American Journal of Hematology 80:232–242 (2005)

Thrombocytopenic Conditions—Autoimmunity and

Hypercoagulability: Commonalities and Differences
in ITP, TTP, HIT, and APS
Martine Szyper Kravitz and Yehuda Shoenfeld*
Center for Autoimmune Diseases and Department of Medicine B, Chaim Sheba Medical Center Tel-Hashomer,
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Immune thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP),

heparin-induced thrombocytopenia (HIT), and antiphospholipid syndrome (APS) are clin-
ical conditions associated with significant morbidity and mortality. These well-defined
clinical syndromes have in common several properties: (1) their pathogenesis is immune
mediated, specifically by autoantibodies; (2) thrombocytopenia is a hallmark in these
four conditions; (3) except for the case of ITP, platelet and endothelial cell activation
occurs in TTP, HIT, and APS, resulting in a prothrombotic state and an increased risk of
thrombosis. Although these four immune-mediated syndromes are well-defined dis-
eases, several case reports and studies have documented the association of two dis-
eases in the same patient, illustrating the concept of the kaleidoscope of autoimmunity.
Am. J. Hematol. 80:232–242, 2005. ª 2005 Wiley-Liss, Inc.
Key words: immune thrombocytopenia purpura; thrombotic thrombocytopenia purpura;
heparin-induced thrombocytopenia; antiphospholipid syndrome

INTRODUCTION together in 50% of sera. IgM is found infrequently

[1]. The antibody-coated platelets are recognized by
Immune thrombocytopenia purpura (ITP), throm-
tissue macrophage Fc receptors, resulting in their
botic thrombocytopenia purpura (TTP), heparin-
phagocytosis, or alternatively platelets are destroyed
induced thrombocytopenia (HIT), and the antiphospho-
by complement-induced lysis [2]. The absence of anti-
lipid syndrome (APS) are clinical conditions associated
bodies in about 40% of ITP patients may indicate
with significant morbidity and mortality. This review
autoantibody against other platelet surface proteins,
focuses on these four immune-related syndromes
a limitation of the assay sensitivity, or the presence of
in adults, in an attempt to shed light on common and
other mechanisms. T and B lymphocytes that react
specific pathogenic mechanisms, predisposing condi-
with platelet autoantigens can be detected in the per-
tions, and etiologies.
ipheral blood and spleen of patients with ITP [3,4], and
autoantibody production by cells from the spleen,
blood, and bone marrow has been demonstrated [4].
PATHOGENIC MECHANISM
Autoantibodies Yehuda Shoenfeld holds the Laura Schwatz-Kipp Chair for
Autoimmunity, Tel Aviv University.
ITP, TTP, HIT, and APS are autoimmune disor-
ders mediated by antibodies directed against specific *Correspondence to: Prof. Yehuda Shoenfeld, M.D., FRCP (Hon.),
antigens. In ITP, anti-platelet antibodies directed Head, Department of Medicine B, Chaim Sheba Medical Center,
against glycoproteins (gp) Ib–IX, IIb–IIIa, IV, and Tel-Hashomer, 52621, Israel. E-mail: shoenfel@post.tau.ac.il
Ia–IIa on the platelet surface can be demonstrated in
Received for publication 14 January 2005; Accepted 8 March 2005
50–60% of patients [1]. One or more classes of immu-
noglobulin (Ig) can be found in patients’ sera, most Published online in Wiley InterScience (www.interscience.wiley.com).
frequently IgG or IgA (70%), and they occur DOI: 10.1002/ajh.20408
ª 2005 Wiley-Liss, Inc.
 Review: ITP, TTP, HIT, and APS—Commonalities and Differences
Also, a skewing of cytokine production suggestive of a
Th0/Th1 activation (elevated interleukin (IL)-2 and
interferon (IFN)-g, and reduced-to-absent IL-10 levels)
and reduced Th3 responses have been demonstrated
[5–7]. In addition, a recent study suggests that T
lymphocyte-induced lysis of platelets may contribute
to platelet destruction [8]. Finally, reduced megakar-
yocyte production and impaired maturation in the
presence of some ITP plasmas provide evidence for auto-
antibody-induced suppression of megakaryocytopoiesis
[9,10].
In summary, although cellular mechanisms can con-
tribute to the thrombocytopenia in ITP, the majority
of adult ITP patients produce autoantibodies that are
involved in platelet destruction. Antiplatelet antibodies
directed against surface gp have also been described in
patients with sepsis [11] and SLE [12]. As such, and
according to current guidelines, their demonstration is
not required for the diagnosis of ITP [13,14].
The pathogenesis of TTP stems from a severe defi-
ciency of the enzyme ADAMTS13 (a disintegrin-like
and metalloprotease with thrombospondin type 1
motif) or from its inhibition. ADAMTS13 prevents
inappropriate microvascular platelet aggregation by
cleaving von-Willebrand factor (vWf) between
Tyr1605 and Met1606, thereby producing small
dimers and multimers. In acute sporadic TTP, IgG
and IgM autoantibodies inhibit the protease activity
of ADAMTS13, resulting in the persistence of un-
usually large multimers of vWf [15–17]. These large
multimers interact more avidly with platelet mem-
brane gp and with the subendothelial matrix, trigger-
ing the aggregation of circulating platelets at sites
with high intravascular shear stress [17], and the for-
mation of platelet-rich and vWf-rich thrombi. In
most patients with TTP, plasma ADAMTS13 activity
is less than 5% of normal [15,16]. Tsai and Lian [16]
described IgG and IgM inhibitory antibodies against
ADAMTS13 activity in 50–80% of patients with
acquired TTP [15,16]. Antibodies with similar activity
have also been described in patients with TTP asso-
ciated with ticlopidine or clopidogrel use [18,19].
Some patients with acquired TTP have unusual
large multimers of vWf, in the absence of severely
reduced levels of metalloprotease activity [20]. Several
authors have suggested that in these cases, the anti-
bodies generated prevent attachment of ADAMTS13
to endothelial-cell binding sites, without interfering
with the active site [17,21,22].
Supporting this hypothesis, autoantibodies against
gp IV (CD36), a cell-surface thrombospondin recep-
tor, have been detected in some patients with TTP
[21], and IgM and IgG antibodies have been demon-
strated in the plasma from a TTP patient, that reacted
with ADAMT13 without inhibiting its activity [22].
233
HIT is a drug-induced, antibody-mediated syn-
drome. Exposure to heparin induces the formation
of IgM, IgG, and IgA antibodies that bind to com-
plexes of platelet factor 4 (PF4) and heparin on plate-
let surfaces, via the Fab portion, and led to platelet
activation via binding of the Fc portion of the anti-
body to platelet receptor FcgRII (CD32) [23]. Similar
to TTP, HIT is a transient disorder, as PF4–heparin
antibodies decline within weeks to months to unde-
tectable levels after an episode of HIT [24,25]. HIT
antibodies are polyspecific, i.e., they are directed
against multiple neoepitope sites [26–28]. The affinity
of HIT IgG for PF4–heparin is intermediate between
that of relatively low-affinity antigens (b2GPI) and
that of high-affinity antigen (tetanus toxoid) [29]. In
addition, sera from HIT patients with thrombosis
have been shown to contain antibodies that activate
endothelial cells and stimulate monocytes to produce
tissue factor [30]. These events contribute to the throm-
bin generation in HIT. HIT antibodies have never been
detected in people not exposed to exogenous heparin,
except in few APS patients in very low titers [31].
The antiphospholipid antibodies (aPLAs) are a
family of autoantibodies that exhibit a broad range
of target specificities, all recognizing various combi-
nations of b2 glycoprotein I (b2GPI) and phospho-
lipids. Anticardiolipin antibodies (aCL) are the most
characteristic aPLA, but several autoantibodies have
been described, directed against phosphatidylserine,
phosphatidylethanolamine, phosphatidylcholine, phos-
phatidic acid, and phosphatidylglycerol. Other charac-
teristic autoantibodies include lupus anticoagulant
(LAC) and anti-b2GPI antibodies [32]. Generally,
there is concordance between LAC and either aCL or
anti-b2GPI antibodies, but they differ in sensitivity and
specificity, aCL being more sensitive and LAC being
more specific for APS. Although IgG, IgM, and IgA
can be present, the specificity of aCL antibodies for
APS is higher for IgG than for the IgM isotype [33].
In summary, although specific autoantibodies are
at the core of the pathogenic mechanism in these four
syndromes, in TTP and APS these are primarily inhi-
bitory antibodies that impair the activity of several
proteins, similar to acquired hemophilia and acquired
von Willebrand syndrome. In contrast, in ITP and
HIT the antibodies bind to platelets or to complexes
on the surface of platelets, leading either to their
clearance by the reticuloendothelial system or to
their destruction by complement-mediated lysis.
Antigenic Target
The antibodies in ITP are directed against specific
regions of gp Ib–IX, IIb–IIIa, IV, and Ia–IIa on the
platelet surface. In a cohort of adult ITP patients,
234 Review: Szyper Kravitz and Shoenfeld
He et al. [1] demonstrated that 93% of sera reacted
with more than one gp, but gp IV and Ia–IIa were
never the sole targets. They also demonstrated the
presence of antibodies against cytosolic epitopes,
always accompanied by antibodies against exosolic
epitopes as well. Interestingly, antibodies against cyto-
solic epitopes can be detected in patients with post-
transfusional purpura and drug purpura, but whereas
antibodies against external gp epitopes are a distinctive
marker for ITP and are considered pathogenic, anti-
bodies against internal gp epitopes are not pathogenic
[1]. Most autoepitopes on gp IIb–IIIa are conforma-
tional and are localized to the N-terminal portion of
gp IIb, while the gp Ib–IX autoepitopes are localized
to the gp Ib amino acids 333–341 [34].
Little is known about epitope specificity and reac-
tivity of anti-ADAMTS13 antibodies. In a recent
study, Klaus et al. [35] evaluated the reactivity of
purified recombinant fragments of ADAMTS13,
with anti-ADAMTS13 autoantibodies from 25
patients with acquired TTP. All TTP plasmas con-
tained antibodies directed against the cysteine-
rich and the spacer domain (cys-rich/spacer) of
ADAMTS13, underscoring the importance of this
region for functional activity of ADAMTS13 [35].
The antibodies associated with HIT are specific for
complexes of heparin and PF4, a heparin-binding
chemokine (C-X-C family), stored in platelet alpha
granules, and secreted after activation [36]. PF4 is a
70-amino acid protein, rich in the basic amino acids
lysine and arginine, whose monomers spontaneously
form tetramers. The four monomers expose lysine
residues at the carboxy-terminal that are critical for
heparin binding [37] but not necessary for antibody
binding. Upon interaction with heparin, PF4 under-
goes conformational changes exposing neoepitopes.
IgG antibodies recognize conformational epitopes
on PF4 that are revealed only after binding of suffi-
ciently large heparin fragments containing at least 10
residues. At least two dominant recognition sites have
been described: using chimeric constructs between
PF4 and a structurally related heparin binding che-
mokine, neutrophil-activating peptide (NAP), Ziporen
et al. [38] found that one antigenic site involves the
third domain of PF4, discrete from the lysine/arginine-
rich ring implicated in heparin binding. Using
human/mouse PF4 chimeras and a monoclonal
anti-human PF4/heparin antibody, a second deter-
minant near the third cysteine was recently identified
by Li et al. [39]. Finally, by creating mutated PF4
molecules at positions 49, 55, and 61, which resulted
in impaired binding of IgG, Visentin et al. [37]
demonstrated that several conformational epitopes
mediate the binding of antibodies to the heparin–
PF4 complex. HIT antibodies can also bind to
other members of PF4 C-X-C chemokine family,
i.e., NAP and interleukin 8 (IL-8), independent of
the presence of heparin [40].
Galli [41] and McNeil [42] independently demon-
strated that aPLA are directed against a complex of
b2GPI and anionic phospholipids. b2GPI is a 326-
amino acid protein, which has anticoagulant proper-
ties, and plays a role in the clearance of apoptotic
bodies from the circulation [43]. It is composed of five
domains. Similar to PF4, b2GPI also undergoes con-
formational changes upon interacting with phospho-
lipids, exposing neoepitopes enabling antibody
binding. aPLA binds to amino acid sequences in the
fifth domain of b2GPI. For some aPLAs, target sites
can also be expressed on the fourth domain, when
they attach to phosphatidyl serine exposed on the
surface of activated or damaged cells [44]. In addi-
tion, a peptide (TLRVYK) identified in bacterial
antigens, which shares sequence similarities with
region III of b2GPI, was shown to induce antibodies
that caused fetal loss in mice [45]. In murine and
rabbit models, the b2GPI molecule was found to be
immunogenic, as immunization resulted in the gen-
eration of anti-b2GPI antibodies, and high titers of
b2GPI-dependent aCL were associated with classical
clinical manifestations of APS, such as fetal resorp-
tions, thrombocytopenia, and prolongation of acti-
vated partial thromboplastin time (aPTT) [46].
aPLAs exhibit a wide range of specificities, binding
to a variety of targets with or without b2GPI, among
them prothrombin, protein C, annexin V, lipopoly-
saccharide binding protein, complement C4b-binding
protein, and thrombin-modified antithrombin [33].
To summarize, the antigenic site in ITP seems to be
restricted to gp commonly expressed on platelet sur-
faces and endothelial cells. In TTP, preliminary data
points to a restricted specificity. In contrast to this
narrow specificity, in HIT and APS the autoantibo-
dies are polyspecific, i.e., are directed against multiple
neoepitope sites. In addition, these antibodies share a
similar pattern of antigenic target; both consist of
protein epitopes bound to polyanions: b2GPI linked
to anionic phospholipids in APS and PF4 linked to
heparin in HIT.
Endothelial Activation and Hypercoagulability
Endothelial injury is a key initiating event in the
pathogenesis of TTP. Possible causes of endothelial
injury include bacterial endotoxins, antibodies,
immune complexes, oxidative injury, and drugs. In
addition, impaired fibrinolysis and reduced produc-
tion of prostacyclin have been implicated in the devel-
opment of TTP [15]. Several authors have
demonstrated that TTP plasma, as opposed to ITP
 Review: ITP, TTP, HIT, and APS—Commonalities and Differences
plasma, causes activation and induces injury to
endothelial cells [47,48], manifested by a significant
increase in endothelial microparticles [47–49], e-selectin,
p-selectin [50], thrombomodulin [51], and b-thrombo-
globulin [52], and all markers of endothelial cell and
platelet activation, and induces increased expression of
adhesion molecules such as ICAM-1 and VCAM-1 [48].
In addition, anti-endothelial cell antibodies (AECA)
have been demonstrated in patients with TTP [53].
These antibodies activate endothelial cells, with
enhanced interleukin-6 (IL-6) and vWf release,
increased expression of adhesion molecules (p-selectin,
e-selectin, and VCAM-1), thrombomodulin, and
increased monocyte adhesion to endothelial cells [53].
These findings suggest an additional antibody-
mediated pathogenic mechanism in TTP, whereas
AECA directed against microvascular endothelial
cells contribute to the development of endothelial
injury leading to thrombosis.
In HIT patients, a significant prothrombotic state
develops as a result of several mechanisms. Thrombin
generation results from procoagulant platelet
changes, mainly due to microparticle release, second-
ary to platelet activation by anti-PF4–heparin IgG
[54], and possibly by tissue factor produced by the
endothelium [55] and monocytes [56]. Blank et al. [57]
have demonstrated that in vitro, anti-PF4–heparin
antibodies can directly activate endothelial cells via
binding of the Fab portion of the IgG. This activation
was manifested by an increased release of IL-6, vWf,
and thrombomodulin [57] and increased expression
of adhesion molecules (p-selectin, e-selectin, and
VCAM-1), inflammatory cytokines (IL-1B, IL-6,
TNFa, and PAI-1), increased monocyte adhesion,
and increased expression of tissue factor [56–59].
Interestingly, in a recent clinical study on patients
with acute coronary syndrome treated with heparin,
the development of HIT antibodies was associated
with a significant increase in recurrent myocardial
infarction within 30 days [60]. These studies support
the notion that platelet activation and an inflammatory
milieu contribute to endothelial activation, and the
induction of prothrombotic state, that distinguish HIT
antibodies from other drug-dependent antiplatelet anti-
bodies [61].
In APS, antibodies are directed against phospholi-
pids-binding proteins, mainly b2GPI, expressed on or
bound to the surface of endothelial cells or platelets
[62,63]. Binding of anti-b2GPI antibodies induces
endothelial cells activation, manifested by upregula-
tion of adhesion molecules expression (e-selectin,
ICAM-1, and VCAM-1), secretion of pro-inflamma-
tory cytokines (IL-1B and IL-6), and interference
with arachidonic acid metabolism [64–67]. Addition-
ally, an increased expression in monocyte tissue factor
235
associated with an increase in procoagulant activity,
and autoantibodies against tissue factor pathway
inhibitor, and endothelial cells have been documented
[68–73].
In conclusion, the concomitant activation of plate-
lets and endothelial cells in HIT, TTP, and APS,
results in a prothrombotic state, even though these
conditions are associated with thrombocytopenia.
PREDISPOSING CONDITIONS AND
MOLECULAR MIMICRY
Several authors have suggested that persistent
infections such as with HIV, hepatitis C virus, and
Helicobacter pylori, are associated with ITP, and sev-
eral small studies have demonstrated improvement of
platelet counts with suppression or eradication of
infection, suggesting a role of persistent antigen expo-
sure to the pathogenesis of ITP [74–77]. In HIV-
infected patients, immune platelet destruction has
been shown to be associated with the presence of a
cross-reactive antibody recognizing both the confor-
mational structure of HIV–gp-120 and platelet gp
IIIa (CD61) [78]. In addition, circulating immune-
complexes from HIV-infected patients have been
found to contain IgM anti-idiotype antibodies against
gp IIIa, which appears to regulate their serum reac-
tivity in vitro and their level of thrombocytopenia in
vivo [79]. This cross-reactivity suggests that molecular
mimicry may be important in the pathogenesis of
immune thrombocytopenia in HIV-infected patients.
The role of H. pylori infection on the development
or persistence of ITP, and its eradication on platelet
counts, emerged from several small studies [75,76].
More recently, Takahashi et al. [80] evaluated the
effect of H. pylori eradication on platelet counts,
and the role of molecular mimicry in the pathogenesis
of ITP. H. pylori infection was detected in 75% of
ITP patients. Among them, eradication was achieved
in 87% of patients, 54% of whom showed increased
platelet counts within 4 months following treatment.
Complete responsive patients showed a significant
decline in platelet-associated IgG levels. Platelet
eluted from 12 patients recognized H. pylori cytotoxic
associated gene A (CagA) protein, and in three com-
pletely responsive patients, levels of anti-CagA anti-
body in platelet eluates declined after eradication
therapy [80]. Cross-reactivity between platelet-asso-
ciated IgG and H. pylori Cag protein suggests that
molecular mimicry may play a key role in the patho-
genesis of a subset of ITP patients. In a recent review
of the literature on the association of ITP and
H. pylori, 58% (278/482) of ITP patients were posi-
tive for H. pylori. Eradication was achieved in 88% of
cases, and was accompanied by a complete or partial
236 Review: Szyper Kravitz and Shoenfeld
platelet response in approximately half the cases [81].
Jackson et al. [82] recently reviewed 13 cohort reports
on adult ITP and found an overall response rate of
52% following H. pylori eradication. Interestingly,
the majority of the studies which demonstrated a
positive association between H. pylori eradication
and platelet counts, reported on cohorts of patients
from Japan and Italy [75,83–86], while studies con-
ducted in the U.S. documented little or no response
[87,88]. The heterogeneity of the populations
reported, the variable study designs, differences in
inclusion criteria, differences in definition of platelet
response, and concurrent ITP therapy, are some of
the variables which may have influenced or con-
founded the results. For example, the highest
response rate, reported by Gasbarrini et al. [75]
(100% response of platelet counts after eradication
of H. pylori), may have been affected by concurrent
steroid treatment, while in one of the studies which
reported no response, a wash-out period of no therapy
was required prior to eradication [88]. In summary, the
current data suggests that H. pylori eradication can be
considered for H. pylori-positive ITP patients [82], and
the British Society of Hematology has listed H. pylori
testing and eradication as a level III treatment for ITP
[14]. Larger studies in several populations with longer
follow-up are needed to better understand the relation-
ship between H. pylori infection and eradication and
recovery of platelet counts in ITP.
In TTP, the trigger event responsible for the develop-
ment anti-ADAMTS13 antibodies has not been identi-
fied yet, but the development of TTP has been associated
with medical conditions such as pregnancy, cancer, che-
motherapy, and bone marrow transplantation [15,17]. In
addition, a variety of infectious agents have been asso-
ciated with the development of TTP, among them
Escherichia coli, Shigella typhi, Campylobacter jejuni,
Streptococcus pneumonia, and Yersinia pseudotubercu-
losis [89,90]. Several case reports have documented the
association of TTP with viral infections, including HIV
[91], CMV [92], parvovirus B19 [90], adenovirus [93],
especially among immunosuppressed patients, and
Mycoplasma pneumoniae [94]. Cases of relapse of TTP
have also been associated with bacteremia with Staphy-
lococcus aureus [95] and Acinetobacter anitratus [96]. The
hypothesis that an infectious agent may be the inciting
factor is reinforced by a report by Watson et al. describing
a fatal case of TTP in a man whose wife died 6 months
later of a very similar illness [97].
HIT is a transient, drug-induced, autoimmune dis-
order, associated with exposure to heparin. The fre-
quency of HIT depends on the type of heparin used
(bovine unfractionated heparin > porcine unfractio-
nated heparin > low molecular weight heparin), and
the patient population (surgical>medical>obstetrical).
The highest frequency of HIT (5%) has been reported
in post-orthopedic surgery patients receiving up to 2
weeks of unfractionated heparin [98–100].
aPLAs are found among healthy subjects (1–5%),
increases with age [101], and also occur in association
with autoimmune diseases, primarily SLE (15–30%)
[101–103]. SLE patients with aPLA are at an
increased risk of developing ‘‘secondary’’ APS, up to
70% within 20 years [104]. Likewise, several reports
have documented the progression of apparently ‘‘pri-
mary’’ APS into SLE [105]. Several infections have
been associated with aPLA, among them pneumonia,
skin and urinary tract infections, HIV, and hepatitis
C virus infections [106–111]. The development of cat-
astrophic APS has been particularly associated with
bacterial infections [112]. Recently, Shoenfeld et al.
[45] elucidated the infectious etiology of APS by
demonstrating bacterial induction of autoantibodies
to b2GPI. Immunization of naı̈ve mice with microbial
pathogens, which share homology with a synthetic
peptide (TLRVYK, which shares sequence similari-
ties with region III of b2GPI), resulted in various
levels of mouse IgG anti-TLRVYK antibodies. Pas-
sive transfer of these purified antibodies into naı̈ve
mice resulted in the generation of anti-b2GPI antibo-
dies, the highest levels detected in mice immunized
with Haemophilus influenzae, Neisseria gonorrhea,
and tetanus toxoid [45]. Mice immunized with these
anti-b2GPI antibodies developed significant thrombo-
cytopenia, prolonged aPTT, and fetal loss. Similarly,
Gharavi et al. [113] induced circulating anti-b2GPI
antibodies in naı̈ve mice by immunization with syn-
thetic peptides conjugated to BSA which share simi-
larity to an adenovirus DNA-binding protein, CMV
HCMVA, and Bacillus subtilis [113,114]. These stu-
dies established a mechanism of molecular mimicry in
experimental APS, demonstrating that b2GPI struc-
ture homologous bacteria are able to induce circulat-
ing anti-b2GPI antibodies along with APS
manifestations. More recently, using the Swiss Pro-
tein Database, several homologies have been found
between anti-b2GPI peptide target epitopes and the
structure of pathogens associated with common med-
ical diseases such as H. pylori (peptic disease and
gastric lymphoma), Streptococcus pyogenes (rheu-
matic fever), and several Saccharomyces cerevisiae
proteins (Crohn’s disease) [111]. Other clinical situa-
tions where aPLA has been detected include drugs,
cancer, and hemodialysis. In these conditions the iso-
type is usually IgM, it is present at low titers, and is
not associated with thrombotic events [111].
In summary, ITP, TTP, and APS have been asso-
ciated with infections, autoimmune diseases, and can-
cer. In addition, drug exposure has been described as
a possible inciting event in TTP, HIT, and APS.
 Review: ITP, TTP, HIT, and APS—Commonalities and Differences
CLINICAL PRESENTATION
In adults, ITP usually manifests insidiously with
the development of purpura. Symptoms and signs
are variable, ranging from the asymptomatic patient
with mild bruising and mucosal bleeding, through
frank hemorrhage, the most serious being intracranial
bleeding. Overall, bleeding symptoms are uncommon
unless platelet counts are lower than 30  109/L.
Women of age 20–40 years are afflicted most often
and outnumber men by a ratio of 3:1. According to
current guidelines [13,14], the diagnosis of ITP is
based on the exclusion of other causes of thrombocy-
topenia using the history, physical examination, com-
plete blood count, and blood smear examination.
Testing for HIV is indicated in patients with risk
factors.
In contrast to ITP, TTP is usually acute in onset.
The historical ‘‘classic pentad’’ includes hemolytic
anemia with fragmentation of erythrocytes and signs
of intravascular hemolysis, thrombocytopenia, dif-
fuse and nonfocal neurological findings, decreased
renal function, and fever. Signs and symptoms occur
variably and depend on the extent of the arteriolar
involvement. The severity of the disease is reflected by
the degree of anemia, thrombocytopenia, and the
serum LDH level. Coagulation studies are usually
normal or mildly abnormal. The diagnosis of TTP is
based on the combination of the clinical and labora-
tory findings. Although not required for diagnosis,
biopsies of skin, muscle, gingiva, and bone marrow
may show typical arteriolar abnormalities. TTP is
distinguished from ITP or Evans syndrome by the
finding of fragmented RBC in the peripheral blood,
and a negative direct Coombs’ test.
Distinguished from the three other disorders, HIT
is a transient, drug-induced condition leading to
thrombocytopenia. Due to platelet activation,
patients are at an increased risk of thrombosis, espe-
cially in the medium and large vessels, predominantly
in the venous bed. The most common thrombotic
complication of HIT is lower-limb deep vein throm-
bosis (DVT), and pulmonary embolus is the most
common cause of mortality. Arterial thrombosis
occurs more commonly in the lower limbs, followed
by cerebral arteries and lastly the coronary arteries,
the reversal order of atherothrombosis. Several retro-
spective cohort studies [115–118] indicate that among
patients who develop isolated HIT, 25–50% will
develop clinically evident thrombosis after stopping
heparin, with or without substitution by coumadin,
usually within the first week [119,120]. The risk of
fatal thrombosis is 5% [115]. Early heparin cessation
does not reduce the risk of thrombosis in patients
with isolated HIT [116], if the response is cessation
237
of heparin rather than substitution with an alternative
anticoagulant. Although several assays have been
developed for the diagnosis of HIT, these are adjuncts
to the development of thrombocytopenia during
heparin treatment and the physician’s assessment of
the clinical probability of HIT.
The APS is characterized by a combination of
arterial and/or venous thrombosis, recurrent fetal
loss, often associated with a mild-to-moderate throm-
bocytopenia, and elevated titers of aPLA. Similar to
ITP, women outnumber men by a ratio of 5:1.
Recently, the Euro-Phospholipid Project group ana-
lyzed the clinical manifestations in a cohort of 1,000
patients [121]. Primary APS occurred in 53% of cases.
In 41% of patients, APS was associated with SLE,
and in 6% with other autoimmune diseases. Similar
to HIT, the most common manifestation was DVT
(39%). Other common manifestations included
thrombocytopenia, livedo reticularis, stroke, pulmon-
ary embolism, heart valve disease, transient ischemic
attack, and obstetrical morbidity. Venous thrombotic
events occurred more frequently than arterial (37%
vs. 27%), and 15% of patients had both. Fetal loss
occurred alone in 12%. Obstetric complications are
characteristic of APS, especially pre-eclampsia,
eclampsia, and placental abruption, and fetal compli-
cations include early and late fetal loss and premature
birth [121]. The diagnosis of APS is based on the
Sapporo criteria, which require the diagnosis of vas-
cular thrombosis and/or pregnancy morbidity and the
demonstration of anticardiolipin antibodies and/or
lupus anticoagulant on two or more occasions [122].
In summary, although thrombocytopenia is a cen-
tral feature in the four syndromes described, with the
exception of ITP, these disorders are manifest mainly
with thrombotic events, especially in the venous sys-
tem. There is a predilection for DVT in HIT and
APS, although arterial thrombosis may develop in
these two diseases, more often in APS. By contrast,
TTP affects mainly the smaller-sized arteries and
arterioles. Hemolysis is specific for TTP, as is RBC
fragmentation. Renal dysfunction and neurological
deficit are characteristic of TTP, although they also
occur in APS. Women outnumber men in both ITP
and APS, but obstetric manifestations occur primar-
ily with APS.
The treatment of ITP, TTP, HIT, and APS is com-
plex and is beyond the scope of this review.
ASSOCIATION OF DISEASES
Although ITP, TTP, HIT, and the APS are four
well-defined diseases or syndromes, several reports
have documented the development of two of these
diseases in the same patient. Sixteen cases of ITP
238 Review: Szyper Kravitz and Shoenfeld

TABLE I. Adult ITP, TTP, HIT, and APS: Comparison of Disease Characteristics

ITP TTP HIT APS

I-Pathogenesis
Autoantibodies IgG, IgA IgG, IgM IgG, IgM, IgA IgG, IgM, IgA
Specificity Restricted Restricted Polyspecific Polyspecific
Target gp on platelet ADAMTS13 PF4–heparin b2GPI–PL complex
Ib–IX, IIb–IIIa, complex on platelet
IV, Ia–IIa
Conformational epitope Conformational epitope
Action Led to clearance or Inhibitory Led to activation and Inhibitory
lysis of coated platelets clearance of platelets
Endothelial None +++ +++ +++
cell activation
Adhesion molecule None ++ ++ ++
expression
II-Predisposing conditions
Infection HIV, HCV HIV, CMV, Parvo, adeno HIV, HCV, Several
bacterial infections
H. pylori E. coli
Shigella typhi C. jejuni
S. pneumoniae
Autoimmunity SLE SLE None SLE, PAN, GCA,
Wegener
Drugs ? Ticlopidine Heparin Hydralazine, quinidine,
Clopidogrel procainamide
Chemotherapy
Cancer + ++ ++ ++
Molecular mimicry HIV gp 120 and gp IIIa In animal models
suggested H. pylori CagA Protein suggested with adeno,
CMV, H. influenza,
N. gonorrhea, and
tetanus toxoid
III-Clinical presentation
Onset Insidious or abrupt Abrupt Abrupt Abrupt
Manifestations Thrombocytopenia Thrombocytopenia Thrombocytopenia Thrombocytopenia
Asymptomatic to cutaneous Hemolytic anemia Thrombosis Venous Thrombosis, arterial and venous
and mucosal bleeding RBC fragmentation > arterial Fetal loss
Renal dysfunction Neurologic deficit
Neurologic deficit

and TTP have been published in the medical litera- CONCLUSIONS

ture. Interestingly, all were younger than 40 years of
age, and half of them were seropositive for HIV
[123,124]. Two patients with HIT followed by ITP
have been reported by Waheed [125]. Recently,
Espinoza et al. [126] described 46 patients with
thrombotic microangiopathic hemolytic anemia
(TMHA) associated with aPLA. TMHA was the
first clinical manifestation of APS in 57% of patients.
LAC was detected in 86% of episodes of TMHA, and
positive aCL in 89%. Amoura et al. [127] described
two cases of TTP occurring in patients with definite
primary APS. Finally, in a study on 82 newly diag-
nosed ITP patients, 38% were found to also have
aPLA [128]. These patients had an increased risk of
thrombosis or fetal loss, suggesting that a significant
proportion of patients, who initially present with ITP
and aPLA, will eventually develop APS.
ITP, TTP, HIT, and APS are autoimmune diseases
leading to thrombocytopenia. Although each of these
diseases is a distinct clinical entity, similarities exist
in their pathogenic mechanism and clinical presenta-
tion (Table I). Moreover, the development of two of
these conditions in the same patient, or the evolve-
ment of one autoimmune disorder into another,
reflects the complexity and redundancy of the
immune system, and provides additional illustrations
for the concept of the kaleidoscope of autoimmunity
[102,129].
Summary Points
1. ITP, TTP, HIT, and APS are autoimmune
disorders mediated by antibodies directed against
 Review: ITP, TTP, HIT, and APS—Commonalities and Differences
specific antigens. Self-reactive T and B lympho-
cytes are involved.
2. In TTP and APS, the antibodies are primarily
inhibitory, and they impair the activity of several
proteins. In contrast, in ITP and HIT the
antibodies bind to platelets or to complexes on
the surface of platelets, leading to platelet clear-
ance by the reticuloendothelial system or destruc-
tion by complement-mediated lysis.
3. In ITP the antigenic site is restricted to gp
commonly expressed on platelet surfaces and
endothelial cells, and in TTP, preliminary data
points to a similar restricted specificity. In
contrast, in HIT and APS the autoantibodies
are polyspecific, i.e., are directed against multiple
neoepitope sites.
4. Even though TTP, HIT, and APS are conditions
associated with thrombocytopenia, a concurrent
activation of platelets and endothelial cells devel-
ops, which results in a prothrombotic state and an
increased risk for thrombosis. ITP is not asso-
ciated with a hypercoagulable state.
5. As with other autoimmune diseases, molecular
mimicry may underlie the pathogenesis of some
autoimmune thrombocytopenic conditions.
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