Idiopathic thrombocytopenic purpura

Infobox_Disease
Name = PAGENAME


Caption =
DiseasesDB = 6673
ICD10 = ICD10|D|69|3|d|65
ICD9 = ICD9|287.31
ICDO =
OMIM = 188030
MedlinePlus =
eMedicineSubj = emerg
eMedicineTopic = 282
MeshID = D016553

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-mediated thrombocytopenic purpura. Although most cases are asymptomatic, very low platelet counts can lead to a bleeding diathesis and purpura.

Epidemiology

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.cite journal |author=Watts RG |title=Idiopathic thrombocytopenic purpura: a 10-year natural history study at the children's hospital of alabama |journal=Clinical pediatrics |volume=43 |issue=8 |pages=691–702 |year=2004 |pmid=15494875|doi=10.1177/000992280404300802] cite journal |author=Treutiger I, Rajantie J, Zeller B, Henter JI, Elinder G, Rosthøj S |title=Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity? |journal=Arch. Dis. Child. |volume=92 |issue=8 |pages=704–7 |year=2007 |pmid=17460024 |doi=10.1136/adc.2006.098442] cite journal |author=Ou CY, Hsieh KS, Chiou YH, Chang YH, Ger LP |title=A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur |journal=Acta paediatrica Taiwanica Taiwan er ke yi xue hui za zhi |volume=47 |issue=5 |pages=226–31 |year=2006 |pmid=17352309 |doi=] 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 adultscite journal |author=Cines DB, Blanchette VS |title=Immune thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=346 |issue=13 |pages=995–1008 |year=2002 |pmid=11919310 |doi=10.1056/NEJMra010501] and the probability of durable remission is 20–40%.cite journal |author=Stevens W, Koene H, Zwaginga JJ, Vreugdenhil G |title=Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights |journal=The Netherlands journal of medicine |volume=64 |issue=10 |pages=356–63 |year=2006 |pmid=17122451 |doi=] 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.cite journal |author=Cines DB, Bussel JB |title=How I treat idiopathic thrombocytopenic purpura (ITP) |journal=Blood |volume=106 |issue=7 |pages=2244–51 |year=2005 |pmid=15941913 |doi=10.1182/blood-2004-12-4598]

igns and symptoms

Usually, ITP patients suffer from bruising; petechiae, nosebleeds and bleeding gums may occur if the platelet count is below 20,000,cite journal |author=Cines DB, McMillan R |title=Management of adult idiopathic thrombocytopenic purpura |journal=Annu. Rev. Med. |volume=56 |issue= |pages=425–42 |year=2005 |pmid=15660520 |doi=10.1146/annurev.med.56.082103.104644] 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.

Pathogenesis

In many cases, the cause is not actually idiopathic but autoimmune, [cite journal |author=Coopamah M, Garvey M, Freedman J, Semple J |title=Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update |journal=Transfus Med Rev |volume=17 |issue=1 |pages=69–80 |year=2003 |pmid=12522773 |doi=10.1053/tmrv.2003.50004] 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.cite journal |author=Schwartz RS |title=Immune thrombocytopenic purpura--from agony to agonist |journal=N. Engl. J. Med. |volume=357 |issue=22 |pages=2299–301 |year=2007 |pmid=18046034 |doi=10.1056/NEJMe0707126]

The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic macrophages.

The IgG autoantibodies are also thought to damage megakaryocytes, the precursor cells to platelets, but this is thought to contribute only slightly to the decrease in platelet numbers.

The stimulus for autoantibody production in ITP is probably abnormal T cell activity. [cite journal |author=Semple JW, Freedman J |title=Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia |journal=Blood |volume=78 |issue=10 |pages=2619–25 |year=1991 |pmid=1840468 |doi=] cite journal |author=Stasi R, Cooper N, Del Poeta G, "et al" |title=Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab |journal=Blood |volume=112 |issue=4 |pages=1147–50 |year=2008 |month=August |pmid=18375792 |doi=10.1182/blood-2007-12-129262 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18375792] cite journal |author=Yu J, Heck S, Patel V, "et al" |title=Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura |journal=Blood |volume=112 |issue=4 |pages=1325–8 |year=2008 |month=August |pmid=18420827 |doi=10.1182/blood-2008-01-135335 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18420827] Preliminary findings suggest that these T cells can be influenced by drugs targetting B cells such as rituximab.cite journal |author=Godeau B, Porcher R, Fain O, "et al" |title=Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study |journal=Blood |volume=112 |issue=4 |pages=999–1004 |year=2008 |month=August |pmid=18463354 |doi=10.1182/blood-2008-01-131029 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18463354]

Diagnosis

The diagnosis of ITP is one 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. In approximately 1% of cases autoimmune hemolytic anemia and immune thrombocytic purpura coexist, which is a condition called Evans syndrome.

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.cite journal |title=Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel |journal=Ann. Intern. Med. |volume=126 |issue=4 |pages=319–26 |year=1997 |pmid=9036806 |doi=] A normal bleeding time does not exclude a platelet disorder.cite journal |author=Liesner RJ, Machin SJ |title=ABC of clinical haematology. Platelet disorders |journal=BMJ |volume=314 |issue=7083 |pages=809–12 |year=1997 |pmid=9081003 |doi=]

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. On examination of the bone marrow, an increase in the production of megakaryotes is seen and can help in determining if it's ITP. 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.

Treatment

teroids/IVIG

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. 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.

plenectomy

Splenectomy (removal of the spleen) is sometimes undertaken, as platelets targeted for destruction will often meet their fate in the spleen. Splenectomy is said to be successful in 60 to 65 percent of cases, although it is less successful in older people. [See http://www.itpsupport.org.uk/american/%205.%20Splenectomy%20in%20ITP.pdf, page 2.]

Anti-D

A relatively new strategy is treatment with anti-D, but the patient must be Rh+. This treatment (with products such as Rhophylac and RhoGAM) is normally administered to Rh- women during pregnancy and after the birth of an Rh+ baby to prevent sensitization to the Rh factor. Anti-D is not recommended for post-splenectomy patients. [See http://www.winrho.com/isi.html for efficacy and safety data on WinRho anti-D.]

teroid-sparing agents

Immunosuppresants like mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness. Rituximab has also been used successfully for some patients. [cite journal |author=Braendstrup P, Bjerrum OW, Nielsen OJ, "et al" |title=Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura |journal=Am. J. Hematol. |volume=78 |issue=4 |pages=275–80 |year=2005 |pmid=15795920 |doi=10.1002/ajh.20276 |url=] [Patel V, Mihatov N, Cooper N, Stasi R, Cunningham-Rundles S, Bussel JB,"Long-term responses seen with rituximab in patients with ITP", Community Oncology Vol. 4 No. 2, February 2007:107 [http://www.communityoncology.net/journal/articles/0402107.pdf PDF] ]

Extreme cases (very rare, especially rare in children) may require vincristine, a chemotherapy agent, to stop the immune system from destroying platelets.

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, IVIg treatment can increase platelet counts, making the splenectomy operation less dangerous. It is also commonly used as a long-term (though monthly) treatment.

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. Fact|date=July 2008

Experimental/novel agents

*Rituximab, a monoclonal antibody against the B cell surface antigen CD20, has been shown in preliminary studies to be a safe and effective alternative to splenectomy in some patients.cite journal |author=Godeau B, Porcher R, Fain O, "et al" |title=Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study |journal=Blood |volume=112 |issue=4 |pages=999–1004 |year=2008 |month=August |pmid=18463354 |doi=10.1182/blood-2008-01-131029 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18463354] However, many patients experience side effects, there is a small risk of death, and randomized controlled trials are lacking.cite journal |author=Arnold DM, Dentali F, Crowther MA, "et al" |title=Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura |journal=Ann. Intern. Med. |volume=146 |issue=1 |pages=25–33 |year=2007 |month=January |pmid=17200219 |doi= |url=]

*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. cite journal |author=Godeau B, Durand JM, Roudot-Thoraval F, "et al" |title=Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases |journal=Br. J. Haematol. |volume=97 |issue=2 |pages=336–9 |year=1997 |pmid=9163598|doi=10.1046/j.1365-2141.1997.412687.x] [ [http://www.itppeople.com/dapsone.htm Dapsone ] ]

*Romiplostim (also known as AMG531, trade name Nplate) is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody). Initial clinical trials show it to be effective in chronic ITP. [cite journal |author=Bussel JB, Kuter DJ, George JN, "et al" |title=AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP |journal=N. Engl. J. Med. |volume=355 |issue=16 |pages=1672–81 |year=2006 |pmid=17050891 |doi=10.1056/NEJMoa054626] . It was approved by the FDA for long-term treatment of adult chronic ITP on August 22, 2008. [http://www.amgen.com/media/pr.jsp?year=2008]

*The novel agent eltrombopag has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. [cite journal|author=Bussel JB, Cheng G, Saleh MN, "et al" |year=2007|title=Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura|journal=N. Engl. J. Med. |volume=357|pages=2237–2247|pmid=18046028|doi=10.1056/NEJMoa073275]

* Promising results have been reported in a small phase II study of an experimental kinase inhibitor tamatinib fosdium (R788). 9 out of 14 patients refractory to other treatments (10 of them failed splenectomy) responded to tamatinib. 6 patients achieved >100,000 platelets/uL count. [cite web |url=http://ir.rigel.com/phoenix.zhtml?c=120936&p=irol-newsArticle&ID=1075637&highlight= |title=Rigel R788 Raises Platelet Counts in Immune Thrombocytopenic Purpura (ITP) Patients in Phase 2 Study |accessdate=2008-02-11 |author=|authorlink= |coauthors= |date=11/09/2007 |format=htm |work=Rigel Pharmaceuticals: News Release |publisher=Rigel Pharmaceuticals |pages= |language= |archiveurl= |archivedate= |quote=]

"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.Fact|date=December 2007

ynonyms

ITP knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an eponym, Werlhof's disease, [WhoNamedIt|synd|3349] 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.

References

External links

* [http://www.itpfoundation.org The ITP Foundation] - A nonprofit organization dedicated to helping children with Immune Thrombocytopenic Purpura
* [http://www.itpeducation.com ITPeducation.com] This educational curriculum is designed to provide evidence-based clinical information on the diagnosis and management of patients with ITP to hematologists, oncologists, and other health care professionals
* [http://www.pdsa.org Platelet Disorder Support Association] A non-profit corporation to provide information, support, and encourage research about ITP and other platelet disorders