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How I approach new onset thrombocytopenia

Fiona Swain & Robert Bird

To cite this article: Fiona Swain & Robert Bird (2019): How I approach new onset
thrombocytopenia, Platelets, DOI: 10.1080/09537104.2019.1637835

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Published online: 03 Jul 2019.

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ISSN: 0953-7104 (print), 1369-1635 (electronic)

Platelets, Early Online: 1–6

© 2019 Taylor & Francis Group, LLC. DOI: https://doi.org/10.1080/09537104.2019.1637835

How I approach new onset thrombocytopenia

1,2,3
Fiona Swain & Robert Bird1,2
1
Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Australia, 2School of Medicine, University of Queensland, Brisbane, Australia, and
3
School of Medicine, Griffith University, Brisbane, Australia

Abstract Keywords
Thrombocytopenia is a common reason for referral to hematologists in community and Immune thrombocytopenia,
hospital practice. A broad differential diagnosis, combined with the potentially life- thrombocytopenia
threatening nature of some presentations necessitates a rapid evaluation of the situation
and potential need for emergency intervention; followed by further comprehensive investiga- History
tion to confirm the diagnosis and institution of longer term management. This review offers an
Received 24 June 2018
approach to the initial assessment, diagnosis, and referral. We then highlight aspects of the
Revised 14 May 2019
clinical history, examination and laboratory investigations which may provide critical insights
Accepted 7 June 2019
into the most likely diagnosis. ITP is the commonest cause of severe isolated thrombocytope-
Published online 5 July 2019
nia in the general community and is the most common cause of thrombocytopenia in patients
referred to our hematology service. It remains a diagnosis of exclusion and a high degree of
vigilance for alternative diagnoses should be maintained, particularly if presentations are
atypical or expected response to treatment is not seen. Adult presentation of hereditary
thrombocytopenia syndromes can mimic new onset thrombocytopenia, however, improving
access to genetic testing will facilitate accurate diagnosis and avoid unnecessary treatment.

Introduction immunosuppression have been continued despite absence of

The point prevalence of thrombocytopenia is higher in hospital
than in the community. In 2017, an Australian metropolitan
hospital-based pathology laboratory performed 230,000 full
blood counts (FBC) and found 6.7% had platelet counts
<100x109/L, 2.5% had platelet counts <50x109/L and 0.75%
had platelet counts <20x109/L. This was approximately 3 times
higher at all cutoff counts than equivalent testing in an Australian
community pathology laboratory (unpublished data). In hospital
settings, depending upon the scope of practice, it can be expected
that the most common causes of severe thrombocytopenia will be
myelosuppression or other drug effects. An excellent article spe-
cifically outlining an approach to hospital patients has been pub-
lished recently [1]. In the community thrombocytopenia is less
common, but a broad differential diagnosis needs to be enter-
tained. Table I provides a list of common causes of thrombocy-
topenia, with those more common in the outpatient setting
highlighted. We prefer this approach than separate differential
lists based on setting, symptoms or degree of thrombocytopenia,
as all causes should be considered to avoid misdiagnosis. Even
this list is not exhaustive, and clinicians should refer to
a comprehensive list of causes of thrombocytopenia if ongoing
diagnostic uncertainty remains, such as the table published by
Bain [2].
Working in a referral center for thrombocytopenia, we see
a steady stream of patients incorrectly diagnosed as having
ITP. In many such cases, steroid therapy and additional
Contributions:Fiona Swain and Robert Bird wrote and reviewed the article
Correspondence: Fiona Swain, Division of Cancer Services, Princess
Alexandra Hospital, Brisbane, Australia. Tel: 07 3176 2111. Fax: 07
3176 7233. E-mail: Fiona.swain@gmail.com
response, and even splenectomy has been performed with no
benefit, and in some cases, significant harm. In general,
thrombocytopenia which is non-immune will not benefit
from immunosuppression, other than a short course of ster-
oids used early in the diagnostic work up to assist in making
a diagnosis.
Evaluation
Assess the Urgency
The primary consideration in any new patient with thrombocy-
topenia is a rapid exclusion of life-threatening disorders, either
due to bleeding risk or other underlying pathology, such as
thrombotic thrombocytopenic purpura (TTP). The bleeding
history and physical signs, such as petechiae and ecchymosis
can be rapidly assessed. Several bleeding assessment tools have
been proposed and validated in ITP and hereditary bleeding
disorders, but these generally relate to chronic bleeding pattern
and are of more use in clinical trials and determining the
impact of a therapeutic intervention over time [3,4] than asses-
sing immediate bleeding risk. “Wet” purpura in the mucous
membranes has traditionally been regarded as a presage of
increased bleeding risk [5], although hard data supporting this
mantra is elusive [6]. An indication of the chronicity, based on
symptoms or historical blood counts is also important, as
newly discovered thrombocytopenia does not always imply
new onset. Prompt confirmation of thrombocytopenia through
the exclusion of pseudothrombocytopenia and review of the
blood film for critical findings (such as schistocytes in micro-
angiopathic hemolytic anemia (MAHA)) should occur concur-
rently to clinical assessment (see Figure 1).
2 F. Swain & R. Bird Platelets, Early Online: 1–6

Table I. Differential diagnosis of new-onset thrombocytopenia.

Condition Comment

Pseudothrombocytopenia
Immune thrombocytopenia
(ITP)
Acute/critical illness
Liver disease/hypersplenism
Medications
Toxins
Marrow disorders
Thrombotic microangiopathies
(TMA)
Specific scenarios
If no prior FBC available also Congenital thrombocytopenia syndromes
consider
If pregnant also consider
If recent transfusion also
consider
If bi or pancytopenia also
consider
Various pre-analytical or analytical errors including platelet clumping and satellitism
Primary or secondary
Especially common in ICU patients and sepsis
Also consider direct toxicity if applicable (eg alcohol)
Includes marrow suppression (eg chemotherapy), drug-induced immune thrombocytopenia (DITP), heparin induced
thrombocytopenia (HIT)
Eg alcohol
Myelodysplasia
Bone marrow infiltration (haematological and non-haematological malignancies)
Including thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and disseminated
intravascular coagulation (DIC)
Gestational thrombocytopenia, pre-eclampsia, haemolysis with elevated liver enzymes and low platelets (HELLP),
acute fatty liver of pregnancy (AFLP)
Post-transfusion purpura (PTP), alloimmune thrombocytopenia, dilutional thrombocytopenia
Nutritional deficiencies, auto-immune disease, systemic lupus erythromatosis (SLE), aplastic anaemia, paroxysmal
nocturnal haemoglobinuria (PNH)

Key Elements of the History Gender

Patient Age
Although the typical ITP patient is widely held to be a young
woman, in fact, large databases, such as the UK-based General
Practice Database, indicate a bimodal distribution of age at diag-
nosis, with a young female peak followed by an older male peak,
and the highest incidence being in those aged over 60 years [7].
Older age is also associated with a higher incidence of clonal
hematopoietic disorders which may present as an isolated throm-
bocytopenia. In a review of patients enrolled to the McMaster ITP
registry between 2010 and 2016, of 295 patients originally diag-
nosed with primary ITP, 7 (2.3%) were subsequently revised to
a diagnosis of myelodysplastic syndrome [8]. Immune thrombo-
cytopenia can occur in B and T cell lymphoproliferative disorders,
though cytopenias may also be due to marrow infiltration, treat-
ment effects and hypersplenism. Thrombocytopenia is reported in
up to 20% of patients with T-large granular lymphocyte leukemia
(T-LGL), but only a minority were diagnosed as ITP [9].
Secondary ITP is reported in 1–5% of chronic lymphocytic leu-
kemia/lymphoma (CLL); the incidence of auto-immune hemolytic
anemia is much higher [10]. A review of ITP in non-Hodgkin
lymphoma (NHL) found a low incidence of ITP (0.76% of
patients); however, half presented prior to the diagnosis of lym-
phoma [11]. As such, we recommend routine bone marrow exam-
ination in all patients over 60 years and imaging (computed
tomography (CT) neck, thorax, abdomen, and pelvis) in all
patients over 60 years refractory to first-line ITP therapy.
While one would expect most individuals with hereditary
thrombocytopenia syndromes with a bleeding phenotype or asso-
ciated dysmorphic features to be diagnosed early in life, milder
phenotypes can often present well into adult life. In a review of 43
cases of hereditary TTP (Upshaw Schulman syndrome), the age
of diagnosis ranged from 0 to 71 years. Often the only feature in
these patients was thrombocytopenia until an exacerbation was
triggered by pregnancy or infection. Neonatal jaundice requiring
exchange transfusion was a feature in only 18 of 43 cases.
Twenty-five cases were diagnosed between ages 0–15 years, 15
cases between 15 and 45 years and three cases after 45 years (all
male, at ages: 55, 63 and 71 years) [12].
Gender is relevant for pregnancy-associated thrombocytopenia
syndromes (beyond the scope of this review) and certain heredi-
tary thrombocytopenias which are more common in men (such as
X linked thrombocytopenia and its genotypic stablemate, Wiscott
Aldrich Syndrome) [13].
Ethnic Origin
H pylori has been implicated as a causal agent for ITP, however,
with respect to the response of ITP to H pylori eradication, there
appears to be a much higher chance of success in Japanese
patients than in others [14]. There is little to be lost in screening
for H pylori infection and treating if positive, but in our experi-
ence of an ethnically diverse population with ITP, recovery of
thrombocytopenia has been elusive.
Comorbidities
A thorough patient history will identify potential causes of sec-
ondary ITP as well as conditions which may be solely responsible
for thrombocytopenia, such as liver disease. Secondary ITP is
recognized in association with auto-immune, immunodeficiency,
lymphoproliferative and infective conditions [15] and has signifi-
cant treatment ramifications, as immunosuppression directed at
ITP alone may only produce a transient response if the underlying
condition is not appropriately managed. Liver disease is com-
monly associated with thrombocytopenia (multiple mechanisms
can co-exist, including decreased thrombopoietin in advanced
liver disease, sequestration secondary to hypersplenism or direct
marrow suppression due to alcohol toxicity) [16]. It is a frequent
reason for referral in our experience but is often easily recogniz-
able from associated clinical and laboratory features.
Medication History
Although the risk of thrombocytopenia with any individual med-
ication is low [17]; lack of awareness, polypharmacy, potential
alternative diagnoses, and lack of standardized routinely available
DOI: https://doi.org/10.1080/09537104.2019.1637835
Figure 1. Initial evaluation of thrombocytopenia.
testing means that DITP is likely to be under-recognized, under-
diagnosed and under-reported. DITP is more commonly recog-
nized with quinine, antimicrobials, anti-platelet agents, and
heparin; though many more drugs have been implicated in the
literature (based on clinical criteria, laboratory criteria or both)
[18,19]. Reasons to suspect DITP include a time frame (1–2
weeks or immediately following the administration of fibans and
abciximab) [18], severe thrombocytopenia with bleeding, and
administration of a drug known to be implicated in DITP. Often
the diagnosis is made in retrospect, with resolution upon cessation
or recurrence with re-exposure (not generally recommended).
Heparin-induced thrombocytopenia (HIT) is a unique immu-
nological complication of heparin therapy which is more likely to
be seen in hospital inpatients; though new thrombocytopenia in
a patient on heparin therapy, particularly in the presence of
progressive or new thrombosis should trigger calculation of the
validated pre-test probability scoring system (4T score) [20] and
HIT antibody or functional testing ordered if an intermediate or
high score is determined. Until the result is available, heparin
should be immediately withheld and alternative non-heparin
anticoagulation should be instituted as per local guidelines.
Travel
Zoonotic infections can be the cause of severe thrombocytopenia,
and exotic infections need to be considered in travelers. Babesiosis
as a cause of isolated thrombocytopenia has been described [21] so
residents or returning travelers from regions of endemic infection
should have blood film examination for parasites [22].
Alcohol
Alcohol can cause myelotoxicity in the absence of apparent toxi-
city to other organs. Thrombocytopenia can be seen in 3–43% of
New Onset Thrombocytopenia 3
alcoholics in the community and 14–81% of hospitalized alco-
holics. The platelet count can be expected to rise after 2–5 days of
abstinence and generally returns to the normal range within one
week. Often rebound to higher than normal levels is seen, unless
other contributors such as splenomegaly (sequestration) or cirrho-
sis (decreased thrombopoietin production) are present [23].
Macrocytosis is usually seen, and this persists for 2–4 months
after abstinence and is the most reliable pointer to potential
alcoholic etiology [24].
Recreational/Occupational Activities
While recreational and occupational activities might put indivi-
duals at increased risk of thrombocytopenia through toxin expo-
sure or infection risk, they also feature strongly in initial
assessment of the need for treatment. Patients engaging in
a professional contact sport or recreational activities such as
horse riding may require initiation of therapy at a higher platelet
threshold, akin to patients with increased bleeding risk or those
needing concomitant anticoagulation.
Family History
While a family history of “ITP” is not unheard of, such a report
should trigger suspicion for a hereditary thrombocytopathy. This
suspicion is further heightened if the response to first-line ITP
therapy has been poor, or additional features associated with the
more common underlying genetic mutations, such as deafness and
renal failure (associated with MYH9 defects) are present [25].
The initial response to such information should be a careful
review of the platelet parameters, looking for macrothrombocyto-
penia (mean platelet volume >11fl) and for inclusion bodies
(Dohle-like bodies) in granulocytes, as seen in MYH9 disorders.
4 F. Swain & R. Bird
Familial platelet disorder with associated myeloid malignancy
due to the RUNX1 R166Q mutation should be considered when
there is a family history of MDS or AML. Platelet size is normal
and blood film examination will reveal no abnormality until
progression to MDS or AML occurs [26]. No preventive inter-
vention is currently available but enrolment to RUNX1 registries,
where available, and genetic counseling should be considered.
Detection of this mutation is also significant where family mem-
bers are being assessed as potential allogeneic stem cell transplant
donors, as family members carrying this mutation should be
excluded as potential donors.
Inherited platelet function disorders may be associated with
thrombocytopenia (e.g. Bernard Soulier Syndrome (BSS)). BSS
should be more readily apparent from a bleeding history dispro-
portionate to the degree of thrombocytopenia and macrothrombo-
cytopenia on film review. Formal diagnosis can be achieved
through more available testing methods such as flow cytometry
or platelet aggregometry.
Clinical Examination
Physical examination should never be omitted and adequate expo-
sure of the patient is vital. The lower leg, palate, and fundi should
be examined for petechiae and purpura. The upper arm should be
looked at if blood pressure cuffs have been used recently. Patients
should always be asked to “show me your bruising,” so that any
areas that might not normally be exposed to protect modesty are
not missed. Lymphadenopathy and splenomegaly should be care-
fully excluded in order that subsequent investigations can be
appropriately ordered. Imaging may be warranted in patients
with increased body mass index (BMI) due to the reduced sensi-
tivity of clinical examination.
Investigation
Immediate Laboratory Investigation
The question “could this be a spurious result?” should always be
asked if any significant abnormality in laboratory investigations
arises which is unexpected or does not correlate with the clinical
picture. The specimen tube should be manually checked for a clot
and the blood film assessed for platelet clumping or satellitism
[27]. Our laboratory has adopted a platelet count threshold of
20x10^9/L to automatically perform and report a fluorescent
platelet count as this has been shown to have improved accuracy
and precision in thrombocytopenia [28]. Other laboratories may
use an abnormal platelet distribution to trigger performance of
optical or fluorescent platelet counts; however, in our experience,
this leads to excessive testing as abnormal platelet distribution is
Table II. Platelet size in inherited thrombocytopenias.
Small platelets (MPV <7fl) Normal platelets (MPV 7-11fl)
Wiskott Aldrich Syndrome Thrombocytopenia with absent radii (TAR)
X-linked thrombocytopenia
Congenital amegakaryocytic thrombocytopenia
Radio-ulnar synostosis and amegakaryocytic thrombocytopenia
Familial platelet disorder with associated myeloid malignancy
Chromosome 10/THC2
(adapted from Drachman, 2004).
Platelets, Early Online: 1–6
commonly flagged in platelet counts <100x10^9/L and when the
mean cell volume (MCV) is decreased.
Blood film examination is pivotal and careful attention should
be directed to all cell lines. Recognition of schistocytes is critical
for assessment and exclusion of MAHAs, such as TTP. Red cells
should be examined for spherocytes and polychromasia, which
would point to associated hemolysis (Evans syndrome). White
cells should be examined for the presence of immature forms,
which would suggest a hematological malignancy; or reactive
lymphocytes, as seen in acute viral infections such as dengue or
cytomegalovirus infection. Platelets should be inspected for num-
ber, size, and granularity. Platelet size, either estimated from
blood film review or measured by the analyzer (reported as
mean platelet volume (MPV)) can be useful to guide molecular
analysis in suspected hereditary thrombocytopenia syndromes as
these can be categorized according to expected platelet size
(Table II).
Basic biochemistry is required to assess renal function, which
is relevant in MAHA and some MYH9 associated hereditary
thrombocytopenias. Lactate dehydrogenase should be included,
and if elevated raises the possibility of underlying MDS, malig-
nancy or hemolysis. Bilirubin, albumin, coagulation studies, and
liver enzyme tests can provide insight into possible underlying
liver disease or demonstrate an unconjugated hyperbilirubinemia
as seen in hemolytic states. The direct antiglobulin test (DAT or
Coombs test) should be ordered in suspected ITP to investigate
for concurrent hemolysis [29]. H pylori screening may be per-
formed, however, in our experience has been of little utility. HIV,
HCV, and thyroid function tests should be performed to evaluate
for secondary causes of ITP. We do not routinely perform bone
marrow examination upfront in suspected ITP: this is reserved for
patients who are over 60 years, do not respond to treatment as
expected, or have any clinical or laboratory features which sug-
gest a bone marrow pathology. HIT antibody testing (including
functional antibody testing if available) must be performed when
there is a moderate or high suspicion of HIT, based on the 4T
score. ADAMTS13 testing should be requested to confirm or
exclude TTP if a MAHA is identified, though this result should
not delay emergent management.
Additional Testing
Platelet Antibody Testing
Platelet antibody testing should ideally be a key investigation in ITP,
as with most other autoimmune disorders, but unfortunately both
the sensitivity and specificity of testing in numerous studies have
demonstrated little utility in the investigation of thrombocytopenia
[30,31]. Whilst some have reported the specificity to be adequate
Large platelets (MPV >11fl)
MYH9 syndromes
- May-Hegglin anomaly
- Fechtner syndrome
- Epstein syndrome
- Sebastian syndrome
Mediterranean thrombocytopenia
Bernard Soulier syndrome
DiGeorge syndrome
Paris-Trousseau
Gray platelet syndrome
GATA1 mutation
DOI: https://doi.org/10.1080/09537104.2019.1637835
(approximately 80% in some studies), in our opinion, this does not
add value in a condition already fraught with misdiagnosis and
mistreatment. Platelet antibody testing has no role in our practice.
Genetic Testing
Genetic testing for hereditary thrombocytopathies should be con-
sidered in patients provisionally diagnosed with ITP who are refrac-
tory to treatment, patients with a family history of thrombocytopenia
and patients with syndromic features. The screening panel will vary
depending upon the region and the laboratory performing the test-
ing; but must include the most common inherited mutations.
A review of a gene panel performed on an Australasian cohort of
patients suspected to have hereditary thromobocytopathy identified
MYH9-related disorders as the most common cause, with patho-
genic MYH9 mutations found in 12.4% of patients [32].
Is There a Role for MPV and IPF?
Whilst not often reported, most modern hematology analyzers are
capable of assessing platelet parameters, including the mean platelet
volume (MPV) and an assessment of the immature platelet count,
given as an absolute count or as the immature platelet fraction (IPF).
The MPV may be useful in guiding genetic testing for suspected
inherited thrombocytopenias as an adjunct to clinical assessment
and blood film review. MPV is also increased in ITP, MDS and
megaloblastic pancytopenia [33]. It has been shown to differentiate
between ITP and hypoproliferative thrombocytopenia, though the
sensitivity and specificity of this varies between studies [34,35].
Limitations at present include the absence of generally accepted
reference ranges, overlap of reference ranges, lack of standardiza-
tion between analyzer methods, platelet transfusion and pre-
analytical error (e.g. storage artifact). Furthermore, whether
analyzer derived MPV is of more use than proficient blood film
review is yet to be established. We do not routinely assess MPV in
our practice as blood film review by an experienced hematologist is
considered of higher yield with the potential to identify other blood
film features which may provide diagnostic insight.
IPF is a flow cytometric assessment of platelets incorporating
a fluorescent nucleic acid dye (akin to automated reticulocyte
counts). A higher IPF is theorized to reflect increased platelet
turn-over and thus be demonstrative of destructive thrombocyto-
penias compared with hypoproliferative processes. Whilst some
studies have demonstrated statistically significant differences
between ITP and bone marrow failure [36], others have shown
an inability to distinguish between these entities [37]. Similarly,
there is conflicting evidence over the ability to differentiate ITP
and hereditary macrothrombocytopenias, with both conditions
demonstrating elevated IPF values [37,38]. Given additional lim-
itations such as a need to establish the stability of measurement
over storage periods, platelet transfusion and skewing by larger
platelets and platelet clumping [38] we do not find it currently has
a role in our practice.
Is Treatment Needed?
Aside from emergent plasma exchange in suspected TTP, and
cessation of heparin/use of non-heparin anticoagulation in HIT,
empiric therapy to reduce bleeding risk will depend on presumed
etiology. Steroids with or without intravenous immunoglobulin is
first-line therapy in immune thrombocytopenia [29]. Platelet
transfusion is generally reserved for situations of transient risk
or when recovery to an improved platelet count is anticipated
within a few days. Bleeding risk generally correlates with the
degree of thrombocytopenia [39], but other important considera-
tions are vascular risk factors, age [40], antiplatelet or
New Onset Thrombocytopenia 5
anticoagulant therapy, and lifestyle. In a patient in whom a life-
threatening etiology (e.g. HIT, MAHAs) has been excluded, and
whom appears to be stable without significantly increased bleed-
ing risk, the default position should be to withhold treatment and
establish a firm diagnosis. One important consideration with ITP
is that the absence of a diagnostic test means a trial of treatment
may contribute to confirming or refuting the diagnosis.
In patients without a clear diagnosis in whom the platelet
count and bleeding risk do not warrant immediate treatment, we
will often use a trial of prednisolone 25 mg daily for 7 days to
assess steroid responsiveness. A response to steroids both pro-
vides support for a diagnosis of immune thrombocytopenia and
confirms the utility of steroids to cover any future transient events
associated with increased bleeding risk. In situations when ITP
does not respond to treatment as expected the opportunity should
be taken to review the diagnosis, rather than committing to
prolonged steroid therapy or splenectomy.
Conclusion
The most common causes of thrombocytopenia are drugs and
critical illness in the hospital population, and ITP in the commu-
nity. A rapid assessment to exclude treatable serious underlying
conditions should be performed, followed by an assessment of the
need for treatment to reduce bleeding risk. If a decision to treat is
made and the response is not as expected, the opportunity should
be taken to review the diagnosis. ITP is a diagnosis of exclusion,
not an assumption; the full differential of causes of thrombocyto-
penia needs to be considered in all patients to ensure appropriate
diagnosis and therapy.
Declaration of Interest
The authors report no declarations of interest.
ORCID
Fiona Swain http://orcid.org/0000-0001-7412-3271
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