European Journal of Haematology ISSN 0902-4441

REVIEW ARTICLE

Characteristics of immune thrombocytopenic purpura: a

guide for clinical practice
Drew Provan
Centre for Haematology, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, UK

Abstract
Immune (idiopathic) thrombocytopenic purpura (ITP) is an autoantibody-mediated condition characterized
by an abnormally low number of platelets in the circulating blood. Originally, the cause of ITP was attrib-
uted to accelerated antibody-mediated platelet destruction where the rate of thrombopoiesis was inade-
quate to offset the increased rate of platelet destruction. However, new evidence has indicated that
insufficient or inadequate platelet production is also responsible for low platelet counts, and research has
focused on the development of treatments that increase platelet production. ITP affects both children and
adults and can be either acute or chronic. To manage and treat ITP effectively, an exhaustive assessment
of the signs and symptoms must be undertaken because the clinical manifestation of ITP can be highly
variable among patients. At the moment, the diagnostic approach in ITP is based largely on a process of
exclusion due to the lack of available data regarding clinical and laboratory parameters. The diagnostic pro-
cedures used in children and adults are similar and involve collecting the patient’s history and performing a
physical examination. Laboratory investigations are kept simple in patients with suspected ITP and include
a full blood count and peripheral blood smear. A number of specialized laboratory assays have been devel-
oped with varying degrees of success. There remains scope for improving and simplifying the diagnostic
process to identify ITP.

Key words clinical; diagnosis; immune; thrombocytopenic; purpura

Correspondence Drew Provan, Centre for Haematology, Institute of Cell and Molecular Science, Bart’s and the London Queen
Mary’s, School of Medicine & Dentistry, The Royal London Hospital, Whitechapel, London, E1 2ES, UK. Tel: +44 203 246 0339; Fax:
+44 203 246 0351; e-mail: a.b.provan@qmul.ac.uk

Immune (idiopathic) thrombocytopenic purpura (ITP) is Platelet destruction

a common haematological disorder characterized by a
reduced peripheral blood platelet count (1). ITP has a
diverse clinical course and its manifestation in adult
patients can be highly variable ranging from mild bruis-
ing to intracranial haemorrhage (2, 3).
ITP has traditionally been recognized as an autoim-
mune disease involving accelerated platelet destruction.
Normal surface proteins on platelets act as antigens and
stimulate the immune system to produce autoantibodies
and cytotoxic T-lymphocytes, resulting in platelet phago-
cytosis (4, 5). More recently, research has indicated that
ITP is associated with suboptimal platelet production
caused by decreased maturation of megakaryocytes (6)
as well as apoptosis of megakaryocytes due to factors
present in the plasma (7).
The pathophysiology of ITP has been the subject of over
50 yrs of research. Initial studies showed that the trans-
fusion of blood or plasma from a patient with chronic
ITP caused thrombocytopenia in normal healthy volun-
teers (8). This provided strong evidence that ITP was
antibody-mediated. Subsequent studies found that anti-
platelet autoantibodies present in the serum of patients
with ITP bind to circulating platelets and cause platelet
destruction (9, 10). Various antigens on the platelet sur-
face seem to be responsible for autoantibody binding in
patients with ITP (11), and a major target antigen of the
autoantibodies is platelet glycoprotein IIb ⁄ IIIa (6) as well
as glycoprotein Ib ⁄ IX (12).
Antiplatelet autoantibodies are only reported in 50–
70% of patients with ITP (13) and remission can occur

8 ª 2009 John Wiley & Sons AlS, 82 (Suppl. 71), 8–12

Provan Characteristics of ITP: a guide for clinical practice

in some patients even in the presence of autoantibodies lation of platelet production have been developed. How-
(14). Therefore, it would appear that other mechanisms ever, even with the introduction of new treatments for
are also involved in platelet destruction. Platelets can be ITP, accurate diagnosis is essential if the patient is to be
destroyed following the binding of cytotoxic thymic- managed successfully.
dependent T-cell lymphocytes (15). Some studies impli-
cate T-cells as another potential initiator of autoantibody
Diagnosis of immune thrombocytopenic
production in ITP. However, only a few studies have
purpura
evaluated the role of the T-cell receptor, and its signifi-
cance in the pathogenesis of ITP is difficult to determine The signs and symptoms of ITP may be generalized into
(16). two categories: dry and wet purpura. Dry purpura (cuta-
neous haemorrhage) appears as bruising or petechiae
[Fig. 1A (24)]. In contrast, wet purpura is associated with
Impaired platelet production bleeding of the mucous membranes including those of
As the antigens to which autoantibodies bind are present the gastrointestinal tract, mouth, nose and eyes [Fig. 1B
on both platelets and their precursors, the megakaryo- (24)]. ITP in children is usually an acute self-limiting dis-
cytes, it is plausible that both megakaryocytopoiesis and ease, characterized by the sudden onset of petechiae or
thrombopoiesis are impaired in patients with ITP. Early purpura approximately 2–3 wks after viral infection or
morphological studies of bone marrow harvested from immunization (25). Boys and girls are affected equally
patients with ITP identified immature megakaryoctyes and the peak of onset is normally around 5 yrs of age.
lacking cytoplasmic granularity and manifesting degener-
ative changes in the nucleus (17). However, it seems that
the mechanism responsible for the destruction of circulat- A
ing platelets does not affect megakaryocytes in the same
way. Stahl et al. (18) discovered that some platelet anti-
bodies react only with megakaryocytes which have
reached the stage of thrombocytopoiesis. This may be
because antibodies are developed to components of
platelet membranes which are not exposed on the surface
of all megakaryocytes.
Megakaryocyte development and platelet production
are controlled by endogenous thrombopoietin (eTPO) or
c-Mpl ligand (3, 19). eTPO is not stored, but is produced
predominantly by the liver and immediately secreted. It
regulates thrombopoiesis by promoting the growth of
megakaryocyte colony-forming cells in the bone marrow
(20) through its binding activity with receptors on
megakaryocytes. Under normal circumstances, eTPO
remains at a constant level and is cleared by binding to
the eTPO receptor. In response to decreased platelet lev-
els, less eTPO is bound and circulating levels increase. B
Generally, eTPO levels are high when platelet and ⁄ or
megakaryocyte numbers are low, as seen in aplastic
anaemia (bone marrow failure) and chemotherapy-
induced thrombocytopenia (21). In ITP, the association
between eTPO levels and low platelet counts is less clear.
Although approximately 40% of patients with ITP have
a reduced platelet turnover (22), levels of eTPO are not
markedly elevated despite the fact that platelet numbers
are reduced because of premature destruction by the
spleen (23).
It seems therefore that ITP can be described as a dis-
ease of suboptimal platelet production and accelerated Figure 1 Purpura – (A) dry purpura (petechiae), (B) wet purpura
platelet destruction. According to this understanding of (bleeding in eye) (24). Copyright ª 2002 Massachusetts Medical
the disease, new treatment options focusing on the stimu- Society. All rights reserved.

ª 2009 John Wiley & Sons AlS, 82 (Suppl. 71), 8–12 9

Characteristics of ITP: a guide for clinical practice
In over 70% of cases, acute ITP resolves within
6 months.
On the other hand, ITP in adults is usually chronic
and has a subtle onset, with no prodromal illness (26).
Some patients with ITP are asymptomatic or have only
mild bruising while others with platelet counts below
30 · 109 ⁄ L are thought to be at a high risk of serious
bleeding events (2, 26). Indeed, the most frequent cause
of death in association with ITP is intracranial bleeding,
with an estimated 5% rate of fatal haemorrhage in adults
(27).
Diagnosis of exclusion
To date, diagnostic and management practices in ITP
tend not to be evidence based, but rather subject to
expert opinion (27, 28). This approach is due to the lack
of available data, namely on clinical and laboratory
parameters – a consequence of the shortage of controlled
clinical trials focusing on patients with ITP. Conse-
quently, ITP is still a diagnosis of exclusion whereby
other causes of thrombocytopenia have to be systemati-
cally ruled out (2).
The diagnostic approach in adults is based on patient
history, a physical examination, full blood count (FBC)
and examination of the peripheral blood smear. The
patient’s history and physical examination is used to
assess the severity, extent and duration of bleeding. It is
important to determine the type of bleeding in order
to distinguish ‘platelet-type’ mucocutaneous bleeding
from ‘coagulation-type’ haematomas. At this stage, the
presence of concomitant medical conditions causing
thrombocytopenia should be determined, including post-
transfusion purpura (immune mechanisms), inherited
non-immune thrombocytopenia, aplastic anaemia, mar-
row infiltration with acute leukaemia and type IIB von
Willebrand’s disease (28). Other conditions which may
be associated with autoimmune thrombocytopenia
include human immunodeficiency virus (HIV) infection,
systemic lupus erythematosus, lymphoproliferative
disorders, myelodysplasia, agammaglobulinaemia, drug-
induced thrombocytopenia, alloimmune thrombocytope-
nia and congenital thrombocytopenia (2). Furthermore,
conditions which increase the risk of bleeding due to
abnormalities of the gastrointestinal, genitourinary and
central nervous systems, should be excluded.
Laboratory investigations
Laboratory investigations are kept simple in patients
with suspected ITP; an FBC is performed to confirm a
low platelet count (<150 · 109 ⁄ L) and a peripheral
blood smear is used to identify pseudo-thrombocytopenia
(EDTA-dependent platelet agglutination), myelodyspla-
10
Provan
sia, haematological malignancies, and red cell fragmenta-
tion syndromes. The morphology of the blood cells,
leucocytes and platelets should be normal, with varying
numbers of large platelets (29). Of note, in some patients,
ITP has been diagnosed ‘accidentally’ following routine
FBC tests (30).
If the history, physical examination, blood count and
blood film examinations produce any atypical findings, it
may be necessary to perform additional investigations
such as bone marrow evaluation. This aids diagnosis in
complex cases, although bone marrow has been reported
as normal in some studies of patients with suspected ITP
(31). Nevertheless, bone marrow examination is recom-
mended for patients over the age of 60 yrs and in those
patients whose disease has relapsed following complete
remission, failed first-line ITP therapies, or who are
being considered for splenectomy (28). A number of spe-
cialized laboratory assays have also been developed, with
varying degrees of success, to aid the diagnosis of ITP in
adult patients with atypical features (Table 1).
The diagnostic process in children is similar to that of
adults and involves eliminating alternative causes of
thrombocytopenia, collecting the patient’s history, per-
forming a physical examination, blood film examination
and FBC. Bone marrow examinations are generally con-
sidered unnecessary in children, as are tests for autoanti-
bodies because the results usually do not influence
management decisions (32).
Table 1 Specialized laboratory tests that have been evaluated as
immune thrombocytopenic purpura (ITP) diagnostic tools
• The direct platelet immunofluorescence test (PIFT) may be used to
detect the presence of platelet-associated autoantibodies, particu-
larly in patients with bone marrow failure and immune-mediated
thrombocytopenia, and drug-dependent immune thrombocytopenia.
PIFT may also be used to monitor the effect of third-line treatment
in ITP patients refractory to first- and second-line treatments (28)
• A thrombopoietin (TPO) assay may be useful in distinguishing
between reduced platelet production (high TPO level) and increased
platelet destruction (normal-to-low TPO level) as a cause of low
platelet levels (33); however, this test is not readily available and its
routine use is not justified in the diagnosis of adult patients
• Measurement of platelet RNA by flow cytometry can be used to
assess platelet maturity; reticulated platelets increase with platelet
production (28, 34), but again this test is not considered to be of
great benefit in ITP patients
• Serological assays and breath tests can be used to detect for the
Helicobacter pylori microorganism that has been reported in some
ITP patients (28). Eradication of H. pylori may result in an increased
platelet number and it is worthwhile testing for it, especially in
countries of high background incidence
• Fluorescent antinuclear antibody testing can be used to indicate
chronicity in adult and childhood ITP (35); however, its routine use in
the diagnosis of ITP patients is not considered beneficial
ª 2009 John Wiley & Sons AlS, 82 (Suppl. 71), 8–12
Provan
Conclusion
An exhaustive assessment of the signs and symptoms of
ITP must be performed to accurately diagnose and effec-
tively manage patients with ITP. The clinical signs and
symptoms of ITP are highly variable among patients and
the diagnostic approach should be one to exclude other
causes of thrombocytopenia. A number of specialized
laboratory assays have also been developed to aid the
diagnosis of ITP in complex cases, although many of
these remain of no real benefit.
Conflicts of interest
Dr Drew Provan is a consultant for Amgen and has pre-
sented data at scientific conferences on behalf of Amgen.
D. Provan has also received research support from Amgen.
References
1. Cines DB, McMillan R. Management of adult idiopathic
thrombocytopenic purpura. Annu Rev Med 2005;56:425–
42.
2. Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Tay-
lor PR, Northern Region Haematology Group. Clinically
significant newly presenting autoimmune thrombocytope-
nic purpura in adults: a prospective study of a popula-
tion-based cohort of 245 patients. Br J Haematol
2003;122:966–74.
3. Stasi R, Evangelista ML, Amadori S. Novel thrombopoi-
etic agents. A review of their use in idiopathic thrombocy-
topenic purpura. Drugs 2008;68:901–12.
4. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic anal-
ysis of autoantibodies in idiopathic thrombocytopenic pur-
pura reveals evidence of clonal expansion and somatic
mutation. Blood 2002;100:1388–98.
5. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Tra-
winska MM, Cooper N, Amadori S. Response to B-cell
depleting therapy with rituximab reverts the abnormalities
of T-cell subsets in patients with idiopathic thrombocyto-
penic purpura. Blood 2007;110:2924–30.
6. Chang M, Nakagawa PA, Williams SA, Schwartz MR,
Imfeld KL, Buzby JS, Nugent DJ. Immune thrombocyto-
penic purpura (ITP) plasma and purified ITP monoclonal
autoantibodies inhibit megakaryocytopoiesis in vitro.
Blood 2003;102:887–95.
7. Houwerzijl EJ, Blom NR, van der Want JJ, Esselink MT,
Koornstra JJ, Smit JW, Louwes H, Vellenga E, de Wolf
JT. Ultrastructural study shows morphologic features of
apoptosis and para-apoptosis in megakaryocytes from
patients with idiopathic thrombocytopenic purpura. Blood
2004;103:500–6.
8. Harrington WJ, Minnich V, Hollingsworth JW, Moore
CV. Demonstration of a thrombocytopenic factor in the
blood of patients with thrombocytopenic purpura. J Lab
Clin Med 1951;38:1–10.
ª 2009 John Wiley & Sons AlS, 82 (Suppl. 71), 8–12
Characteristics of ITP: a guide for clinical practice
9. Karpatkin S, Siskind GW. In vitro detection of platelet
antibody in patients with idiopathic thrombocytopenic
purpura and systemic lupus erythematosus. Blood
1969;33:795–812.
10. McMillan R. Chronic idiopathic thrombocytopenic pur-
pura. N Engl J Med 1981;304:1135–47.
11. Fujisawa K, Tani P, McMillan R. Platelet-associated anti-
body to glycoprotein IIb ⁄ IIIa from chronic immune
thrombocytopenic purpura patients often binds to divalent
cation-dependent antigens. Blood 1993;81:1284–9.
12. He R, Reid DM, Jones CE, Shulman NR. Extracellular
epitopes of platelet glycoprotein Ib alpha reactive with
serum antibodies from patients with chronic idiopathic
thrombocytopenic purpura. Blood 1995;86:3789–96.
13. Warner MN, Moore JC, Warkentin TE, Santos AC, Kel-
ton JG. A prospective study of protein-specific assays used
to investigate idiopathic thrombocytopenic purpura. Br J
Haematol 1999;104:442–7.
14. Stockelberg D, Hou M, Jacobsson S, Kutti J, Wadenvik
H. Detection of platelet antibodies in chronic idiopathic
thrombocytopenic purpura (ITP). A comparative study
using flow cytometry, a whole platelet ELISA, and an
antigen capture ELISA. J Haematol 1996;56:72–7.
15. Olsson B, Andersson P-O, Jernås M, Jacobsson S, Carls-
son B, Carlsson LMS, Wadenvik H. T-cell-mediated cyto-
toxicity toward platelets in chronic idiopathic
thrombocytopenic purpura. Nature Med 2003;9:1123–4.
16. Hedlund-Treutiger I, Wahlström J, Elinder G. Role of the
T cell receptor in idiopathic thrombocytopenic purpura
(ITP). Acta Paediatr Suppl 1998;424:46–50.
17. Diggs LW, Hewlett JS. A study of the bone marrow from
thirty-six patients with idiopathic hemorrhagic (thrombo-
penic) purpura. Blood 1948;3:1090–104.
18. Stahl CP, Zucker-Franklin D, McDonald TP. Incomplete
antigenic cross-reactivity between platelets and mega-
karyocytes: relevance to ITP. Blood 1986;67:421–8.
19. Kaushansky K. Thrombopoietin: accumulating evidence
for an important biological effect on the hematopoietic
stem cell. Ann N Y Acad Sci 2003;996:39–43.
20. Geddis AE, Linden HM, Kaushansky K. Thrombopoie-
tin: a pan-hematopoietic cytokine. Cytokine Growth Factor
Rev 2002;13:61–73.
21. Nichol JL. Endogenous TPO (eTPO) levels in health and
disease: possible clues for therapeutic intervention. Stem
Cells 1998;16(Suppl 2):165–75.
22. Louwes H, Zeinali Lathori OA, Vellenga E, de Wolf JT.
Platelet kinetic studies in patients with idiopathic throm-
bocytopenic purpura. Am J Med 1999;106:430–4.
23. Stasi R, Provan D. Management of immune thrombocyto-
penic purpura in adults. Mayo Clin Proc 2004;79:504–22.
24. Cines DB, Blanchette VS. Immune thrombocytopenic pur-
pura. N Engl J Med 2002;346:995–1008.
25. Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti
A, Amadori S. Idiopathic thrombocytopenic purpura: cur-
rent concepts in pathophysiology and management.
Thromb Haemost 2008;99:4–13.
11
Characteristics of ITP: a guide for clinical practice
26. Provan D, Newland A. Idiopathic thrombocytopenic pur-
pura in adults. J Pediatr Hematol Oncol 2003;25(Suppl
1):S34–8.
27. George JN, Woolf SH, Raskob GE, et al. Idiopathic
thrombocytopenic purpura: a practice guideline developed
by explicit methods for the American Society of Hemato-
logy. Blood 1996;88:3–40.
28. Provan D, Newland AC, Norfolk D, Bolton-Maggs P,
Lilleyman J, Greer I, May A, Murphy M, Ouwehand W,
Watson S. British Committee for Standards in Haematol-
ogy General Haematology Task Force. Guidelines for the
investigation and management of idiopathic thrombocyto-
penic purpura in adults, children and in pregnancy. Br J
Haematol 2003;120:574–96.
29. Sandler SG, Bhanji R. Immune Thrombocytopenic Pur-
pura. Available at http://emedicine.com/med/
topic1151.htm; 2006. Last accessed 26 June 2008.
30. Stasi R, Amadori S, Osborn J, Newland AC, Provan D.
Long-term outcome of otherwise healthy individuals with
incidentally discovered borderline thrombocytopenia.
PLoS Med 2006;3:e24.
12
Provan
31. Mak YK, Yu PH, Chan CH, Chu YC. The management
of isolated thrombocytopenia in Chinese adults: does bone
marrow examination have a role at presentation? Clin Lab
Haematol 2000;22:355–8.
32. Halperin DS, Doyle JJ. Is bone marrow examination justi-
fied in idiopathic thrombocytopenic purpura? Am J Dis
Child 1988;142:508–11.
33. Porcelijn L, Folman CC, Bossers B, Huiskes E, Overbeeke
MA, v d Schoot CE, de Haas M, von dem Borne AE.
The diagnostic value of thrombopoietin level measure-
ments in thrombocytopenia. Thromb Haemost
1998;79:1101–5.
34. Saxon BR, Blanchette VS, Butchart S, Lim-Yin J, Poon
AO. Reticulated platelet counts in the diagnosis of acute
immune thrombocytopenic purpura. J Pediatr Hematol
Oncol 1998;20:44–8.
35. Altintas A, Ozel A, Okur N, Okur N, Cil T, Pasa S, Ay-
yildiz O. Prevalence and clinical significance of elevated
antinuclear antibody test in children and adult patients
with idiopathic thrombocytopenic purpura. J Thromb
Thrombolysis 2007;24:163–8.
ª 2009 John Wiley & Sons AlS, 82 (Suppl. 71), 8–12