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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

To link to this article: https://doi.org/10.1080/09537104.2019.1637835

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

response, and even splenectomy has been performed with no
The point prevalence of thrombocytopenia is higher in hospital
benefit, and in some cases, significant harm. In general,
than in the community. In 2017, an Australian metropolitan
thrombocytopenia which is non-immune will not benefit
hospital-based pathology laboratory performed 230,000 full
from immunosuppression, other than a short course of ster-
blood counts (FBC) and found 6.7% had platelet counts
oids used early in the diagnostic work up to assist in making
<100x109/L, 2.5% had platelet counts <50x109/L and 0.75%
a diagnosis.
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 Evaluation
settings, depending upon the scope of practice, it can be expected Assess the Urgency
that the most common causes of severe thrombocytopenia will be
myelosuppression or other drug effects. An excellent article spe- The primary consideration in any new patient with thrombocy-
cifically outlining an approach to hospital patients has been pub- topenia is a rapid exclusion of life-threatening disorders, either
lished recently [1]. In the community thrombocytopenia is less due to bleeding risk or other underlying pathology, such as
common, but a broad differential diagnosis needs to be enter- thrombotic thrombocytopenic purpura (TTP). The bleeding
tained. Table I provides a list of common causes of thrombocy- history and physical signs, such as petechiae and ecchymosis
topenia, with those more common in the outpatient setting can be rapidly assessed. Several bleeding assessment tools have
highlighted. We prefer this approach than separate differential been proposed and validated in ITP and hereditary bleeding
lists based on setting, symptoms or degree of thrombocytopenia, disorders, but these generally relate to chronic bleeding pattern
as all causes should be considered to avoid misdiagnosis. Even and are of more use in clinical trials and determining the
this list is not exhaustive, and clinicians should refer to impact of a therapeutic intervention over time [3,4] than asses-
a comprehensive list of causes of thrombocytopenia if ongoing sing immediate bleeding risk. “Wet” purpura in the mucous
diagnostic uncertainty remains, such as the table published by membranes has traditionally been regarded as a presage of
Bain [2]. increased bleeding risk [5], although hard data supporting this
Working in a referral center for thrombocytopenia, we see mantra is elusive [6]. An indication of the chronicity, based on
a steady stream of patients incorrectly diagnosed as having symptoms or historical blood counts is also important, as
ITP. In many such cases, steroid therapy and additional newly discovered thrombocytopenia does not always imply
new onset. Prompt confirmation of thrombocytopenia through
the exclusion of pseudothrombocytopenia and review of the
Contributions:Fiona Swain and Robert Bird wrote and reviewed the article
blood film for critical findings (such as schistocytes in micro-
Correspondence: Fiona Swain, Division of Cancer Services, Princess angiopathic hemolytic anemia (MAHA)) should occur concur-
Alexandra Hospital, Brisbane, Australia. Tel: 07 3176 2111. Fax: 07
3176 7233. E-mail: Fiona.swain@gmail.com 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 Various pre-analytical or analytical errors including platelet clumping and satellitism
Immune thrombocytopenia Primary or secondary
(ITP)
Acute/critical illness Especially common in ICU patients and sepsis
Liver disease/hypersplenism Also consider direct toxicity if applicable (eg alcohol)
Medications Includes marrow suppression (eg chemotherapy), drug-induced immune thrombocytopenia (DITP), heparin induced
thrombocytopenia (HIT)
Toxins Eg alcohol
Marrow disorders Myelodysplasia
Bone marrow infiltration (haematological and non-haematological malignancies)
Thrombotic microangiopathies Including thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and disseminated
(TMA) intravascular coagulation (DIC)
Specific scenarios
If no prior FBC available also Congenital thrombocytopenia syndromes
consider
If pregnant also consider Gestational thrombocytopenia, pre-eclampsia, haemolysis with elevated liver enzymes and low platelets (HELLP),
acute fatty liver of pregnancy (AFLP)
If recent transfusion also Post-transfusion purpura (PTP), alloimmune thrombocytopenia, dilutional thrombocytopenia
consider
If bi or pancytopenia also Nutritional deficiencies, auto-immune disease, systemic lupus erythromatosis (SLE), aplastic anaemia, paroxysmal
consider nocturnal haemoglobinuria (PNH)

Key Elements of the History Gender

Patient Age Gender is relevant for pregnancy-associated thrombocytopenia
syndromes (beyond the scope of this review) and certain heredi-
Although the typical ITP patient is widely held to be a young
tary thrombocytopenias which are more common in men (such as
woman, in fact, large databases, such as the UK-based General
X linked thrombocytopenia and its genotypic stablemate, Wiscott
Practice Database, indicate a bimodal distribution of age at diag-
Aldrich Syndrome) [13].
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 Ethnic Origin
hematopoietic disorders which may present as an isolated throm-
bocytopenia. In a review of patients enrolled to the McMaster ITP H pylori has been implicated as a causal agent for ITP, however,
registry between 2010 and 2016, of 295 patients originally diag- with respect to the response of ITP to H pylori eradication, there
nosed with primary ITP, 7 (2.3%) were subsequently revised to appears to be a much higher chance of success in Japanese
a diagnosis of myelodysplastic syndrome [8]. Immune thrombo- patients than in others [14]. There is little to be lost in screening
cytopenia can occur in B and T cell lymphoproliferative disorders, for H pylori infection and treating if positive, but in our experi-
though cytopenias may also be due to marrow infiltration, treat- ence of an ethnically diverse population with ITP, recovery of
ment effects and hypersplenism. Thrombocytopenia is reported in thrombocytopenia has been elusive.
up to 20% of patients with T-large granular lymphocyte leukemia
(T-LGL), but only a minority were diagnosed as ITP [9]. Comorbidities
Secondary ITP is reported in 1–5% of chronic lymphocytic leu-
kemia/lymphoma (CLL); the incidence of auto-immune hemolytic A thorough patient history will identify potential causes of sec-
anemia is much higher [10]. A review of ITP in non-Hodgkin ondary ITP as well as conditions which may be solely responsible
lymphoma (NHL) found a low incidence of ITP (0.76% of for thrombocytopenia, such as liver disease. Secondary ITP is
patients); however, half presented prior to the diagnosis of lym- recognized in association with auto-immune, immunodeficiency,
phoma [11]. As such, we recommend routine bone marrow exam- lymphoproliferative and infective conditions [15] and has signifi-
ination in all patients over 60 years and imaging (computed cant treatment ramifications, as immunosuppression directed at
tomography (CT) neck, thorax, abdomen, and pelvis) in all ITP alone may only produce a transient response if the underlying
patients over 60 years refractory to first-line ITP therapy. condition is not appropriately managed. Liver disease is com-
While one would expect most individuals with hereditary monly associated with thrombocytopenia (multiple mechanisms
thrombocytopenia syndromes with a bleeding phenotype or asso- can co-exist, including decreased thrombopoietin in advanced
ciated dysmorphic features to be diagnosed early in life, milder liver disease, sequestration secondary to hypersplenism or direct
phenotypes can often present well into adult life. In a review of 43 marrow suppression due to alcohol toxicity) [16]. It is a frequent
cases of hereditary TTP (Upshaw Schulman syndrome), the age reason for referral in our experience but is often easily recogniz-
of diagnosis ranged from 0 to 71 years. Often the only feature in able from associated clinical and laboratory features.
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. Medication History
Twenty-five cases were diagnosed between ages 0–15 years, 15 Although the risk of thrombocytopenia with any individual med-
cases between 15 and 45 years and three cases after 45 years (all ication is low [17]; lack of awareness, polypharmacy, potential
male, at ages: 55, 63 and 71 years) [12]. alternative diagnoses, and lack of standardized routinely available
DOI: https://doi.org/10.1080/09537104.2019.1637835 New Onset Thrombocytopenia 3

Figure 1. Initial evaluation of thrombocytopenia.

testing means that DITP is likely to be under-recognized, under- alcoholics in the community and 14–81% of hospitalized alco-
diagnosed and under-reported. DITP is more commonly recog- holics. The platelet count can be expected to rise after 2–5 days of
nized with quinine, antimicrobials, anti-platelet agents, and abstinence and generally returns to the normal range within one
heparin; though many more drugs have been implicated in the week. Often rebound to higher than normal levels is seen, unless
literature (based on clinical criteria, laboratory criteria or both) other contributors such as splenomegaly (sequestration) or cirrho-
[18,19]. Reasons to suspect DITP include a time frame (1–2 sis (decreased thrombopoietin production) are present [23].
weeks or immediately following the administration of fibans and Macrocytosis is usually seen, and this persists for 2–4 months
abciximab) [18], severe thrombocytopenia with bleeding, and after abstinence and is the most reliable pointer to potential
administration of a drug known to be implicated in DITP. Often alcoholic etiology [24].
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- Recreational/Occupational Activities
nological complication of heparin therapy which is more likely to
be seen in hospital inpatients; though new thrombocytopenia in While recreational and occupational activities might put indivi-
a patient on heparin therapy, particularly in the presence of duals at increased risk of thrombocytopenia through toxin expo-
progressive or new thrombosis should trigger calculation of the sure or infection risk, they also feature strongly in initial
validated pre-test probability scoring system (4T score) [20] and assessment of the need for treatment. Patients engaging in
HIT antibody or functional testing ordered if an intermediate or a professional contact sport or recreational activities such as
high score is determined. Until the result is available, heparin horse riding may require initiation of therapy at a higher platelet
should be immediately withheld and alternative non-heparin threshold, akin to patients with increased bleeding risk or those
anticoagulation should be instituted as per local guidelines. needing concomitant anticoagulation.

Travel Family History

Zoonotic infections can be the cause of severe thrombocytopenia, While a family history of “ITP” is not unheard of, such a report
and exotic infections need to be considered in travelers. Babesiosis should trigger suspicion for a hereditary thrombocytopathy. This
as a cause of isolated thrombocytopenia has been described [21] so suspicion is further heightened if the response to first-line ITP
residents or returning travelers from regions of endemic infection therapy has been poor, or additional features associated with the
should have blood film examination for parasites [22]. 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
Alcohol
review of the platelet parameters, looking for macrothrombocyto-
Alcohol can cause myelotoxicity in the absence of apparent toxi- penia (mean platelet volume >11fl) and for inclusion bodies
city to other organs. Thrombocytopenia can be seen in 3–43% of (Dohle-like bodies) in granulocytes, as seen in MYH9 disorders.
4 F. Swain & R. Bird Platelets, Early Online: 1–6

Familial platelet disorder with associated myeloid malignancy commonly flagged in platelet counts <100x10^9/L and when the
due to the RUNX1 R166Q mutation should be considered when mean cell volume (MCV) is decreased.
there is a family history of MDS or AML. Platelet size is normal Blood film examination is pivotal and careful attention should
and blood film examination will reveal no abnormality until be directed to all cell lines. Recognition of schistocytes is critical
progression to MDS or AML occurs [26]. No preventive inter- for assessment and exclusion of MAHAs, such as TTP. Red cells
vention is currently available but enrolment to RUNX1 registries, should be examined for spherocytes and polychromasia, which
where available, and genetic counseling should be considered. would point to associated hemolysis (Evans syndrome). White
Detection of this mutation is also significant where family mem- cells should be examined for the presence of immature forms,
bers are being assessed as potential allogeneic stem cell transplant which would suggest a hematological malignancy; or reactive
donors, as family members carrying this mutation should be lymphocytes, as seen in acute viral infections such as dengue or
excluded as potential donors. cytomegalovirus infection. Platelets should be inspected for num-
Inherited platelet function disorders may be associated with ber, size, and granularity. Platelet size, either estimated from
thrombocytopenia (e.g. Bernard Soulier Syndrome (BSS)). BSS blood film review or measured by the analyzer (reported as
should be more readily apparent from a bleeding history dispro- mean platelet volume (MPV)) can be useful to guide molecular
portionate to the degree of thrombocytopenia and macrothrombo- analysis in suspected hereditary thrombocytopenia syndromes as
cytopenia on film review. Formal diagnosis can be achieved these can be categorized according to expected platelet size
through more available testing methods such as flow cytometry (Table II).
or platelet aggregometry. Basic biochemistry is required to assess renal function, which
is relevant in MAHA and some MYH9 associated hereditary
thrombocytopenias. Lactate dehydrogenase should be included,
Clinical Examination and if elevated raises the possibility of underlying MDS, malig-
Physical examination should never be omitted and adequate expo- nancy or hemolysis. Bilirubin, albumin, coagulation studies, and
sure of the patient is vital. The lower leg, palate, and fundi should liver enzyme tests can provide insight into possible underlying
be examined for petechiae and purpura. The upper arm should be liver disease or demonstrate an unconjugated hyperbilirubinemia
looked at if blood pressure cuffs have been used recently. Patients as seen in hemolytic states. The direct antiglobulin test (DAT or
should always be asked to “show me your bruising,” so that any Coombs test) should be ordered in suspected ITP to investigate
areas that might not normally be exposed to protect modesty are for concurrent hemolysis [29]. H pylori screening may be per-
not missed. Lymphadenopathy and splenomegaly should be care- formed, however, in our experience has been of little utility. HIV,
fully excluded in order that subsequent investigations can be HCV, and thyroid function tests should be performed to evaluate
appropriately ordered. Imaging may be warranted in patients for secondary causes of ITP. We do not routinely perform bone
with increased body mass index (BMI) due to the reduced sensi- marrow examination upfront in suspected ITP: this is reserved for
tivity of clinical examination. 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
Investigation functional antibody testing if available) must be performed when
there is a moderate or high suspicion of HIT, based on the 4T
Immediate Laboratory Investigation score. ADAMTS13 testing should be requested to confirm or
The question “could this be a spurious result?” should always be exclude TTP if a MAHA is identified, though this result should
asked if any significant abnormality in laboratory investigations not delay emergent management.
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 Additional Testing
[27]. Our laboratory has adopted a platelet count threshold of
Platelet Antibody Testing
20x10^9/L to automatically perform and report a fluorescent
platelet count as this has been shown to have improved accuracy Platelet antibody testing should ideally be a key investigation in ITP,
and precision in thrombocytopenia [28]. Other laboratories may as with most other autoimmune disorders, but unfortunately both
use an abnormal platelet distribution to trigger performance of the sensitivity and specificity of testing in numerous studies have
optical or fluorescent platelet counts; however, in our experience, demonstrated little utility in the investigation of thrombocytopenia
this leads to excessive testing as abnormal platelet distribution is [30,31]. Whilst some have reported the specificity to be adequate

Table II. Platelet size in inherited thrombocytopenias.

Small platelets (MPV <7fl) Normal platelets (MPV 7-11fl) Large platelets (MPV >11fl)

Wiskott Aldrich Syndrome Thrombocytopenia with absent radii (TAR) MYH9 syndromes
X-linked thrombocytopenia - May-Hegglin anomaly
Congenital amegakaryocytic thrombocytopenia - Fechtner syndrome
- Epstein syndrome
Radio-ulnar synostosis and amegakaryocytic thrombocytopenia - Sebastian syndrome
Mediterranean thrombocytopenia
Familial platelet disorder with associated myeloid malignancy Bernard Soulier syndrome
DiGeorge syndrome
Chromosome 10/THC2 Paris-Trousseau
Gray platelet syndrome
GATA1 mutation

(adapted from Drachman, 2004).

DOI: https://doi.org/10.1080/09537104.2019.1637835 New Onset Thrombocytopenia 5

(approximately 80% in some studies), in our opinion, this does not anticoagulant therapy, and lifestyle. In a patient in whom a life-
add value in a condition already fraught with misdiagnosis and threatening etiology (e.g. HIT, MAHAs) has been excluded, and
mistreatment. Platelet antibody testing has no role in our practice. 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
Genetic Testing is that the absence of a diagnostic test means a trial of treatment
Genetic testing for hereditary thrombocytopathies should be con- may contribute to confirming or refuting the diagnosis.
sidered in patients provisionally diagnosed with ITP who are refrac- In patients without a clear diagnosis in whom the platelet
tory to treatment, patients with a family history of thrombocytopenia count and bleeding risk do not warrant immediate treatment, we
and patients with syndromic features. The screening panel will vary will often use a trial of prednisolone 25 mg daily for 7 days to
depending upon the region and the laboratory performing the test- assess steroid responsiveness. A response to steroids both pro-
ing; but must include the most common inherited mutations. vides support for a diagnosis of immune thrombocytopenia and
A review of a gene panel performed on an Australasian cohort of confirms the utility of steroids to cover any future transient events
patients suspected to have hereditary thromobocytopathy identified associated with increased bleeding risk. In situations when ITP
MYH9-related disorders as the most common cause, with patho- does not respond to treatment as expected the opportunity should
genic MYH9 mutations found in 12.4% of patients [32]. be taken to review the diagnosis, rather than committing to
prolonged steroid therapy or splenectomy.
Is There a Role for MPV and IPF?
Conclusion
Whilst not often reported, most modern hematology analyzers are
capable of assessing platelet parameters, including the mean platelet The most common causes of thrombocytopenia are drugs and
volume (MPV) and an assessment of the immature platelet count, critical illness in the hospital population, and ITP in the commu-
given as an absolute count or as the immature platelet fraction (IPF). nity. A rapid assessment to exclude treatable serious underlying
The MPV may be useful in guiding genetic testing for suspected conditions should be performed, followed by an assessment of the
inherited thrombocytopenias as an adjunct to clinical assessment need for treatment to reduce bleeding risk. If a decision to treat is
and blood film review. MPV is also increased in ITP, MDS and made and the response is not as expected, the opportunity should
megaloblastic pancytopenia [33]. It has been shown to differentiate be taken to review the diagnosis. ITP is a diagnosis of exclusion,
between ITP and hypoproliferative thrombocytopenia, though the not an assumption; the full differential of causes of thrombocyto-
sensitivity and specificity of this varies between studies [34,35]. penia needs to be considered in all patients to ensure appropriate
Limitations at present include the absence of generally accepted diagnosis and therapy.
reference ranges, overlap of reference ranges, lack of standardiza-
tion between analyzer methods, platelet transfusion and pre- Declaration of Interest
analytical error (e.g. storage artifact). Furthermore, whether
analyzer derived MPV is of more use than proficient blood film The authors report no declarations of interest.
review is yet to be established. We do not routinely assess MPV in
our practice as blood film review by an experienced hematologist is ORCID
considered of higher yield with the potential to identify other blood
film features which may provide diagnostic insight. Fiona Swain http://orcid.org/0000-0001-7412-3271
IPF is a flow cytometric assessment of platelets incorporating
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