DOI: 10.

2478/rjim-2019-0014
ROM. J. INTERN. MED., 2019, 0, 0, 1-16

Idiopathic thrombocytopenic purpura (ITP) – new era for an old disease

MINODORA ONISÂI1,2, ANA-MARIA VLĂDĂREANU1,2, ANDREEA SPÎNU1,

MIHAELA GĂMAN1,2, HORIA BUMBEA1,2

Affiliation:
1. Hematology Clinic, Emergency University Hospital Bucharest
2. University of Medicine and Pharmacy Carol Davila Bucharest

RUNNING HEAD: ITP updated

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Abstract
Immune thrombocytopenia is an autoimmune hematological disorder characterized by
severely decreased platelet count of peripheral cause: platelet destruction via antiplatelet
antibodies which may also affect marrow megakaryocytes. Patients may present in critical
situations, with cutaneous and/or mucous bleeding and possibly life-threatening organ
hemorrhages (cerebral, digestive, etc.) Therefore, rapid diagnosis and therapeutic intervention
are mandatory.
Corticotherapy represents the first treatment option, but as in any autoimmune
disorder, there is a high risk of relapse. Second line therapy options include: intravenous
immunoglobulins, thrombopoietin receptor agonists, rituximab or immunosuppression, but
their benefit is usually temporary. Moreover, the disease generally affects young people who
need repeated and prolonged treatment and hospitalization and therefore, it is preferred to
choose a long term effect therapy. Splenectomy – removal of the site of platelet destruction –
represents an effective and stable treatment, with 70-80% response rate and low
complications incidence.
A challenging situation is the association of ITP with pregnancy, which further
increases the risk due to the immunodeficiency of pregnancy, major dangers of bleeding, vital
risks for mother and fetus, potential risks of medication, necessity of prompt intervention in
the setting of specific obstetrical situations – delivery, pregnancy loss, obstetrical
complications, etc.
We present an updated review of the current clinical and laboratory data, as well as a
detailed analysis of the available therapeutic options with their benefits and risks, and also
particular associations (pregnancy, relapsed and refractory disease, emergency treatment).

Key words: ITP, physiopathology, diagnosis, treatment, pregnancy.

INTRODUCTION
Immune thrombocytopenia – primary immune thrombocytopenic purpura (ITP) is
defined as an isolated thrombocytopenia, without changes of the bone marrow and in the
absence of other causes of thrombocytopenia [1]. The main characteristic of this pathology is
increased peripheral destruction of platelets, the majority of patients showing anti-platelet
membrane glycoproteins antibodies. The most severe complication is hemorrhage, the
intracranial one presenting the highest risk. Mortality by hemorrhage is 1% in children and
5% in adults. In the case of adults with ITP, there is a major risk of severe hemorrhage in the
elderly patients and with history of hemorrhage [2].
Primary ITP is characterized by isolated thrombocytopenia, as opposed to ITP
secondary to other disorders, such as: autoimmune pathology (e.g. systemic lupus
erythematosus), viral infections (chronic hepatitis C virus), lymphoproliferative neoplasms,
etc.
The term of acute ITP, recently replaced by newly diagnosed ITP, has less than 3
months from diagnosis. Persistent ITP refers to immune thrombocytopenia with 3 months to
1-year evolution, whereas chronic ITP is the disease longer than 12 months. Refractory ITP
comprises cases which did not respond to splenectomy or relapsed after surgery, with high
risk of bleeding, which makes it necessary to continue therapy [3].

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 ETIOPATHOGENESIS
As stated before, thrombocytopenia may be primary or secondary to an immune or
infectious process [4-7]. The loss of tolerance to the glycoproteins expressed on the platelet
or megakaryocyte surface is in fact the ITP pathogenic mechanism [6-13].
Classification of the immune tolerance disorders within ITP:
- disorders of peripheral immune tolerance – arising in the setting of immune
stimulation
- differentiation lines with denatured B lymphocytes subsets
- disorders of central immune tolerance – during maturation or at the bone marrow
level [6].
If the pathogenic mechanism is based on peripheral destruction, the response to
therapy is good and post-treatment relapse rate is low. In this case, only platelets are affected.
If there is also a production shortage (antibodies affecting megakaryocytes as well), the
patients have a higher risk of relapse [3].
 Secondary ITP
The pathogenic mechanism of ITP in children is increased peripheral destruction of
platelets; in two thirds of cases, the onset of the disease is preceded by an infectious episode;
in 80% of patients there is spontaneous remission [14,15]. ITP secondary to infectious
exposure or vaccines is another example of ITP with pathogenic mechanism of peripheral
platelet destruction. Helicobacter pylori, varicella-zoster or cytomegalovirus infections may
induce ITP. Incidence of ITP secondary to MMR vaccine is 1 in 40,000 administrations [16].
About 20% of the patients with ITP have chronic infection with hepatitis C virus (HCV), this
being the most frequent ITP-associated infection [17].
The pathogenic mechanism of HCV-associated ITP involves the activation of B-
lymphocytes with production of anti HCV antibodies which cross-interact also with GP IIIa
[18]. A similar mechanism is incriminated in thrombocytopenia related to HIV-infection,
along with a direct inhibition of platelet production via HIV-infection of the megakaryocytes
[19] and increased platelet destruction by reactive oxygen species [20]. The risk of
thrombocytopenia in HIV-infected patients is directly proportional with disease progression
and inversely proportional with the response to antiretroviral treatment [3].
Studies reported that eradication of Helicobacter pylori infection was associated with
resolution of otherwise “typical” ITP, especially for patients presenting with only mild
thrombocytopenia. There are many theories suggested for H pylori associated
thrombocytopenia, but most of those discuss mimicry and cross-reactivity of the antibodies
[7].
Chronic lymphocytic leukemia can associate ITP, with a prevalence of 1-5% [21].
The pathogenic mechanism is the differentiation blockage with the emergence of abnormal B
cells. The low survival rate and the negative prognosis markers are common elements of this
association. Although very rare (less than 1% of the cases), ITP can also occur in
hematological diseases such as nonHodgkin lymphoma or Hodgkin disease. The pathogenic
mechanism associated with secondary ITP in lymphoproliferative syndromes is platelet
production shortage. A disorder of B and T lymphocytes apoptosis associated with mutations
of the genes encoding Fas, Fas-L or other apoptosis mediators (caspases) is the mechanism
underlying the autoimmune lympho-proliferative syndromes [22]. About 20% of the patients
develop immune thrombocytopenia; additionally, neutropenia and/or autoimmune hemolytic
anemia can occur. Association between autoimmune hemolytic anemia and immune
thrombocytopenia is defined as Evans syndrome [23].
One third of the patients diagnosed with antiphospholipid syndrome can also present
immune thrombocytopenia. The direct role of antiphospholipid antibodies in

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thrombocytopenia is unclear, since also anti-GP IIIa antibodies were found in
thrombocytopenic patients with antiphospholipid syndrome [3].
Systemic lupus erythematosus (SLE) is another pathology associated with immune
thrombocytopenia. Sustained response to corticotherapy in patients presenting both SLE and
immune thrombocytopenia is lower compared to the response observed in primary
thrombocytopenia, because most patients with secondary thrombocytopenia require also
additional therapy with danazol or hydroxychloroquine in order to achieve a higher response
rate [24].
Another situation of thrombocytopenia caused by production shortage is in the post-
transplant settings, one of the mechanisms involved hereby being the alloantibodies
production to the donor’s platelets.
 Primary ITP
Typically, primary ITP has a CD4+ Th0/Th1 cytokine profile [9,25]. The levels of
interferon gamma and interleukin-2 are high, and the number of regulatory T and Th2+ cells
is lower in the peripheral blood [26]. Platelet count correlates inversely to the increased
Th1/Th2 ratio. In ITP patients, the alteration of the regulatory factors of T-cells apoptosis
level adjusts the expression of T cells subsets and triggers the survival of T cell self-reactive
clones [27]. Following splenectomy or Rituximab therapy, the Th1/Th2 ratio decreases, and
the Vβ domain of T-lymphocytes becomes normal [13]. Additionally, if there is a response to
Rituximab therapy or to thrombopoietic agents, a normal value of the regulatory T cells will
be noticed; this response suggests a complex mechanism of Rituximab action (better than B
CD20+ cell depletion) [28,29]. In ITP, the somatic mutations as well as the B-cell dependent
and antigen-induced clonal expansion are the autoantibodies production triggers [30].
CD8+ cytotoxic T-lymphocytes cause platelet lysis using A/B, Apol and perphorine
granzymes expressed on their surface [31]. ITP patients show an increased number of
VLA4+CD3+CD8+ T-cells in their bone marrow, which express the CX3Cr1+ receptor [32].
 Antiplatelet antibodies
The studies performed in the 70’s showed an increased level of the platelet-associated
IgG immunoglobulin in ITP patients [3]; further studies have showed that this was related to
platelet α granules and was not specifically linked to platelet surface. The development of the
test for detecting antigen-specific antiplatelet antibodies in the 80’s led to the identification in
60% of the ITP patients of IgG reacting to the platelet membrane glycoproteins, mainly
GPIIbIIIa (αIIbβ3 integrine) and GP Ib/IX [11,33]. The antiplatelet antibodies are initially
directed against a single glycoprotein on the platelet surface. Further on, by assimilating the
platelets on whose surface antibodies are found and by processing the antigenic peptides in
the platelet membrane of the glycoprotein structure which are not targeted by the antibodies,
the antibody production against these new glycoproteins can be a result of epitope
dissemination [34].
 The antibody-dependent mechanism of platelet destruction
In ITP patients, the platelet life span is short; a high percentage of platelets are
destroyed in the spleen and liver [3]. Splenic macrophages phagocytize the platelets with
antibodies attached to their membrane by means of the Fcγ receptor [12]. The polymorphism
of the gene which encodes FcγRIII (FcγRIIIA -581 V/V), a subtype of the Fcγ receptor, is
overexpressed; the V/V isoform of the Fcγ receptor has increased affinity for the IgG1 and
IgG3 immunoglobulins, as compared to the F/V or F/F isoforms. A monoclonal antibody of
the FcγRIII (mAb 3G8) receptor is able to increase the platelet value in patients with
refractory ITP [3].
The existence of alternative mechanisms of platelet destruction, alongside with the
primary mechanism of intrasplenic destruction, is reflected by the post-splenectomy relapse
in one third of the patients [13]. In over one half of a cohort of 240 patients, the antiplatelet

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antibodies fixed the complement at the platelet membrane level, some of them inducing in
vitro complement-dependent platelet lysis [35]. In HIV infected patients, amino acids 49-66
of antiGPIIIa antibodies induce total complement-independent destruction of platelets; in this
process, peroxides of NADH/NADPH system are involved [20].

CLINICAL DIAGNOSIS OF PRIMARY ITP

The clinical features are correlated to the platelet number. Platelet counts
below 20,000/μl increase the risk of spontaneous bleeding like epistaxis or gum hemorrhage
and menorrhagia, petechiae or ecchymoses, especially at the extremities [2,3]. Mucosal
spontaneous bleeding may occur under 10,000/μl; the bleeding time also increases. In
extreme cases, when platelet number is below 5,000/μl, ITP patients may present severe
hemorrhagic complications (subarachnoid, intracerebral hemorrhage, digestive hemorrhage
or other internal bleedings. [2,3,7].
Signs and symptoms associated with secondary ITP to different disorders are:
- rash, arthralgia, serositis – suggesting SLE;
- hepatomegaly and elevated transaminase values – associated to virus C hepatitis;
- fever and lymphadenopathies – associated to infections or lymphoproliferative neoplasms.
Hemorrhages involving the skin, mucosae, gastrointestinal tract or any other organ
are the most frequent clinical trait in ITP patients. The “dry purpura” usually occurs in
absence of a preceding event. The mucosal hemorrhage can manifest as epistaxis,
menorrhagia, gum bleeding and digestive hemorrhage [36]. Patients with severe
thrombocytopenia present oral hemorrhagic lesions; additionally, they can have severe
hemorrhagic manifestations without any clinical expression.
The most severe complication of ITP, more frequent in adults than in children,
occurring at a platelet count lower than 10,000/μl, is the intracranial hemorrhage [15,37,38].
There is a higher risk of hematological neoplasms in ITP patients, with a 5-year
cumulative risk of 4.7 (95% CI, 1.7-12.7) for hematologic malignancies determined on a
Danish population-based cohort study of 407 primary chronic ITP patients [39]. A high
occurrence of CLL phenotype lymphocytes was demonstrated [40].
The overall incidence of hemorrhagic events was 3.2% per patient per year, in a study
conducted by Cortelazzo. Although the patients had similar platelet counts, 10.4% of the
patients over the age of 60 presented hemorrhagic events, as compared to the 0.4% of the
patients under 40. A previous history of hemorrhage predicted an increased risk of bleeding
with a relative risk of 27.5 [2,3].
Studies did not demonstrate a direct correlation between the severity of bleeding and
the platelet count. This hypothesis might be explained by binding of antiplatelet antibodies to
highly restrictive areas of the β-helix of GP IIb domain, near fibrinogen ligand site, a process
which can interfere with platelet aggregation.
Fatigability occurs in 22% of children and 22-39% of adults [41]. Treatment response
correlates with the significant improvement of fatigue and other parameters quantifying
health-related quality of life measurements [42]. A study performed by Mathias (2007)
demonstrated that fatigability occurs in patients with platelets under 10.000/μl, with ongoing
hemorrhages and during corticotherapy; on the other hand, there is no connection between
fatigability and ITP duration, patient age or gender [43]. In ITP patients, fatigability can
result from a high level of inflammatory cytokines, particularly IL-2 and IFN-γ, associated
with the Th1 profile.
Thrombosis – recent studies show that ITP patients have a high thrombosis risk.
Aledort reported 18 thromboembolic accidents in 186 adult ITP patients [44]. The severity of
thrombocytopenia correlates with the thrombosis development risk.

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 The mechanism is unclear – an explanation of this process could be the occurrence of
antiphospholipid antibodies in these patients, which increase the risk of thrombosis onset45.
Although the guidelines do not recommend in ITP patients routine screening for
antiphospholipid antibodies [46,47], the latter should be considered in patients who develop
thrombosis. Other factors involved in the pathogenesis of thrombosis are the increased level
of prothrombotic microparticles derived from platelets and the activation of the complement
on the platelet surface covered by antibodies [48].
The guidelines do not discuss the management of thrombosis in thrombocytopenic
patients with ITP. Experts consider that for a platelet count over 40,000/μl, anticoagulant
treatment can be used, but the decision depends on the severity of thrombosis and the
patient’s characteristics. During anticoagulant therapy, concomitant aggressive treatment for
ITP is mandatory.

LABORATORY DIAGNOSIS
ITP is defined by isolated thrombocytopenia, with normal morphology and otherwise
normal CBC. If present, abnormal platelet morphology should result in a diagnosis of an
inherited platelet disorder, such as macrothrombocytopenia in the presence of the MYH9
mutation [49]. A careful examination of the peripheral blood smear (PBS) is necessary to
exclude other causes of thrombocytopenia, such as the microangiopathic disorders, platelet
satellitism or pseudothrombocytopenia. Sometimes, isolated thrombocytopenia can be
identified in acute or chronic leukemia, myelodysplastic syndromes, but in such settings,
CBC and PBS reveal different other alterations suggestive for the underling hematological
disorder. A 2011 report shows a decrease of platelet precursors in ITP patients; Eltrombopag
increases the number of platelet precursors [50].
In ITP patients, a normal or increased number of megakaryocytes can be present in
the bone marrow, sometimes with an increased number of immature megakaryocytes. The
ultrastructural analysis can reveal the megakaryocyte apoptosis [51].
Bone marrow examination is not usually mandatory in ITP. It is recommended to be
performed if another hematological pathology is suspected (other anomalies on the CBC,
unexpected systemic signs and symptoms, such as adenopathies, organ enlargement, etc), if
patients are over 60 years old, and before splenectomy [47].
For the diagnosis of ITP, the sensitivity of antiplatelet IgG-antibody testing is 91%,
although the specificity is only 27%; therefore, the positive predictive value is only 48% and
the diagnostic value is low. The lack of utility of antiplatelet antibody testing has been
illustrated by several studies. For this reason and the lack of correlations with clinical
outcomes, the test is not routinely recommended in the diagnosis or management of ITP
[34,52].
The ITP international working group guidelines recommend the following lab tests:
the reticulocyte count and the Coombs tests to rule out autoimmune hemolytic anemia, blood
group and Rh type - useful for therapeutic purposes [anti-Rh(D) therapy], screening for HIV,
C hepatitis (viral infections that often cause thrombocytopenia, in some cases as a form of
secondary ITP) and Helicobacter pylori, as stated before, due to the association between
thrombocytopenia and H. pylori infection, especially found in some geographical regions
[7,47].

DIFFERENTIAL DIAGNOSIS
Diagnosis of primary ITP is an exclusion one, considering the non-immune causes of
thrombocytopenia and secondary immune thrombocytopenia. Drug-induced immune
thrombocytopenia (DITP) is induced and/or perpetuated by the presence of a drug or other

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ingested substance (eg, quinine, quinine-containing beverages, some antibiotics such as
Vancomycin or trimethoprim-sulfamethoxazole, heparin, Valproic acid, etc) and is expected
to resolve after drug discontinuation [3]. The thrombocytopenia of non-immune etiology
includes drug or toxin administration (eg. alcohol, chemotherapy - which inhibit platelet
production), platelet splenic sequestration, primary disorders of the bone marrow, prior
radiation exposure (therapeutic or accidental) and hereditary thrombocytopenias.
Hereditary thrombocytopenias can be misdiagnosed as ITP [53]. There is diagnostic
suspicion when there is a family history of thrombocytopenia or there is no response to
standard therapy. The family history of thrombocytopenia is supported in some cases by the
absence of the radius syndrome (the TAR syndrome), anomalies in the right cavities of the
heart (the di George syndrome) or platelets increased in size and Döhle bodies in neutrophils
(gene MYH9-connected anomalies) [54].
Bernard-Soulier syndrome is an autosomal recessive familial thrombocytopenia,
characterized by the absence of the GPIb-IX platelet complex with large platelets, with
decreased platelet aggregation at increased doses of ristocetine and hemorrhages [55].
Wiskott-Aldrich syndrome is an X-linked syndrome, characterized by severe
immunodeficiency and small size platelets. Congenital amegakayriocytic thrombocytopenia
is a recessive autosomal disorder, caused by the mutations at c-Mpl gene which further cause
the absence of megakaryocytes accompanied by severe thrombocytopenia.
The pathology of hereditary thrombocytopenias is represented by mutations at the
transcription factors – such as GATA1 (sex-connected heredity) and RUNX1 (dominant
autosomal) – with abnormal megakaryocyte maturation.

THERAPEUTIC OPTIONS IN ITP

As compared to the general population, the morbidity and mortality rate in ITP
patients is higher, especially if under treatment the platelet count is lower than 30,000/μl [39;
56]. Mortality is equally influenced by hemorrhage and infections [56].
Because the majority of cases evolve to chronic disease and the hemorrhage risk is
higher than in children, the ITP management in adults is more complex [36,39]. The
therapeutic objective is to achieve a hemorrhage risk-free platelet count, considered 20-
30,000/μl [56], with the lowest toxicity of medication. For a platelet count above 50,000/μl,
treatment in unnecessary, the indication being set according to the individual hemorrhage
risk, age, patient’s life style and option.

 First-line treatment
Corticosteroids are the most widely used treatment. Initially, at least 80% of the ITP
patients respond; a high percentage of patients relapse when attempting to reduce the
corticosteroid doses [47,57]. Studies have been conducted to analyze if in the newly
diagnosed ITP patients, an increased dose of corticosteroids results in a longer remission. The
results of Cheng’s study reveal a sustained response – a platelet value over 50,000/μl –
maintained 6 months later in 50% of the patients treated with 40 mg of dexamethasone per
day for 4 days [58]. Mazzucconi’s study noticed a 15-month survival rate with no relapse in
newly diagnosed patients treated with 4-6 cycles of dexamethasone, administered every two
weeks [57]. A comparative study by Zaja showed the superiority of associating
dexamethasone and Rituximab against the single-drug therapy with dexamethasone as first
line treatment, leading to better response in 6 months; for a longer monitoring period, these
differences become unremarkable [59].
Increased dose dexamethasone has similar effects to the standard dose of
prednisolone, as demonstrated by a 2010 prospective multicentric study [60].

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 Intravenous immunoglobulins (IVIg) are often administered in association with
corticotherapy, particularly when it is necessary to raise the platelet count in a short time.
Another indication is the use in order to preserve a risk-free platelet count in patients with
thrombocytopenia after reduction of corticosteroid doses, until a more permanent therapeutic
solution is applied. In 60-80% of the patients, IVIg increase the platelet count, sometimes
within days, but the response is short (1 to 3 weeks); the therapy is efficient both in
splenectomized and in non-splenectomized patients. Although multiple regimens have been
suggested, clinicians prefer the dose of 1g/kg/day, administered intravenously for 1-2 days
[13]. The mechanisms of action of IVIg include: inhibition of megakaryocyte apoptosis and
activation of cytotoxic T-cells, modulation of cytokines and the expression and activity of the
Fcγ receptor, and neutralization of the complement [61,62]. Adverse reactions include aseptic
meningitis, edema, nephrotoxicity, thrombosis and rarely severe hemolytic anemia.
Anti-Rh(D) antibody links to the Rh(D) antigen on the erythrocyte membrane, thus
inducing clearance of the cells with antibodies on their surface and inhibition of the
opsonized platelet clearance by the reticulo-endotelial system [62]; other mechanisms
involved include Fcγ receptor and inflammatory cytokine modulation and reduction of the
antigens specific for the B-lymphocyte membrane. The Anti-D therapy is efficient only in
patients with intact spleen function and Rh(D) positive. The hemolysis determined by Anti-D
is reflected in the decrease by 0.5-2 g/dl of the hemoglobin value; about 1 patient in 1000
may suffer severe hemolysis, rarely associated with disseminated intravascular coagulation
features, kidney failure and exitus [63]. Response is achieved in 70% of the patients treated
with the approved dose of 50μg/kg; a higher dose (75μg/kg) correlates with a higher response
rate. Cooper et al showed that repeated immunoglobulin administration for recurrent
thrombocytopenia has a long-term result in 43% of patients [64].

 Second-line therapy
For ITP resistant to corticotherapy, IVIg or anti-D Ig, there are some secondary
therapy lines. As compared to the older agents, Rituximab and the thrombopoietin receptor
agonists have increased efficacy with minor adverse reactions [65,66].
Rituximab is a chimeric antiCD20 antibody frequently used as a secondary treatment
line. It induces long-term response in about 21% of adults [67]. The recommended dose is
375mg/m2 weekly for 4weeks, although a dose of 100mg/m2 has similar efficiency [68]. The
mechanism of action involves a complex immunological modulation. The success of the
treatment was correlated in one study with the normalization of T-lymphocyte distribution
[69] and in another with a normal value and function of the regulatory T-lymphocytes [29].
The adverse reactions of Rituximab include immediate infusion-related reactions, vasculitis,
and cardiac rhythm disorders.
Splenectomy is the treatment method which offers the most long-term remission,
considered the “gold standard” [70]. It was the first successful method in the ITP treatment.
According to a systematic review which included 135 cases, 66% of the patients fully
responded to splenectomy [87]. Another systematic review including 1223 patients with ITP
treated by laparoscopic splenectomy reveals a 72% 5-year success rate; most relapses occur
during the first two years post-splenectomy [71].
Splenectomy has been associated with a high risk of infections and post-surgery
sepsis. It is not certain yet if the splenectomized ITP patients have a high risk for infection
post-splenectomy as compared to other ITP patients who have not undergone surgery. A
Danish study reports that – as compared to the non-splenectomized patients but
recommended for surgery (ITP) – in the splenectomized patients for ITP the infection was
seen only within the first 90 days post-surgery. Afterwards there was no such infectious risk,
with a relative risk of 1 between days 91 and 365 and 1.4 over 1 year post-splenectomy.

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Enterobacterias are the etiology of early infections [72]. Despite this, the morbidity connected
to long-term infections and the post-splenectomy morbidity can be considerably reduced by
encapsulated anti-microorganism immunization and the aggressive treatment of the fever
syndrome.
The place of splenectomy within the ITP management is different according to
present day guidelines. The International Working Group [47] as well as the American
Society of Hematology guidelines [46] classify it among the second-line treatment options,
recommending it for cases resistant to corticotherapy; Rituximab and thrombopoietic agents
are considered alternative second-line methods. In clinical practice, the therapeutic decision
is particularized on a case by case situation [73].
Thrombopoietin receptor agonists (TRA) – Some clinicians keep this type of
treatment strictly for the refractory ITP patients; in contrast, other doctors recommend them
in newly diagnosed cases, with the aim of supporting the platelet count during the first year
of diagnosis, hoping to attain spontaneous hematological remission [74]. None of the two
approved TRAs (Romiplostin and Eltrombopag) is homologous to the thrombopoietin
structure. By linking to the thrombopoietin receptor c-Mpl on the megakaryocytes, both drugs
stimulate the differentiation and proliferation of the megakaryocytes and thereby increase the
platelet production [75].
Romiplostim (Nplate) is a fusion protein containing four thrombopoietin
peptodomimetic regions, linked to an Fc domain ensuring in vivo stability [76]. The dose is
dictated by the platelet count; it is administered subcutaneously, weekly. The efficacy of this
drug was assessed in two placebo-controlled phase III trials, which enrolled 63
splenectomized patients and 62 non-splenectomized patients, respectively, the latter being
diagnosed with severe chronic ITP [77]. In 38% of the splenectomized patients (as compared
to 0% in the placebo group) and in 61% of the non-splenectomized ones (as compared to 5%
of the placebo group) who had received Romiplostim, there was a long-term response,
defined by a platelet value higher than 50,000/μl, preserved 6 of the last 8 treatment weeks.
The patients treated with Romiplostim were more susceptible to reduce or interrupt treatment
(corticotherapy) and very few salvage treatment [77].
Eltrombopag is a small molecule whose action mechanism is similar to that of
Romiplostim, although Eltrombopag links to the transmembrane region of c-Mpl and not to
the link site of the ligand (thrombopoietin) [78]. After the phase I trials, the drug was tested
on patients with severe chronic ITP at 6-week and 6-month intervals, respectively [79]; 59-
79% of the patients treated with the pharmacoactive product (as compared to 16-28% of the
patients treated with placebo) responded; similar responses were noticed in the
splenectomized patients, as compared to the non-splenectomized ones. Also, the treated
patients had fewer hemorrhagic episodes, and a higher percentage of them reduced the ITP
associated medication. The EXTEND study analyzed the long-term safety and efficacy [80]:
88% of patients had a platelet count over 50,000/μl at least once during the study period; the
value before treatment, the splenectomy history or the prior ITP medication were not
predictive for the response.
Both TRAs are well tolerated, although some adverse reactions have been identified
[81]. In 8-10% of patients who cease treatment, there is a thrombocytopenia rebound, which
may cause consistent hemorrhage [81,82]. Within the first two weeks after treatment
cessation, careful monitoring of the platelet number is necessary. A higher platelet value, in
response to the TRAs, correlates with arterial and venous thrombosis risk [83]. Two (0.5%)
of the 407 patients treated with Romiplostim suffered a cerebro-vascular accident, deep
venous thrombosis or pulmonary embolism [84]; in contrast, in 19 of the 301 patients treated
with Eltrombopag, a total of 25 thromboembolic events occurred [80]. There was no
correlation between the platelet value and thrombosis in any of the studies. In about 5% of

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the patients treated with TRAs, a higher degree of reticulin fibrosis was noticed in the bone
marrow [81]. In most cases, the process was not associated with clinical signs of bone
marrow dysfunction [85].
In patients treated with TRAs, it is mandatory to monitor the platelet count and
peripheral blood smear; the loss of response or the development of fibrosis impose cessation
of the treatment.

ITP AND PREGNANCY

Antiplatelet autoantibodies have the ability to cross the fetoplacental barrier, as they
are IgG type. Therefore, in pregnant ITP patients, antiplatelet autoantibodies can also destroy
the fetus’s platelets. Thus, ITP is the main etiology of the fetal or neonatal immune
thrombocytopenia. As compared to the children diagnosed with neonatal alloimmune
thrombocytopenia, about 10% of the newborn affected by ITP will have a platelet count
below 50,000/μl and the risk of intracerebral hemorrhage will exist in 1-2% [3].
Although neonatal thrombocytopenia cannot be discovered by lab tests, risk factors
should be taken into consideration. Splenectomy antecedents for the maternal ITP, an ITP
sibling or gestational thrombocytopenia (platelet value lower than 100,000/μl) will increase
the risk of neonatal thrombocytopenia [3].
It is recommended to test for antiplatelet antibodies in ITP or thrombocytopenic
patients. It is necessary to start the treatment – corticotherapy or immunoglobulins – in the
case of symptomatic thrombocytopenia and presence of antiplatelet antibodies.
Because the thrombocytopenia secondary to maternal ITP has a lower risk than the
neonatal autoimmune thrombocytopenia, the fetus’s platelet value is not to be measured.
During the newborn’s first days of life, it is recommended to monitor the platelet value,
though. According to the severity of thrombocytopenia, transfusions with platelet
concentrates can be administered [3].

EMERGENCY TREATMENT IN ITP

Hospitalization is mandatory for patients with severe thrombocytopenia and
especially for the newly diagnosed ones. The aim of therapy is to increase the platelet value
as soon as possible. Corticotherapy or immunoglobulins are administered i.v., and in critical
situations the number of platelets can be temporarily increased by platelet concentrate
transfusions. In some patients, the life span of the transfused platelets can be raised by the
simultaneous administration of immunoglobulins [86]. In order to increase the platelet
number very rapidly, splenectomy may be used; it was performed as an ITP treatment method
in patients with severe intracranial hemorrhage [3].

 Refractory ITP
The management of this form relies on chemotherapy and immunosuppressive agents,
such as azathioprine, cyclophosphamide, vinca alcaloids, danazol, cyclosporine and
mycophenolat mofetil [66].
Refractory ITP is diagnosed when the patient relapses or does not respond to
splenectomy, and there is a severely decreased platelet count or active hemorrhage is present,
requiring treatment. The last criterion does not include the treatment preceding an invasive
procedure or the hemorrhage prophylaxis after major trauma. Refractory patients can get
temporary response to i.v. corticosteroids or immunoglobulins. Literature highlights that in
over 60% of the cases, splenectomy is curative; this result was not obtained by any of the
other treatment methods [87,88,89]. In non-splenectomized ITP patients, refractory disease is
out of the question. Keeping in mind the benign feature of the pathology in children and the
postponement of splenectomy, criteria for refractory ITP in children have not been defined.

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ITP in non-splenectomized patients who do not respond to medication must be described as
newly diagnosed ITP, persistent or chronic (in accordance with the duration of the disease),
non-responsive to one or more agents.
The main purpose of treatment in refractory ITP is achieving an optimal platelet
value, in order to prevent significant hemorrhage, with minimum toxicity of the therapy
[90,91]. In case of a severe hemorrhage, in any stage of the pathology, adjuvant treatment or
even platelet transfusions are mandatory [27].

CONCLUSIONS
Immune thrombocytopenia is an autoimmune hematological disorder usually
characterized by severely decreased platelet count of peripheral cause. Patients may present
in critical situations, with cutaneous and/or mucous bleeding and possibly life-threatening
organ hemorrhage (cerebral, digestive, etc.). Therefore, rapid diagnosis (considering multiple
differential diagnoses) and therapeutic intervention is mandatory. First line treatment
indications are quite clear, but most patients relapse and a good knowledge of available
options and their benefits is required.
Trombocitopenia imuna reprezinta o patologie hematologica autoimuna caracterizata
prin scaderea marcata a numarului de trombocite de cauza periferica: distructie plachetara
prin anticorpi antitrombocitari, care pot afecta de asemenea si megakariocitele medulare.
Pacientii se pot prezenta in situatii critice, cu hemoragii cutanate si/sau mucoase severe si
chiar cu hemoragii amenintatoare de viata (cerebrala, digestiva, etc). Astfel, se impun
diagnosticul si interventia rapida.
Corticoterapia reprezinta prima optiune de tratament, dar, ca in orice patologie
autoimuna, exista un risc mare de recaderi. A doua linie de tratament este reprezentata de:
imunoglobulinele intravenoase, agonistii de receptori de trombopoietina, rituximab sau
agenti imunosupresori, dar beneficiul acestora este de regula temporar. In plus, boala
afecteaza de regula persoanele tinere care astfel necesita tratamente si spitalizari repetate si
prelungite, astfel incat este de ajutor o optiune terapeutica cu efect prelungit. Splenectomia –
indepartarea situsului de distructie trombocitara – reprezinta un tratament eficient si stabil,
cu o rata de raspuns de 70-80% si rata mica de complicatii.
O situatie particulara este trombocitopenia imuna in sarcina, care asociaza risc
crescut si prin imunodeficienta specifica sarcinii, pericolele semnficative in cazul aparitiei
hemoragiilor, riscurile vitale pentru mama si fat, riscurile potentiale ale medicatiei,
necesitatea unei interventii rapide in anumite situatii obstetricale specifice – nasterea,
pierderea sarcinii, complicatii obstetricale, etc.
Prezentam un review al datelor actuale clinice si de laborator, precum si al optiunilor
terapeutice disponibile din punct de vedere al riscurilor si beneficiilor, precum si cateva
situatii particulare – sarcina, boala refractara sau cu recadere, terapia in urgenta.
Correspondence to: Mihaela Găman MD, PhD
University Assistant Carol Davila University of Medicine and Pharmacy
Hematology Clinic, Emergency University Hospital Bucharest
email: [email protected]
tel: +40721262638

Declaration of interest: The authors declare that there are not conflicts of interest.

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Received February 20th 2018

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