by Robert Seltzer
The disease “idiopathic thrombocytopenic purpura” (ITP), also known as immune thrombocytopenic purpura, is classified as an autoimmune disease. Its very name suggests how little we know about the disease. The term “idiopathic” indicates that the disease is of an unknown cause or origin: in other words, modern medicine has not yet figured out what it is. “Thrombocytopenic” comes from thrombocytopenia, which indicates a low blood platelet count. And the word “purpura” comes from a description of the bruise-colored skin of someone afflicted with the disease: the purple color caused by blood that leaked under the skin.
As implied by its name, ITP is a disease where the immune system inappropriately attacks the body in such a way that the platelet count is greatly reduced. The autoantibodies either target the platelets directly, or target megakaryocytes, the cells that produce platelets. Both of those mechanisms of action are explored in the section “Mechanisms of Action.”
Typical platelet counts in a healthy adult are 150,000 to 400,000 platelets in one milliliter of blood. However, ITP patients have significantly reduced counts: severe cases may have counts near zero, while more mild cases will have counts upwards of 100,000. A minority of ITP patients (about 5-10%) have stable form of the disease, with a platelet count of 30,000 - 100,000 that persists for months to years, and rarely requires treatment. It is the low platelet count that leads to the “purpura,” or bruising of the skin. A patient with a low platelet count has greatly increased risk of internal bleeding. Generally, a count of 30,000 is considered high enough to protect against cerebral hemorrhage. While ITP can usually be controlled as a chronic disease, it can be fatal in a small percentage of patients. The mortality rate from chronic ITP is about 4%. 1
Approximately 200,000 people in the US have ITP. ITP is a chronic disease that is two to three times more common in females than in males .2 It is considered a common autoimmune disorder, and may be the most common autoimmune disorder where one of the possible targets of the auto-reaction – the platelet – has been clearly identified. 3 The disease affects all age groups, and the rate of ITP cases appear to be increasing. An estimated 10 to 125 per 1,000,000 persons develop ITP each year. 4
There are many types of ITP, and ITP in children is not the same as adult ITP. This paper deals with adult chronic ITP.
ITP leads to a low platelet count; as such, a discussion of platelets
will precede a discussion of ITP.
Platelets are specialized cell fragments that are the “first line of defense” against bleeding. 5 They do not contain a nucleus and do not replicate. They are small (<3um diameter), and have a life span of 9-10 days from the time they are created in the bone marrow to when they are used or destroyed.
The central role of platelets is in blood clotting. The platelets circulate with the blood and are prevented from binding to blood vessels by the endothelium. When a blood vessel is damaged, however, the platelets can stick to the edges of the ruptured vessel in a process called adhesion. They also bind to each other in a process called activation. When platelets are activated, they release agents which recruit and activate the surrounding platelets. The adhesion and activation of platelets leads to the formation of fibrin which stabilizes the platelet plug, stops bleeding and allows injuries to heal .6
Platelets are created by megakaryocyte cells in the bone marrow. Megakaryocytes are rare, and represent only 0.1% of nucleated cells in the bone marrow. 7 They are large (50-100 um diameter), and undergo endomitosis, a process that enables the nucleus to carry several times the normal number of chromosomes. The megakaryocytes have specialized structures that enables fragments to be released – platelets are an example of such fragments. 8
Platelets are also associated with other activities beyond clotting. Platelets collect antigen-antibody complexes in the blood. These complexes are carried to the spleen where the platelet and complex is eliminated. 9 Platelets also carry 2% of the body’s serotonin, as well as L-tryptophan (a precursor chemical to serotonin that can pass through the blood brain barrier). Serotonin is associated with processes involving mood regulation, appetite, and sleep/wake cycles. Loss of platelets is associated with depression and changes in temperament. The activities of platelets are still being discovered. In a paper in the March 15, 2004 issue of Blood, researchers showed that platelets release over 300 proteins. Only 37% of those proteins are known. 10
The primary clinical assay used to directly test a patient for ITP is considered unreliable. 12 This non-specific test measures platelet-associated IgG and detects any IgG antibody associated with the platelet. The IgG could be antiplatelet antibody, but it could also be any other kind of IgG associated with the platelet. While this test gives positive results in about 90% of chronic ITP patients, it runs significant risks of giving false positives in patients who have other causes of a low platelet count. Overall, because this test does not specifically measure antiplatelet antibody, “most people in the field do not recommend it.” 13
The ITP tests used in research are summarized by Robert McMillan, MD, of The Scripps Research Institute. These research tests can diagnose chronic ITP directly by measuring antiplatelet antibodies, either antibodies bound to the patient’s platelets (“platelet-associated autoantibody”), or autoantibodies circulating in the plasma (“plasma autoantibody”). 14
There are two tests for measuring antiplatelet antibodies: the immunobead assay and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. Both tests measure autoantibody whose antigen is a specific platelet glycoprotein complex. The glycoprotein complex is usually glycoprotein IIb/IIIa (a combination of platelet glycoprotein IIb and platelet glycoprotein IIIa) or glycoprotein Ib/IX (a combination of platelet glycoprotein Ib and platelet glycoprotein IX).
These tests are only positive for ITP patients, and not positive in patients with other causes of thrombocytopenia. However, the test is only positive in 75% of ITP patients, and thus a sizable fraction of patients are given a false negative. It is likely that in this remaining 25% of cases, the autoantibody is directed against a different platelet glycoprotein complex than the two tested, or is perhaps directed against some other platelet-associated antigen. 15 Since this test is primarily used in research, it is rarely used for clinical purposes.
Overall, the non-specific test has many false positives, and is not recommended in the clinic. The two specific ITP tests used in research give a large percent of false negatives and are rarely used in the clinic. As a result, patients with ITP are usually given a diagnosis based on the exclusion of other diseases. Tests are rarely used to confirm the diagnosis, leading to ambiguity and confusion for some patients.
Interestingly, diagnostic measures have not improved since 1995, when a panel of hematologist experts gathered to share their thoughts on ITP.16 At that time, diagnosis of ITP was explicitly based on the systematic exclusion of other causes of low platelet counts. As more is understood about the mechanism of action of the disease, the possibility exists of creating better diagnostic tests.
The disease ITP describes a specific physiological state: the patient has a low platelet count, and other conditions or diseases that would lead to a low platelet count have been eliminated. As described in the “Diagnosis” section above, ITP is primarily diagnosed by the exclusion of other disease types.
As such, there may be multiple possible mechanisms underlying ITP. There are broadly two types of mechanisms found in the literature: autoantibodies targeted against platelets, and autoantibodies targeted against megakaryocytes (the cells that produce platelets). It may be that one mechanism will ultimately be proven to be more correct than the other. More likely, some ITP conditions are due to one mechanism of action, and other ITP conditions are due to the other. Indeed, based on the false negatives of the laboratory tests described in the “Diagnosis” section, one can infer that multiple mechanisms of action could account for the collection of maladies that are grouped under the common disease name ITP.
Studies as early as the 1950's showed that thrombocytopenia could be induced by transfusing blood from a patient with chronic ITP into a normal volunteer. 19 Further research isolated the substance in ITP patients that caused the destruction of platelets, and led to its identification as an autoantibody. 20
When autoantibodies bind to platelets, the platelets are marked for destruction in two ways: via phagocytosis and via complement activation. In phagocytosis, the platelets are marked for destruction by the Fc region of the bound immunoglobulins. For example, the platelets bound by IgM autoantibodies fix C3, and are cleared by CR1- and CR3-bearing macrophages, often in the fixed mononuclear phagocytic system. The macrophages phagocytose and destroy the platelets. This clearance often occurs in the spleen, but can also occur in the bone marrow or liver. The bound immunoglobulins can also fix complement, leading to the formation of a membrane-attack complex on the platelet. This process also leads to platelet destruction. 21
Technically, the immunopathogenic mechanism of ITP is a Type II antibody to cell-surface antigen. 22 The cell surface antigen is most likely a glycoprotein complex on the surface of the platelet. As indicated from the “Diagnosis” section, the most common two complexes that serve as antigens are glycoprotein IIb/IIIa (a combination of platelet glycoprotein IIb and platelet glycoprotein IIIa) and glycoprotein Ib/IX (a combination of platelet glycoprotein Ib and platelet glycoprotein IX). Some forms of ITP may target other glycoprotein complexes that are not yet identified.
According to this model, the platelets – tagged with autoantibodies – are primarily removed from circulation via phagocytosis in the spleen. The spleen is the primary location of removal for several reasons. At any given time, approximately one third of the body’s circulating platelets are in the spleen. Moreover, much of the autoantibody production occurs in the spleen; thus, platelets in the spleen are exposed to high concentrations of autoantibody. In addition, the spleen is rich in macrophages that phagocytose cells that are marked for destruction by antibodies. Based on the role of the spleen in ITP, it should not be surprising that removal of the spleen often results in the cure of many ITP patients (treatments are discussed in more detail in the “Treatments” section of this paper).
There is some evidence that in some forms of ITP, the platelets are not only targeted in the blood. As noted by Robert McMillan MD of The Scripps Research Institute, the bone marrow can increase the production of platelets up to 6 to 8 times normal, if necessary. Yet in many ITP patients, platelet production is less than would be expected given the ongoing platelet destruction. Based on this observation, Dr. McMillan suggests that “the autoantibody, in some patients, may inhibit platelet production or destroy platelets in the bone marrow before they can be released into the blood.” 23 For such patients, spleen removal would not help fight the disease at all. Dr. McMillan’s suggestion is also consistent with the second model of ITP mechanism, where the autoantibodies are directed against the megakaryocytes.
This study is supported by other pieces of evidence. For example, according to the Platelet Disorder Support Organization (PDSO), studies have shown that 30% to 50% of patients with ITP have a reduced rate of platelet production. Researchers in the Netherlands have found evidence that the reduced platelet production may be associated with injured or abnormal megakaryocytes. According to the researchers, the megakaryocytes in ITP patients were surrounded by neutrophils and macrophages, indicating an inflammatory response against the megakaryocytes. In addition, the megakaryocytes appeared to be displaying characteristic signals similar to the signals of dying cells. Based on these findings, the researchers concluded that the lowered platelet count in ITP could possibly be due to the action of autoantibodies against the megakaryocytes. 25
Overall, the mechanism of action of ITP is still being studied and understood. It could be that ITP represents a collection of specific diseases, each with a slightly different mechanism. It could also be that the autoantibodies act in multiple ways. For example, platelets and megakaryocytes share some surface glycoproteins. If an autoantibody recognizes one of these “shared” glycoproteins as its antigen, then the autoantibody would bind to both platelets circulating in the blood as well as megakaryocytes in the bone marrow.
It is the opinion of this author that ITP does indeed represent a collection
of mechanisms of action. Based on the lack of a diagnostic test,
as well as the wide range of severities of the cases, it appears as if
not all cases of ITP are created equal. For some of the mild cases,
just the platelets may be targeted. In those cases, the megakaryocytes
are able to partially compensate with increased platelet production.
Such patients can have chronic but stable ITP, with low platelet counts
at a safe level (upwards of 100,000 platelets per milliliter of blood).
In severe cases, the autoantibody may be directed against an antigen that
is both on platelets as well as megakaryocytes. In those cases, platelet
production is greatly diminished, and the patient must undergo treatment
to avoid the dangers of internal bleeding.
There are, broadly, three theories on the possible causes of autoimmune diseases: the “Microbial Trigger Theory,” the “DNA Damage Theory,” and the “Molecular Mimicry Theory.” They are each outlined below. It is likely that an autoimmune disease develops due to a combination of events.
Microbial Trigger Theory
This theory was explored in Science News in the article "Microbial
Trigger for Autoimmunity?" 26
Lymphocytes exist in the body that are autoreactive, yet remain inactive.
Researchers found that in mice, these dormant cells can become activated
if the cells are near a bacterial infection. When the body fights
the bacterial infection and interleukin-12 is created, the interleukin-12
creates an array of additional compounds specific to the pathogen.
These anti-microbial compounds released near the infection site could accidentally
activate a dormant, self-reactive lymphocyte. If the dormant lymphocyte
targets platelets, then the microbial invasion may have triggered autoimmunity
against platelets.
DNA Damage Theory
According to this theory, autoimmune diseases are developed due to
a genetic defect that arises in a key part of the immune system.
There are many complex processes involved with avoiding autoimmunity. According to clonal deletion, T cells that react to self-molecules in the thymus are eliminated. If the presentation of self-antigen and subsequent elimination of autoreactive T cells does not proceed perfectly, a self-reactive T cell could mature, and an autoimmune disease could develop. Autoreactive T cells that are not eliminated in the thymus can be suppressed through other mechanisms. However, when those suppression mechanisms break down, an autoimmune disease can develop.
If a process becomes altered because of a genetic defect, then there is increased risk of the development of an autoimmune disease. The genetic defect could be due to free radical damage or through other causes of somatic genetic mutation. 27 The defect could also be genetic, as a small nucleotide polymorphism in one or both alleles could make an individual more susceptible to acquiring an autoimmune disease.
Indeed, there is evidence that some individuals are genetically more prone to autoimmune diseases than others. A twins study was conducted for several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and IDDM. 28 Monozygotic twins were compared with dizygotic twins. For each disease, the monozygotic twins showed disease concordance 20% of the time, compared with only 5% for dizygotic twins. In particular, it is thought that the MHC genotype is particularly important. 29
Molecular Mimicry Theory
According to this theory, autoimmune diseases are caused when pathogens
are detected in the body that are similar to self-molecules. Lymphocytes
are activated to target the intended antigen, but as they attack the pathogen,
they also attack the similar self-molecules. 30
By itself, it is unlikely that this theory explains the onset of an autoimmune
disease. However, molecular mimicry may be an important factor when
combined with either the Microbial Trigger Theory or DNA Damage Theory.
Autoimmunity often occurs spontaneously in patients, and science does not know what events trigger the onset of the disease. It is likely that autoimmune diseases arise from a confluence of factors. For example, in one experiment, it was shown that it is possible to induce an autoimmune disease through a combination of the three theories above. Genetically susceptible strains of animals (DNA damage) were injected with “self” tissues (Molecular Mimicry) mixed with strong adjuvants containing bacteria (Microbial Trigger). The combination of those events provoked autoimmunity. 31
Generally, patients with a stable platelet count above 30,000 do not need additional treatment. However, platelet counts less than 30,000 represent risk to the patient of internal bleeding. Platelet counts significantly lower than 20,000 represent significant risk. Thus, the purpose of treatment of chronic ITP is to bring the platelet count to a stable, safe level.
The typical treatment of adult chronic ITP has four lines of defense. If a certain therapy does not work, then the next therapy is attempted. The first defense is putting the patient on a corticosteroid such as prednisone. If the corticosteroid is ineffective, then the patient is given an anti-D treatment. If Anti-D is ineffective, a splenectomy is recommended (removal of the spleen). If the patient still has dangerously low platelet count levels after a splenectomy, then a variety of fourth line treatments are considered. Each of these treatments is discussed in turn.
First line: Corticosteroids.
Corticosteroids are the preferred first treatment because of its convenience
(taking pills) and low cost. A common corticosteroid used is prednisone.
The disadvantage of using a corticosteroid is that in the long run, a drug
such as prednisone has a variety of negative side effects, including weight
gain, osteoporosis and an increased risk of infection. If taken in
large quantities over a long period of time, the side effects can become
quite serious. To minimize the patient’s exposure to prednisone,
treatment is often started at high doses (e.g., 50-100 mg/ day).
Dosage is then tapered as the platelet count increases. The goal
is to bring the count to acceptable levels using a dose that does not cause
significant side effects (e.g., 10-15 mg/ day).
Overall, approximately three-fourths of patients immediately respond to this treatment with an increased platelet count. The question is what level of prednisone is required to maintain safe levels of platelets.
Second line: Anti-D.
Anti-D polyclonal antibody is a treatment that is only useful in Rh
positive patients. 33 An example of
such a treatment is available under the brand name Winrho SDF, and is marketed
by Nabi Biopharmaceuticals. 34 The treatment
is administered when the patient’s platelet count falls below 25,000.
The duration of treatment is generally 6-12 months; however, there are
no studies available that indicate how long this treatment should be continued
before it is considered ineffective. The side effects of anti-D therapy
are minimal (fever, chills and headache), and occur during or shortly after
anti-D injection.
One study of the anti-D therapy was recently published. 35 Twenty-eight Rh+ ITP patients were give anti-D therapy whenever their platelet count fell below 30,000. In total, 68% of the patients responded consistently to anti-D. 36
The clinical dogma used to suggest that treatments such as corticosteroids and anti-D could only be helpful temporarily, and that ultimately, a chronic ITP patient would need a splenectomy. That view is now challenged. Many clinicians now believe that if the platelet count can be maintained at a safe level over a long interval, with some form of therapy, then some patients may be able to improve or recover completely without the need for splenectomy. 37
Third line: Splenectomy.
If the first two therapies are ineffective, then the currently accepted
clinical practice is to remove the patient’s spleen. As described
in the “Mechanism of Action” section, for many types of ITP (but not all),
the spleen is an important organ involved in platelet removal. The
spleen is the organ where the three ingredients for platelet destruction
all coexist in high concentrations: the autoantibodies, the platelets,
and the macrophages. While the spleen is an important organ for combating
infection, it is not vital, and patients can survive without a spleen.
Historically, splenectomy has yielded the highest cure rate of all treatments. According to one source that combined the results of several large studies, splenectomy resulted in a permanent complete response (normal platelet count) in 59.9% of 667 patients. An additional 12.3% of patients achieved a stable partial response (safe platelet counts). In total, 72.2% of these ITP patients required no additional treatment after undergoing a splenectomy. 38
While 72.2% is a high number, that leaves a large number of patients for whom splenectomy was not successful. As suggested in the “Mechanism of Action” section, perhaps the patients who did not respond to splenectomies had a different form of ITP. For example, instead of having autoantibodies against platelets circulating in the blood, perhaps those unresponsive patients had autoantibodies against megakaryocytes. Interestingly, the percent of patients unresponsive to splenectomies is near the percentage of patients for whom the research-based diagnostic test yields a false negative (see the “Diagnostic” section). While this observation could be a coincidence, it is the opinion of this author ITP likely represents a collection of different specific kinds of diseases that each lower platelet counts through an autoimmune mechanism.
There is currently no way to predict who will respond to splenectomy prior to the surgery. One article suggested that patients whose platelet count increases after treatment with intravenous gammaglobulin are more likely to respond to splenectomy. 39 However, this result has not been confirmed by other studies. 40
Fourth lines
If none of the first three lines are effective, then the patient has
a wide array of fourth line options, each of which has advantages and disadvantages.
A couple of such treatments are briefly described here.
• Vinca Alkaloids. Approximately 30-40% of patients will respond
to vinca alkaloids: for example, vincristine (Oncovin) or vinlastine (Velban).
However, most responses are temporary, and only occasionally will a dramatic
and permanent response occur.
• Danazol. About 50% of patients will respond to Danazol.
However, responses may be slow (85% of responses occur within 4 months,
with an average response time of 2.7 months).
• Colchicine is only used occasionally for ITP, but is an extremely
safe drug which is usually used in the treatment of gout. Approximately
25% of ITP patients respond to Colchicine. The response generally occurs
during the first 3 months. Unfortunately, withdrawing the use of
colchicine usually results in relapse.
Information about current clinical trials was obtained from Platelet
Disorder Support Organization: http://www.itppeople.com/aboutitp.htm and
at www.ClinicalTrials.gov. Current ITP Clinical trials include:
• Thrombopoietin - "A Dose finding Study Evaluating the Safety
and Efficacy of Amgen Megakaryopoiesis Protein 2 [AMP2(AMG 531)] in Thrombocytopenic
Subjects with Immune Thrombocytopenic Purpura (ITP)". Preliminary results
of this compound have been promising, according to information shared in
the 2003 American Society of Hematology meeting. 41
• Daclizumab - Hematologists are testing a new monoclonal antibody
treatment (Daclizumab) for people with ITP. The study is being performed
at the National Institutes of Health (NIH). 42
• Enbrel - "Prospective Trial of Etanercept (Enbrel) in the Treatment
of Chronic Immune Thrombocytopenic Purpura (ITP) in Children and Adults".
This a pilot study of a commonly used arthritis drug that may help people
with chronic ITP. 43
ITP is a disease that is reasonably common and reasonably well characterized.
Yet much is still unknown about its origin or mechanism of action.
Hopefully, future research will shed light on this autoimmune disease,
potentially paving the way to a greater understanding of the mechanisms
of other, related autoimmune diseases.
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