cancers

Review
The Challenge for a Correct Diagnosis of Refractory
Thrombocytopenia: ITP or MDS with Isolated
Thrombocytopenia?
Aikaterini Kosmidou 1, * , Eleni Gavriilaki 2 and Athanasios Tragiannidis 3

1 2nd Department of Internal Medicine, General Hospital of Kavala, 65500 Kavala, Greece
2 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of
Thessaloniki, 54642 Thessaloniki, Greece; [email protected]
3 2nd Department of Pediatrics, AHEPA University Hospital, Aristotle University of Thessaloniki,
54636 Thessaloniki, Greece; [email protected]
* Correspondence: [email protected] or [email protected]; Tel.: +30-6976464499

Simple Summary: The aim of the present review is to summarize the main characteristics of immune
thrombocytopenia (ITP) and to determine cases where persistent, isolated thrombocytopenia is
misclassified as ITP. One of the most common misdiagnoses of ITP is myelodysplastic syndrome
presented with thrombocytopenia as an isolated abnormality (MDS-IT). As MDS-IT has been poorly
described in the literature, the precise characterization of patients with MDS-IT is essential and the
extend diagnostic, clinical and laboratory work-up is necessary for determining which of the cases of
persistent thrombocytopenia are refractory and which of them have mistakenly been attributed to a
diagnosis other than MDS-IT.

Abstract: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated

thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter
in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally
one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild
mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for
ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and
Citation: Kosmidou, A.; Gavriilaki, E.;
rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid
Tragiannidis, A. The Challenge for a
treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical
Correct Diagnosis of Refractory
and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The
Thrombocytopenia: ITP or MDS with
aim of this review is to summarize the conditions associated with isolated thrombocytopenia and
Isolated Thrombocytopenia? Cancers
2024, 16, 1462. https://doi.org/ highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome
10.3390/cancers16081462 presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in
the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-
Academic Editor: Eishi Ashihara
IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk
Received: 29 February 2024 prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients
Revised: 8 April 2024 are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases
Accepted: 9 April 2024 of persistent thrombocytopenia a detailed diagnostic work-up is applied—including evaluation of
Published: 11 April 2024 peripheral-blood smear, bone marrow examination and cytogenetic testing—to avoid unnecessary
therapy delay.

Keywords: isolated thrombocytopenia; ITP; refractory thrombocytopenia; myelodysplastic syndrome;

Copyright: © 2024 by the authors.
MDS-IT
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
1. Introduction
creativecommons.org/licenses/by/ Thrombocytopenia is a very common hematologic finding, but presented with multi-
4.0/). variable clinical expression. It is defined as a platelet count below 150 × 109 /L, which is

Cancers 2024, 16, 1462. https://doi.org/10.3390/cancers16081462 https://www.mdpi.com/journal/cancers

Cancers 2024, 16, 1462 2 of 15

considered the lower limit of normal [1]. Thrombocytopenia can be further subdivided into
three categories of severity: mild (100 × 109 /L to 149 × 109 /L), moderate (50 × 109 /L to
99 × 109 /L) and severe (<50 × 109 /L), which indicate the laboratory reference ranges with
potential clinical significance [2,3]. Given that patients with a platelet count ranging from
100 to 150 × 109 /L—especially when stable for over 6 months—do not always present with
major clinical symptoms, the adoption of a cutoff value of 100 × 109 /L, or an adjusted one
according to the acuity of presentation and the underlying disease, has been proposed as a
more appropriate indication of a pathologic condition [2].
Although thrombocytopenia is associated with a defect of primary hemostasis, the
correlation between platelet count and bleeding risk is not always straightforward. That
means not only that patients may present with a wide spectrum of clinical signs, from
asymptomatic disease to spontaneous bleeding, but also that the prediction of bleeding
risk is imprecise, lacks evidence-based recommendations and depends on the individual
patient and the underlying condition [3,4]. Along with the broad differential diagnosis
of thrombocytopenia and the need for comprehensive investigation, physicians face the
potentially life-threatening nature of some presentations, which requires rapid evaluation
and emergency intervention. Therefore, the establishment of the cause of thrombocytopenia
is crucial and necessitates a structured diagnostic approach with the integration of clinical
findings, laboratory tests and other medical disciplines.
The major mechanisms of a reduced platelet count include decreased platelet pro-
duction, increased peripheral destruction, dilution and redistribution of platelets [4,5].
Decreased production of platelets occurs in bone marrow failure syndromes (e.g., aplas-
tic anemia, paroxysmal nocturnal hemoglobinuria—PNH), bone marrow suppression
(e.g., certain drugs, chemotherapy agents, irradiation, chronic alcohol abuse, viral infec-
tions), bone marrow infiltration (hematologic and non-hematologic malignancies), inherited
thrombocytopenia or systemic conditions (sepsis, nutrient deficiencies, myelodysplastic
syndrome—MDS) [4,6]. One typical example of increased destruction is the immune-
mediated clearance of platelets and possibly megakaryocytes by antiplatelet autoanti-
bodies, which bind to platelets and megakaryocytes and drive them to early destruction
by the reticuloendothelial system. Such antiplatelet antibodies are present in immune
thrombocytopenia-ITP (primary or secondary), drug-induced immune thrombocytopenia
(most commonly by antibiotics and older antiepileptic agents), systemic autoimmune dis-
orders (e.g., systemic lupus erythematosus-SLE) and chronic infections (e.g., hepatitis C
virus-HCV, human immunodeficiency virus-HIV, Helicobacter Pylori) [7–9]. Furthermore,
non-immune mediated increased platelet clearance takes place in disseminated intravas-
cular coagulation-DIC, thrombotic microangiopathies-TMA, in which platelets are being
consumed within thrombi (e.g., thrombotic thrombocytopenic purpura-TTP, hemolytic
uremic syndrome-HUS), mechanical valve replacement and the preeclampsia/HELLP
syndrome [3,10]. The less common mechanism of dilution includes patients who have
received massive fluid resuscitation or blood transfusion, whereas the redistribution of
platelets occurs in conditions that cause splenomegaly and hypersplenism [11].
The aim of the present review is to summarize the pathologic conditions that are associ-
ated with thrombocytopenia—especially when this is presented as an isolated abnormality—
and to emphasize cases where diagnosis of the underlying disease is unclear or confusing.
The current literature was thoroughly searched, based on specific keywords, in electronic
databases—mainly PubMed.

2. Isolated Thrombocytopenia
The aim of the present review is to emphasize the differential diagnosis of isolated
thrombocytopenia, which is much narrower but has been proved challenging, as rare
mechanisms of isolated thrombocytopenia are sometimes overlooked. According to the
American Society of Hematology (ASH), isolated thrombocytopenia is defined as a low
platelet count in the absence of abnormalities of other blood cell lineages and an absence
of symptoms and signs of systemic disorder [2]. In the diagnostic approach of isolated
Cancers 2024, 16, 1462 3 of 15

thrombocytopenia, it is well-established that the most prevalent etiology is immune throm-

bocytopenia (ITP). Overall differential diagnosis is summarized in Table 1.

Table 1. Differential diagnosis of isolated thrombocytopenia.

Differential Diagnosis of Isolated Thrombocytopenia

Immune Thrombocytopenia (ITP) 1
Drug-Induced Immune Thrombocytopenia
Infections
HIV 2
HCV 3
CMV 4
Helicobacter pylori
Myelodysplastic Syndrome with Isolated Thrombocytopenia (MDS-IT) 5
Acquired Amegakaryocytic Thrombocytopenia
Nutritional Deficiency
1ITP Immune thrombocytopenia; 2 HIV Human immunodeficiency virus; 3 HCV Hepatitis C virus; 4 CMV
Cytomegalovirus; 5 MDS-IT Myelodysplastic syndrome with isolated thrombocytopenia.

3. Immune Thrombocytopenia, ITP

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder char-
acterized by low platelet count (<100 × 109 /L) resulting from the combination of an
immune-mediated increased clearance and impaired platelet production [12]. The annual
incidence of the disease is calculated at 1.6–3.9 cases per 100,000 individuals, and the me-
dian age of the total affected population is 56 years old [13]. Epidemiological studies have
shown that the disease is not homogeneously distributed between different age groups in
the total affected population, but presents more frequently in children < 6 years old, women
20–34 years of age and the elderly > 65 years old, with relatively equal distribution in that
age group [13]. Clinical presentations of ITP are often limited to bruising and petechiae,
even in the setting of severe thrombocytopenia. However, more serious mucosal bleed-
ing may occur, including menorrhagia, epistaxis, gastrointestinal hemorrhage, hematuria
or intracranial hemorrhage. It has been suggested that bleeding events of ITP are often
unpredictable, and they are not always related to the severity of thrombocytopenia. This
means that patients with very low platelet counts do not necessarily present with bleeding
manifestations. Additionally, limited data show that patients with a relatively low platelet
count have an increased platelet activity, which is associated with decreased bleeding
risk [14].

3.1. Clinical Definitions

ITP is categorized into three different phases of disease [15]. ‘Newly diagnosed ITP’ is
used for all cases of ITP at the time of presentation which are self-limited within 3 months
from diagnosis. ‘Persistent ITP’ refers to patients with ITP lasting from 3 to 12 months from
diagnosis or patients who are not achieving spontaneous remission or not maintaining
their response after stopping treatment between 3 and 12 months from diagnosis. ‘Chronic
ITP’ is used for patients who suffer from ITP lasting more than 12 months [15].
The main clinical problem of ITP is the increased risk of bleeding, although such
clinical signs may not always be present. There are few bleeding assessment tools which
have not been validated in large prospective studies, making the evaluation of bleeding
risk in ITP individuals rather challenging. Conventionally, the terms ‘mild’, ‘moderate’
and ‘severe’ have been used to indicate the degree of thrombocytopenia and the presence
of bleeding [15]. ‘Severe’ ITP is considered the condition in which the clinical expression
at presentation is sufficient to necessitate treatment, or the occurrence of new symptoms
Cancers 2024, 16, 1462 4 of 15

requires additional therapeutic intervention with a different platelet-enhancing agent or an

increased dose [15].

3.2. Pathophysiology of ITP

Although it is well-known that the pathophysiology of ITP is associated with com-
plex immunological mechanisms, it remains incompletely understood. Shortened sur-
vival of platelets in ITP patients is attributed to the presence of IgG antibodies directed
against platelet membrane glycoproteins (GPs)—especially GPIIb/IIIa and GPIb/IX/V [16].
Platelets are being autoantibody-coated and destroyed as their opsonization facilitates
their phagocytosis by macrophages in the reticuloendothelial system, through interaction
with Fcγ receptors [17,18]. Moreover, antiplatelet antibodies have been shown to play a
role in damaging bone marrow megakaryocytes, resulting in decreased megakaryopoiesis
and thrombopoiesis. Given that megakaryocytes express GPIIb/IIa and GPIb/IX, they are
being targeted by ITP autoantibodies which, in conjunction with the reduced stimulation
by thrombopoietin (TPO), leads to insufficient formation of megakaryocytes and thrombo-
cytes [17,18]. However, antiplatelet antibodies are not detected in up to 50% of patients,
which raises the possibility of alternative mechanisms of platelet destruction.
Abnormalities in regulatory T cells have been described, where limited data suggest
that cytotoxic CD8+ T-lymphocytes participate in platelets destruction—due to an increase
in the expression of their cytotoxic proteins (perforin, granzyme A and granzyme B) and
their strong recruitment into the bone marrow [19,20].
Complement-dependent cytotoxicity has been also demonstrated to participate in the
complex mechanisms mediating ITP pathophysiology, as the deposition and activation
of complement on the membrane of platelets leads to their lysis [21]. IgG autoantibodies
in ITP can be potent activators of the classical complement pathway through enhancing
C1q binding [22]. Moreover, platelets express receptors for complement cleavage proteins,
C3a and C5a, leading possibly to platelet activation and thromboinflammation [23]. In
recognition of these pathophysiological mechanisms, several ongoing trials have been
designed to study therapeutics targeting the complement pathway in ITP.

3.3. Diagnosis of ITP

ITP is diagnosed in patients with a platelet count below 100 × 109 /L—when other
causes of thrombocytopenia have been ruled out. The use of history, physical examination,
complete blood count and peripheral-blood smear is crucial not only for the exclusion of
other thrombocytopenic disorders, but also for the diagnosis of potential secondary causes
of ITP (Table 2) [24]. History should include elements such as systemic disease, drugs,
infection, vaccination and primary hematologic disorders. Physical examination should be
normal aside from bleeding manifestations. When symptoms such as fever, weight loss,
hepatomegaly, splenomegaly or lymphadenopathy are present, there is a clear indication
for an underlying condition. Examination of the complete blood count in a patient with ITP
results in isolated thrombocytopenia, whereas the peripheral-blood smear shows reduced
numbers of platelets—normal or increased in size—with no other abnormalities (e.g.,
schistocytes, dysplastic cells). The presence of giant or small platelets may indicate an
inherited thrombocytopenia or bone marrow failure syndrome. Pseudo-thrombocytopenia
should also be excluded. Serologic evaluation for HCV, HIV and H.Pylori infections is
recommended to be performed routinely in all adult patients, regardless of geographic
locale [24,25]. There is no accurate diagnostic test for ITP, as the detection of antiplatelet
antibodies is seen in only 50–60% of ITP patients [25]. Bone marrow examination should
be considered in selected patients—especially those older than 60 years of age, those with
uncertain diagnosis, constitutional symptoms or non-responsive disease [25].
Cancers 2024, 16, 1462 5 of 15

Table 2. Secondary causes of ITP.

Secondary Causes of ITP 1

Disease Findings Confirmative of Disease
Certain drugs (e.g., acetaminophen, abciximab, carbamazepine,
Initiation of new medication
rifampicin and vancomycin)
Constitutional symptoms and signs; positive serological and
Infection (e.g., HIV 2 , HBV 3 , HCV 4 , CMV 5 , EBV 6 ,
PCR 7 tests for HCV 4 , HBV 3 , CMV 5 , EBV 6 , HIV 2 , urea breath
Helicobacter pylori)
test for H. pylori
Thrombocytopenia; positive direct antiglobulin test for
Evans syndrome
hemolytic anemia
Weight loss, night sweats, lymphadenopathy, splenomegaly;
Lymphoproliferative disorders abnormal complete blood count and bone marrow
aspirate/biopsy
Systemic autoimmune disease (e.g., SLE 8 , rheumatoid arthritis, Arthralgias/arthritis, hair loss, sun sensitivity, mouth ulcers,
antiphospholipid syndrome) rash, thromboembolism
1 ITP Immune thrombocytopenia; 2 HIV Human immunodeficiency virus; 3 HBV Hepatitis B virus; 4 HCV
Hepatitis C virus; 5 CMV Cytomegalovirus; 6 EBV Epstein–barr virus; 7 PCR Polymerase chain reaction; 8 SLE
Systemic lupus erythematosus.

Other testing methods with potential diagnostic significance include measurement of

immature platelet fraction or percentage of reticulated platelets. As those are thought to be
associated with thrombopoietic activity and platelet production, they could supposedly
separate ITP from hypoproductive bone marrow failure syndromes. However, there is a lack
of clinical studies which confirm the clinical value of immature platelet measurements and
standardize this method for the discrimination of ITP from bone marrow failure syndromes,
thus they have limited availability [24,25]. Lastly, measurement of thrombopoietin (TPO)
levels shows elevated results in bone marrow failure syndromes, in comparison to ITP
normal levels. Although it is not routinely used in the diagnostic procedure of ITP, it
could be proved helpful in confusing cases and for predicting response to treatment with
thrombopoietin-receptor agonists (TPO-RAs) [24,25].

Diagnosis of ITP in Childhood

Diagnosis of ITP in childhood should be made after careful exclusion of other causes
of isolated thrombocytopenia. A child with a presumed newly diagnosed ITP should be
repeatedly evaluated with complete blood count and peripheral-blood smear for evolution
to bone marrow dysplasia or another hematologic condition [25]. Aside from the patient’s
history, family history is also important in children with suspected ITP to exclude inherited
thrombocytopenia [26]. Bone marrow evaluation is recommended to pediatric patients
whose thrombocytopenia is accompanied by anemia and/or leukopenia, or whose blood
smear is abnormal, when constitutional symptoms or splenomegaly are present, and the
disease does not respond to first-line therapies [27].

3.4. Treatment of ITP

The decision on which ITP patients are going to benefit from treatment is made
upon their risk of future bleeding. There is no standardized scoring system to assess the
risk of future bleeding. However, treatment is rarely indicated in patients with platelet
counts above 50 × 109 /L in the absence of bleeding due to platelet dysfunction or another
hemostatic defect, trauma or surgery [25]. Generally, it has been recommended that a
platelet count between 20 × 109 /L and 30 × 109 /L is used as a criterion for selecting
patients for treatment [28]. Regarding the quality of response to treatment, this is defined
as a function of the platelet count achieved and an assessment of the change in the severity
of bleeding [29]. A complete response (CR) is considered a platelet count ≥100 × 109 /L
measured on 2 occasions more than 7 days apart and the absence of bleeding, whereas
response (R) is defined as a platelet count ≥30 but <100 × 109 /L and a 2-fold increase from
Cancers 2024, 16, 1462 6 of 15

baseline and the absence of bleeding [15,29]. The term no response (NR) refers to cases
where there is a platelet count <30 × 109 /L or a less than 2-fold increase in platelet count
from baseline or the presence of bleeding [15,29].
The need for inpatient management of ITP individuals is determined by the severity of
thrombocytopenia and bleeding manifestations, and by the acuity of disease presentation.
This means that patients with ITP and a platelet count <20 × 109 /L, regardless of the
severity of their bleeding symptoms, are recommended to be admitted to hospital rather
than be observed as outpatients. On the other hand, for patients with an established
diagnosis of ITP and a platelet count of <20 × 109 /L, who are asymptomatic or have minor
mucocutaneous bleeding, outpatient management is preferred over hospitalization.

3.4.1. First-Line Treatment

Corticosteroids
Corticosteroids are the standard first-line treatment for newly diagnosed ITP patients,
as they act not only by raising the platelet count, but also by having a direct effect on blood
vessels [30]. According to the recommendation from the American Society of Hematology
(ASH), treatment with corticosteroids is indicated in adult patients with a platelet count
below 30 × 109 /L when they are asymptomatic or have minor mucocutaneous bleeding [31].
Especially for those who are older than 60 years of age, have additional comorbidities, take
anticoagulant or antiplatelet medications, or are going to undertake a surgical procedure,
corticosteroids are still being proposed as an initial therapeutic plan rather than observation,
even if their platelet count is at the lower end of this threshold [31]. In all other cases of
patients with a platelet count of ≥30 × 109 /L who are asymptomatic or have minor
mucocutaneous bleeding, the ASH guidelines recommend management with observation
of clinical presentations and laboratory results [31].
As for the preferred type of corticosteroid therapy, prednisone is usually used at
0.5 to 2 mg/kg/day until the platelet count increases (≥30–50 × 109 /L), but response
is expected after several weeks [25]. Due to the major risk of developing corticosteroid-
related complications, prednisone should be rapidly tapered and/or stopped in responders,
and especially in non-responders after 4 weeks [25,31]. If it is important to have a more
rapid response on platelet count, use of dexamethasone at 40 mg per day for 4 days may
be preferred over prednisone, given that dexamethasone produced an increased initial-
response effect at 7 days and a sustained response in 50% of newly diagnosed adults with
ITP [25,32].
Corticosteroid therapy in children with ITP is not recommended for those with no or
minor bleeding (skin manifestations) only, even when the platelet count is <20 × 109 /L [31].
In these cases, ASH guidelines suggest management with initial observation, unless they
are patients with uncertain diagnosis, or patients for whom follow-up cannot be guaranteed.
In children with a diagnosis of ITP and mucosal bleeding, it is recommended initiation of
prednisone at 2–4 mg/kg/day (maximum 120 mg daily) no longer than 7 days [31].

Rituximab
In newly diagnosed adults with ITP, rituximab in combination with corticosteroids
could be considered as first-line treatment if the patient’s priority is placed on possible
sustained remission over concerns for potential side effects [31]. Rituximab has achieved
sustained response in 60% of patients at 6 months and 30% at 2 years [33,34]. In addition,
rituximab can be effective when used as a retreatment, which is especially important for
ITP patients in whom disease mostly relapses [28].
However, rituximab has been associated with important infusion-related side effects
(chills, upper respiratory discomfort, bronchospasm), as well as neutropenia and hypogam-
maglobulinemia. Additionally, its use raises safety concerns due to the increased risk of
infections, even minor. It should not be used in patients with evidence of active HBV
infection (positive HBV surface antigen) or previous HBV infection (present antibodies
against hepatitis B core antigen) [28].
Cancers 2024, 16, 1462 7 of 15

3.4.2. Second-Line Treatment

Thrombopoietin-Receptor Agonists, TPO-RAs
Eltrombopag and romiplostim are TPO-RAs, which have been approved by the Food
and Drug Administration (FDA) and proposed for the treatment of ITP patients with
persistent disease (≥3 months), who are corticosteroid-dependent or unresponsive to
corticosteroids [31]. TPO-RAs are preferred in those patients over rituximab when used
as a second-line therapy. Eltrombopag is administered as a daily tablet (with dietary
restrictions), whereas romiplostim is administered in weekly subcutaneous injections, and
the selection should be guided by individual patient preference and anticipated adherence.
An initial response to TPO-RAs usually occurs within 1 to 2 weeks [25]. Studies on
eltrombopag and romiplostim have shown that response is achieved and maintained in
40–60% of patients receiving continuing therapy, and is maintained after discontinuation in
10–30% of patients [35,36].
The main adverse effect of TPO-RAs is the risk of venous thromboembolism, predom-
inantly in patients with other coexisting conditions and risk factors. Other side effects
of eltrombopag include gastrointestinal symptoms, transaminitis and cataract, whereas
side effects of romiplostim are headache and muscle aches. Both agent’s intake has been
associated with a possible increased risk of myelofibrosis [28].
TPO-RAs in children with ITP are proposed as a second-line treatment over rituximab
and splenectomy only for those with non-life-threatening mucosal bleeding who had not
responded to first-line treatment with corticosteroids.

Splenectomy
Splenectomy is a second-line choice for patients who had not responded to or could not
receive standard medical therapies due to side effects, with the condition of waiting at least
1 year from time of diagnosis to allow for remission to occur [37]. Use of splenectomy is not
preferred in elderly patients who are more prone to peri- and postoperative complications,
as well as in secondary cases of ITP. Short-term adverse effects of splenectomy include
venous thromboembolism and sepsis. Clinicians should also take into consideration the
need for potential prolonged and/or repeated hospitalization, as well as the increased risk
of infection with encapsulated bacteria, which would require recurrent vaccinations in the
long-term [28,37]. In addition, there is no widely accepted test predicting the response to
splenectomy, which renders the consideration of splenectomy limited.
In pediatric patients, splenectomy is overall less desirable because of the lifelong risk
of infection and/or sepsis starting at a young age and prior to full immunity for vaccines.

3.4.3. Emergency Treatment

In the case of patients in whom serious active central nervous system (CNS), gastroin-
testinal or genitourinary bleeding is present, urgent treatment is required, which could
include the withdrawal of anticoagulant or antiplatelet agents, control of blood pressure,
minimization of external trauma and treatment with platelet transfusions, corticosteroids or
intravenous immune globulin (IVIG), or a combination of the above measures [28]. Platelet
transfusions have a confirmed limiting effect on bleeding, but their action is not long-lasting
(commonly for a few hours). They should not be used alone, but in combination with IVIG
and corticosteroids, as they have been proven to have the most rapid onset of action and
increase the platelet count within 1 to 4 days [25]. IVIG is indicated in patients with active
serious bleeding and in those with very low platelet counts (<10 × 109 /L), with or without
bleeding manifestations [25,38].
Additional treatment with antifibrinolytic agents such as tranexamic acid (at dosage
of 1 g, 3 times daily orally) may be helpful for patients with life-threatening active bleeding
and severe thrombocytopenia [25,28].
 Additional treatment with antifibrinolytic agents such as tranexamic acid (at dοsage
Cancers 2024, 16, 1462 of 1 g, 3 times daily οrally) may be helpful fοr patients with life-threatening active bleed-
8 of 15
ing and severe thrombocytopenia [25,28].

4. Refractory ITP:ITP:
4. Refractory TheThe
Challenge for for
Challenge a Correct Diagnosis
a Correct of ITP
Diagnosis of ITP
According
According to the existing
to the existingliterature, 10%10%
literature, of patients
of patients withwithITPITPbecome
become refractory
refractory to to
treatment within 1 year [39]. Given the absence of a specific diagnostic
treatment within 1 year [39]. Given the absence of a specific diagnostic test for ITP and thetest for ITP and the
presence
presenceof other
of othermedical conditions
medical conditions with which
with ITPITP
which shares common
shares common clinical features,
clinical thethe
features,
diagnostic procedure can be challenging and long-term. This is associated
diagnostic procedure can be challenging and long-term. This is associated with significant with significant
difficulty in clinical
difficulty in clinicalmanagement
management andand
a poor
a poorquality
qualityof life for for
of life these patients.
these patients.
Traditionally,
Traditionally, ‘refractory
‘refractory ITP’ waswas
ITP’ defined
definedas the absence
as the absenceof response
of response or relapse
or relapseafter after
splenectomy
splenectomy [15].[15].
However,
However, as discussed
as discussed above, splenectomy
above, splenectomy doesdoesnot not
constitute
constitute a treat-
a treat-
mentmentsolution
solutionfor all
forITP
all patients, as theaselderly
ITP patients, or those
the elderly with major
or those comorbidities
with major comorbiditieswill notwill
benefit from a splenectomy, thus the indication in them is weak.
not benefit from a splenectomy, thus the indication in them is weak. In addition, there In addition, there is a is
current, not well-documented but widely accepted, consensus that,
a current, not well-documented but widely accepted, consensus that, when other treat- when other treatments
have proved
ments have ineffective, splenectomy
proved ineffective, will likelywill
splenectomy be likely
ineffective also [40].also
be ineffective Miltiadous et al.
[40]. Miltiadous
proposed a definition
et al. proposed of refractory
a definition ITP as the
of refractory ITPcondition in which
as the condition in patients ‘do not‘do
which patients re-not
spond—with
respond—with regards to their
regards platelet
to their counts—to
platelet ≥2 treatments,
counts—to ≥2 treatments,there is no single
there medica-
is no single medi-
tioncation
to which they they
to which respond, and and
respond, theirtheir
platelet counts
platelet are very
counts lowlow
are very andandaccompanied
accompanied by by
bleeding’
bleeding’[41]. This
[41]. Thisdefinition
definition does
doesnot
notnecessarily
necessarilyinclude
includesplenectomy.
splenectomy.In Inclinical
clinical prac-
practice,
tice,refractory
refractoryITP ITPis is considered
considered thethe absence
absence of response
of response to conventional
to all all conventional therapies,
therapies, which
which
havehave
beenbeen selected
selected forindividual
for the the individual patient
patient regardless
regardless of theirof bleeding
their bleeding manifes- or
manifestations,
tations, or relapse.
relapse. A proposed A proposed
approach approach for identification
for identification of patientsof with
patients with refractory
refractory ITP
ITP is presented
with a flowchart
is presented in Figure 1.
with a flowchart in Figure 1.

Figure
Figure 1. Diagnostic
1. Diagnostic approach
approach of refractory
of refractory ITP.ITP.
ITP:ITP: immune
immune thrombocytopenia;
thrombocytopenia; PLTs:
PLTs: platelets;
platelets;
CBC: complete blood count; TPO-RA: thrombopoietin-receptor agonist; IVIG: intravenous
CBC: complete blood count; TPO-RA: thrombopoietin-receptor agonist; IVIG: intravenous immune immune
globulin; BM: bone marrow; CMV: cytomegalovirus; HCV: hepatitis C virus; HIV:
globulin; BM: bone marrow; CMV: cytomegalovirus; HCV: hepatitis C virus; HIV: human immuno-human immun-
odeficiency virus; ANA: antinuclear antibodies; H.pylori: Helicobacter pylori; MDS: myelodysplas-
deficiency virus; ANA: antinuclear antibodies; H.pylori: Helicobacter pylori; MDS: myelodysplastic
syndrome.
tic syndrome.

TheThefactfact
thatthat patients
patients with
with a proposed
a proposed initial
initial diagnosis
diagnosis of ITP
of ITP may may notnot present
present a clini-
a clin-
ical response strongly questions an ITP diagnosis and necessitates a thorough clinical andand
cal response strongly questions an ITP diagnosis and necessitates a thorough clinical
laboratory
laboratory work-up
work-up to decide
to decide whether
whether it ais case
it is a case
ofof refractoryITP
refractory ITPorora acase
caseofofa amisdiag-
misdiagno-
sis. Data
nosis. Data from
from two
two large
large studies
studies support
support that thatthe
themost
mostpredominant
predominantmisdiagnosis—after
misdiagnosis—
secondary
after secondary ITP—is
ITP—isMDSMDS [42,43].
[42,43].
5. Myelodysplastic Syndrome with Isolated Thrombocytopenia, MDS-IT
Myelodysplastic syndrome (MDS) constitutes a heterogeneous group of clonal hemato-
logic neoplasms [44]. It is characterized by ineffective hematopoiesis, cytopenias, dysplastic
cellular morphology and a variable risk for transformation to leukemia [45]. Epidemiologi-
cal features of MDS include male predominance and a median age of diagnosis at 71 years
old [45]. MDS is presented with an annual incidence of 4 cases per 100,000 individuals
Cancers 2024, 16, 1462 9 of 15

with ~40,000 new cases diagnosed each year [46]. MDS is initially suspected in patients
with a combination of cytopenias. Cytopenia, in the context of clonal hematopoiesis, is
defined as ‘the presence of acquired and sustained anemia (hemoglobin < 12 g/dL in
females and <13 g/dL in males), neutropenia (absolute neutrophil count <1.8 × 109 /L),
and/or thrombocytopenia (platelets < 150 × 109 /L), that is not explained by another con-
dition’ [47]. Anemia occurs in 80–85% of MDS patients, constituting the most common
laboratory finding among them, while neutropenia is observed in 40% of patients at the time
of diagnosis [48]. Thrombocytopenia is also commonly found, namely in 30–45% of MDS
cases [48]. Although isolated thrombocytopenia is considered a much rarer presentation of
MDS, there have been described cases of MDS with ‘isolated’ thrombocytopenia and milder
degrees of anemia and/or neutropenia, and their distinction and differential diagnosis is
unclear in the literature [48–50]. MDS presenting with thrombocytopenia as an isolated
abnormality (MDS-IT) has not been described thoroughly and data regarding its diagnosis,
progression and prognosis are still limited. Recent studies on MDS-IT cohorts showed
that MDS-IT is commonly associated with multilineage dysplasia, favorable cytogenetics,
lower-risk on prognostic scoring systems, high survival rate and a lower risk of AML
evolution, compared to general MDS [51]. There are a few previous studies presenting
the characteristics and natural history of MDS-IT, and comparing MDS-IT with other non-
clonal disorders with isolated thrombocytopenia, especially ITP [51–54]. A summary of the
studies on MDS-IT and their main findings regarding patient characteristics, diagnostic
and prognostic features are presented in Table 3.

Table 3. Main findings of studies on MDS-IT 1 .

Main Findings of Studies on MDS-IT 1

Median Median Median Median Median IPSS 6 /
Cytogenetics Median
Number of Age of PLT 2 Hb 3 WBC 4 BM 5 IPSS-R
Study Risk Karyotype OS 7 ,
Patients Diagnosis, Count, Count, Count, Blasts Risk
Score, % Months
Years ×109 /L g/dL ×109 /L Count, % Score, %
Flores-Moran Very Low 104
Normal
MS et al. 20 74 84 – – – (45%)/Low – (range
(60%)
(2022) [49] (45%) 28–206)
109
Liapis K. et al. Low Favorable Normal
77 66 87 13.6 4.6 2 (95% CI 8
(2021) [51] (73.5%) (83.1%) (51.9%)
103–115)
Waisbren J. 29
Very Low + Normal
et al. 50 72 64 12 4.4 4 – (range
Low (46%) (56%)
(2016) [48] 2.7–74.5)
Sashida G. Low + In- 32.2
Normal
et al. 13 57 55 12.6 5.5 1.6 termediate – (range
(38.5%)
(2009) [50] (100%) 5–72)
1 MDS-IT myelodysplastic syndrome with isolated thrombocytopenia; 2 PLT platelet; 3 Hb hemoglobin; 4 WBC

white blood cell; 5 BM bone marrow; 6 IPSS/IPSS-R International Prognostic Scoring System/revised International
Prognostic Scoring System; 7 OS overall survival; 8 CI confidence interval.

5.1. Challenges in Diagnosis of MDS-IT

5.1.1. Blood and Bone Marrow Examination
The diagnosis of MDS is supported by clinical findings and blood and bone marrow
examination. Symptoms associated with cytopenia, such as fatigue, poor quality of life,
infection and variable bleeding manifestations are usually present in MDS patients. On
blood examination, anemia is typically found in 90% of patients, but it may present as
milder degrees of anemia, where small numbers of circulating blasts can be found, rarely
exceeding 5% [55]. Bone marrow generally shows hypercellularity and dysplastic features
in one or more myeloid series, with or without excess marrow blasts. MDS may be confused
with ITP because it has a similar combination of hypercellular marrow and increased
megakaryocytes, while signs of dysplasia may not be overt at the time of examination. In
these cases, progression may be required to clarify the diagnosis.
Generally, bone marrow aspiration—without biopsy—is sufficient for verification
of MDS diagnosis. Although trephine biopsy is not routinely used, it can prove useful
Cancers 2024, 16, 1462 10 of 15

when the bone marrow is hypocellular, to differentiate MDS from aplastic anemia or acute
myeloid leukemia [44].

5.1.2. Cytogenetic Findings

Cytogenetic analysis of MDS is characterized by partial or complete loss or gain of
chromosomes, and results in an abnormal karyotype in 40–50% of cases. The most frequent
findings are deleted 5q, −7 or deleted 7q, +8, deleted 20q and deleted 17p. Except for its
prognostic value, cytogenetic analysis can be useful in cases where diagnosis of MDS is not
clear, namely in patients with isolated thrombocytopenia (deleted 20q), elderly women with
mild anemia (deleted 5q) and younger patients with moderate cytopenias (−7 or +8) [56].
While deleted 5q with up to one additional cytogenetic abnormality (except −7/deleted 7q)
is sufficient to confirm MDS, other clonal karyotypic changes lack diagnostic specificity
by themselves for a diagnosis of MDS. These include primarily deleted 20q which, in
the absence of dysplasia or overt cytopenia(s), is not a sufficient criterion for diagnosis
of MDS [44]. Limited studies have described cases in which MDS with isolated del 20q
presented, mimicking ITP, and in these cases mild dysplasia upon marrow examination
and predominant isolated thrombocytopenia led frequently to misdiagnosis [55,56].

5.2. Prognostic Factors

Due to their variable risk of leukemic transformation, MDS cases need a prognostic
system to allow for the assessment of disease-related risk and the optimization of clinical
decision-making. For these reasons, the International Prognostic Scoring System (IPSS) was
initially created to evaluate different features with independent prognostic value. This was
based on the percentage of bone marrow blasts, number of peripheral blood cytopenias
and presence of specific clonal cytogenetic abnormalities. In 2012, a revised version of
IPSS (IPSS-R) was proposed, introducing five cytogenetic risk groups together with refined
categories for bone marrow blasts and cytopenias (Supplementary Materials Table S1) [57].
Marrow cytogenetic subset, marrow blast percentage and cytopenias were considered
as the basis of the new prognostic system (Supplementary Materials Table S2). With the
IPSS-R, 27% of lower-risk MDS cases, according to the original IPSS, are reclassified as
having a higher risk and potentially needing more intensive treatment, whereas 18% of
high-risk patients defined by the original IPSS are reclassified as low risk [58].
The IPSS-R prognostic risk categories are determined as Very Low/Low/Intermediate/
High/Very High risk, combining the scores of the 5 main features (Supplementary Materials
Table S3) [57].

6. Misdiagnosed Thrombocytopenia
Given that isolated thrombocytopenia constitutes a very extended clinical field, it
may be tempting for physicians to attribute thrombocytopenia to primary ITP when no
other diagnosis seems appropriate. However, the practice of confirming ITP diagnosis
by response to treatment is not reliable in cases of refractory ITP, as those patients do not
respond to standard ITP treating plans. The general practice of performing only a limited
number of tests creates a higher likelihood of incorrect diagnosis which, in the case of MDS,
could result in inappropriate and ineffective treatment and a greater risk of uncontrolled
transformation to leukemia with poor outcome. There are limited data comparing MDS-IT
and ITP. Results from a recent study show that MDS-IT is uncommon in patients < 50 or
>80 years, while its incidence reaches a peak between the ages of 70–79 years [51]. On the
other hand, ITP occurs at a more constant level over time. Women predominate in ITP
and men in MDS-IT. Finally, ITP is associated with more marked thrombocytopenia than
MDS-IT, thus a platelet count below 25 × 109 /L favors a diagnosis of ITP over MDS-IT [51].
In Table 4, clinical, diagnostic and molecular characteristics of primary ITP and MDS-
IT are presented in contrast, in order to allow for a directed diagnostic approach of iso-
lated thrombocytopenia.
Cancers 2024, 16, 1462 11 of 15

Table 4. Directed approach of isolated thrombocytopenia.

Directed Approach of Isolated Thrombocytopenia

Primary ITP 1 MDS 2
Any age, median age of diagnosis
Age at presentation Most common in older adults
56 years old
Incidence 1–6.4:100,000 1–4:1,000,000
Clinical characteristics
Isolated thrombocytopenia with Other abnormalities on CBC
Distinguishing features petechiae/bruising in a 3 /dysplasia in BM 4 , possibly

healthy-looking patient associated with trisomy 8 or 21, etc.

• BM 4 evaluation
• Cytogenetics: 5q del, 7 del,
CBC 3 , peripheral-blood smear: trisomy 8
• Reduced PLTs 5 /normal or • Genetic panel and WES 8
Diagnostic tests increased in size
• Normal RBCs 6 Rule out viral infections: CMV 9 ,
HCV 10 , HIV 11
• Normal WBCs 7
Rule out drugs/toxins
Rule out other causes Rule out renal, hepatic, thyroid
dysfunction
Molecular characteristics None identified Monosomy 7, trisomy 8 or 21
Standard first- and second-line Chemotherapy, HSCT 12 ,
Clinical approach
treatment TPO-RA 13
1 ITP immune thrombocytopenia; 2 MDS myelodysplastic syndrome; 3 CBC complete blood count; 4 BM bone
marrow; 5 PLTs platelets; 6 RBCs red blood cells; 7 WBCs white blood cells; 8 WES whole-exome sequencing;
9 CMV cytomegalovirus; 10 HCV hepatitis C virus; 11 HIV human immunodeficiency virus; 12 HSCT hematopoietic

stem cell transplantation; 13 TPO-RA thrombopoietin-receptor agonists.

7. Refractory Cytopenia of Childhood, RCC

A very common and well-recognized subtype of pediatric MDS is refractory cytopenia
of childhood (RCC). Most children and adolescents with MDS present with RCC, and
this entity is characterized by persistent cytopenia, <5% blasts in the bone marrow and
<2% blasts in the peripheral blood [59,60]. RCC mostly presents with thrombocytopenia,
and/or anemia and/or neutropenia secondary to ineffective hematopoiesis [60]. Due to the
marked bone marrow hypocellularity found in ≥80% of children with RCC, its recognition
requires a bone marrow biopsy examination to identify its characteristic histopathologic
appearance [47]. Most of the children with RCC have a normal karyotype and a low
risk of progression to a myeloid neoplasm, while about 10–15% display an abnormal
karyotype with monosomy 7, del(7q) or complex karyotype [59]. In some cases, a germline
predisposition may have been present that preceded the evolution to RCC. These conditions
include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, GATA2
deficiency and SAMD9/SAMD9L syndromes [47].
Along with misdiagnosed thrombocytopenia in adults, cytopenia in childhood con-
stitutes another health problem which could be mistakenly attributed to ITP (primary
or secondary), as ITP is one of the commonest causes of thrombocytopenia in childhood.
Given that pediatric ITP with non-life-threatening thrombocytopenia, and with the ab-
sence of major clinical manifestations, is being managed without an initial bone marrow
examination, physicians could be disorientated and driven to a delayed diagnosis of RCC.

8. Discussion
Overall, ITP and MDS are heterogenous hematological disorders of uncertain etiology
whose features vary from case to case and may even overlap. Their diagnosis requires the
exclusion of other hematological or immunological disorders. However, there are some
confusing cases with thrombocytopenia, where the differential diagnosis is complex.
Cancers 2024, 16, 1462 12 of 15

Patients with MDS who present with isolated thrombocytopenia constitute a poorly
described subgroup, and the exact clinico-hematologic features of such MDS patients
are still obscure. Given that thrombocytopenia has been reported to be rare, with an
incidence of between 1 and 4% among monopathic cytopenias in MDS patients, this entity
presents a challenge to clinicians based on its rarity, lack of classification among other MDS
neoplasms and lack of established treatment options. The morphologic identification of
MDS-IT is also difficult because features of dysplasia may not be identified at the time of
evaluation and bone marrow hypercellularity may be confused with ITP. According to the
limited previous studies on populations with MDS-IT, patients present most commonly
with multilineage dysplasia, normal karyotype and low risk prognostic score, based on
IPSS-R. Single gene mutations can be seen in the presence of a normal karyotype. The
most common isolated cytogenetic abnormality found is del 20q, and it has been shown
that persistent, unexplained thrombocytopenia is a common manifestation of MDS with
isolated del 20q. Additionally, it has been demonstrated that patients with del 20q and
isolated thrombocytopenia have relatively indolent disease [55].
Data reveal that a significant proportion of MDS-IT patients (even pediatric patients
with RCC) are misdiagnosed as having the more common ITP, are managed as such and
have clinical outcomes (including a lack of response to therapy) typical of MDS. All of
the challenges discussed above necessitate the precise characterization of patients with
MDS-IT, which is best served by conducting large prospective studies that compare these
patients to other MDS patients and include additional parameters of interest, including
next generation sequencing.

9. Conclusions and Future Directions

We suggest that patients with isolated thrombocytopenia are subject to misclassifica-
tion as ITP, and that the peripheral-blood smear is frequently abnormal, which can prevent
this misclassification if carefully reviewed. Thus, it is recommended that patients with
an isolated, non-inherited idiopathic thrombocytopenia have a detailed clinical history to
exclude secondary causes of isolated thrombocytopenia and a careful morphologic review
of peripheral-blood and bone marrow aspirates, serum antiplatelet antibody studies, CMV,
HBV, HIV antibody studies and examination for H.pylori, in order to optimize diagno-
sis and avoid ineffective treatments and potentially adverse effects of long-term steroid
therapy or splenectomy in these patients.

Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/cancers16081462/s1, Table S1: Cytogenetic Scoring System in MDS
patients; Table S2: IPSS-R prognostic values; Table S3: IPSS-R prognostic risk categories and scores.
Author Contributions: All authors (A.K., E.G. and A.T.) have contributed equally to this study. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

ANA antinuclear antibodies

ANC absolute neutrophil count
ASH American Society of Hematology
CBC complete blood count
CI confidence interval
CMV Cytomegalovirus
CNS central nervous system
CR complete response
Cancers 2024, 16, 1462 13 of 15

DIC disseminated intravascular coagulation

EBV epstein–barr virus
FDA Food and Drug Administration
GPs Glycoproteins
Hb Hemoglobin
HBV hepatitis B virus
HCV hepatitis C virus
HELLP hemolysis, elevated liver enzymes, low platelet count
HIV human immunodeficiency virus
HSCT hematopoietic stem cell transplantation
HUS hemolytic uremic syndrome
IPSS international prognostic scoring system
IPSS-R revised international prognostic scoring system
ITP immune thrombocytopenia
IVIG intravenous immune globulin
MDS myelodysplastic syndrome
MDS-IT myelodysplastic syndrome with isolated thrombocytopenia
NR no response
PNH paroxysmal nocturnal hemoglobinuria
R response
RBCs red blood cells
RCC refractory cytopenia of childhood
SLE systemic lupus erythematosus
TMA thrombotic microangiopathies
TPO thrombopoietin
TPO-RA thrombopoietin-receptor agonists
TTP thrombotic thrombopenic purpura
WBCs white blood cells

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