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Immune thrombocytopenic purpura

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Immune thrombocytopenic purpura
SpecialtyHematology Edit this on Wikidata

Idiopathic thrombocytopenic purpura (ITP) is the condition of having an abnormally low platelet count (thrombocytopenia) of unknown cause (idiopathic).[1] As most incidents of ITP appear to be related to the production of antibodies against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to describe this condition. Often ITP is asymptomatic (devoid of obvious symptoms) and can be discovered incidentally, but a very low platelet count can lead to an increased risk of bleeding and purpura.

ITP is diagnosed with a complete blood count (a common blood test). In some situations, additional investigations (such as a bone marrow biopsy) may be necessary to ensure that the platelet count is not decreased due to other reasons. Treatment may not be necessary in mild cases, but very low counts or significant bleeding might prompt treatment with steroids, intravenous immunoglobulin, anti-D immunoglobulin, or stronger immunosuppresive drugs. Refractory ITP (ITP not responsive to conventional treatment) may require splenectomy, the surgical removal of the spleen. Platelet transfusions may be used in severe bleeding together with a very low count. Sometimes the body may compensate by making abnormally large platelets.

Signs and symptoms

Petechiae on the lower extremities.

Visible symptoms of ITP include the spontaneous formation of bruises (purpura) and petechiae (tiny bruises), especially on the extremities, bleeding from the nostrils, bleeding at the gums, and menorrhagia (excessive menstrual bleeding), any of which may occur if the platelet count is below 20,000 per μl.[2] A very low count (<10,000 per μl) may result in the spontaneous formation of hematomas (blood masses) in the mouth or on other mucous membranes. Bleeding time from minor lacerations or abrasions is usually prolonged.

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

Pathogenesis

In many cases, ITP's cause is not idiopathic but autoimmune,[3] 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 immunoglobulin G (IgG) type.  The famous Harrington–Hollingsworth experiment established the immune pathogenesis of ITP.[4]

The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic macrophages, as well by Kupffer cells in the liver.  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.  Recent research now indicates that impaired production of the glycoprotein hormone thrombopoietin, which is the stimulant for platelet production, may be a contributing factor to the reduction in circulating platelets.  This observation has led to the development of a class of ITP-targeted drugs referred to as thrombopoietin receptor agonists.

The stimulus for auto-antibody production in ITP is probably abnormal T cell activity.[5][6][7]  Preliminary findings suggest that these T cells can be influenced by drugs that target B cells, such as rituximab.[8]

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, onyalai and others.[9][2]  In approximately one percent of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome.[9]

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 usually prolonged in ITP patients.  However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines.[10]  A normal bleeding time does not exclude a platelet disorder.[11]

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.[9]  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.[9]

Treatment

A platelet count below 20,000 per μl is generally an indication for treatment.  Patients with a count between 20,000 and 50,000 per μl 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 per μl.[9] Hospitalization may be recommended in cases of very low counts, and is highly advisable if significant internal or mucocutaneous bleeding has developed. A count below 10,000 per μl is potentially a medical emergency, as the individual may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma.[citation needed] Treatment is typically administered under the direction of a hematologist and treatment recommendations sometimes differ for adult and pediatric ITP.[12]

Steroids

The first line of treatment usually consists of steroids, a group of medications that suppresses the immune system. The dose and mode of administration is determined by the platelet count and whether there is active bleeding: in emergencies, infusions of dexamethasone or methylprednisolone may be used, while in milder forms the treatment may consist of oral prednisone or prednisolone. Once the platelet count has improved, the dose of steroid is gradually reduced while monitoring for relapses. 60–90% percent of people will experience a relapse during dose reduction or cessation.[13][9] Long-term steroids are usually avoided, as they can cause numerous side-effects such as osteoporosis, diabetes and cataracts.[citation needed]

Anti-D

Another strategy that is suitable for Rh-positive patients is treatment with Rho(D) immune globulin (Anti-D), which is intravenously administered.  Anti-D 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 in the newborn.  Anti-D has been demonstrated effective on some ITP patients, but is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.[14]

Steroid-sparing agents

Immunosuppresants such as mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness.  In chronic refractory cases where the immune pathogenesis has been confirmed, the off-label use of vincristine, a chemotherapy agent, may be attempted.  However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution, especially in children.

Intravenous immunoglobulin (IVIg) may be infused in some cases.  IVIg, while sometimes effective, is costly and produces a short-term improvement that generally lasts less than a month.  However, in the case of an ITP patient scheduled for surgery who has a dangerously low platelet count and has experienced a poor response to other treatments, IVIg can increase the count and reduce bleeding risk.

Thrombopoietin receptor agonists

Thrombopoietin receptor agonists are pharmaceutical agents that treat ITP by stimulating platelet production instead of attempting to curtail platelet destruction.  As of 2011, two such products are available:

  • Eltrombopag (trade name Promacta) is an orally-administered agent with an effect similar to that of romiplostim.  It too has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.[18]  Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.[19]

Medicare in the USA will cover most of the cost of romiplostim or eltrombopag treatment under Part-A.

Surgery

Splenectomy (removal of the spleen) may be considered, as platelets targeted for destruction will usually meet their fate in the spleen.  The procedure is potentially risky in ITP cases due to the increased possibility of significant bleeding during surgery.  Durable remission following splenectomy is achieved in 60 to 65 percent of ITP cases, less so in older subjects.[20]  As noted in the introduction, the use of splenectomy to treat ITP has diminished since the development of steroid therapy and other pharmaceutical remedies.

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.

H. pylori eradication

In adults, particularly those living in areas with a high prevalence of Helicobacter pylori (which normally inhabits the stomach wall and has been associated with peptic ulcers), identification and treatment of this infection has been shown to improve platelet counts in a third of patients. In a fifth, the platelet count normalized completely; this response rate is similar to that found in treatment with rituximab, which is more expensive and less safe.[21] In children, this approach is not supported by evidence, except in high prevalence areas. Urea breath testing and stool antigen testing perform better than serology-based tests; moreover, serology may be false-positive after treatment with IVIG.[22]

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 has had some application 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.[23][24]
  • 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.[8][25][26]  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 have yet to be conducted.[27]
  • 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 platelet counts greater than 100,000.[28]

Epidemiology

A normal platelet count is considered to be in the range of 150,000–450,000 per microlitre (μl) 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, even without treatment.[29][30][31]  Moreover, a third of the remaining chronic cases will usually remit during follow-up observation, and another third will end up with only mild thrombocytopenia (defined as a platelet count above 50,000).[29]

ITP is usually chronic in adults[32] and the probability of durable remission is 20–40 percent.[13]  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.[9]  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.[33]

The mortality rate due to chronic ITP varies but tends to be higher relative to the general population for any age range.  In a study conducted in Great Britain, it was noted that ITP causes an approximately 60 percent higher rate of mortality compared to gender- and age-matched subjects without ITP.  This increased risk of death with ITP is largely concentrated in the middle-aged and elderly.  Ninety-six percent of reported ITP-related deaths were individuals 45 years or older.  No significant difference was noted in the rate of survival between males and females.[34]

History

After initial reports by the Portugese physician Amato Lusitano in 1556 and Lazarus de la Rivière (physician to the King of France) in 1658, it was the German physician and poet Paul Gottlieb Werlhof who in 1735 wrote the most complete initial report of the purpura of ITP. Platelets were unknown at the time.[35] The name "Werlhof's disease" was used more widely before the current descriptive name became more popular.[35][36] Platelets were described in the early 19th century, and in the 1880s several investigators linked the purpura with abnormalities in the platelet count.[35][37] The first report of a successful therapy for ITP was in 1916, when a young Polish medical student, Paul Kaznelson, described a female patient's response to a splenectomy.[35] Splenectomy remained a first-line remedy until the introduction of steroid therapy in the 1950s.[35]

Synonyms

ITP is known by a number of synonyms, but idiopathic or immune thrombocytopenic purpura are the most common names.  Others 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 and thrombocytolytic purpura.

References

  1. ^ "idiopathic thrombocytopenic purpura" at Dorland's Medical Dictionary
  2. ^ 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.
  3. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Schwartz RS (2007). "Immune thrombocytopenic purpura--from agony to agonist". N. Engl. J. Med. 357 (22): 2299–301. doi:10.1056/NEJMe0707126. PMID 18046034.
  5. ^ Semple JW, Freedman J (1991). "Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia". Blood. 78 (10): 2619–25. PMID 1840468.
  6. ^ Stasi R, Cooper N, Del Poeta G; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Yu J, Heck S, Patel V; et al. (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. PMC 2515134. PMID 18420827. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ a b Godeau B, Porcher R, Fain O; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ 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.
  10. ^ "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.
  11. ^ Liesner RJ, Machin SJ (1997). "ABC of clinical haematology. Platelet disorders". BMJ. 314 (7083): 809–12. PMC 2126215. PMID 9081003.
  12. ^ Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA (2011). "The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia". Blood. 117 (16): 4190–207. doi:10.1182/blood-2010-08-302984. PMID 21325604. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ See http://www.winrho.com/isi.html for efficacy and safety data on WinRho anti-D.
  15. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  16. ^ Kuter, DJ (2010 Nov 11). "Romiplostim or standard of care in patients with immune thrombocytopenia". The New England journal of medicine. 363 (20): 1889–99. doi:10.1056/NEJMoa1002625. PMID 21067381. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ http://www.amgen.com/media/pr.jsp?year=2008
  18. ^ Bussel JB, Cheng G, Saleh MN; et al. (2007). "Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura". N. Engl. J. Med. 357 (22): 2237–2247. doi:10.1056/NEJMoa073275. PMID 18046028. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ "FDA approves Promacta (eltrombopag), the first oral medication to increase platelet production for people with serious blood disorder" (Press release). GlaxoSmithKline. 2008-11-20. Retrieved 2008-11-25.
  20. ^ See http://www.itpsupport.org.uk/american/%205.%20Splenectomy%20in%20ITP.pdf, page 2.
  21. ^ Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, Provan D, Newland A, Amadori S, Bussel JB (2009). "Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review". Blood. 113 (6): 1231–40. doi:10.1182/blood-2008-07-167155. PMID 18945961.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Provan D, Stasi R, Newland AC; et al. (2010). "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood. 115 (2): 168–86. doi:10.1182/blood-2009-06-225565. PMID 19846889. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  23. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ Dapsone
  25. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ 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 PDF
  27. ^ Arnold DM, Dentali F, Crowther MA; et al. (2007). "Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura". Ann. Intern. Med. 146 (1): 25–33. PMID 17200219. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ "Rigel R788 Raises Platelet Counts in Immune Thrombocytopenic Purpura (ITP) Patients in Phase 2 Study". Rigel Pharmaceuticals: News Release. Rigel Pharmaceuticals. 11/09/2007. Retrieved 2008-02-11. {{cite web}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  29. ^ 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.
  30. ^ 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. PMC 2083887. PMID 17460024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ^ Cines DB, Blanchette VS (2002). "Immune thrombocytopenic purpura". N. Engl. J. Med. 346 (13): 995–1008. doi:10.1056/NEJMra010501. PMID 11919310.
  33. ^ "Amgen to Discuss Romiplostim BLA". drugs.com. March 12, 2008. Retrieved 2008-11-04.
  34. ^ Schoonen WM, Kucera G, Coalson J; et al. (2009). "Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database". Br. J. Haematol. 145 (2): 235–44. doi:10.1111/j.1365-2141.2009.07615.x. PMID 19245432. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  35. ^ a b c d e Stasi R, Newland AC (2011). "ITP: a historical perspective". Br. J. Haematol. 153 (4): 437–50. doi:10.1111/j.1365-2141.2010.08562.x. PMID 21466538. {{cite journal}}: Unknown parameter |month= ignored (help)
  36. ^ synd/3349 at Who Named It?
  37. ^ Liebman HA (2008). "Immune thrombocytopenia (ITP): an historical perspective". Hematology Am Soc Hematol Educ Program. 2008 (1): 205. doi:10.1182/asheducation-2008.1.205. PMID 19074083.
  • 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.

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