Idiopathic thrombocytopenic purpura

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Idiopathic thrombocytopenic purpura
Classification and external resources
ICD-10 D69.3
ICD-9 287.31
OMIM 188030
DiseasesDB 6673
eMedicine emerg/282 
MeSH D016553

Idiopathic thrombocytopenic purpura (ITP) is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic).[1] As most causes appear to be related to antibodies against platelets, ITP is also known as immune thrombocytopenic purpura or immune-mediated thrombocytopenic purpura. Often ITP is asymptomatic, however a very low platelet count can lead to visible symptoms, such as purpura (bruises), or more seriously, bleeding diathesis.

Contents

[edit] Epidemiology

A normal platelet count is considered to be in the range of 150,000–400,000 per cubic millimeter (mm3) of blood for most healthy individuals.  Hence one may be considered thrombocytopenic below that range, although the threshold for a diagnosis of ITP is not tied to any specific number.

The incidence of ITP is estimated at 50–100 new cases per million per year, with children accounting for half of that amount.  At least 70 percent of childhood cases will end up in remission within six months, whether treated or not.[2][3][4]  Moreover, a third of the remaining chronic cases remitted during follow-up observation, and another third ended up with only mild thrombocytopenia (defined as a platelet count above 50,000).[2]

ITP is usually chronic in adults[5] and the probability of durable remission is 20–40 percent.[6]  The male to female ratio in the adult group varies from 1:1.2 to 1.7 in most age ranges (childhood cases are roughly equal for both genders) and the median age of adults at the diagnosis is 56–60.[7]  The ratio between male and female adult cases tends to widen with age.  In the USA, the adult chronic population is thought to be approximately 60,000—with women outnumbering men approximately 2 to 1, which has resulted in ITP being designated an orphan disease.[8]

[edit] Signs and symptoms

Symptoms of ITP include the development of bruises (purpura) and petechiae, especially on the extremities, bleeding from the nostrils and bleeding at the gums, any of which may occur if the platelet count is below 20,000 per mm3.[9]  A very low count (<10,000 per mm3) may result in the formation of hematomas in the mouth or on other mucous membranes.

Serious and possibly fatal complications due to an extremely low count (<5,000 per mm3) may include subarachnoid or intracerebral hemorrhage, lower gastrointestinal bleeding or other internal bleeding.  An ITP patient with an extremely low count is also vulnerable to major internal bleeding caused by abdominal trauma, as might be experienced in a motor vehicle crash.  Fortunately, these complications are not likely in a patient whose platelet count is above 20,000.

[edit] Pathogenesis

In many cases, ITP's cause is not idiopathic but autoimmune,[10] with antibodies against platelets being detected in approximately 60 percent 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.[11]

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 auto-antibody production in ITP is probably abnormal T cell activity.[12][13][14]  Preliminary findings suggest that these T cells can be influenced by drugs that target B cells, such as rituximab.[15]

[edit] Diagnosis

The diagnosis of ITP is a process of exclusion.  First, the clinician has to determine that there are no blood abnormalities other than low platelet count, and no physical signs except for signs of bleeding.  Then, the secondary causes (usually 5–10 percent 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.[7][9]  In approximately one percent of cases, autoimmune hemolytic anemia and immune thrombocytopenic purpura coexist, which is a condition called Evans syndrome.[7]

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.[16]  A normal bleeding time does not exclude a platelet disorder.[17]

A bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt.[7]  On examination of the bone marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP.  An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80 percent specificity of this test is sufficient.[7]

[edit] Treatment

A platelet count below 20,000 is generally an indication for treatment.  Patients with a count between 20,000 and 50,000 are usually evaluated on a case-by-case basis, and, with rare exceptions, there is usually no need to treat patients with a count above 50,000.[7]  Hospitalization may be recommended in cases of very low counts, and is highly advisable if the patient presents with significant internal or mucocutaneous bleeding.  A count below 10,000 is potentially a medical emergency, as the patient may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma.

[edit] Steroids/IVIG

Treatment usually is initiated with intravenous steroids (methylprednisolone or prednisone), intravenous immunoglobulin (IVIg) or a combination of these drugs.  A platelet infusion may be administered in an emergency bleeding situation in order to attempt to quickly raise the count.  After the platelet count has increased to a safe level, an orally administered steroid, such as prednisone (1–2 mg/kg per day), is usually prescribed.  Most cases respond during the first week of treatment.  After several weeks of oral steroid therapy, the dose is gradually reduced.  However, 60 to 90 percent of patients relapse after the dose is decreased below 0.25 mg/kg per day and subsequently stopped.[6][7]

[edit] Surgery

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, less so in older patients.[18]  The procedure is potentially risky in ITP cases due to the increased possibility of significant bleeding during surgery.

[edit] Anti-D

A relatively new strategy is treatment with anti-D, but the patient must be Rh-positive.  This treatment (with products such as WinRho, Rhophylac or RhoGAM) is normally administered to Rh-negative women during pregnancy and after the birth of an Rh-positive infant to prevent sensitization to the Rh factor, but has been demonstrated effective on some Rh-positive ITP patients.  Treatment with anti-D is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.[19]

[edit] Steroid-sparing agents

Immunosuppresants like mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness.  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 the count, making splenectomy less dangerous.  IVIg is also commonly used as a long-term (though monthly) treatment.

Extreme cases (very rare, especially in children) may require the infusion of vincristine, a chemotherapy agent, to stop the immune system from destroying platelets.  However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution.

[edit] Thrombopoietin Receptor Agonists

  • Romiplostim (trade name Nplate®) is a new treatment for stimulating platelet production.  Designated an orphan drug in 2003 under USA law, it is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injection.  Clinical trials showed it to be effective in treating chronic ITP, especially in post-splenectomy patients.[20]  Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.[21]
  • Eltrombopag (trade name Promacta®) is an orally-administered agent with an effect similar to that of romiplostim.  It has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.[22]  Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008. [23]

[edit] Experimental and novel agents

  • 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 in 40–50 percent of patients administered the drug.[24][25]
  • The off-label use of rituximab, a chimeric monoclonal antibody against the B cell surface antigen CD20, has been shown in preliminary studies to be an effective alternative to splenectomy in some patients.[15][26][27]  However, many patients experience significant side-effects, there is a small risk of fatality due to progressive multifocal leukoencephalopathy caused by a reactivated JC virus, and randomized controlled trials are lacking.[28]
  • Promising results have been reported in a small phase II study of the experimental kinase inhibitor tamatinib fosdium (R788).  In a population of 14 patients refractory to other treatments (ten of them having relapsed following splenectomy), nine responded to tamatinib and six achieved >100,000 platelets/uL counts.[29]

[edit] Platelet transfusion

Platelet transfusion alone is normally not recommended except in an emergency, and is usually unsuccessful in producing a long-term platelet count increase.  This is because the underlying autoimmune mechanism that is destroying the patient's platelets will also destroy donor platelets.

[edit] 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.[30]

[edit] Synonyms

ITP is known by a number of synonyms, but idiopathic or immune thrombocytopenic purpura are the most common names.  There is also an eponym, Werlhof's disease,[31] 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.

[edit] Notable individuals diagnosed with ITP

[edit] References

  1. ^ idiopathic thrombocytopenic purpura at Dorland's Medical Dictionary
  2. ^ a b Watts RG (2004). "Idiopathic thrombocytopenic purpura: a 10-year natural history study at the children's hospital of alabama". Clinical pediatrics 43 (8): 691–702. doi:10.1177/000992280404300802. PMID 15494875. 
  3. ^ Treutiger I, Rajantie J, Zeller B, Henter JI, Elinder G, Rosthøj S (2007). "Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity?". Arch. Dis. Child. 92 (8): 704–7. doi:10.1136/adc.2006.098442. PMID 17460024. 
  4. ^ Ou CY, Hsieh KS, Chiou YH, Chang YH, Ger LP (2006). "A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur". Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi 47 (5): 226–31. PMID 17352309. 
  5. ^ Cines DB, Blanchette VS (2002). "Immune thrombocytopenic purpura". N. Engl. J. Med. 346 (13): 995–1008. doi:10.1056/NEJMra010501. PMID 11919310. 
  6. ^ a b Stevens W, Koene H, Zwaginga JJ, Vreugdenhil G (2006). "Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights". The Netherlands journal of medicine 64 (10): 356–63. PMID 17122451. 
  7. ^ a b c d e f g Cines DB, Bussel JB (2005). "How I treat idiopathic thrombocytopenic purpura (ITP)". Blood 106 (7): 2244–51. doi:10.1182/blood-2004-12-4598. PMID 15941913. 
  8. ^ "Amgen to Discuss Romiplostim BLA". drugs.com. March 12, 2008. http://www.drugs.com/nda/romiplostim_080312.html. Retrieved on 2008-11-04. 
  9. ^ a b Cines DB, McMillan R (2005). "Management of adult idiopathic thrombocytopenic purpura". Annu. Rev. Med. 56: 425–42. doi:10.1146/annurev.med.56.082103.104644. PMID 15660520. 
  10. ^ Coopamah M, Garvey M, Freedman J, Semple J (2003). "Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update". Transfus Med Rev 17 (1): 69–80. doi:10.1053/tmrv.2003.50004. PMID 12522773. 
  11. ^ Schwartz RS (2007). "Immune thrombocytopenic purpura--from agony to agonist". N. Engl. J. Med. 357 (22): 2299–301. doi:10.1056/NEJMe0707126. PMID 18046034. 
  12. ^ Semple JW, Freedman J (1991). "Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia". Blood 78 (10): 2619–25. PMID 1840468. 
  13. ^ Stasi R, Cooper N, Del Poeta G, et al. (August 2008). "Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab". Blood 112 (4): 1147–50. doi:10.1182/blood-2007-12-129262. PMID 18375792. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18375792. 
  14. ^ Yu J, Heck S, Patel V, et al. (August 2008). "Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura". Blood 112 (4): 1325–8. doi:10.1182/blood-2008-01-135335. PMID 18420827. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18420827. 
  15. ^ a b Godeau B, Porcher R, Fain O, et al. (August 2008). "Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study". Blood 112 (4): 999–1004. doi:10.1182/blood-2008-01-131029. PMID 18463354. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18463354. 
  16. ^ "Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel". Ann. Intern. Med. 126 (4): 319–26. 1997. PMID 9036806. 
  17. ^ Liesner RJ, Machin SJ (1997). "ABC of clinical haematology. Platelet disorders". BMJ 314 (7083): 809–12. PMID 9081003. 
  18. ^ See http://www.itpsupport.org.uk/american/%205.%20Splenectomy%20in%20ITP.pdf, page 2.
  19. ^ See http://www.winrho.com/isi.html for efficacy and safety data on WinRho anti-D.
  20. ^ Bussel JB, Kuter DJ, George JN, et al. (2006). "AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP". N. Engl. J. Med. 355 (16): 1672–81. doi:10.1056/NEJMoa054626. PMID 17050891. 
  21. ^ http://www.amgen.com/media/pr.jsp?year=2008
  22. ^ Bussel JB, Cheng G, Saleh MN, et al. (2007). "Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura". N. Engl. J. Med. 357: 2237–2247. doi:10.1056/NEJMoa073275. PMID 18046028. 
  23. ^ GlaxoSmithKline (2008-11-20). FDA approves Promacta® (eltrombopag), the first oral medication to increase platelet production for people with serious blood disorder. Press release. http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10127.htm. Retrieved on 2008-11-25. 
  24. ^ Godeau B, Durand JM, Roudot-Thoraval F, et al. (1997). "Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases". Br. J. Haematol. 97 (2): 336–9. doi:10.1046/j.1365-2141.1997.412687.x. PMID 9163598. 
  25. ^ Dapsone
  26. ^ Braendstrup P, Bjerrum OW, Nielsen OJ, et al. (2005). "Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura". Am. J. Hematol. 78 (4): 275–80. doi:10.1002/ajh.20276. PMID 15795920. 
  27. ^ 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 2007:107PDF
  28. ^ Arnold DM, Dentali F, Crowther MA, et al. (January 2007). "Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura". Ann. Intern. Med. 146 (1): 25–33. PMID 17200219. 
  29. ^ "Rigel R788 Raises Platelet Counts in Immune Thrombocytopenic Purpura (ITP) Patients in Phase 2 Study" (htm). Rigel Pharmaceuticals: News Release. Rigel Pharmaceuticals. 11/09/2007. http://ir.rigel.com/phoenix.zhtml?c=120936&p=irol-newsArticle&ID=1075637&highlight=. Retrieved on 2008-02-11. 
  30. ^ Stasi R. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009 Feb 5;113(6):1231-40. Epub 2008 Oct 22.
  31. ^ synd/3349 at Who Named It?

[edit] External links

  • The ITP Foundation - A nonprofit organization dedicated to helping children with Immune Thrombocytopenic Purpura
  • 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
  • Platelet Disorder Support Association A non-profit corporation to provide information, support, and encourage research about ITP and other platelet disorders
  • ITP Support Association. A UK registered charity which aims to promote and improve the general welfare of patients, and the families of patients, with Idiopathic Thrombocytopenic Purpura.
v • d • e
Pathology: hematology · myeloid hematologic disease (primarily D50-D77 · 280-289)
Red
blood cells
↑
↓
Aplastic
(mostly Normo-)
Other
Coagulation/
coagulopathy/
bleeding
diathesis
↑
↓
Monocytes/
macrophages
↑
↓
Granulocytes
↑
↓
↑ means increased, ↓ means decreased
v • d • e
Immune disorders: hypersensitivity and autoimmune diseases
Type I/allergy/atopy
(IgE)
Foreign
Autoimmune
none
Type II/ADCC
(IgM, IgG)
Foreign
Autoimmune
Type III
(Immune complex)
Foreign
Autoimmune
Type IV/cell-mediated
(T-cells)
Foreign
Autoimmune
Unknown/
multiple
Foreign
Autoimmune
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