European Hematology Association

tions, is their ability to induce reactive oxygen species
through activation of 12-lipoxygenase and NADPH oxi-
dase, leading to complement-independent platelet frag-
mentation.57 This mechanism has not been described for
antiplatelet antibodies with other epitope specificities.
Pathophysiology of secondary ITP
Secondary forms of immune thrombocytopenia are
legion and include those associated with autoimmune and
lymphoproliferative disorders, acute and chronic infec-
tions, and certain drugs. Secondary ITP differs in specific
aspects of pathobiology from primary ITP. We will con-
fine our discussion to Systemic Lupus Erythematous (SLE)
and lymphoproliferative disorders.
SLE is a multisystem disorder with wide-ranging clin-
ical and laboratory manifestations. Of these, thrombo-
cytopenia is a more common finding, with platelet
counts less than 100 × 109/L found in 7–30% of
patients.58 However, less than 3% of patients have
counts below 20 × 109/L, which is associated with a sig-
nificant risk of bleeding and usually requires treatment.59
Several genes correlated with ITP have been shown to
be associated with expression signatures in systemic
lupus erythematosis,60 indicating an overlap between
the two autoimmune disorders. Purported mechanisms
leading to thrombocytopenia in SLE include anti-
GPIIb/IIIa antibody-mediated platelet destruction and
inhibition of megakaryopoiesis by antibodies directed

Figure 1. Simplified representation of the pathophysiology of ITP. The primary mechanism for the loss of tolerance in ITP
remains unknown, although in some cases, infections may play a causative role. The emergence of antiplatelet autoan-
tibodies remains the central pathogenetic mechanism. Platelet glycoproteins are cleaved to peptides by macrophages or
another antigen-presenting cell (APC) and expressed on the APC cell surface via MHC class II molecules. APCs are crucial
in generating a number of new or cryptic epitopes (“epitope spreading”). Genetic factors may be crucial in how the
immune complexes are processed in APCs and expressed on MHC class II molecules. The T-cell receptor (TCR) of the Th
cell can then bind the peptide-MHC complex and signal activation that upregulates CD154 (CD40 ligand) to interact with
CD40 on the APC and cause additional costimulatory interactions to occur. An additional co-stimulatory signal can orig-
inate from the binding of the CD80 molecule, overexpressed on the cell membrane of ITP platelets, with CD28 expressed
on Th cells. The activated Th cell produces cytokines (interleukin-2 and interferon-g) that promote B-cell differentiation
and autoantibody production. Tregs normally inhibit Th cell activity and proliferation, but their function in ITP is impaired.
Autoantibodies opsonize platelets, which are taken up and destroyed by macrophages predominantly in the spleen. They
also bind bone marrow megakaryocytes, thereby impairing megakaryocyte maturation and platelet production. An alter-
native pathway of platelet destruction is by autoreactive cytotoxic T cells, although the relevance of this mechanism in
vivo is not known. Tc cells in the bone marrow might also inhibit megakaryopoiesis and thrombopoiesis, although this
has not been formally demonstrated. The role of infections such as H. pylori has not been completely elucidated, but
cross-reactivity has been shown between bacterial antigens and platelet glycoproteins.

| 176 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)

against the TPO receptor (cMpl).61 Predictably, the anti-
body present dictates the clinical features: patients with
anti-GPIIb/IIIa antibodies have normal or increased
bone marrow megakaryocyte density and, similar to
patients with immune thrombocytopenic purpura (ITP),
show a good response to conventional immunosuppres-
sion. Those with anti-TPO receptor antibodies demon-
strate megakaryocytic hypoplasia and have a poor
response to steroids and intravenous immunoglobulin.61
Patients with some lymphoproliferative disorders,
particularly those with chronic lymphocytic leukemia
(CLL) and CD8 T-lymphocyte large granular lympho-
cytic leukemia (LGL), appear to have an increased inci-
dence of immune thrombocytopenia. ITP occurs in
approximately 5% of patients with CLL when stringent
diagnostic criteria are applied.62 The development of
ITP is significantly associated with unmutated IgVH, a
positive direct antiglobulin test, and the development
of autoimmune hemolytic anemia. Patients with CLL
and IT have poorer survival than other patients with
CLL, and this effect appears to be independent from
common clinical prognostic variables.62 Severe throm-
bocytopenia occurs in about 1% of patients with LGL,
and has been associated with clonal suppression of
megakaryopoiesis.63,64
Conclusions
The pathophysiology of ITP is much more complex
than once believed; we can depict a simplified view of
our current understanding in this area (Figure 1). While
abnormalities of both the B cell and the T cell compart-
ments have been identified, the mechanisms of the fail-
ure of the immune tolerance remain poorly understood.
Recent studies have focused on the specificity of the
antiplatelet immune response in patients with ITP and
showed that GPIIIa is the most important target of the
autoantibodies. GPIIIa is known to contain important B-
and T-cell determinants, and seven immunodominant
epitopes. Identification of GPIIIa sequences that are rec-
ognized by autoreactive Th cells from most patients
with ITP is the first step towards specific peptide
immunotherapy to re-induce Th tolerance.
There is now greater understanding of the mecha-
nisms of thrombocytopenia in ITP, which involve both
increased platelet destruction and, in a significant pro-
portion of cases, impaired platelet production. In fact,
stimulation of platelet production with thrombopoietin
receptor agonists has been a recent successful therapeu-
tic application deriving from this concept.
Many important issues still need to be adequately
addressed in future research. Major gaps remain the
understanding of the role played by T cell and B cell
subtypes, as well as the role of factors modulating the
clinical phenotype of the disease, including response to
treatment and spontaneous remissions.
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