Pathophysiology of platelet destruction in ITP

..
immunoglobulin or PAIG) that leads to immune-mediated
Pathophysiology of platelet ..
..
.. platelet destruction by the reticuloendothelial system.4–6 The
.. sensitized platelet interacts with splenic macrophages via the
destruction in immune ..
.. Fc receptor (FcR), and is subsequently phagocytosed. Imbach
..
.. et al. determined that IVIg was an effective therapy for ITP be-
(idiopathic) ..
.. cause the infused IgG molecules competed with FcR-mediated
.. platelet binding by macrophages, thus producing immuno-
thrombocytopenic purpura ..
..
.. logic RES blockade.7
.. Although this model for platelet destruction is widely
..
J. McFarland .. accepted, it is unclear what the exact trigger for autoanti-
..
.. body production is and how characteristics of the antibody
Blood Center of Southeastern Wisconsin, Milwaukee .. contribute to severity of disease. Further, the site of platelet
..
.. destruction, in the spleen or liver, may play a role in the clin-
..
Abstract The mechanism of platelet destruction in immune .. ical severity of the disease as well as the degree of platelet
..
(idiopathic) thrombocytopenic purpura (ITP) is thought to .. activation.
involve production of autoantibody to platelet surface antigens. ..
.. Autoantibody production in ITP may be related to molec-
Once coated with antibody, circulating platelets undergo .. ular mimicry. Examples of this are acute ITP of childhood or
..
sequestration via interaction with Fc receptors of macrophages .. HIV-related immune thrombocytopenia in which the body’s
..
in the reticuloendothelial system. A number of questions remain .. response to a viral infection whether acute or chronic, results
..
about the mechanism of platelet destruction in this disease: 1) .. in production of an antibody that cross-reacts with a protein
What is the nature of the stimulus to the immune system that ..
.. epitope on the virus and on the platelet. In the case of HIV
generates antiplatelet antibodies? 2) What is the role of .. thrombocytopenia, anti-HIV antibodies that cross-react with
..
interactions between T-helper lymphocytes and .. platelet membrane glycoproteins (eg, GPIIIa) have been de-
..
antigen-presenting cells in ITP? 3) What role, if any, is played by .. tected on the platelet surface.8,9 Several recent studies suggest
..
the targeting of single or multiple platelet surface glycoproteins .. that cellular immune responses may play a role. Semple et al.
by the autoimmune response? 4) Is the site of platelet ..
.. reviewed a number of studies of cellular immune response in
destruction, intravascular or extravascular, or the state of .. chronic ITP and found that in order to produce an autoreactive
..
activation of platelets important in the destruction of platelets? .. antibody against platelets, it was necessary that a population
°C 2002, Elsevier Science Ltd. All rights reserved.
..
.. of autoreactive T helper cells be generated which then interact
..
.. with B cells producing antibodies.10
..
.. Most of the focus to date in the immunology of ITP has
.. been on the antibodies that are circulating and bound to
..
mmune (idiopathic) thrombocytopenic purpura (ITP) is .. ITP platelets. The first study to demonstrate the detection

I an acquired disease of adults and children that is defined

by a low platelet count in the absence of other causes
of thrombocytopenia, such as drug-induced, systemic lupus
..
..
..
..
..
..
..
of autoantibody and the clinical significance of antibody lev-
els in ITP was reported by Dixon.5 In this study, patients
with lower antibody titers had a better clinical outcome.
erythematosis, human immunodeficiency disease (HIV), or .. Subsequent studies, however, found that detection of an-
lymphoproliferative disorders.1 In children, the onset of ITP .. tiplatelet antibodies was nonspecific, since platelet-associated
..
is usually acute and it often resolves without treatment in .. immune globulin could be elevated in the thrombocytope-
..
weeks to months. In adults, the onset is often insidious with .. nia of sepsis and in other nonimmune platelet destruction
purpura with or without clinical bleeding. The peak age at .. processes.11–13
..
onset in adults is 15–40, and the disease is 2.6 times more .. Platelet glycoprotein-based assays now demonstrate that
..
common in women than men. While 83% of children have .. more than 80% of ITP patients have antibodies reactive with
..
a spontaneous remission of their disease, only 2% of adults .. multiple platelet surface glycoproteins, many of which are im-
..
experience this and 43% develop chronic disease.2 Disease .. portant to normal platelet function and hemostasis.14–16 Most
remission with therapy occurs in 89% of children and 64% of .. of these antibodies are directed against glycoprotein IIB-IIIA,
..
adults. .. GPIa/IIa, or GPIb/IX. Despite this, a convincing correlation
..
The destruction of platelets by a humoral factor in ITP .. between specific glycoprotein targets and disease severity has
..
plasma was first identified by Harrington in 1951. He in- .. not been demonstrated. Moreover, most patients have antibod-
..
fused himself with plasma from a patient with active ITP and .. ies that react with multiple glycoprotein targets.17 The site of
promptly developed severe thrombocytopenia and purpura.3 .. platelet destruction in ITP is most likely within the reticuloen-
..
He recovered within a few days and was able to demonstrate .. dothelial system in the spleen, liver, or bone marrow. Evidence
..
similar platelet destruction and recovery in normal volunteers. .. for intravascular as well as extravascular destruction is present
..
Schulman subsequently demonstrated that the humoral factor .. in some cases of immune platelet destruction. The role of
..
important in this reaction was the IgG fraction of plasma. Fol- .. platelet activation in the eventual destruction of ITP platelets
lowing, a number of laboratories developed methods for de- .. is unclear, but there is evidence that a subset of circulating ITP
..
tecting both platelet-associated immune globulin and serum .. platelets do become activated. Cahill et al. have demonstrated
..
platelet reactive antibody.4 .. that in patients who respond to effective therapy for ITP, the
..
ITP is characterized by the presence of autoreactive .. P selectin levels decrease, indicating that platelet activation
..
immunoglobulin on the platelet surface (platelet-associated may well play a role.18

°
c 2002, Elsevier Science Ltd. All rights reserved. Blood Reviews (2002) 16, 1–2 1
doi: 10.1054/blre.2001.0169, available online at http://www.idealibrary.com on
 McFarland
The heterogeneity of disease mechanisms in ITP is best .. 8. Bettaieb A, Oksenhendler E, Duedari N, Bierling P. Cross-reactive
..
demonstrated by variable platelet life span and platelet .. antibodies between HIV-gp120 and platelet gpIIIa (CD61) in
..
turnover measurements. It now appears that a significant num- .. HIV-related immune thrombocytopenic purpura. Clin Exp Immunol
..
ber of ITP patients (up to 40%) experience decreased produc- .. 1996; 103(1): 19–23.
..
tion as well as increased peripheral destruction of platelets.19 .. 9. Bettaieb A, Fromont P, Louache F et al. Presence of cross-reactive
Recent reports of thrombopoietin measurements suggest that .. antibody between human immunodeficiency virus and platelet
..
this test may distinguish patients with normal to increased .. glycoproteins in HIV-related immune thrombocytopenic purpura.
..
platelet turnover from those with depressed megakaryocyte .. Blood 1992; 80: 162–169.
..
reserves.20,21 The mechanism of decreased platelet production .. 10. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A,
..
in this autoimmune disease remains unclear. .. Blanchette V, Freedman J. Differences in serum cytokine levels in
In conclusion, while a functional working model for .. acute and chronic autoimmune thrombocytopenic purpura:
..
platelet destruction in ITP exists, a number of questions .. relationship to platelet phenotype and antiplatelet T-cell reactivity.
..
remain regarding the etiology of the autoantibody response, .. Blood 1996; 87: 4245–4254.
..
the sites of platelet destruction, and the role of other platelet .. 11. Berchtold P, Muller D, Bearsley D et al. International study to
..
activating events in mediating platelet destruction. .. compare antigen-specific methods used for the measurement of
.. antiplatelet antibodies. Br J Haematol 1997; 96: 477–483.
..
.. 12. Lescale KB, Eddleman KA, Cines DB et al. Antiplatelet antibody
..
.. testing in thrombocytopenic pregnant women. Am J Obstet
..
Correspondence to: Janice McFarland, MD, Director, Platelet and Neutrophil .. Gynecol 1996; 174: 1014 –1018.
..
Antibody Laboratory, Blood Center of Southeastern Wisconsin, PO Box .. 13. Raife TH, Olsen JD, Lentz SR. Platelet antibody testing in idiopathic
.. thrombocytopenic purpura. Blood 1997; 89: 1112–1114.
2178, Milwaukee, WI 53201-2178 ..
.. 14. Berchtold P, Wenger M. Autoantibodies against platelet
..
.. glycoproteins in autoimmune thrombocytopenia purpura: their
..
.. clinical significance and response to treatment. Blood 1993; 81:
..
.. 1246–1250.
References .. 15. Fujizawa K, Tani P, Piro L et al. The effect of therapy on
..
1. George JN, Woolf SH, Raskob GE et al. Idiopathic .. platelet-associated autoantibody in chronic immune
..
thrombocytopenic purpura: A practice guideline developed by .. thrombocytopenic purpura. Blood 1993; 81: 2872–2877.
..
explicit methods for the American Society of Hematology. Blood .. 16. He R, Reid D, Jones CE et al. Spectrum of Ig classes, specificities,
1996; 88: 3–40.
.. and titres of serum antiglycoproteins in chronic idiopathic
..
2. George JN, El-Harake MA, Aster RH. Thrombocytopenia due to .. thrombocytopenic purpura. Blood 1994; 83: 1024–1032.
..
enhanced platelet destruction by immune mechanisms. New York, .. 17. McFarland JG, Collins J, Aster RH, Moghaddam M, Bussel J.
..
NY: McGraw Hill, 1996; pp 1315–1355. .. Evaluation of a platelet glycoprotein (GP) specific assay in the
..
3. Harrington WJ, Minnich V, Hollingsworth JW et al. Demonstration .. diagnosis of autoimmune thrombocytopenia (TP). Blood 1999;
of a thrombocytopenic factor in the blood of patients with
.. 94(suppl 1): 15a (abstr).
..
thrombocytopenic purpura. J Lab Clin Med 1951; 115(5): 636–645. ... 18. Cahill MR, Macey MG, Cavenagh JD, Newland AC. Protein A
.
4. McMillan R, Longmire RL, Yelenosky R et al. Quantitation of platelet .. immunoadsorption in chronic refractory ITP reverses increased
..
binding IgG produced in vitro by spleens from patients with .. platelet activation, but fails to achieve sustained clinical benefit. Br J
..
idiopathic thrombocytopenic purpura. N Eng J Med 1974; 291: .. Haematol 1998; 100(2): 358–364.
812–817.
.. 19. Ballem PJ, Segal GM, Stratton J, Gernsheimer T, Adamson JW,
..
5. Dixon R, Rosse W, Ebbert L. Quantitative determination of .. Slichter SJ. Mechanisms of thrombocytopenia in chronic
..
antibody in idiopathic thrombocytopenic purpura. Correlation of .. autoimmune thrombocytopenic purpura. Evidence of both impaired
..
serum and platelet-bound antibody with clinical response. N Eng J .. platelet production and increased platelet clearance. J Clin Invest
..
Med 1975; 292: 265–275. .. 1987; 80: 33– 40.
6. Ware R, Kinney TR. Immunopathology of childhood idiopathic
.. 20. Porcelijn L, Folman CC, Bossers B et al. The diagnostic value of
..
thrombocytopenic purpura. Crit Rev Hematol Oncol 1987; 7: .. thrombopoietin level measurements in thrombocytopenia. Thromb
..
169–181. .. Haemost 1998; 79(6): 1101–1105.
..
7. Imbach P, Wagner HP, Berchtold W et al. Intravenous .. 21. Hou M, Andersson PO, Stockelberg D, Mellqvist UH, Ridell B,
..
immunoglobulin versus oral corticosteroids in acute immune .. Wadenvik H. Plasma thrombopoietin levels in thrombocytopenic
thrombocytopenic purpura in childhood. Lancet 1985; 2:
.. states: implication for a regulatory role of bone marrow
..
464–468. .. megakaryocytes. Br J Haematol 1998; 101(3): 420–424.

2 Blood Reviews (2002) 16, 1–2 °

c 2002, Elsevier Science Ltd. All rights reserved.