1 s2.0 S2211594316300338

Immune
T h ro m b o c y t o p e n i a
a, b,c
Iris Ma, MD *, Alexander T. Sandhu, MD, MS
KEYWORDS
Immune thrombocytopenia Idiopathic thrombocytopenic purpura Splenectomy
Thrombopoietin mimetics Anti-D immunoglobulin
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Immune thrombocytopenia is a diagnosis of exclusion with no confirmatory

diagnostic test.
2. Secondary immune thrombocytopenia occurs due to multiple distinct etiol-
ogies—including infections, autoimmune disease, and malignancy—but repre-
sents less than 20% of adult immune thrombocytopenia cases.
3. Bone marrow biopsy is not necessary for diagnosis but should be pursued in
select cases: abnormalities on peripheral smear, abnormal white blood cell or
hemoglobin count, or treatment-refractory immune thrombocytopenia.
4. Treatment for immune thrombocytopenia should be initiated in patients with
less than 30,000 platelets per microliter or with significant bleeding. First-line
treatment for primary ITP is high-dose dexamethasone, intravenous immuno-
globulin, or anti-D immunoglobulin. A choice should be made based on rapidity
of onset needed, side effect profile, and cost.
5. Immune thrombocytopenia is typically a chronic disease but improves over time
in many cases. Splenectomy should be deferred for at least 6 months in favor of
treatments with lower long-term morbidity to allow time for disease regression.
DEFINITION
What is immune thrombocytopenia?
Immune thrombocytopenia (ITP) is a syndrome of low platelet count (<100,000 plate-

lets per microliter) caused by autoimmune platelet destruction. It results from the
The authors have nothing to disclose.

a
California Pacific Medical Center, 2333 Buchanan Street, San Francisco, CA 94115, USA;
b
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; c Department of Medicine,
Center for Health Policy and Center for Primary Care and Outcomes Research, Stanford Univer-
sity, 117 Encina Commons, Stanford, CA 94305, USA
* Corresponding author.
E-mail address: MaIH1@sutterhealth.org
Hosp Med Clin 6 (2017) 53–66

http://dx.doi.org/10.1016/j.ehmc.2016.07.005
2211-5943/17/ª 2016 Elsevier Inc. All rights reserved.
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54 Ma & Sandhu
spontaneous or disease-associated development of platelet autoantibodies. In the

pediatric population, ITP is most commonly a self-limited postviral phenomenon; how-
ever, in adults, it typically results in a chronic disease with multiple remissions and re-
lapses. This review focuses on adult ITP. See Box 1 for a description of key definitions
of ITP disease classifications.1
What is the difference between primary and secondary immune thrombocytopenia?

Primary ITP does not have an associated cause. Secondary forms of ITP have many
overlapping features with primary ITP but are triggered by various illnesses including
viral infections, bacterial infections, rheumatologic disease, and malignancies, partic-
ularly hematologic cancers.2 Fig. 1 displays the relative frequency of ITP etiologies.
The most common secondary ITP disease associations are listed in Box 2.2,3 Distin-
guishing primary and secondary ITP is important because secondary ITP may improve
or resolve after treating the underlying cause. There are many options for treating ITP,
and choosing a treatment for secondary ITP that also targets concurrent diseases is
preferred.
PATHOPHYSIOLOGY
What is the mechanism of immune thrombocytopenia?

The autoimmune nature of ITP was first elucidated by a hematology fellow and his
colleagues who famously performed self-experimentation to investigate the mecha-
nism of the disease.4 These audacious investigators transfused themselves with
the blood from patients afflicted with what was then termed idiopathic thrombocyto-
penic purpura. Lo and behold, the experimenters developed severe symptomatic
thrombocytopenia within 60 minutes of blood transfusion. The platelet decrease
persisted for about 1 week before resolving. This experiment firmly established
the concept that there existed a factor in patients’ blood that caused platelet
destruction.
Box 1
Definitions
Term Definition
Thrombocytopenia <150,000 platelets/microliter
Immune thrombocytopenia Autoimmune destruction of platelets resulting in blood
platelet count <100,000 platelets/microliter
Idiopathic thrombocytopenic Historic name for ITP now replaced by immune
purpura thrombocytopenia
Primary ITP ITP with no associated trigger
Secondary ITP (disease ITP with an associated triggering condition such as infection,
associated) immune disease, or medication related as shown in Box 2
Phases of Disease
Newly diagnosed ITP Within 3 mo of first diagnosis
Chronic ITP Persistent ITP >12 mo
Severe ITP Significant bleeding symptoms requiring treatment
Response Classification
Partial response >30,000 platelets/microliter, doubling of platelet count from
nadir, and absence of bleeding
Complete Response Platelet count >100,000 platelets/microliter and absence of
bleeding
Immune Thrombocytopenia 55
Fig. 1. Expert estimates of etiology of ITP. ALPS, post-tx, autoimmune lymphoproliferative

syndrome, post-transplant; APLS, antiphospholipid antibody syndrome; CLL, chronic lym-
phocytic lymphoma; CVID, common variable immunodeficiency; HCV, hepatitis C virus;
HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus. (Data from Cines
DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathogenic and clinical diversity. Blood
2009;113(26):6511–21.)
Subsequent studies implicated autoantibodies as the primary drivers of platelet

destruction.5,6 However, there are multiple additional mechanisms for ITP, including
decreased production of platelets by megakaryocytes, inadequate thrombopoietin
release by hepatocytes, and increased clearance of platelets.7
Box 2
Secondary immune thrombocytopenia
Autoimmune
Systemic lupus erythematosus
Antiphospholipid antibody syndrome
Thyroid disease
Evans syndrome
Autoimmune lymphoproliferative syndrome
Postvaccination
Lymphoproliferative disorders
Chronic lymphocytic leukemia
Hodgkin disease
Large granular T-lymphocyte leukemia
Infections
Human immunodeficiency virus
Hepatitis C virus
Helicobacter pylori
Varicella zoster virus
Cytomegalovirus
Immunodeficiency
Posttransfusion purpura
Drug-induced thrombocytopenia
56 Ma & Sandhu
EPIDEMIOLOGY
What is the incidence/prevalence of immune thrombocytopenia?
The incidence of ITP is low at 1 to 4 cases per 100,000 patient-years in adults.8–11 This
incidence is comparable with that of amyotrophic lateral sclerosis or acute myeloid leu-
kemia.12,13 The adult prevalence of 10 to 24 cases per 100,000 patients, based on the
largest US studies, is consistent with the paradigm of ITP as a chronic disease.14–16
Women have a higher incidence rate compared with men at 1.2 to 4.0:1, but this sex
difference decreases with increasing age.8–11 Pregnant women have the highest inci-
dence rates of ITP at 100 cases per 100,000 pregnancies.17–19 For the entire popula-
tion, incidence increases considerably with age (Fig. 2).8–10
Are there racial differences in rates of immune thrombocytopenia?

Small case studies suggested a lower rate of ITP in black Americans than in white
Americans.20 However, a large study in veterans, better matching for access to health
care resources, showed no race-based difference in rates of ITP.21
HISTORY AND EXAMINATION
What is the clinical presentation in a patient with immune thrombocytopenia?
Many patients present without clinical symptoms after laboratory findings incidentally
show isolated thrombocytopenia. Patients with severe thrombocytopenia may pre-
sent with bleeding, typically of the mucocutaneous variety, such as gingival bleeding,
epistaxis, petechiae, gastrointestinal bleeding, or menorrhagia.22,23 Intracranial hem-
orrhage is rare, occurring in 0.4% of newly diagnosed ITP patients and 1.6% of
chronic ITP patients.24
Fig. 2. Incidence of ITP by age and sex. (Data from Age group incidence rates in men and
women in Abrahamson PE, Hall SA, Feudjo-Tepie M, et al. The incidence of idiopathic
thrombocytopenic purpura among adults: a population-based study and literature review.
Eur J Haematol 2009;83(2):83–9.)
DIAGNOSIS
How can immune thrombocytopenia be diagnosed?
ITP is a diagnosis of exclusion. Platelet autoantibody assays have been developed,

but they are neither sensitive nor specific enough for broad clinical utility. Thus, ITP
is diagnosed by ruling out common alternative causes of thrombocytopenia based
on a detailed patient history and limited laboratory workup. Recommended workup
is shown in Box 3.23
History must include a careful drug history, recent transfusion history, medical his-
tory, bleeding history, and family history. Diagnostic tests must include a peripheral
smear and complete blood count to assess for additional cytopenias that may suggest
an alternate disorder, inherited platelet disorder, or other systemic disease.25,26
The diagnostic workup for ITP should also include diseases that are associated with
stimulating ITP, namely human immunodeficiency virus and hepatitis C virus. Although
some studies found an association between Helicobacter pylori and ITP with improve-
ment in platelet counts after H pylori treatment, others have not shown a benefit.27–30
Therefore, the decision to test for H pylori remains an area of much practice variation.
It is reasonable to test for and treat for H pylori in selected high-risk populations such
as persons of Asian or Italian heritage.26,30
Which patients with thrombocytopenia should undergo bone marrow biopsy?

Bone marrow biopsy is not necessary for the diagnosis of ITP in most patients.31
Although earlier guidelines recommended bone marrow biopsy for patients consid-
ering splenectomy or those older than 60 years, more recent guidelines—based on
current evidence—do not recommend bone marrow biopsy for these indications
alone. Bone marrow biopsy is warranted in patients who show abnormalities on pe-
ripheral smear, have anemia or leukopenia, and who are refractory to therapy, espe-
cially older patients.23,26,32
MANAGEMENT
Which patients with immune thrombocytopenia should receive treatment?

Patients with greater than 30,000 platelets per microliter without bleeding do not
require treatment. Most patients with less than 30,000 platelets per microliter or
Box 3
Diagnostic evaluation for immune thrombocytopenia
Recommended for all Patients Consider for Selected Patients
Complete blood count Bone marrow biopsy
Peripheral smear Helicobacter pylori testing
HIV testing Reticulocyte count
HCV testing Direct antiglobulin test
Thyroid function tests
Antiphospholipid antibodies
Antinuclear antibodies
Parvovirus testing
CMV testing
Abbreviations: HCV, Hepatitis C virus; HIV, Human immunodeficiency virus.
58 Ma & Sandhu
clinically significant bleeding should receive treatment. Patients with less than 20,000
platelets per microliter with significant mucocutaneous bleeding or life-threatening
bleeding should be hospitalized.23
Patients with chronic ITP may need additional treatment or platelet transfusion
before planned procedures. Evidence-based platelet thresholds are listed in
Box 4.23,33–36
What is first-line therapy for immune thrombocytopenia?

There are 3 acceptable first-line treatments for ITP: glucocorticoids, intravenous
immunoglobulin (IVIg), and anti-D antibody.37–40 Selecting an agent is based on pa-
tient characteristics, medication side effects, comorbid conditions, and rapidity of
onset desired as shown in Table 1.25,41–45
Which glucocorticoid agent should be used?

Although glucocorticoid therapy is inexpensive and has a long history of effectiveness,
it has more adverse side effects with chronic use than either IVIg or anti-D antibody.
Thus, glucocorticoids are often used for newly diagnosed ITP but less frequently for
chronic ITP. If the decision is made to select a glucocorticoid agent for therapy, the
2 principal options are intermediate-dose prednisone and high-dose dexamethasone.
Traditionally, initial steroid therapy was with prolonged oral glucocorticoids. However,
recent randomized, controlled trial evidence suggests that short courses of high-dose
dexamethasone have higher response rates, faster rates of onset, similar sustained
remission rates, and fewer side effects than prolonged intermediate-dose prednisone
therapy.46 It is the authors’ opinion that current evidence best supports high-dose,
short-course dexamethasone as the initial glucocorticoid regimen of choice.
What is the mechanism of intravenous immunoglobulin? When should it be used?

IVIg is human immunoglobulin (Ig) collected from the pooled plasma of donors. It re-
sults in diverse effects on the immune system, which are only partially understood.
Box 4
Platelet threshold recommendation for safe platelet counts in various procedural settings
Recommendations for safe platelet counts in adults

Most dental procedures, greater than 10,00023
Dental extractions, greater than 30,000 (BHJ)23
Neurosurgery, greater than 100,00035
Most major surgery, greater than 50,00035
Lumbar puncture, greater than 40,00033
Spinal anesthesia, greater than 80,00033
Bone marrow biopsy, greater than 20,00035
Vaginal delivery, greater than 50,00034
Paracentesis, greater than 20 to 30,00036
Of note, units are platelets per microliter.

Data from Refs.23,33–36
Table 1
First-line therapies
Initial Response, d
Treatment, (Dose25) (Maximal Response)25 Costa Mechanism48 Adverse Effects
Dexamethasone (40 mg/d 4 d) 2–14 (4–28) $4.24 Alter cytokine function, Osteoporosis, weight gain, skin
inhibit T-cell function fragility, cataracts, cardiovascular
disease, adrenal insufficiency42
IVIg (1 g/kg) 1–3 (2–7) $5032 plus prolonged Multifactorial immune Hypersensitivity and anaphylactic
facility infusion time effects reactions, hemolytic anemia,
viral contamination43
Anti-D Ig (75 mcg/kg) 1–3 (3–7) $5588 plus brief facility Rh antibodies bind to Hemolytic anemia, neutropenia,
infusion time macrophage Fc receptors hypersensitivity reactions44,45
in spleen in Rh1 patients
a
Costs are the average wholesale acquisition cost of a course of therapy in 2015 US dollars in The Red Book.25 For dexamethasone, this includes 4 doses. For IVIg,
Immune Thrombocytopenia
cost included is for a single dose of WinRho brand for a 60-kg person. For Anti-D Ig, cost included is for a single dose of Flebogamma therapy. Weight-based dosing
based on 60 kg person.
Data from Refs.25,42–45
59
60 Ma & Sandhu
One of the various mechanisms by which IVIg is thought to be effective in the treat-
ment of ITP is through the presence of antibodies that are bound by Fc receptors in
macrophages, thus, inhibiting the ability of these macrophages to bind to platelet au-
toantibodies.47 There are also idiotype antibodies that bind and inactivate antiplatelet
antibodies. In addition, cytokine profiles are altered, and animal models have shown
modification of dendritic cell function.48
What is the mechanism of anti-D immunoglobulin? When should it be used?

Anti-D (D corresponds to Rh1) Ig works by binding directly to Rh1 red blood cells
(RBCs); these complexes are then bound to Fc receptors on macrophages, which
phagocytose RBCs and destroy them. By saturating macrophage Fc receptors with
Ig-bound RBCs, Ig-bound platelets are spared. Anti-D antibodies are not effective in
Rh– patients who lack the target antigen.49 Splenectomized patients respond less
well to Anti-D Ig, which is attributed to the important role of splenic architecture in hous-
ing macrophages and facilitating clearance of antibody coated RBCs and platelets.37
Anti-D Ig has advantages over IVIg including lower cost, shorter infusion time, and a
smaller donor pool, which is assumed to cause lower infection and allergic reaction
risks.40 However, anti-D Ig is contraindicated in patients with anemia, as it results in
varying degrees of hemolysis. The hemoglobin decrease is 1 g/dL on average, but a
significant minority (w5%) have decreases of about 3 g/dL within 1 week.37
How should patients with emergent bleeding be treated?
If a response is needed within hours, patients with emergent bleeding should be

treated with a combination of IVIg, high-dose parenteral steroid therapy, and platelet
transfusion.1,23,50 If an immediate response within minutes is required, recombinant
factor VIIa, antifibrinolytics, or splenectomy have reportedly been used with
success.26
What are second-line therapies for immune thrombocytopenia?

Second-line therapies are initiated if patients continue to have clinically significant
bleeding or persistently low platelet counts (some use a threshold of <20,000 platelets
per microliter as opposed to <30,000 platelets per microliter for first-line therapy)
despite first-line therapy. Preferred second-line therapies are rituximab, thrombopoie-
tin (TPO) agonists, and splenectomy. Because of the long history of success with sple-
nectomy, it has traditionally been the preferred second-line therapy. However, as
experience with rituximab and TPO agonists has increased, they have been viewed
as increasingly viable alternatives for patients who prefer to avoid or defer surgical
therapy. These agents are especially good second-line choices for use early in the dis-
ease course before it is prudent to proceed with splenectomy, because disease
regression remains a possibility, as described below.
When should splenectomy be pursued?

Splenectomy remains a highly effective method for inducing remission of ITP and is
the only modality that doesn’t require maintenance therapy. Two-thirds of patients
experience complete remission with splenectomy, and an additional 22% have a par-
tial response.51 However, because 30% of ITP patients experience complete remis-
sion at 6 months regardless of the choice of therapy, it is recommended to delay
splenectomy until a minimum of 6 to 12 months.23,25,52
Splenectomy is beneficial for patients who prefer to minimize follow-up with the
health care system. Splenectomy can induce long-term remission, requires fewer total
treatments, and is associated with fewer follow-up appointments and laboratory tests
than many other second-line treatments. Given the definitive nature of splenectomy, it
is the traditionally preferred second-line therapy for patients who do not respond to
corticosteroid therapy. Recently, the trend has been toward medical second-line ther-
apy as a reasonable alternative.
The risks of splenectomy include surgical complications, increased short- and long-
term rates of thrombosis, and increased risk of infections, particularly bacterial
sepsis.53 Vaccination with polyvalent pneumococcal vaccine, quadrivalent meningo-
coccal vaccine, and Haemophilus influenzae type B vaccine should be provided, pref-
erably 2 weeks preoperatively. If preoperative vaccination is not performed, the
preferred timing of vaccination is a minimum of 14 days postoperatively, as this results
in superior antibody function.54
How does rituximab work for second-line therapy?

Rituximab is a monoclonal antibody to CD20, an antigen present on B lymphocytes,
which leads to B lymphocyte destruction. Treatment of ITP with rituximab leads to
a complete response rate of 35% and a partial response rate of 19%.55 However,
the median time to response is long at 4.5 weeks, and the median response duration
is only 10.5 months.56 The response rate at 5 years was only 21%.55 The main
adverse effects of rituximab are infusion reactions and infections related to
immunosuppression.57
How are thrombopoietin agonists used?
TPO agonists are novel drugs that stimulate megakaryocytes to produce increased
numbers of platelets.58 TPO agonists require long-term use as maintenance
therapy. Discontinuation may lead to rebound decreases in platelet count.59 Use
in refractory and poorly responsive ITP has resulted in response rates of 80%
to 88%.60
Because of the novelty of TPO agonists, there remains caution regarding possible
long-term adverse consequences that have not yet been elucidated. However, to
date, findings have been favorable, and their use continues to expand.
PROGNOSIS
What is the prognosis of patients with immune thrombocytopenia?

Most patients improve with no therapy or first-line treatment only. Approximately 32%
of patients require additional treatment.9 Splenectomy results in at least partial remis-
sion in 88% of patients.51 Of the subset of patients who are refractory to splenectomy,
75% of patients achieved remission, with a median time to remission of 4 years. These
patients often require multiple therapies that may include third-line treatment with
chemotherapy agents.61
Older patients with low platelet counts are more likely to have bleeding complica-
tions than younger patients.62 Although fatal hemorrhage is rare, patients with chronic
ITP have a 4-fold increase in their mortality rates. Half of the excess mortality is sec-
ondary to bleeding and half to infectious complications likely related to chronic immu-
nosuppressive therapies.63
62 Ma & Sandhu
PERFORMANCE IMPROVEMENT
Real-world adherence to practice guidelines was assessed in a study conducted in

Spain.64 Failure to perform peripheral blood smears was found in 23% of patients,
excessive bone marrow assessments with biopsies were performed in 51% of
patients, and overly early splenectomy was performed at a median of 161 days (guide-
lines recommend waiting 180–365 days).
Restraint in approaching ITP is a focus of performance improvement initiatives, as
diagnostic tests are commonly inappropriately ordered and patients are often over-
treated leading to unnecessary morbidity and costs. As part of the American Board
of Internal Medicine’s Choosing Wisely initiative, American medical professional spe-
cialty societies have identified tests or procedures in their respective specialties that
are wasteful or unnecessary. One of the 10 evidence-based recommendations chosen
by The American Society of Hematology was not to treat ITP in patients who did not
have bleeding or did not have platelet counts greater than 30,000, as overtreating
leads to potential side effects and high costs with little clinical benefit.65
CLINICAL GUIDELINES
Neunert C, Lim W, Crowther M, et al. The American society of Hematology 2011
evidence-based practice guideline for immune thrombocytopenia. Blood
2011;117(16):4190–206.
Provan D, Stasi R, Newland AC, et al. International consensus report on the inves-
tigation and management of primary immune thrombocytopenia. Blood
2010;115(2):168–86.
British Committee for Standards in Haematology General Haematology Task Force.
Guidelines for the investigation and management of idiopathic thrombocytopenic
purpura in adults, children and in pregnancy. Br J Haematol 2003;120:574–96.
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Immune

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Immune thrombocytopenia is a diagnosis of exclusion with no confirmatory

What is immune thrombocytopenia?

Immune thrombocytopenia (ITP) is a syndrome of low platelet count (<100,000 plate-

The authors have nothing to disclose.

Hosp Med Clin 6 (2017) 53–66

spontaneous or disease-associated development of platelet autoantibodies. In the

What is the difference between primary and secondary immune thrombocytopenia?

What is the mechanism of immune thrombocytopenia?

Fig. 1. Expert estimates of etiology of ITP. ALPS, post-tx, autoimmune lymphoproliferative

Subsequent studies implicated autoantibodies as the primary drivers of platelet

What is the incidence/prevalence of immune thrombocytopenia?

Are there racial differences in rates of immune thrombocytopenia?

HISTORY AND EXAMINATION

What is the clinical presentation in a patient with immune thrombocytopenia?

How can immune thrombocytopenia be diagnosed?

ITP is a diagnosis of exclusion. Platelet autoantibody assays have been developed,

Which patients with thrombocytopenia should undergo bone marrow biopsy?

Which patients with immune thrombocytopenia should receive treatment?

What is first-line therapy for immune thrombocytopenia?

Which glucocorticoid agent should be used?

What is the mechanism of intravenous immunoglobulin? When should it be used?

Recommendations for safe platelet counts in adults

Of note, units are platelets per microliter.

What is the mechanism of anti-D immunoglobulin? When should it be used?

How should patients with emergent bleeding be treated?

If a response is needed within hours, patients with emergent bleeding should be

What are second-line therapies for immune thrombocytopenia?

When should splenectomy be pursued?

How does rituximab work for second-line therapy?

How are thrombopoietin agonists used?

What is the prognosis of patients with immune thrombocytopenia?

Real-world adherence to practice guidelines was assessed in a study conducted in

1. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, def-

8. Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura

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