International Journal of Laboratory Hematology

The Official journal of the International Society for Laboratory Hematology

REVIEW INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Thrombocytopenia: an update
K. J. SMOCK, S. L. PERKINS

Department of Pathology, S U M M A RY
University of Utah Health
Sciences Center and ARUP Thrombocytopenia is a common clinical problem with numerous
Laboratories, Salt Lake City, UT, potential causes including decreased bone marrow platelet produc-
USA
tion, increased peripheral platelet destruction, increased splenic
Correspondence: sequestration, and dilution. Investigation of the etiology of throm-
Sherrie L. Perkins, Department bocytopenia requires careful consideration of clinical history and
of Pathology, University of Utah laboratory features. A complete blood count and peripheral smear
Health Sciences Center and
ARUP Laboratories, 500 Chipeta review are essential components of the diagnostic work-up, and
Way, Mail Stop 100-G02, Salt physicians should be knowledgeable about appropriate selection
Lake City, UT 84108, USA. and interpretation of more specialized tests, including bone marrow
Tel.: +1 801 583 2787;
examination, to assist with diagnosis. This review article aims to
Fax: +1 801 585 3831;
E-mail: Sherrie.Perkins@hsc. summarize and address appropriate work-up of the major and/or
utah.edu life-threatening causes of thrombocytopenia and some of the bet-
ter-characterized congenital thrombocytopenias.
doi:10.1111/ijlh.12214

Received 7 January 2014;

accepted for publication 14
February 2014

Keywords
Congenital thrombocytopenia,
thrombopoiesis, immune-
mediated thrombocytopenia,
microangiopathic hemolytic
anemia, laboratory testing

patient age, baseline platelet count, medical and surgical

INTRODUCTION
history, including any bleeding or thrombotic manifes-
Thrombocytopenia is a common clinical problem tations, family history, medication history, results of any
defined as a platelet count less than 150 9 109/L pertinent laboratory testing, and physical examination
although many feel that a cutoff value of 100 9 109/L is findings. A complete blood count (CBC) and peripheral
more appropriate to identify clinically significant throm- smear review are essential for initial evaluation. Ethy-
bocytopenia. Causes of thrombocytopenia can be subdi- lenediaminetetraacetic acid (EDTA)-induced pseudo-
vided into decreased platelet production, increased thrombocytopenia, a laboratory artifact characterized by
platelet destruction, increased splenic sequestration, in vitro platelet clumping in EDTA anticoagulant, must
and dilution. Investigation requires consideration of be excluded [1].

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278 269
270 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

The spleen harbors 30% of the total platelet mass and lies in an infant. Usually there is no family history.
splenomegaly can result in thrombocytopenia due to CAMT is associated with mutations in the MPL gene
platelet sequestration. Dilutional thrombocytopenia is that encodes the megakaryocytic receptor for TPO and
seen after major surgery or with transfusion of large can be caused by deletions, missense and nonsense
amounts of non-platelet-containing blood products [2]. mutations. Patients will develop progressive bone
Incidental or gestational thrombocytopenia in preg- marrow failure/aplasia. Two clinical patterns are seen:
nancy is characterized by mild or moderate thrombocy- Type 1 with early progression to pancytopenia and
topenia. Although the cause is unknown, it should be Type 2 with transient increases in platelet numbers in
carefully discriminated from other more serious causes the first year of life and much later progression to
of thrombocytopenia [3]. bone marrow failure. The clinical pattern is mutation-
This review article, while not exhaustive, aims to associated with more severe disease seen with total
summarize the major and/or life-threatening causes of loss of TPO signaling and less severe disease with
thrombocytopenia and some molecularly characterized retention of partial activity. Bone marrow transplant
congenital causes of thrombocytopenia. (BMT) is the only curative therapy [6, 7].
Thrombocytopenia with absent radius (TAR) syn-
drome presents in infants as thrombocytopenia, low
DECREASED BONE MARROW PRODUCTION
numbers of megakaryocytes in the marrow, and asso-
Causes of decreased bone marrow platelet production ciated physical malformations including bilateral
include congenital thrombocytopenias as well as absence of the radii with presence of thumbs. Other
acquired causes associated with myeloid malignancies musculoskeletal and cardiac abnormalities (commonly
and chemical or infectious agents that directly or indi- tetralogy of Fallot and atrial septal defects) may be
rectly suppress thrombopoiesis. Diagnosis of a bone mar- present. Patients are often intolerant to cow’s milk,
row etiology for thrombocytopenia requires evaluation and exposure may exacerbate thrombocytopenia.
of megakaryocytic numbers and morphology. Often Patients have elevated TPO levels, normal MPL and
bone marrow defects are not considered in the diagnos- HOX genes, but a defect in megakaryocytic differentia-
tic work-up until patients do not respond to treatment tion and platelet production [7, 8]. The genetic cause
for more common causes of thrombocytopenia. remains uncertain and may involve multiple muta-
tions. An interstitial microdeletion at chromosome
1q21.1 is described, although this alone does not
C O N G E N I TA L T H R O M B O C Y TO P E N I A
cause disease as it is seen in unaffected relatives. A sec-
Hereditary causes of thrombocytopenia are rare but ond mutation in the exon junction complex subunit
must be considered when there is a family history of RBM8A, controlling production of protein Y14, has
bleeding or persistent, unexplained thrombocytopenia been observed. Low levels of this protein lead to low
in infants and children. Although some of the better- platelet production [9]. Thrombocytopenia is usually
characterized causes of congenital thrombocytopenia greatest at birth with platelet counts increasing over
are discussed below, these represent only a fraction of time. Although platelet transfusions may be required
the inherited thrombocytopenias [4]. The disorders that in infancy, platelet counts usually stabilize, further
have been described are characterized by the mode of transfusions are not required, and other cytopenias
inheritance (autosomal dominant, autosomal recessive are not seen [8].
or X-linked recessive) and the clinical features including Bernard–Soulier syndrome is a deficiency of plate-
bleeding tendency and platelet size (Table 1) [4, 5]. let membrane proteins (GP1b, GPIX, GPV) that is
associated with significant platelet dysfunction, bleed-
ing, and thrombocytopenia. Patients have mild to
Autosomal recessive thrombocytopenias
severe thrombocytopenia with giant platelets, abnor-
Congenital amegakaryocytic thrombocytopenia mal bleeding times, and abnormal-ristocetin-induced
(CAMT) is characterized by severe thrombocytopenia, platelet aggregation studies. The disorder arises due to
lack of marrow megakaryocytic precursors, elevated mutations in the genes for GP1BA, GP1BB, or GP9
thrombopoietin (TPO) levels, and no physical anoma- which causes the characteristic decreased expression

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
 Table 1. Genetic and clinical features of congenital (inherited) thrombocytopenias

Mode of Degree of Platelet

Disease inheritance thrombocytopenia size Other clinical/pathologic features Genetic defect

Congenital AR Severe – Type 1 Normal Absence of megakaryocytes in marrow. Mutations in MPL gene
amegakaryocytic Mild to moderate – Develop bone marrow failure/
thrombocytopenia Type 2 pancytopenia, markedly elevated TPO
levels
Thrombocytopenia with AR Severe at birth but Normal Congenital malformations including Unknown. Mutation in
absent radii (TAR) usually less severe bilateral absent radii, skeletal and cardiac exon junction complex
with age abnormalities, often have cow’s milk subunit RBM8A gene.
intolerance, elevated TPO levels. Decreased Microdeletion of
to absent megakaryocytes in marrow at chromosome 1q21.1 (not
birth, low to normal numbers later in life causative)
Bernard-Soulier syndrome AR Mild Large Abnormal platelet function. Decreased GPIb Mutations in GP1BA,
complex on platelets. Marrow has normal GP1BB or GP9 genes
to slightly increased normal
megakaryocytes.

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
MYH9-related disorders AD Mild–moderate Large All will have Dohle-like bodies in myeloid Mutation in MYH9 gene
cells on 22q12.3–13.1,
May-Hegglin anomaly Mild–moderate Large variable penetrance
Sebastian syndrome Mild–moderate Large
Fechtner syndrome Mild–moderate Large Nephritis, hearing loss and cataracts
Epstein syndrome Mild–moderate Large Nephritis and hearing loss
Familial platelet disorder AD Moderate Normal Predisposition to develop AML or MDS. Heterozygous
with predisposition to Abnormal platelet aggregation/prolonged RUNX1 mutation on
acute myelogenous bleeding times. Abnormal platelet function. 8q22
leukemia Decreased megakaryocytes in marrow
Mediterranean AD Mild Large Seen in patients from Italy and Balkan Mutation in GP1A gene
macrothrombocytopenia peninsula. May represent carrier state for on chromosome 17
Bernard-Soulier syndrome
Paris-Trousseau syndrome AD Moderate to severe at Large Congenital abnormalities including Mutation in FLI1 gene on
birth but improve psychomotor retardation, trigonocephaly, 11q23.3
with age to near facial dysmorphism, and cardiac
normal abnormalities. Dysmegakaryopoiesis with
many micromegakaryocytes and abnormal
a-granules
Gray platelet syndrome AR Mild to moderate Large Develop myelofibrosis and splenomegaly. Unknown. Mutations in
Platelets lack a-granules and appear NBEAL2 gene in AR
agranular and ‘gray.’ Variable bleeding disease
K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

(continued)
271
272 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

of the GPIb complex. Bone marrow shows normal or

AR, autosomal recessive; AD, autosomal dominant; X, X-linked; TPO, thrombopoietin; AML, acute myelogenous leukemia; MDS, myelodysplastic syn-
Mutation in WAS gene at

Mutation in GATA1 gene

slightly increased morphologically normal megakaryo-
cytes. Treatment is focused on control of bleeding and
avoidance of antiplatelet medications [5, 10].
Xp11.4-p11.21
Genetic defect

at Xp11.23
Autosomal dominant thrombocytopenias

Autosomal dominant thrombocytopenias are rare and

usually are associated with normal numbers of megak-
aryocytes in the marrow, mild to moderate thrombocy-
Splenic destruction thought to cause small

topenia (20–100 9 109/L), increased platelet size

erythroid and megakaryocytic precursors
Usually have bleeding and bruising with
autoimmune disorders and lymphoma

Hypercellular marrow with dysplastic

(>10 fL), and increased bruising. Several of these disor-

Patients may have eczema and T-cell
lymphopenia. Increased incidence of
Normal to increased megakaryocytes.

abnormal platelet function. Anemia.

platelet size and thrombocytopenia.

ders (May–Hegglin anomaly, Sebastian, Fechtner, and

Other clinical/pathologic features

Epstein syndromes) have mutations in the MYH9 gene

(nonmuscle myosin heavy chain) at chromosome
22q12.3–13.1, including single nucleotide substitutions,
in-frame insertions or deletions, nonsense and frame-
shift mutations with varying degrees of penetrance [9,
11]. Nonmuscle myosin is a cytoskeletal protein, and
mutations affect platelet formation and megakaryocytic
maturation. The macrothrombocytopenia is associated
with leukocyte inclusions (Dohle-like bodies), and
there may be associated deafness or nephritis (Table 1)
depending on the mutation. Treatments include plate-
Large to
normal

let transfusions, use of TPO agonists, or BMT [4, 11].

Platelet

Small

Mediterranean macrothrombocytopenia is a mild

size

thrombocytopenia seen in patients from Italy or the

Balkan peninsula that arises due to a mutation on chro-
Variable-usually mild

mosome 17 in the area that contains the GP1BA gene,

Moderate to severe
thrombocytopenia

similar to the defect seen in Bernard–Soulier syndrome

to moderate

and may represent a heterozygous carrier state. Bleed-

ing is usually mild [12]. Another rare autosomal domi-
Degree of

nant disorder is familial platelet disorder with

predisposition to acute myelogenous leukemia (FPD/
AML) characterized by moderate thrombocytopenia
inheritance

and platelet functional defects. Patients have an

Mode of

increased incidence of myeloid malignancies, in partic-

ular AML and myelodysplasia. Genetic defects in the
X

core-binding factor A2 transcription factor (RUNX1)

define this disorder, including substitutions or large
microthrombocytopenia

thrombocytopenia with

deletions [13]. Paris–Trousseau syndrome is associated

Table 1. (Continued)

with congenital abnormalities including psychomotor

dyserythropoiesis

retardation, heart defects and facial dysmorphism,

(Wiskott-Aldrich

severe thrombocytopenia at birth, and dysmegakaryo-

syndrome)

poiesis with megakaryocytes containing abnormal or

(GATA1)

giant a-granules. This disorder is associated with FLI1

X-linked

X-linked
Disease

drome.

transcription factor gene mutations on chromosome 11.

Often platelet counts improve with age, but the

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE 273

abnormal platelet function causes a lifelong bleeding cytic precursors, or infections. In addition, decreased or
tendency [9]. Gray platelet syndrome may be inherited abnormally functioning megakaryocytic precursors may
as autosomal dominant or recessive disease and is char- be seen in a variety of neoplastic conditions including
acterized by macrothrombocytopenia with an associated myelodysplasia, acute leukemia, or bone marrow meta-
bleeding tendency and lack of a-granules, giving rise to static disease. The term ‘acquired amegakaryocytic
the characteristic gray appearance with Wright–Giemsa thrombocytopenic purpura’ (AATP) has been used to
staining [4]. A mutation in the NBEAL2 (neurobeachin- describe those cases with isolated megakaryocytic hypo-
like 2) gene involved in vessel trafficking is thought to plasia/aplasia in otherwise normal appearing marrows.
be the cause of autosomal recessive cases [14]. Patients The etiology of AATP is uncertain and may include
may develop myelofibrosis with splenomegaly and may drug/toxin effects, infections, or immune-based mecha-
have variable bleeding due to platelet dysfunction. nisms. Patients will not have a palpable spleen and will
respond well to platelet transfusions. Often treatment
with immunosuppressive agents is required [16].
X-linked thrombocytopenias
Bone marrow suppression by physical and chemical
X-linked microthrombocytopenia or Wiskott–Aldrich agents including chemotherapeutic drugs, antimetabo-
syndrome (WAS) is characterized by combined immu- lites, and ionizing radiation often leads to decreased
nodeficiency, thrombocytopenia, small platelet size, platelet production, although isolated thrombocytope-
eczema, and a propensity to develop autoimmune disor- nia is rare. However, platelet recovery is often the last to
ders or lymphoma. There is a broad spectrum of disease occur after marrow suppression. Commonly used drugs
manifestations and severity, with mutations in the WAS including chlorothiazides, estrogens, and ethanol will
gene at Xp11.4-p11.21. Mutations include single nucle- directly suppress megakaryocytic proliferation and dif-
otide substitutions, splice site mutations, and small ferentiation [17]. Ethanol will directly suppress platelet
insertions or deletions that occur at multiple sites within production, contributing to the commonly seen mild
the gene. The gene functions in interactions between thrombocytopenia in alcoholic patients. This thrombo-
cytoskeletal actin and translocation of nuclear factor jb cytopenia is usually multifactorial with elements of
(NFjb) in signal transduction. Megakaryocytes are pres- increased platelet destruction, splenic sequestration,
ent in normal to increased numbers, but platelet half-life and inhibition of platelet production [18]. Chlorothiaz-
is decreased with premature splenic removal. Splenec- ides may lead to formation of antiplatelet antibodies as
tomy will often increase platelet counts, but BMT is well as suppression of thrombopoiesis [17]. Vitamin B12
required for treatment of the associated immunodefi- and folate deficiencies may also lead to ineffective
ciency [15]. X-linked macrothrombocytopenia may be thrombopoiesis and mild thrombocytopenia [19].
seen in patients with GATA1 mutations encoding a Infections may cause clinically significant thrombo-
transcription factor that is essential for development of cytopenia due to marrow suppression. Viral infections
megakaryocytes and red cells. There is associated dysery- may impair thrombopoiesis due to direct infection of the
thropoiesis and anemia. Thrombocytopenia may be megakaryocyte, toxic effects of viral proteins or cyto-
severe, and megakaryocytes may be increased but appear kines, hemophagocytosis, or production of antibodies
dysplastic. Platelet function may also be impaired [4]. that bind to platelets and enhance immune destruction.
Measles, mumps, cytomegalovirus, hepatitis, varicella,
parvovirus B19, adenovirus, Epstein–Barr virus, and
AC Q U I R E D C AU S E S O F D E C R E A S E D B O N E
HIV have all been associated with development of
M A R R OW P L AT E L E T P R O D U C T I O N
thrombocytopenia [20]. Bacterial and protozoal infec-
Thrombocytopenia due to acquired marrow platelet pro- tions may also cause thrombocytopenia, most com-
duction defects may arise due to a decrease in megakary- monly in infants and young children. Patients should be
ocytic precursors, ineffective thrombopoiesis, or tested for possible disseminated intravascular coagula-
abnormal regulation of thrombopoiesis. Decreased tion (DIC) (described below), but thrombocytopenia
megakaryocytic precursors may arise due to variety of may also be caused by direct toxicity of the infectious
disease states including aplastic anemia, exposure to agent or by induction of hemophagocytic histiocytosis.
toxins, drugs, immune-based destruction of megakaryo- Malaria is the most common protozoal organism

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274 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

associated with thrombocytopenia. Malaria-associated immune or nonimmune mediated. Table 2 summa-

thrombocytopenia is thought to arise due to direct infec- rizes laboratory tests used in the work-up of increased
tion of the platelets, altered cytokines with increased peripheral platelet destruction.
pro-inflammatory cytokines, and altered cellular and
humoral immune function as well as increased splenic
Immune-mediated destruction
removal of platelets [21].
Immune thrombocytopenia (ITP) is a relatively com-
mon disorder caused by a combination of platelet
INCREASED PERIPHERAL DESTRUCTION
autoantibodies and suppressed platelet production.
After release from the bone marrow, platelets circulate Immune thrombocytopenia can be primary or sec-
for 7–10 days [1]. Accelerated clearance can be ondary to other disorders [22, 23]. The platelet

Table 2. Laboratory tests used in the workup of thrombocytopenia due to increased platelet destruction

Test Indication/utility

Bone marrow evaluation Usually not necessary

Chemistry and urine testing Widely available
Abnormalities in MAHA include decreased haptoglobin, increased indirect/unconjugated
bilirubin, increased lactate dehydrogenase, hemoglobinuria, and hemosiderinuria
Coagulation testing Widely available
(PT, aPTT, fibrinogen, Normal or mild derangements in HIT and TTP
D-dimer) Significant derangements in overt DIC, used in DIC scoring systems that demonstrate
good sensitivity and specificity in patients with a DIC-associated disorder
Platelet antibody testing Not recommended for ITP due to problems with sensitivity and specificity, possibly
useful in select cases
Essential component of NAIT diagnosis, used in conjunction with platelet genotyping,
phenotyping, or cross-matching
Useful to confirm PTP
Evaluation of drug-dependent platelet antibodies has limited sensitivity, but may be
useful in DITP, not widely available
Heparin-PF4 antibodies Treatment decisions made before results available
Immunoassays have high sensitivity (>90%) but low specificity (approximately 80%
or less) for clinical HIT, good negative predictive value
Functional assays, such as the SRA, have >90% sensitivity and specificity for clinical
HIT, strong positive results have particularly good correlation with clinical HIT, but
limited availability
ADAMTS-13 testing Limited availability, treatment decisions made before results available
Severe ADAMTS-13 deficiency (activity <5–10%) compatible with TTP, rare TTP cases
lack severe deficiency
ADAMTS-13 activity correlates with risk of TTP relapse
ADAMTS-13 antibody testing differentiates acquired from inherited TTP and correlates
with response to therapy and risk of relapse
Shiga toxin Supports diagnosis of classical HUS in a patient with diarrheal prodrome and MAHA
Complement studies Not widely available
Useful to support diagnosis of aHUS, only approximately 50% of causative abnormalities
are identified

MAHA, microangiopathic hemolytic anemia; PT, prothrombin time; aPTT, activated partial thromboplastin time; HIT,
heparin-induced thrombocytopenia; TTP, thrombotic thrombocytopenic purpura; DIC, disseminated intravascular coag-
ulation; ITP, immune thrombocytopenia; NAIT, neonatal alloimmune thrombocytopenia; PTP, post-transfusion pur-
pura; DITP, drug-induced thrombocytopenia; PF4, platelet factor 4; SRA, serotonin release assay; ADAMTS-13, a
disintegrin and metalloproteinase with thrombospondin type 1 motif 13; HUS, hemolytic uremic syndrome; aHUS,
atypical hemolytic uremic syndrome.

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE 275

count threshold for primary ITP has recently been includes discontinuation of heparins and alternative
defined as less than 100 9 109/L, but thrombocyto- anticoagulation with a nonheparin anticoagulant,
penia may be severe [22]. Traditional therapies con- such as a direct thrombin inhibitor [25, 26].
sist of corticosteroids, intravenous immunoglobulin Suspicion for HIT arises when a patient develops
(IVIg), anti-(Rh)D, and splenectomy in those with new thrombocytopenia 5–10 days after heparin expo-
suboptimal response to drug therapy. Newer thera- sure [28]. Heparin-induced thrombocytopenia typi-
pies, such as rituximab and TPO receptor agonists, cally results in a 50% drop from baseline platelet
may be considered [22]. count. Severe thrombocytopenia with platelet counts
In most cases, diagnosis of ITP relies on history and below 20 9 109/L is not characteristic [28]. Routine
physical exam, CBC data, and blood film review. Use of coagulation tests such as prothrombin time (PT),
platelet parameters such as mean platelet volume, activated partial thromboplastin time (aPTT), and
immature platelet fraction, and reticulated platelet frac- D-dimer may be normal or demonstrate mild
tion is not recommended in current guidelines [22]. derangements [26].
Peripheral smears from ITP patients may demonstrate Heparin-induced thrombocytopenia is a clinico-
scattered larger platelets due to release of immature pathologic diagnosis, but laboratory results may not
forms. Bone marrow evaluation is not a required com- be rapidly available and treatment needs to be initi-
ponent of the diagnostic work-up when additional he- ated immediately. Clinical scoring systems are often
matologic abnormalities are not present. Although there used to assess pretest probability, with the 4Ts scor-
are laboratory tests to identify platelet antibodies in ing system being most widely known [28]. In a
patient sera (indirect) or attached to patient platelets 2012 meta-analysis of 13 studies involving 3068
(direct), ITP is considered a diagnosis of exclusion and patients, a low probability 4Ts score was shown to
platelet antibody testing is not routinely recommended have excellent negative predictive value (NPV)
due to problems with sensitivity and specificity of the (0.998, 95% CI, 0.970–1.000) for HIT [29]. How-
assays. ever, intermediate and high probability scores car-
Drug-induced thrombocytopenia (DITP) is associ- ried positive predictive values (PPVs) of only 0.14
ated with many different medications, commonly (95% CI, 0.09–0.22) and 0.64 (95% CI, 0.40–0.82),
quinine drugs and sulfonamides. Thrombocytopenia respectively [29].
develops 1–2 weeks after exposure with several caus- Laboratory testing for HIT includes immunoassays
ative immune mechanisms described [24]. Thrombo- to detect antibodies to heparin-PF4 complexes and
cytopenia can be severe, with platelet counts often functional assays to detect platelet-activating proper-
<10 9 109/L. Potential therapies include withdrawal ties of the antibodies [27]. Immunoassays have high
of the suspected medication, corticosteroids, IVIg, and sensitivity (>90%), low specificity (approximately
sometimes platelet transfusions. Clinical criteria have 80% or less), and good NPV [25–27]. The specificity
been used to diagnose DITP. Laboratory testing for and predictive value can be improved by considering
drug-dependent platelet antibodies requires significant the optical density (OD) of the reaction where
expertise, is available only at specialized reference higher OD values correlate with higher likelihood of
laboratories, and is not pursued in most cases. Posi- a positive functional test and clinical HIT [27]. The
tive results are supportive of the diagnosis, but the combination of clinical impression and ELISA results
tests have limited sensitivity. (particularly negative or strongly positive results)
Heparin-induced thrombocytopenia (HIT) occurs provides adequate evidence for or against HIT in
in 0.5–5% of patients receiving heparin. It is caused many instances. Functional assays, such as the gold
by antibodies against heparin/platelet factor 4 (PF4) standard serotonin release assay (SRA), are charac-
immune complexes that engage platelet Fc receptors terized by similar sensitivity but greater specificity
resulting in platelet activation, thrombocytopenia, for HIT as they evaluate whether patient sera can
and risk of arterial or venous thrombosis, with fatal activate platelets [25, 26]. However, they require
consequences in 5–10% of patients [25, 26]. With- significant technical expertise, leading to very lim-
out treatment, thrombotic events occur in up to ited availability and turnaround times of several
50% of patients [25, 27]. Appropriate therapy days.

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276 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

Neonatal alloimmune thrombocytopenia (NAIT) is croangiopathic hemolytic anemia (MAHA), and

a disorder caused by maternal alloantibodies directed thrombocytopenia secondary to microvascular (arteri-
against fetal platelet antigens inherited from the olar) platelet thrombi.
father that occurs in 1 in 2000 pregnancies. The Thrombotic thrombocytopenic purpura is described
maternal antibodies cross the placenta resulting in as having a pentad of features including MAHA
fetal thrombocytopenia and possible bleeding compli- (mechanical red blood cell destruction with schisto-
cations [30]. Maternal antibodies to human platelet cyte formation), thrombocytopenia, renal dysfunc-
antigen 1a (HPA-1a) account for approximately 80% tion, neurologic symptoms, and fever. Renal and
of NAIT cases in Caucasian populations. neurologic dysfunction and fever do not occur in
Thrombocytopenia in NAIT is often severe with every case, and idiopathic TTP is clinically defined as
platelet counts <20 9 109/L [30]. Pregnancies in MAHA and thrombocytopenia without an alternative
women with previously affected pregnancies should cause [33]. Thrombocytopenia in TTP is often severe
be closely monitored with imaging and are often (counts <50 9 109/L). Derangements in routine coag-
empirically treated with IVIg and/or corticosteroids. ulation tests such as PT, aPTT, and D-dimer are less
Fetal platelet counts and intrauterine platelet trans- pronounced.
fusions have become less commonplace. Platelet Severe ADAMTS-13 deficiency (activity <5–10% of
transfusions are used in the postnatal setting for normal) is present in many, but not all, cases of idio-
severe thrombocytopenia and/or bleeding. Laboratory pathic TTP [32, 33]. Treatment needs to be initiated
diagnosis is centered on demonstrating incompatibil- before results of testing are available. Persistent
ity between maternal and paternal (as a representa- severe ADAMTS-13 deficiency in clinical remission
tion of possible fetal platelet type) platelets through may predict higher relapse risk [32, 33]. Testing for
platelet genotyping, phenotyping, or cross-matching, ADAMTS-13 autoantibodies is potentially useful as
and identification of maternal serum antibodies detection of antibodies at diagnosis is compatible with
directed against any discrepant antigens. acquired rather than congenital TTP and seems to
HPA-1a negative patients (both males and females) correlate with response to therapy and risk of relapse
are also at risk of a rare complication of blood transfu- [33]. Thrombotic thrombocytopenic purpura (regard-
sion called posttransfusion purpura (PTP). The disor- less of ADAMTS-13 level) should be treated with
der is characterized by severe, immune-mediated therapeutic plasma exchange (TPE) [33]. The disorder
thrombocytopenia (often with platelet counts has a 90% fatality rate without appropriate therapy.
<10 9 109/L) that develops 5–14 days after platelet Therapeutic plasma exchange is often supplemented
transfusion [31]. The disorder has features of both with corticosteroids, cytotoxic agents, or rituximab
allo- and autoantibodies as the patient’s own antigen- [32].
negative platelets are also destroyed. Hemolytic uremic syndrome (HUS) is classically
caused by Shiga toxin-producing bacterial enterocoli-
tis (STEC, often due to E. coli 0157:H7), which
Non-immune-mediated destruction
results in bloody diarrhea, renal failure (secondary to
The rare (four cases per million) disorder of throm- microthrombi), MAHA, and thrombocytopenia [33].
botic thrombocytopenic purpura (TTP) is caused by Typical HUS is treated with supportive care rather
acquired autoantibodies to the von Willebrand factor than TPE. The clinical distinction between TTP and HUS
(vWF) cleaving protease ADAMTS-13 (a disintegrin is often difficult, but HUS is associated with a greater
and metalloproteinase with thrombospondin type 1 degree of renal dysfunction and no severe ADAMTS-13
motif 13) [32]. There is also a very rare form of con- deficiency [32, 33].
genital TTP called Upshaw–Schulman syndrome. von In the absence of a diarrheal prodrome and Shiga
Willebrand factor is a multimeric protein that facili- toxin positivity, the HUS syndrome is called atypical
tates platelet adhesion to damaged endothelium, and HUS (aHUS). aHUS is caused by heritable abnormali-
multimer size is regulated by ADAMTS-13. Without ties of alternative complement regulation [32], leading
ADAMTS-13, ultra-high-molecular-weight vWF multi- to complement-mediated vascular damage, activation
mers accumulate, resulting in organ dysfunction, mi- of coagulation, and recurrent aHUS episodes [32].

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE 277

Figure 1. A simplified algorithm

for the work-up of MAHA.
MAHA and thrombocytopenia
without an identifiable cause
should be treated with
therapeutic plasma exchange
pending additional laboratory
studies. MAHA,
microangiopathic hemolytic
anemia; ADAMTS13, a
disintegrin and metalloproteinase
with thrombospondin type 1
motif 13; DIC, disseminated
intravascular coagulation; HUS,
hemolytic uremic syndrome;
aHUS, atypical hemolytic uremic
syndrome; TTP, thrombotic
thrombocytopenia purpura.

Laboratory assays are not widely available and do not levels are not specific for DIC in that they are also
identify all of the causative abnormalities (approxi- observed in patients with other etiologies of clot for-
mately 50% remain unknown) [32]. Use of ecu- mation [34]. However, levels are generally much
lizumab (humanized monoclonal antibody to higher in DIC [35]. Scoring systems have been devel-
complement component C5) has become the mainstay oped to assist with laboratory diagnosis of both overt
of aHUS therapy. and nonovert DIC [34, 35]. A simple system for overt
Disseminated intravascular coagulation involves DIC using platelet count, PT, fibrinogen, and D-dimer
systemic activation of the coagulation system and is has shown good sensitivity and specificity (>90%) in
another disorder of MAHA with schistocyte formation patients with an underlying DIC-associated disorder
and thrombocytopenia. In DIC, arteriolar thrombi are [34].
composed of both fibrin and platelets. In addition to A simplified algorithm for the work-up of MAHA is
systemic microvascular fibrin formation (leading to presented in Figure 1.
organ failure) and consumption of clotting factors,
there is impairment of anticoagulant and fibrinolytic
CONCLUSION
mechanisms, leading to a picture that can include
both thrombosis and bleeding [34]. Disseminated Thrombocytopenia is a common disorder with myriad
intravascular coagulation can be either overt (decom- underlying causes. Careful attention to clinical history
pensated) or nonovert (compensated) [35]. Treatment and physical examination, supplemented by carefully
should be aimed at correcting the underlying etiology selected laboratory tests, is critical for accurate and
and providing supportive care. timely diagnosis. Because some rare causes of throm-
Laboratory features of DIC include anemia and bocytopenia are immediately life-threatening, physi-
thrombocytopenia. Only 10–15% of patients have cians should be familiar with both common and
platelet counts <50 9 109/L [34]. Consumption of uncommon etiologies.
coagulation factors leads to prolongations in the PT
and aPTT (>95% of DIC patients) [34]. However,
AC K N OW L E D G E M E N T S
these are nonspecific findings. Hypofibrinogenemia is
only approximately 30% sensitive for DIC diagnosis Both authors Perkins and Smock wrote significant
[34]. Assays of fibrin-related markers, specifically D- portions of the manuscript. We wish to thank LuAnn
dimer, are considered most useful. Elevated D-dimer Reeve for secretarial assistance.

© 2014 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 269–278
278 K. J. SMOCK AND S. L. PERKINS | THROMBOCYTOPENIA UPDATE

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