Immune Thrombocytopenia
Immune Thrombocytopenia
Immune Thrombocytopenia
Author Manuscript
Semin Hematol. Author manuscript; available in PMC 2010 January 1.
Published in final edited form as:
NIH-PA Author Manuscript
Douglas B. Cines, MD1, Howard Liebman, MD2, and Roberto Stasi, MD3
1From the University of Pennsylvania School of Medicine, Philadelphia, PA
2University of Southern California, Los Angeles, CA
3Ospedale “Regina Apostolorum,” Albano Laziale, Italy
Abstract
Primary immune thrombocytopenic purpura (ITP) remains a diagnosis of exclusion both from
nonimmune causes of thrombocytopenia and immune thrombocytopenia that develops in the context
of other disorders (secondary immune thrombocytopenia). The pathobiology, natural history, and
response to therapy of the diverse causes of secondary ITP differ from each other and from primary
NIH-PA Author Manuscript
Keywords
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Introduction
Primary immune thrombocytopenic purpura (ITP) is a disorder of unknown etiology caused
by antibody-, and possibly T-cell mediated, platelet destruction by tissue macrophages and
suppression of platelet production.1 ITP remains a diagnosis of exclusion.2,3 This means not
only excluding nonimmune causes of thrombocytopenia, but also other conditions in which an
Correspondence to: Douglas B. Cines, M.D., Department of Pathology and Laboratory Medicine, University of Pennsylvania School of
Medicine, 513A Stellar-Chance Labs. 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, Phone: (215) 622-3966, Fax: (215)
573-2012, Email: E-mail: [email protected].
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Cines et al. Page 2
antiplatelet antibodies, they differ in specific aspects of pathobiology, natural history, and
responsiveness to ITP-directed therapy. Moreover, optimal treatment strategies include
management of the underlying disorder.
capable, under the influence of thrombopoietin (TPO) and interleukin (IL)-3 and Steel factor,
of producing up to several hundred mature megakaryocytes. Another form of mature
progenitor, the colony-forming unit (CFU-MK) produce colonies that consist of 3 to 50 MKs
responsive to TPO, though ∼25% require both TPO and IL-3 to generate platelets.9,10 Each
MK produces up to about 4,000 platelets before undergoing apoptosis. A normal adult human
produces about 1011 platelets daily, and this rate can increase 20-fold, if needed, with
exogenous TPO.4
TPO and its receptor, c-Mpl, are the major identified regulators of megakaryocyte and platelet
production and also have key roles in the differentiation of hematopoietic stem cells. TPO
signals via c-Mpl through the Jak-STAT,11-14 Ras-Raf-MAPK,15 and PI3K pathways,16
which promotes survival, proliferation, and polyploidy in megakaryocytes. In vitro studies
have shown that TPO induces expression of c-MYC in, a proto-oncogene active in various
physiologic processes and in the dysregulation of megakaryocyte production.17 The
implications of this finding are yet to be addressed in vivo. The stages of thrombopoiesis
include regulation of transcription, megakaryocyte development, endomitotic spindling of the
megakaryocyte nucleus, cytoplasmic maturation, formation of active projections (propellants)
from the megakaryocyte cytoplasm, extrusion of these propellants from the bone marrow
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stroma into the circulation, and lastly, separation and maturation into individual platelets.18
Primary ITP
Increased platelet destruction
There is extensive evidence that patients with ITP develop autoantibodies, generally IgG, that
bind to platelets, which leads to their phagocytosis via Fcγ receptors expressed on tissue
macrophages located predominantly in the spleen and liver.1,19-22 What provokes
autoantibody production is unknown, but most ITP patients have antibodies against integrin
αIIbβ3 (glycoprotein IIa/IIIb), glycoprotein Ib/IX, or multiple platelet proteins by the time
clinical disease, characterized by thrombocytopenia and mucocutaneous bleeding, is evident.
23 Platelet destruction within macrophages or dendritic cells degrades platelet antigens to
peptides. Peptides are expressed on the cell surface in the context of MHCII and costimulatory
help for presentation to T cells, amplifying the initial immune response and possibly generating
cryptic epitopes from other platelet glycoproteins, which spreads the immune response to
involve multiple platelet antigens.24 ITP is characterized by reducing T-regulatory cells
(reviewed in Stasi et al25) and Thy-2 cytokines,26 leading to a Thy1/Thy0 profile (reviewed
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inhibit megakaryocyte development in vitro 35,36,40 and may cause apoptosis and
intramedullary destruction of platelets in vivo,41 contributing to failure of splenectomy and
other treatments that act by inhibiting clearance. These findings also provide additional
rationale for the effectiveness of TPO-receptor agonists.
response rates to ITP-directed therapy, including splenectomy, are less than in primary disease.
Over 50% of children and some adults with ES have a clinical and pathological presentation
that overlaps with the autoimmune lymphoproliferative syndrome (ALPS). ALPS is
characterized by the chronic accumulation of nonmalignant lymphocytes leading to
lymphadenopathy and (hepato)splenomegaly, >1% CD3+, CD4-, CD8- (double negative) T
cells, impaired Fas-receptor/ligand mediated apoptosis in vitro due to mutations in Fas (CD95/
Apo-1), or less commonly Fas ligand (Fas-L), caspase-8 or -10. Immune thrombocytopenia
develops in ∼20% of patients 71 72-74,75,76 and may respond relatively poorly to ITP
therapies, although recent experience with rituximab and mycophenylate have been
encouraging. Immune thrombocytopenia and ES also occur in approximately 10%-15% of
patients with common variable hypogammaglobulinemia. The onset of immune
thrombocytopenia is typically in the third decade, though onsets from childhood to old age
have been reported and typically precede the diagnosis of common variable immune deficiency
(CVID) by several years. The diagnosis should be sought in any patient with recurrent infection,
as immunosuppressive therapy poses some risk and replacement with immune globulin is
indicated.
Lymphoproliferative disorders
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Infectious agents
Human immunodeficiency virus—The association between immune thrombocytopenia
and the acquired immunodeficiency syndrome and subsequently as a presenting feature of HIV
infection has been recognized since the early to mid 1980s.86,87,88 Thrombocytopenia is
characterized both by an immune component similar in presentation and response to ITP most
evident in the early stages of disease,89 and progressive ineffective hematopoiesis with a
HIV should be excluded in at-risk patients who present with ITP. Patients who present with
immune thrombocytopenia early in the course of HIV infection respond to medical therapy
(corticosteroids, IV anti-D, and IVIG) and splenectomy as well as patients with ITP without
proliferation of HIV infection or untoward incidence of opportunistic infection.
Thrombocytopenia in patients with more advanced disease generally responds to highly active
antiretroviral therapy.
Hepatitis C virus—In some parts of the world, HCV infection has been detected in up to
30% of patients presenting with immune thrombocytopenia, even in the absence of overt
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the process of molecular mimicry134; (2) cross-reactivity between platelet antibodies and H
pylori cytotoxin-A protein135; (3) adsorption to platelets of Lewis antigens, which are induced
by H pylori in a strain-specific manner, where they are targets for anti-Lewis antibodies in
patients with appropriate genetic backgrounds;136 (4) platelet activation and clearance through
an interaction with H pylori-bound von Willebrand factor via platelet glycoprotein Ib137; (5)
somatic mutation of antibacterial antibodies from which antigen-independent autoantibodies
emerge138; (6) monocytes from H pylori-positive patients demonstrate low levels of the
inhibitory Fc-γ receptor IIB and enhanced platelet phagocytosis, both of which are reversed
after successful eradication,139 and (7) genetic variation, eg, the frequency of HLA-
DRB*11,*14, and HLA-DQB1*03 is higher in patients with immune thrombocytopenia
positive for H pylori than in those who are H pylori-negative, and those expressing HLA-
DQB1*03 have a higher probability of a platelet response to eradication therapy.140 Of
interest, titers of autoantibodies fall 12-24 weeks after successful eradication, whereas
responses often occur in 1-2 weeks, suggesting additional mechanisms are operative.
Many, but not all studies indicate that H pylori is found more commonly in patients with disease
that is milder in severity and of more recent onset.141 Thus, H pylori should be sought in all
patients who come from regions where there is a strong association, but no consensus has
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emerged in the US as to whether all ITP patients should be tested and/or treated.
homozygous for HPA1b allele on GPIIIa, although other specificities have been reported.
Patients not only develop anti-HPA1a antibodies, but also self-reactive antibodies of
undetermined specificity, presumably as a result of epitope spread. Remarkably, PTP is not
seen in women with neonatal alloimmune thrombocytopenia due to anti-HPA1a antibodies.
Patients are at a high risk of bleeding and the clinical course is often protracted without therapy.
IV immune globulin is the standard of care. The utility of preventing subsequent exposure to
the inciting antigen using washed HPA1b blood products is logical but unproven.
Drug-induced thrombocytopenia
The first case of drug-induced thrombocytopenia (DITP) was identified with quinine 140 years
ago.155 DITP can result from bone marrow toxicity or immune-mediated destruction of
platelets. Several hundred therapeutic agents have been implicated,156 but few reports are
compelling.157 The diagnosis of DITP is generally based on this clinical scenario: (1) therapy
with a candidate drug precedes thrombocytopenia by sufficient time to develop antibody; (2)
there is no such temporal relationship with another drug; (3) all other reasonable causes have
been excluded; (4) recovery occurs upon the discontinuation of the drug, and (5) re-exposure
to the drug, if attempted, leads to recurrent thrombocytopenia. However, these criteria are rarely
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met, as underlying clinical circumstances are often complex and introduction and withdrawal
of multiple drugs within a short time frame is common. Moreover, testing for drug-dependent
antibodies is fraught with difficulty (solubility, concentration, effect on platelet activation, in
vivo metabolism, lack of control patients on drug but without thrombocytopenia, etc), and few
patients require rechallenge.
DITP typically affects only a small percentage of exposed patients, with the exception of
heparin-induced thrombocytopenia (see below), and no known genetic predispositions or
environmental criteria have been identified. Diverse mechanisms have been postulated to cause
DITP, including immune complexes (heparin); induction of autoantibody (gold salts); anti-
drug-specific antibodies (abciximab); drugs that induce conformational changes in platelet
antigens that are recognized by antibody (fiban drugs); drug-induced antibodies that bind to
platelet membranes in the presence of soluble drug (quinine); and hapten-dependent antibodies
(some beta-lactam antibiotics)158, 157 (Table 1). Immune or nonimmune marrow suppression
formation of autoantibodies that target platelets in the absence of the inciting drug.168
Autoantibodies with an affinity for platelet glycoprotein V have developed in a few patients
with rheumatoid arthritis treated with gold salts.169 Drug-independent autoantibodies have
also been reported in occasional patients treated with quinine, procainamide, sulfonamide
antibiotics, and interferons alfa and beta.157,170 Thrombocytopenia is often protracted and
may require ITP-directed therapy.
Approximately 25% of patients develop arterial and/or venous thrombi,171 a number that may
exceed 50% if the disease is not recognized and managed promptly.172 In naïve subjects, an
unexplained fall in the platelet count of greater than 40% begins 5-10 days after exposure;
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thrombosis typically follows soon after but can occur concomitantly or on occasion precede
the fall in platelet count.173 Thrombocytopenia may occur within hours after exposure to
heparin in patients who had been treated within the preceding 100 days in whom circulating
antibodies may persist.174. Rarely, thrombocytopenia may be discovered or develop 1-2 weeks
after the last known exposure (delayed HIT).175
HIT antibodies recognize oligomeric complexes formed between platelet factor 4 (PF4)
released from activated platelets and heparin or glycosaminoglycans expressed on
endothelium, monocytes, and platelets.176-178 Heparin/PF4-IgG complexes bind to FcγRIIa
(CD32) on platelets, targeting them for clearance, but also stimulating cell activation with
release of additional PF4. Binding of these complexes to endothelial cells179 and
monocytes180,181 stimulates the expression of tissue factor, accelerating coagulation and
reinforcing platelet activation. Heparin-independent anti-PF4 antibodies have been postulated
to account for delayed HIT.175
Diagnosis rests on clinical recognition of the temporal relationship between heparin exposure
and the signature clinical manifestation. ELISA-based assays that detect IgG, IgA, and IgM
antibodies have a high sensitivity and negative predictive value but a false positive rate that
can exceed 50% in patients post-bypass surgery,182 with unacceptably high false positive rates
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in other settings as well. The performance characteristics may be improved using newer assays
that measure only IgG antibodies and using higher diagnostic cut-off optical density
measurements, with little loss of negative predictive value.183 Assays based on platelet
activation are more specific but less sensitive and the results are not routinely available in real-
time. Once the diagnosis is strongly suspected (moderate-high pretest probability), exposure
to all forms of heparin (including flushes, heparin-bonded catheters, etc) must be discontinued
and anticoagulation begun with either a direct thrombin inhibitor, such as hirudin or argatroban
or an anti-Xa agent such as danaparoid, where available.184 Therapy reduces new
thromboembolic events by approximately two-thirds, but mortality rates and amputations due
to preexisting clots are not affected. Therapy is continued until thrombocytopenia resolves and
is overlapped with coumadin at a therapeutic international normalized ratio (INR) for 3-5 days.
Anticoagulation is generally continued for 3 months, but may be extended depending on the
underlying reason for the initial use of heparin and the sequelae of HIT-induced thrombosis.
Conclusion
There is compelling reason why the diagnosis of ITP requires the exclusion of other causes of
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References
1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995–1008.
NIH-PA Author Manuscript
[PubMed: 11919310]
2. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline
developed by explicit methods for the American Society of Hematology. Blood 1996;88:3–40.
[PubMed: 8704187]
3. 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;120:574–596. [PubMed: 12588344]
4. Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood 2008;111:981–986.
[PubMed: 18223171]
5. Martin DI, Zon LI, Mutter G, Orkin SH. Expression of an erythroid transcription factor in
megakaryocytic and mast cell lineages. Nature 1990;344:444–447. [PubMed: 2320112]
6. Tsang AP, Visvader JE, Turner CA, et al. FOG, a multitype zinc finger protein, acts as a cofactor for
transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 1997;90:109–119.
[PubMed: 9230307]
7. Roth GJ, Yagi M, Bastian LS. The platelet glycoprotein Ib-V-IX system: regulation of gene expression.
Stem Cells 1996;14:188–193. [PubMed: 11012220]
8. Hodohara K, Fujii N, Yamamoto N, Kaushansky K. Stromal cell-derived factor-1 (SDF-1) acts together
with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK).
NIH-PA Author Manuscript
16. Nakao T, Geddis AE, Fox NE, Kaushansky K. PI3K/Akt/FOXO3a pathway contributes to
thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation
of p27(Kip1). Cell Cycle 2008;7:257–266. [PubMed: 18256550]
17. Chanprasert S, Geddis AE, Barroga C, Fox NE, Kaushansky K. Thrombopoietin (TPO) induces c-
myc expression through a. Cell Signal 2006;18:1212–1218. [PubMed: 16380230]
18. Battinelli EM, Hartwig JH, Italiano JE Jr. Delivering new insight into the biology of megakaryopoiesis
and thrombopoiesis. Curr Opin Hematol 2007;14:419–426. [PubMed: 17934346]
19. Cines DB, McMillan R. Pathogenesis of chronic immune thrombocytopenic purpura. Curr Opin
Hematol 2007;14:511–514. [PubMed: 17934360]
20. Tavassoli M, McMillan R. Structure of the spleen in idiopathic thrombocytopenic purpura. Am J Clin
Pathol 1975;64:180–191. [PubMed: 1171614]
21. Handin RI, Stossel TP. Phagocytosis of antibody-coated platelets by human granulocytes. N Engl J
Med 1974;290:989–993. [PubMed: 4594526]
22. McMillan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R. In vitro platelet phagocytosis
by splenic leukocytes in idiopathic thrombocytopenic purpura. N Engl J Med 1974;290:249–251.
[PubMed: 4855568]
NIH-PA Author Manuscript
23. McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin
Hematol 2000;37:239–248. [PubMed: 10942218]
24. He R, Reid DM, Jones CE, Shulman NR. Spectrum of Ig classes, specificities, and titers of serum
antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 1994;83:1024–1032.
[PubMed: 8111044]
25. Stasi R, Cooper N, Del PG, Stipa E, Laura EM, Abruzzese E, Amadori S. Analysis of regulatory T-
cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy
with rituximab. Blood 2008;112:1147–1150. [PubMed: 18375792]
26. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, Amadori S. Response to
B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with
idiopathic thrombocytopenic purpura. Blood 2007;110:2924–2930. [PubMed: 17548576]
27. Ho-Yen DO, Hardie R, Sommerville RG. Varicella-induced thrombocytopenia. J Infect 1984;8:274–
276. [PubMed: 6736670]
28. Solanilla A, Pasquet JM, Viallard JF, et al. Platelet-associated CD154 in immune thrombocytopenic
purpura. Blood 2005;105:215–218. [PubMed: 15191945]
29. Nagahama M, Nomura S, Kanazawa S, Ozaki Y, Kagawa H, Fukuhara S. Significance of chemokines
and soluble CD40 ligand in patients with autoimmune thrombocytopenic purpura. Eur J Haematol
2002;69:303–308. [PubMed: 12460235]
NIH-PA Author Manuscript
30. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of autoantibodies in idiopathic
thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood
2002;100:1388–1398. [PubMed: 12149222]
31. Olsson B, Ridell B, Carlsson L, Jacobsson S, Wadenvik H. Recruitment of T cells into bone marrow
of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood 2008;112:1078–
1084. [PubMed: 18519809]
32. Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B, Carlsson LM, Wadenvik H. T-cell-
mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med
2003;9:1123–1124. [PubMed: 12937414]
33. Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic
thrombocytopenic purpura. Eur J Haematol 2006;76:427–431. [PubMed: 16480433]
34. Stoll D, Cines DB, Aster RH, Murphy S. Platelet kinetics in patients with idiopathic thrombocytopenic
purpura and moderate thrombocytopenia. Blood 1985;65:584–588. [PubMed: 4038614]
35. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production
by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004;103:1364–1369.
[PubMed: 14576051]
36. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of
thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired
platelet production and increased platelet clearance. J Clin Invest 1987;80:33–40. [PubMed:
NIH-PA Author Manuscript
3597777]
37. Nagata Y, Shozaki Y, Nagahisa H, Nagasawa T, Abe T, Todokoro K. Serum thrombopoietin level is
not regulated by transcription but by the total counts of both megakaryocytes and platelets during
thrombocytopenia and thrombocytosis. Thromb Haemost 1997;77:808–814. [PubMed: 9184382]
38. Kosugi S, Kurata Y, Tomiyama Y, et al. Circulating thrombopoietin level in chronic immune
thrombocytopenic purpura. Br J Haematol 1996;93:704–706. [PubMed: 8652398]
39. Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR. Human
thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low
when due to increased platelet destruction. Blood 1996;87:4068–4071. [PubMed: 8639762]
40. Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, Nugent DJ. Immune
thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit
megakaryocytopoiesis in vitro. Blood 2003;102:887–895. [PubMed: 12676790]
41. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features
of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic
purpura. Blood 2004;103:500–506. [PubMed: 12969975]
NIH-PA Author Manuscript
42. Nossent JC, Swaak AJ. Prevalence and significance of haematological abnormalities in patients with
systemic lupus erythematosus. Q J Med 1991;80:605–612. [PubMed: 1946940]
43. Kuwana M, Okazaki Y, Kajihara M, Kaburaki J, Miyazaki H, Kawakami Y, Ikeda Y. Autoantibody
to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus: relationship to
thrombocytopenia with megakaryocytic hypoplasia. Arthritis Rheum 2002;46:2148–2159. [PubMed:
12209520]
44. Ziakas PD, Routsias JG, Giannouli S, Tasidou A, Tzioufas AG, Voulgarelis M. Suspects in the tale
of lupus-associated thrombocytopenia. Clin Exp Immunol 2006;145:71–80. [PubMed: 16792676]
45. Gernsheimer T. Epidemiology and pathophysiology of immune thrombocytopenic purpura. Eur J
Haematol. 2008
46. Arnal C, Piette JC, Leone J, et al. Treatment of severe immune thrombocytopenia associated with
systemic lupus erythematosus: 59 cases. J Rheumatol 2002;29:75–83. [PubMed: 11824975]
47. Stasi R, Stipa E, Masi M, et al. Prevalence and clinical significance of elevated antiphospholipid
antibodies in patients with idiopathic thrombocytopenic purpura. Blood 1994;84:4203–4208.
[PubMed: 7994034]
48. Diz-Kucukkaya R, Hacihanefioglu A, Yenerel M, Turgut M, Keskin H, Nalcaci M, Inanc M.
Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune
thrombocytopenic purpura: a prospective cohort study. Blood 2001;98:1760–1764. [PubMed:
NIH-PA Author Manuscript
11535509]
49. Dash S, Marwaha RK, Mohanty S. Lupus anticoagulant in immune thrombocytopenic purpura. Indian
J Pediatr 2004;71:505–507. [PubMed: 15226559]
50. Bidot CJ, Jy W, Horstman LL, Ahn ER, Yaniz M, Ahn YS. Antiphospholipid antibodies (APLA) in
immune thrombocytopenic purpura (ITP) and antiphospholipid syndrome (APS). Am J Hematol
2006;81:391–396. [PubMed: 16680753]
51. Bidot CJ, Jy W, Horstman LL, et al. Antiphospholipid antibodies in immune thrombocytopenic
purpura tend to emerge in exacerbation and decline in remission. Br J Haematol 2005;128:366–372.
[PubMed: 15667539]
52. Galli M, Daldossi M, Barbui T. Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with
antiphospholipid antibodies. Thromb Haemost 1994;71:571–575. [PubMed: 8091382]
53. Macchi L, Rispal P, Clofent-Sanchez G, Pellegrin JL, Nurden P, Leng B, Nurden AT. Anti-platelet
antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody
syndrome: their relationship with the observed thrombocytopenia. Br J Haematol 1997;98:336–341.
[PubMed: 9266930]
54. Godeau B, Piette JC, Fromont P, Intrator L, Schaeffer A, Bierling P. Specific antiplatelet glycoprotein
autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br
J Haematol 1997;98:873–879. [PubMed: 9326182]
55. Fabris F, Steffan A, Cordiano I, Borzini P, Luzzatto G, Randi ML, Girolami A. Specific antiplatelet
NIH-PA Author Manuscript
60. Nojima J, Suehisa E, Kuratsune H, et al. Platelet activation induced by combined effects of
anticardiolipin and lupus anticoagulant IgG antibodies in patients with systemic lupus
erythematosus--possible association with thrombotic and thrombocytopenic complications. Thromb
NIH-PA Author Manuscript
68. Pratt EL, Tarantino MD, Wagner D, Hirsch Pescovitz O, Bowyer S, Shapiro AD. Prevalence of
elevated antithyroid antibodies and antinuclear antibodies in children with immune
thrombocytopenic purpura. Am J Hematol 2005;79:175–179. [PubMed: 15981229]
69. Pegels JG, Helmerhorst FM, van Leeuwen EF, van de Plas-van Dalen C, Engelfriet CP, von dem
Borne AE. The Evans syndrome: characterization of the responsible autoantibodies. Br J Haematol
1982;51:445–450. [PubMed: 7104228]
70. Miller BA, Shultz Beardsley D. Autoimmune pancytopenia of childhood associated with multisystem
disease manifestations. J Pediatr 1983;103:877–881. [PubMed: 6644422]
71. Wang W, Herrod H, Pui CH, Presbury G, Wilimas J. Immunoregulatory abnormalities in Evans
syndrome. Am J Hematol 1983;15:381–390. [PubMed: 6606357]
72. Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis
in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935–946. [PubMed: 7540117]
73. Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP. Mutations
in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science
1995;268:1347–1349. [PubMed: 7539157]
74. Le Deist F, Emile JF, Rieux-Laucat F, Benkerrou M, Roberts I, Brousse N, Fischer A. Clinical,
immunological, and pathological consequences of Fas-deficient conditions. Lancet 1996;348:719–
723. [PubMed: 8806292]
NIH-PA Author Manuscript
80. Landgren O, Engels EA, Pfeiffer RM, et al. Autoimmunity and susceptibility to Hodgkin lymphoma:
a population-based case-control study in Scandinavia. J Natl Cancer Inst 2006;98:1321–1330.
[PubMed: 16985251]
NIH-PA Author Manuscript
81. Martinelli G, Zinzani PL, Magagnoli M, Vianelli N, Tura S. Incidence and prognostic significance
of idiopathic thrombocytopenic purpura in patients with Hodgkin's disease in complete hematological
remission. Haematologica 1998;83:669–670. [PubMed: 9718878]
82. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol
2006;33:230–239. [PubMed: 16616070]
83. Montillo M, Tedeschi A, Leoni P. Recurrence of autoimmune thrombocytopenia after treatment with
fludarabine in a patient with chronic lymphocytic leukemia. Leuk Lymphoma 1994;15:187–188.
[PubMed: 7858499]
84. Ergas D, Tsimanis A, Shtalrid M, Duskin C, Berrebi A. T-gamma large granular lymphocyte leukemia
associated with amegakaryocytic thrombocytopenic purpura, Sjogren's syndrome, and polyglandular
autoimmune syndrome type II, with subsequent development of pure red cell aplasia. Am J Hematol
2002;69:132–134. [PubMed: 11835350]
85. Lai DW, Loughran TP Jr, Maciejewski JP, Sasu S, Song SX, Epling-Burnette PK, Paquette RL.
Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult
large granular lymphocyte leukemia. Leuk Res 2008;32:823–827. [PubMed: 17915315]
86. Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in
homosexual men. Ann Intern Med 1982;96:714–717. [PubMed: 6178333]
87. Walsh CM, Nardi MA, Karpatkin S. On the mechanism of thrombocytopenic purpura in sexually
NIH-PA Author Manuscript
99. Sakaguchi M, Sato T, Groopman JE. Human immunodeficiency virus infection of megakaryocytic
cells. Blood 1991;77:481–485. [PubMed: 1991165]
100. Zucker-Franklin D, Cao YZ. Megakaryocytes of human immunodeficiency virus-infected
NIH-PA Author Manuscript
individuals express viral RNA. Proc Natl Acad Sci U S A 1989;86:5595–5599. [PubMed: 2748605]
101. Zucker-Franklin D, Termin CS, Cooper MC. Structural changes in the megakaryocytes of patients
infected with the human immune deficiency virus (HIV-1). Am J Pathol 1989;134:1295–1303.
[PubMed: 2757119]
102. Karpatkin S, Nardi MA, Hymes KB. Sequestration of anti-platelet GPIIIa antibody in rheumatoid
factor immune complexes of human immunodeficiency virus 1 thrombocytopenic patients. Proc
Natl Acad Sci U S A 1995;92:2263–2267. [PubMed: 7892259]
103. Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related
immunologic thrombocytopenia. Blood 2005;106:572–576. [PubMed: 15774614]
104. Bettaieb A, Fromont P, Louache F, Oksenhendler E, Vainchenker W, Duedari N, Bierling P.
Presence of cross-reactive antibody between human immunodeficiency virus (HIV) and platelet
glycoproteins in HIV-related immune thrombocytopenic purpura. Blood 1992;80:162–169.
[PubMed: 1611083]
105. Hohmann AW, Booth K, Peters V, Gordon DL, Comacchio RM. Common epitope on HIV p24 and
human platelets. Lancet 1993;342:1274–1275. [PubMed: 7694021]
106. Nardi M, Tomlinson S, Greco MA, Karpatkin S. Complement-independent, peroxide-induced
antibody lysis of platelets in HIV-1-related immune thrombocytopenia. Cell 2001;106:551–561.
[PubMed: 11551503]
NIH-PA Author Manuscript
107. Karpatkin S, Nardi M, Lennette ET, Byrne B, Poiesz B. Anti-human immunodeficiency virus type
1 antibody complexes on platelets of seropositive thrombocytopenic homosexuals and narcotic
addicts. Proc Natl Acad Sci U S A 1988;85:9763–9767. [PubMed: 3200854]
108. Karpatkin S, Nardi M. Autoimmune anti-HIV-1gp120 antibody with antiidiotype-like activity in
sera and immune complexes of HIV-1-related immunologic thrombocytopenia. J Clin Invest
1992;89:356–364. [PubMed: 1737832]
109. Koefoed K, Ditzel HJ. Identification of talin head domain as an immunodominant epitope of the
antiplatelet antibody response in patients with HIV-1-associated thrombocytopenia. Blood
2004;104:4054–4062. [PubMed: 15315970]
110. Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and
laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J
Haematol 2005;129:818–824. [PubMed: 15953010]
111. Pyrsopoulos NT, Reddy KR. Extrahepatic manifestations of chronic viral hepatitis. Curr
Gastroenterol Rep 2001;3:71–78. [PubMed: 11177698]
112. Pockros PJ, Duchini A, McMillan R, Nyberg LM, McHutchison J, Viernes E. Immune
thrombocytopenic purpura in patients with chronic hepatitis C virus infection. Am J Gastroenterol
2002;97:2040–2045. [PubMed: 12190174]
113. Yabu K, Kiyosawa K, Ako S, et al. Type C chronic hepatitis associated with thrombocytopenia in
two patients. J Gastroenterol Hepatol 1994;9:99–104. [PubMed: 8155875]
NIH-PA Author Manuscript
114. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic”
thrombocytopenia. J Clin Invest 1966;45:645–657. [PubMed: 5327481]
115. Espanol I, Gallego A, Enriquez J, Rabella N, Lerma E, Hernandez A, Pujol-Moix N.
Thrombocytopenia associated with liver cirrhosis and hepatitis C viral infection: role of
thrombopoietin. Hepatogastroenterology 2000;47:1404–1406. [PubMed: 11100362]
116. Adinolfi LE, Giordano MG, Andreana A, et al. Hepatic fibrosis plays a central role in the
pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. Br J Haematol
2001;113:590–595. [PubMed: 11380442]
117. Jiang XH, Xie YT, Tan DM. Study on the influencing factors of thrombocytopenia in viral hepatitis.
Zhonghua Gan Zang Bing Za Zhi 2004;12:734–736. [PubMed: 15619340]
118. Peck-Radosavljevic M, Zacherl J, Meng YG, et al. Is inadequate thrombopoietin production a major
cause of thrombocytopenia in cirrhosis of the liver? J Hepatol 1997;27:127–131. [PubMed:
9252085]
119. Goulis J, Chau TN, Jordan S, Mehta AB, Watkinson A, Rolles K, Burroughs AK. Thrombopoietin
concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after
orthotopic liver transplantation. Gut 1999;44:754–758. [PubMed: 10205219]
NIH-PA Author Manuscript
120. Panzer S, Seel E, Brunner M, Kormoczi GF, Schmid M, Ferenci P, Peck-Radosavljevic M. Platelet
autoantibodies are common in hepatitis C infection, irrespective of the presence of
thrombocytopenia. Eur J Haematol 2006;77:513–517. [PubMed: 17042765]
121. Hamaia S, Li C, Allain JP. The dynamics of hepatitis C virus binding to platelets and 2 mononuclear
cell lines. Blood 2001;98:2293–2300. [PubMed: 11588022]
122. Kajihara M, Kato S, Okazaki Y, Kawakami Y, Ishii H, Ikeda Y, Kuwana M. A role of autoantibody-
mediated platelet destruction in thrombocytopenia in patients with cirrhosis. Hepatology
2003;37:1267–1276. [PubMed: 12774004]
123. Doi T, Homma H, Mezawa S, Kato J, Kogawa K, Sakamaki S, Niitsu Y. Mechanisms for increment
of platelet associated IgG and platelet surface IgG and their implications in immune
thrombocytopenia associated with chronic viral liver disease. Hepatol Res 2002;24:23. [PubMed:
12243789]
124. Bordin G, Ballare M, Zigrossi P, et al. A laboratory and thrombokinetic study of HCV-associated
thrombocytopenia: a direct role of HCV in bone marrow exhaustion? Clin Exp Rheumatol
1995;13:S39–S43. [PubMed: 8730475]
125. de Almeida AJ, Campos-de-Magalhaes M, de Melo Marcal OP, et al. Hepatitis C virus-associated
thrombocytopenia: a controlled prospective, virological study. Ann Hematol 2004;83:434–440.
[PubMed: 14963696]
NIH-PA Author Manuscript
139. Asahi A, Nishimoto T, Okazaki Y, et al. Helicobacter pylori eradication shifts monocyte Fcgamma
receptor balance toward inhibitory FcgammaRIIB in immune thrombocytopenic purpura patients.
J Clin Invest 2008;118:2939–2949. [PubMed: 18654664]
NIH-PA Author Manuscript
140. Veneri D, De Matteis G, Solero P, et al. Analysis of B- and T-cell clonality and HLA class II alleles
in patients with idiopathic thrombocytopenic purpura: correlation with Helicobacter pylori infection
and response to eradication treatment. Platelets 2005;16:307–311. [PubMed: 16011982]
141. Stasi R, Rossi Z, Stipa E, Amadori S, Newland AC, Provan D. Helicobacter pylori eradication in
the management of patients with idiopathic thrombocytopenic purpura. Am J Med 2005;118:414–
419. [PubMed: 15808140]
142. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic
purpura and MMR vaccine. Arch Dis Child 2001;84:227–229. [PubMed: 11207170]
143. Abramson JS, Pickering LK. US Immunization Policy. JAMA 2002;287:505–509. [PubMed:
11798374]
144. Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. Br J Clin
Pharmacol 2003;55:107–111. [PubMed: 12534647]
145. Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of
autoimmune manifestations after viral vaccines. Vaccine 2005;23:3876–3886. [PubMed:
15917108]
146. Neau D, Bonnet F, Michaud M, Perel Y, Longy-Boursier M, Ragnaud JM, Guillard JM. Immune
thrombocytopenic purpura after recombinant hepatitis B vaccine: retrospective study of seven cases.
Scand J Infect Dis 1998;30:115–118. [PubMed: 9730294]
NIH-PA Author Manuscript
147. Naidu S, Messmore H, Caserta V, Fine M. CNS lesions in neonatal isoimmune thrombocytopenia.
Arch Neurol 1983;40:552–554. [PubMed: 6615286]
148. Beeler J, Varricchio F, Wise R. Thrombocytopenia after immunization with measles vaccines:
review of the vaccine adverse events reporting system (1990 to 1994). Pediatr Infect Dis J
1996;15:88–90. [PubMed: 8684885]
149. Nieminen U, Peltola H, Syrjala MT, Makipernaa A, Kekomaki R. Acute thrombocytopenic purpura
following measles, mumps and rubella vaccination. A report on 23 patients. Acta Paediatr
1993;82:267–270. [PubMed: 8495082]
150. Jadavji T, Scheifele D, Halperin S. Thrombocytopenia after immunization of Canadian children,
1992 to 2001. Pediatr Infect Dis J 2003;22:119–122. [PubMed: 12586974]
151. Chou AL, Huang WW, Tsao SM, Li CT, Su CC. Human herpesvirus type 8 in patients with cirrhosis:
correlation with sex, alcoholism, hepatitis B virus, disease severity, and thrombocytopenia. Am J
Clin Pathol 2008;130:231–237. [PubMed: 18628092]
152. Hui DS. Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection.
Respirology 2008;13:S10–S13. [PubMed: 18366521]
153. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe cytomegalovirus infection in
apparently immunocompetent patients: a systematic review. Virol J 2008;5:47. [PubMed:
18371229]
NIH-PA Author Manuscript
154. Yang M, Ng MH, Li CK. Thrombocytopenia in patients with severe acute respiratory syndrome
(review). Hematology 2005;10:101–105. [PubMed: 16019455]
155. Vipan W. Quinine as a cause of purpura. Lancet 1865;2:37.
156. Drug-induced thrombocytopenia. 2008. No authors
listedhttp://moon.ouhsc.edu/jgeorge/DITP.html9-11-2008
157. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580–
587. [PubMed: 17687133]
158. van den Bemt PM, Meyboom RH, Egberts AC. Drug-induced immune thrombocytopenia. Drug Saf
2004;27:1243–1252. [PubMed: 15588119]
159. Visentin GP, Newman PJ, Aster RH. Characteristics of quinine- and quinidine-induced antibodies
specific for platelet glycoproteins IIb and IIIa. Blood 1991;77:2668–2676. [PubMed: 1710517]
160. Asvadi P, Ahmadi Z, Chong BH. Drug-induced thrombocytopenia: localization of the binding site
of GPIX-specific quinine-dependent antibodies. Blood 2003;102:1670–1677. [PubMed: 12738668]
161. Parker CW. Hapten immunology and allergic reactions in humans. Arthritis Rheum 1981;24:1024–
1036. [PubMed: 7284049]
162. Bougie DW, Wilker PR, Aster RH. Patients with quinine-induced immune thrombocytopenia have
NIH-PA Author Manuscript
177. Rauova L, Poncz M, McKenzie SE, et al. Ultralarge complexes of PF4 and heparin are central to
the pathogenesis of heparin-induced thrombocytopenia. Blood 2005;105:131–138. [PubMed:
15304392]
178. Rauova L, Zhai L, Kowalska MA, Arepally GM, Cines DB, Poncz M. Role of platelet surface PF4
antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and
therapeutic implications. Blood 2006;107:2346–2353. [PubMed: 16304054]
179. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated
thrombocytopenia. N Engl J Med 1987;316:581–589. [PubMed: 3807952]
180. Arepally GM, Mayer IM. Antibodies from patients with heparin-induced thrombocytopenia
stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood 2001;98:1252–
1254. [PubMed: 11493478]
181. Thachil J. Heparin induced thrombocytopenia with thrombosis: a two step process? Hematology
2008;13:181–182. [PubMed: 18702877]
182. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without
thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997;95:1242–
1246. [PubMed: 9054855]
NIH-PA Author Manuscript
183. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical
density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost
2008;6:1304–1312. [PubMed: 18489711]
184. Greinacher A, Eichler P, Lubenow N, Kiefel V. Drug-induced and drug-dependent immune
thrombocytopenias. Rev Clin Exp Hematol 2001;5:166–200. [PubMed: 11703814]
185. Liebman H. Other immune thrombocytopenias. Semin Hematol 2007;44:S24–S34. [PubMed:
18096469]
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Table 1
Mechanisms underlying drug-induced thrombocytopenia
Hapten-dependent antibody (Penicillin, some Hapten links covalently to membrane protein Very rare
cephalosporin antibiotics) and induces drug-specific immune response
Quinine-type drug (Quinine, sulfonamide Drug induces antibody that binds to membrane 26 cases per 1 million users of
antibiotics, nonsteroidal antiinflammatory protein in presence of soluble drug quinine per week, probably fewer
drugs) cases with other drugs
Fiban-type drug (Tirofiban, eptifibatide) Drug reacts with glycoprotein αIIbβ3 to induce 0.2–0.5%
a conformational change by antibody (not yet
confirmed)
Drug-specific antibody (Abciximab) Antibody recognizes murine component of 0.5–1.0% after first exposure,10–
chimeric Fab fragment specific for platelet β3 14% after second exposure
Autoantibody (Gold salts, procainamide) Drug induces antibody that reacts with 1.0% with gold, very rare with
autologous platelets in absence of drug procainamide and other drugs
Immune complex (Heparins) Drug binds to platelet factor 4, producing 3–6% among patients treated with
immune complex for which antibody is specific; unfractionated heparin for 7 days,
immune complex activates platelets through Fc rare with low-molecular-weight
receptors heparin
Table adapted from Aster and Bougie157[INSERT CORRECT LANGUAGE HERE IF TABLE IS USED]
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