Idiopathic thrombocytopenic purpura

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Overview
Idiopathic thrombocytopenic purpura (ITP) is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic). As most causes appear to be related to antibodies against platelets, it is also known as immune thrombocytopenic purpura. Although most cases are asymptomatic, very low platelet counts can lead to a bleeding diathesis and purpura.

Synonyms
ITP knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an eponym, Werlhof's disease, but this is used infrequently.

Other synonyms include: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura, thrombocytolytic purpura.

Signs and symptoms
The incidence of ITP is 50–100 new cases per million per year, with children accounting for half of that amount.

More than 70% of the cases in children end up in remission within 6 months whether treated or not. Moreover, a third of the remaining chronic cases remitted during the follow-up observation, and another third ended up with only mild thrombocytopenia (>50,000 platelets per μL). ITP is usually chronic in adults and the probability of durable remission is 20–40%. The male:female ratio in the adult group is 1:1.2–1.7 (for children it is 1:1) and the median age of adults at the diagnosis is 56–60. Usually, ITP patients suffer from bruising; petechiae, nosebleeds and bleeding gums may occur if the platelet count is below 20,000, compared to a normal range of 150,000–400,000 per mm3.Subarachnoid, intracerebral hemorrhage or other internal bleeding are very serious possible complications of this disease. Fortunately, these are unlikely in patients with the platelets count above 20,000.

Evan's syndrome can occur in ~1% of cases and is manifest by an autoimmune (Coombs +)hemolytic anemia with ITP. The bone marrow biopsy in ITP can show increased (thought not always) megakaryocytes, bizarre giant platelets and platelet fragments. (Large platelets are often seen in the peripheral blood smear though this can be seen in other diseases.) When the spleen is removed it may show increased lymphatic nodularity. Platelet-associated antibody (IgG), which was the standard test of past years, is not now considered mandatory to diagnose ITP. Test for platelet antibody are not helpful as both their sensitivity and specificity are limited.

Pathogenesis
In many cases, the cause is not actually idiopathic but autoimmune, with antibodies against platelets being detected in approximately 60% of patients. Most often these antibodies are against platelet membrane glycoproteins IIb-IIIa or Ib-IX, and are of the IgG type. The famous Harrington–Hollingsworth Experiment established the immune pathogenesis of ITP.

The cause of ITP is thought to be related to chronic infections such as HIV, hepatitis C and H. Pylori. The mechanism involved is thought to be MOLECULAR MIMICRY, that is, antibody is formed against the infection and this cross-reacts with platelets. Autoantibodies in ITP react with platelet IIb/IIIa glycoprotein, less commonly with GPIb/IX. Lymphocytes in the spleen make the antiplatelet antibody; this is why splenectomy works so well. There is a correlation between a platelet's short survival and high turnover rate and the subsequent excellent response to splenectomy.

The antibodies also appear to damage megakaryocytes, preventing them from releasing platelets. Autoantibody-mediated phagocytosis of platelets has long been thought to be the primary mechanism of the disease. Platelet kinetic studies show that platelet production is normal or reduced rather than increased in about two thirds of ITP patients. Also, autoantibodies from patients with ITP inhibit megakaryocyte growth in vitro. IgG from ITP-plasma inhibits megakaryocyte production. Ultrastructural studies of the bone marrow in ITP show increased signs of megakaryocyte apoptosis and reduced platelet shedding.

ITP has a strong association with immune thyroid disease.

Recent evidence suggests that the stimulus for autoantibody production in ITP is due to abnormal T helper cells reacting with platelet antigens on the surface of antigen presenting cells. This important finding suggests that therapies directed towards T cells may be effective in treating ITP.

Diagnosis
The diagnosis of ITP is a diagnosis of exclusion. First, one has to make sure that there are no other blood abnormalities except for low platelet count and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5-10% of suspected ITP cases) should be excluded. Secondary causes could be leukemia, medications (e.g. quinine, heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency and others.

Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate other possible causes for the thrombocytopenia.

Bleeding time is prolonged in ITP patients; however, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines as useless. For example the BMJ review of the basics of hematology states: "The bleeding time may or may not be prolonged in congenital or acquired platelet dysfunction, and therefore a normal bleeding time does not exclude these conditions."

A bone marrow examination may be performed on patients over the age of 60 and people who do not respond to treatment, or when the diagnosis is in doubt. The blood analysis for the antiplatelet antibodies is a matter of clinician's preference, as there is a disagreement whether the 80% specificity of this test is sufficient. In conditions associated with bone marrow failure (aplastic anemia) thrombopoietin (TPO)levels are high whereas in ITP thrombopoietin levels are low. Thus TPO could distinguish between decreased platelets due to bone marrow failure or increased due to their destruction. The bone marrow in ITP contains normal or high numbers of megakaryocytes but they may be small or immature (& may have been damaged by antibodies).

The ITP in AIDS has a thrombocytopenia that is multifactorial involving both TPO and platelet problems. Mechanisms may involve portal hypertension that leads to splenomegaly causing platelet sequestration. Hepatits C (HCV) causes decreased TPO production leading to decreased platelet production. Steroids may be helpful but, with their taper, the count usually decreases again. Intravenous immunoglobulin's effect is transient. For ITP-HIV the primary treatment should be directed at HIV suppression with HAART. HIV patients whose platelet count fails to increase to > 50,000 with HAART can be treated with steroids. Splenectomy is safe and effective in ~80% of patients with refractory HIV-related thrombocytopenia and treated with interferon (IFN) may be effective in refractory cases of patients coinfected with HCV. A decrease in platelets in HIV can arise secondary to both HCV and hepatitis B (HBV).

Pregnant patients with ITP and platelet counts < 30,000 can be treated with intravenous immunoglobulin (IV-IgG) or steroids at the lowest dose possible to avoid hypertension, eclampsia and adrenal suppression of the fetus. ~10-30% of pregnant females with ITP have an infant with platelets <50,000, however, intracranial hemorrhage is rare. For these females administer prednisone during the last month of pregnancy to decrease the likelihood of thrombocytopenia in the fetus. Mothers with ITP who have previously given birth to infants without thrombocytopenia tend not to be thrombocytopenic. The maternal platelet count doesn't correlate with fetal and females with a prior history of ITP with ITP in remission (eg after splenectomy) may still deliver severely thrombocytopenic infants. This likely occurs because asplenic patients in clinical remission may not necessarily be in immunologic remission and circulating platelet-reactive IgG may still be present in their plasma.

Treatment
Mechanism-based Approach to Treatment; 1) Inhibit phagocyte-mediated clearance of antibody-coated platelets; Steroids; Splenectomy; Anti-D; IV-IgG 2) Decreased autoantibody production; Rituximab; Steroids; Azathioprine & other immunosuppressants (eg cytoxan, cyclosporine, etc) 3) Impair T & B cell interactions.; Steroids; Rituximab 4) Enhance platelet production.; Thrombopoietic agents; IL-11.

Observation
Most children with ITP will recover even without specific treatment. Among adults ITP is typically a chronic disease. It is insidious in onset and, in some patients, refractory to treatment. 90% of childhood ITP cases are an acute, self-limited disease, developing several weeks after a viral illness, lasting for 4-6 weeks, then spontaneously remitting. The bleeding risk is low and treatment is reserved only for the most severely affected patients. Because spontaneous recovery is expected in children wit ITP some pediatric hematologists recommend supportive care only, no drugs. In less than 20% of children thrombocytopenia may persist for >6-12 months and even many of these kids can experience a spontaneous remission.

Steroids/IVIgG
Platelet count below 20,000 is an indication for treatment; the patients with 20,000–50,000 platelets/μL are considered on a case by case basis, and there is generally no need to treat the patients with above 50,000 platelets/μL. Hospitalization is recommended in the cases of significant internal or mucocutaneous bleeding. The treatment begins with intravenous steroids (methylprednisolone or prednisone), intravenous immunoglobulin (IVIg) or their combination and sometimes platelet infusions in order to raise the count quickly. After the platelet count stabilized and in the less severe cases oral prednisone (1–2 mg/kg) is used. Most cases respond during the first week of treatment (RR ~70%). After several weeks of prednisone therapy, the dose is gradually reduced. However, 60–90% of patients relapse after the dose decreased below 0.25 mg/kg and stopped. Pulsed high-dose dexamethasone shows (in untreated patients) a high RR of ~90% with a long-term RR of ~80% when several cycles of treatment are given. However long term high dose steroids have a myriad of toxicities and should be avoided if possible.

Splenectomy
Splenectomy offers a 2nd line treatment for those who fail steroids. The criteria for surgery are severe thrombocytopenia (<10,000), high risk of bleeding or the requirement of frequent steroids/IVIgG/anti-D treatment to maintain an adequate platelet count. Of the ~15% of children with persistent thrombocytopenia bleeding symptoms are uncommon and splenectomy is rarely required. However splenectomy is an effective treatment option for children with severe / symptomatic thrombocytopenia with a CR of ~75%. Because of the risk for overwhelming sepsis after splenectomy it should be deferred until after 5 years of age. Remember to give immunizations before splenectomy and perioperative antibiotics. Response to IV-IgG often predicts a response to splenectomy (increasing the platelet count to >50,000 with IgG means a >90% RR to splenectomy).

Anti-D
A relatively new strategy is treatment with anti-D, an agent also used in mothers who have been sensitized to rhesus antigen by a Rh+ baby, but the patient must be Rh+. IV anti-D (WinRhoSD) can also increase the platelet count especially at a higher dose of 75 mcg / kg. IV anti-D is effective in patients who are Rh-positive and non-splenectomized with a RR equal to 70%. Its toxicities include mild hemolysis, fever, chills, headache, nausea and vomiting.

Steroid-sparing agents
Immunosuppresants like mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness. Rituximab has also been used successfully for some patients. Rituximab is used in refractory ITP with success; circulating B-cells become undetectable after a single dose of Rituximab but recover after 3-6 months. Rituximab can be detected in the serum of patients 3-6 months after treatment. The duration of Rituximab correlates with the stability of hte platelet response. However, although the short-term CR = 46% the long-term CR is only 18%. The typical schedule is 375 mg / m2 qwk x4 wks. Rituximab (375 mg / m2 d7, 14, 21, 28) / Dexamethasone was compared to Dexamethasone alone (40 mg QD, d1 through 4, given in qmonthly cycles. Initial and sustained response rates were better with the combination therapy (reference; Zaja R et al ASH 2008).

Extreme cases (very rare, especially rare in children) may require vincristine, a chemotherapy agent, to stop the immune system from destroying platelets. For the most part this and other agents such as cytoxan, cyclosporine and danazol have fallen into disuse.

Intravenous immunoglobulin, while sometimes effective, is expensive and the improvement is temporary (generally lasting less than a month). However, in the case of a pre-splenectomy ITP patient with dangerously low platelet counts, and a poor response to other treatments, IVIgG treatment can increase platelet counts, making the splenectomy operation less dangerous. It is also commonly used as a long-term (though monthly) treatment. The administration of IV-IgG is safe for maternal and fetal platelet counts during pregnancy, delivery and in the neonatal period. IV-IgG is administered at 400-1000 mg/kg/day over 1 to 5 days and gives a better RR than prednisone. The duration of action is only 2 to 4 weeks. Its toxicities are nausea, headache, chills and occasional vascular events (eg MI, CVA) in older patients. The possible mechanmism of action is a transient impairment of the reticulendothelial clearance or macrophage blockade, inhibition of complement binding to platelets and interference of immune complexes binding to platelets. IV-IgG and WinRho essentially are the same type of treatment.

Splenic Radiation
Splenic radiation (RT) is usually given for steroid-resistant ITP. One to six weeks of 75-1370 cGy with or without concomittant post-RT steroids. Patients can respond for >1 year. It is a safe alternative for patients too old for splenectomy.

Platelet transfusion
Platelet transfusion is not normally recommended and is usually unsuccessful in raising a patient's platelet count. This is because the underlying autoimmune mechanism that destroyed the patient's platelets to begin with will also destroy donor platelets. An exception to this rule is when a patient is bleeding profusely, when transfusion of platelets can quickly form a platelet plug to stop bleeding, a life-threatening hemorrhage. Intravenous immunoglobulin administration, with the platelet transfusion, may improve their survival.

Experimental/novel agents

 * AMG 531 (Romiplostum; Nplate) is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody), a TPO peptide mimetic. Initial clinical trials show it to be effective in chronic ITP.

Toxicities. 1) Hepatotoxicity is manifest as an increase in the SGOT / SGPT to 3-4xnormal but no liver failure has been reported. Rarely does the bilirubin increase.  It is recommended to discontinue the medication just the same.  2) Promacta can cause the development and progression of reticulin fiber deposition in the bone marrow. Also excessive Promacta will cause thrombotic or thromboembolic problems. 3) Cataracts. 4) Approximately 5% of patients on Promacta will have a "rebound thrombocytopenia" on discontinuation of the medication. This thrombocytpenia is usually worse that that which was treated initially and it occurs very quickly. This can lead to bleeding especially if the patient is on anticoagulants or antiplatelet agents. Patients must be monitored with qwk CBC / platelet checks for at least 4 weeks after the discontinuation of Promacta. 5) Promacta may increase the risk of progression of underlying MDS or hematologic malignancies. There are thrombopoietin receptors on malignant cells of hematologic malignancies and they can POTENTIALLY be stimulated by Promacta.
 * The novel agent eltrombopag (AKA Promacta) has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. It is indicated for the treatment of thrombocytopenia in patients with chronic ITP refractory to steroids, immunoglobulins or splenectomy.  It is NOT indicated for the treatment of thrombocytopenia due to any cause other than ITP (eg NOT MDS). It is a thrombopoietin receptor agonist.  It is of note that UGT type enzymes (eg UGT1A1 / UDP-glucoronosyltransferase) are inhibited by Promacta.  UGT1A1 polymorphisms, under exposure from Promacta, have a decrease in glucoronidation which means to increased susceptibility to toxicity from some chemotherapy agents such as Irinotecan, for example.  Promacta has a rapid onset of action and neither the presence of a spleen nor coadministration of steroids affects its efficacy.  Greater than 70% of patients treated had an increase of the platelet count to greater than or equal to 50,000 after 6 weeks.  Promacta should ONLY be given to patients with decreased platelets that have an increased risk of bleeding.  It should NOT be given to simply normalize the counts.  The goal is to increase the platelet count to greater than 50,000.  The usual dose of Promacta is 50 mg; given 25 mg for asian patients or those with hepatic impairment.  It must be given on an empty stomach and not with multivitamins (containing cations).  Decrease the dose to 25 mg if the platelet count exceeds 200,000; increase the dose to 75 mg if the platelet count decreases to less than 50,000.  If the count exceeds 400,000 discontinue the medication; if the count then decreases to less than 150,000 restart the drug at 25 mg QD.  Monitor the CBC weekly and the liver function studies q2 weeks.


 * Dapsone (also called Diphenylsulfone, DDS, or Avlosulfon) is an anti-infective sulfone drug. In recent years Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts of around 40–50% of patients taking the drug.


 * TPO is normally produced at a steady rate in the liver. TPO improves the platelet production rate in the bone marrow.  Patients can form antibodies against recombinant TPO (rHuTPO) (ref Li et al Blood 2001;98:3241).  Pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) has activity but, like rHuTPO, antibody formation has prohibited its usefullness.

H. pylori eradication
Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between H. Pylori (Helicobacter Pylori) infection and ITP. Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.