Idiopathic thrombocytopenic purpura overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Immune thrombocytopenia(ITP) is autoimmune condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic)[1]. The major of cases appear to be related to antibodies against platelets. Historically, it is has also been known as immune thrombocytopenic purpura or idiopathic thrombocytopenia purpura[2] Although most cases are asymptomatic, very low platelet counts can lead to a bleeding diathesis and purpura.
Historical Perspective
Classification
- Primary ITP - immune thrombocytopenia as a result for autoimmune antibodies and not related to another identifiable cause/condition of thrombocytopenia[3]. Based on international consensus, it is preferred to avoid the term "idiopathic" and use the term immune to denote this is an antibody-mediated cause[1]. It is also preferred to avoid the use of purpura as the vast majority of cases occur without bleeding/bruising symptoms[1].
- Secondary ITP - immune thrombocytopenia contributed or induced by an associated conditions, such as systemic lupus erythematosus (SLE), autoimmune thrombocytopenia (Evans syndrome), Human Immunodeficiency Virus (HIV), or drug/treatment[3].
| Conditions that cause secondary ITP[3] |
| Systemic lupus erythematosus (SLE), |
| autoimmune thrombocytopenia (Evans syndrome) |
| Human immunodeficiency virus (HIV) |
| Hepatitis C virus (HCV) |
| Helicobacter Pylori |
| Varicella Zoster |
| Antiphospholipid Syndrome |
| Drug-induced immune thrombocytopenia |
In addition to the above classification, ITP can be further characterized by the both the timing of diagnosis and degree of severity[1]:
- Timing criteria:
- Newly diagnosed - Applies to cases within 3 months since diagnosis.
- Persistent - Applies to cases three to 12 months since diagnosis.
- Chronic - Applies to cases more than 12 months since diagnosis.
- Severity:
- Severe ITP - Denotes the presence of any bleeding symptoms which mandate treatment or bleeding which requires additional treatment or change in current treatment (e.g. change in dose) in patient who has previously been stabilized.
Pathophysiology
The exact mechanism of ITP is still not completely understood. However, platelet destruction by antibodies and T-cells as well as impaired megakaryocyte (MK) function seem to play an important role [4].
The antibody mediated destruction of platelets is through the loss of immunological tolerance to the cell surface receptors on platelets. The production of autoantibodies, mainly IgG, target cell surface receptors, mainly GPIIbIIIa and GP Ib/IX, on platelets. These cell surface receptors are also expressed by megakaryocytes which are also impaired in patients with ITP. Targeting by autoantibodies leads to increased phagocytosis of platelets by macrophages in the spleen. The phagocytosis and destruction of platelets leads to a potential increase in cell surface targets by the immune system [5] [6]. This leads to an impairment in thrombopoiesis and a decrease in thrombocyte production. The role of autoantibody production explains the potential benefit of using rituximab, a monoclonal antibody against CD20 antigen on B-cells, in patients who do not respond to initial therapy. However, only 60% of patients with ITP have detectable levels of autoantibodies, suggesting other pathways play an important role in presentation of patients [5] [7] .
Patients with primary ITP tend to have increased levels of IFN-γ and IL-2 with decreased numbers of peripheral Th2+ and Tregs (T-regulatory cells)[5] [8]. The specific T-regulatory cells decreased in ITP include [CD8+ Tregs; CD4+ Tregs; CD4+CD25+FoxP3[9]. In addition to T-regulatory cells, B-regulatory cells (Bregs) are also shown to be decreased in number and function particularly in refractory ITP patients[9] [10].
Increases in Th17 and Th22, which contribute to proinflammatory responses, have been also been identified in patients with ITP. (30015642, 25621490, 19734430) The effect that ITP has on cytokines and T cells may lead to further increases in B cell activation[4] [11]. Additional toxicity toward megakaryocytes may involve cytotoxic T cells in a study showing an increased number of Tcell expressed in the bone marrow of patients with ITP [5] [12].
Causes
The underlying pathophysiology of ITP involves both
(1) Decreased production of platelets.
(2) Increased destruction of platelets.
Regarding the latter mechanism, this is thought to be due to B cells producing IgG, which binds to GPIIb/IIIa (fibrinogen receptor) on the platelet surface. The reason for the development of anti-GPIIb/IIIa antibodies is not very clear but is thought to related to immune or infectious phenomena. Immune etiologies involves loss of self-tolerance, whereby the body produces antibodies against its own cells. Immunosuppressive hematological conditions can precipitate this. These include CLL, APLS, SLE, and Evan's syndrome. Infectious agents that can lead to development of anti-platelet antibodies include HIV, hepatitis C and H. pylori. Molecular mimicry between infectious agents and platelets leads to the development of the antibodies. It is important to evaluate for these etiologies in patients with suspected ITP.
Differentiating Idiopathic thrombocytopenic purpura from Other Diseases
Epidemiology and Demographics
Lack of data collection outside of Europe prevents accurate estimates of incidence worldwide. Over 80% of adult ITP have primary ITP while the other 20% have secondary ITP [4]. The age-adjusted estimated prevalence of ITP in the United States is around 9.5/100,000 persons [13]. Adult incidence in ITP is 3.3/100,000-person years and in children incidence estimates vary from 2.4-5.3/100,000-person years [14]. A nationwide study in Korea involving 10,814 patients showed an incidence in female children under 15 to be 3.8 per 100,000-person years and 1.3 per 100,000-person years in males [15].
Risk Factors
- Gender – Studies have shown that adult women have a higher risk than adult men aged 30-60. [16] [17]
- Infection - Recent specific viral or bacterial infections may increase risk in pediatric patients. [18] [19] [20]
- Genetics – Some research has shown a link between genetic polymorphisms in cytokines and chemokines in the development of ITP. [3] [21] [22] [23]
Screening
Essential components to diagnosis of ITP[24]:
- Physician examination
- Evidence of thrombocytopenia (i.e. Signs of bleeding, petechiae, bruising)
- Complete Blood Count (CBC)
- Results for this test should be normal and used to rule out other etiologies of thrombocytopenia
- Peripheral blood smear
- Allows for the evaluation of platelet size and shape (morphology) which is important to rule out other etiologies of thrombocytopenia.
To rule out the causes of thrombocytopenia the following tests may be beneficial for specific patients:
- Bone morrow examination
- Recommended for patients who have failed first-line therapies or present with systemic symptoms, in children with newly diagnosed ITP with additional abnormalities from blood work, patients >60 years of age, and in a cases who are candidates for splenectomy.
- Helicobacter Pylori testing
- Hepatitis C Virus and Human Immunodeficiency Virus testing
- Baseline immunoglobulin testing
- Direct antiglobulin testing (DAT)
- Blood group testing Rh(D)
Natural History, Complications, and Prognosis
Natural History
Complications
Prognosis
Remission occurs spontaneously in up to 10% of adults with ITP in the first 6 months with increasing platelet counts documented over years [25] [26] [16]. The rate of successful first-line remission varies but may be as high as 60% [16]. Over 12% of adult patients may require a splenectomy as a treatment option due to failing first line therapy. [16].
A retrospective cohort in the US from 2008-2012 showed 57% of adults with ITP experienced >1 bleeding event with intracranial hemorrhage making up less than 1% of events. The most common bleeding that occurred during these events were gastrointestinal hemorrhage, hematuria, ecchymosis, and epistaxis
Acute ITP resolves in over 80% of children regardless of treatment approach. Eight of ten of the remaining children who have chronic ITP and undergo a splenectomy will be in remission with few having a relapse[27]. However, one study in hospitalized pediatric patients in the United States showed that in 2009 there were 4499 ITP patients discharged from hospitalization. These pediatric patients ranged from 6 months to 17 years of age, with 686 having bleeding events. The mortality rate of patients with any bleeding was 1.5%. Pediatric patients with ICH (Intercranial Hemorrhage) had a mortality rate of 20.8%. However, of the 686/4499 pediatric patients with bleeding the incidence of two events were 15.2% and 3.9%, respectively[28].
Though patients are at increased risk of bleeding, many other studies have shown either no increase in mortality or only slightly higher than the population average [16] [29] [25][30][26]. Based on the rates of remission for adults and children, and proper treatment options, most patients should live a normal lifespan.
Diagnosis
Diagnostic Criteria
History and Symptoms
Many patients with ITP may be asymptomatic.
If a patient presents with symptoms, they may experience the following[31]:
- Bleeding (e.g. gastrointestinal hemorrhage, hematuria, ecchymosis, blood in the stool, blood in urine, increased bleeding during menarche)
- Bruising
- Purpura
- Petechiae
- Epistaxis
- Severe intracranial hemorrhage
Risk of bleeding in adults based on a retrospective cohort including 6651 patients with primary ITP in the US from (2008-2012)
| Bleeding Event | Percent of patients with event |
| Hemorrhage of GI tract, unspecified | 6% |
| Hemorrhage of rectum and anus | 5% |
| Blood in stool | 4% |
| Hematuria, unspecified | 6% |
| Hematuria | 1% |
| Spontaneous ecchymosis | 6% |
| Epistaxis | 5% |
Bleeding estimates in 4499 hospitalized pediatric patients (aged 6 months – 17 years) in the US in 2009 [28]:
| Bleeding Event | Percent of Patients with Event | Mortality of Patients with Event |
| Nonbleeding | 85% | 0.07% |
| All Bleeding | 15.2% | 1.5% |
| ICH | 0.6% | 20.8% |
| Upper or lower GI bleeding | 0.4% | 0.0% |
| Other GI bleeding | 1.6% | 1.95% |
| Hematuria | 1.3% | 2.65% |
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
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 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.
Treatment
Medical Therapy
Recommended first line treatment in adults[24][32] :
| Medication | Time to Response | Complications |
| Corticosteroids | ||
| Prednisolone
0.5 – 2 mg/kg/d for 2-4 weeks |
Up to several weeks |
Vary based on dose and length of treatment: weight gain, fluid retention, hypertension, iatrogenic Cushing syndrome, hyperglycemia, immunosuppression, cataracts, GI distress, ulcers, mood swings |
| Methylprednisolone
30mg/kg/d for 7 days |
Up to several weeks | |
| Dexamethasone
40mg daily for 4 days every 2-4 wk for 1-4 cycles |
Typically, within one week | |
| IV anti-D* | ||
| IV anti-D
50-75 μg/kg for one dose |
4-5 days | Hemolytic anemia, fever/chills**
Rare but serious complications: renal failure, intravascular hemolysis, intravascular coagulation, death |
| Immunoglobulin | ||
| IVIG
0.4g/kg/d for 5 d or Infusion of 1g/kg/d for 1-2 d |
Typically, within 5 days, may see a response within 24hrs | Headache, flushing, fever, chills, fatigue, tachycardia, thrombosis, renal insufficiency, nausea |
*Required testing of blood group with a positive Rhesus Antigen (RH+), direct antiglobulin test (DAT), and a reticulocyte count before administration. [24][33]
**Premedication with APAP or corticosteroids are recommended to reduce the risk of chills and fever with the 75 μg/kg dose. [24]
Surgery
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.
Primary Prevention
The causes and risk factors are unknown, except in children when it may be related to a viral infection. Prevention methods are unknown.
Secondary Prevention
References
- ↑ 1.0 1.1 1.2 1.3 Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM; et al. (2009). "Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group". Blood. 113 (11): 2386–93. doi:10.1182/blood-2008-07-162503. PMID 19005182.
- ↑ Bromberg ME (2006). "Immune thrombocytopenic purpura--the changing therapeutic landscape". N Engl J Med. 355 (16): 1643–5. doi:10.1056/NEJMp068169. PMID 17050888.
- ↑ 3.0 3.1 3.2 3.3 Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG (2018). "Emerging Concepts in Immune Thrombocytopenia". Front Immunol. 9: 880. doi:10.3389/fimmu.2018.00880. PMC 5937051. PMID 29760702.
- ↑ 4.0 4.1 4.2 Zufferey A, Kapur R, Semple JW (2017). "Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)". J Clin Med. 6 (2). doi:10.3390/jcm6020016. PMC 5332920. PMID 28208757.
- ↑ 5.0 5.1 5.2 5.3 Kistangari G, McCrae KR (2013). "Immune thrombocytopenia". Hematol Oncol Clin North Am. 27 (3): 495–520. doi:10.1016/j.hoc.2013.03.001. PMC 3672858. PMID 23714309.
- ↑ Cines DB, Blanchette VS (2002). "Immune thrombocytopenic purpura". N Engl J Med. 346 (13): 995–1008. doi:10.1056/NEJMra010501. PMID 11919310.
- ↑ McMillan R (2003). "Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes". J Pediatr Hematol Oncol. 25 Suppl 1: S57–61. PMID 14668642.
- ↑ Sakakura M, Wada H, Tawara I, Nobori T, Sugiyama T, Sagawa N; et al. (2007). "Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura". Thromb Res. 120 (2): 187–93. doi:10.1016/j.thromres.2006.09.008. PMID 17067661.
- ↑ 9.0 9.1 Li J, Sullivan JA, Ni H (2018). "Pathophysiology of immune thrombocytopenia". Curr Opin Hematol. 25 (5): 373–381. doi:10.1097/MOH.0000000000000447. PMID 30015642.
- ↑ HARRINGTON WJ, MINNICH V, HOLLINGSWORTH JW, MOORE CV (1951). "Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura". J Lab Clin Med. 38 (1): 1–10. PMID 14850832.
- ↑ Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V; et al. (1996). "Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity". Blood. 87 (10): 4245–54. PMID 8639783.
- ↑ Olsson B, Ridell B, Carlsson L, Jacobsson S, Wadenvik H (2008). "Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1". Blood. 112 (4): 1078–84. doi:10.1182/blood-2008-02-139402. PMID 18519809.
- ↑ Michel M (2009). "Immune thrombocytopenic purpura: epidemiology and implications for patients". Eur J Haematol Suppl (71): 3–7. doi:10.1111/j.1600-0609.2008.01206.x. PMID 19200301.
- ↑ Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN (2010). "The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports". Am J Hematol. 85 (3): 174–80. doi:10.1002/ajh.21616. PMID 20131303.
- ↑ Lee JY, Lee JH, Lee H, Kang B, Kim JW, Kim SH; et al. (2017). "Epidemiology and management of primary immune thrombocytopenia: A nationwide population-based study in Korea". Thromb Res. 155: 86–91. doi:10.1016/j.thromres.2017.05.010. PMID 28525829.
- ↑ 16.0 16.1 16.2 16.3 16.4 Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR, Northern Region Haematology Group (2003). "Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients". Br J Haematol. 122 (6): 966–74. PMID 12956768.
- ↑ Segal JB, Powe NR (2006). "Prevalence of immune thrombocytopenia: analyses of administrative data". J Thromb Haemost. 4 (11): 2377–83. doi:10.1111/j.1538-7836.2006.02147.x. PMID 16869934.
- ↑ Zhang W, Nardi MA, Borkowsky W, Li Z, Karpatkin S (2009). "Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia". Blood. 113 (17): 4086–93. doi:10.1182/blood-2008-09-181073. PMC 2673130. PMID 19023115.
- ↑ Li Z, Nardi MA, Karpatkin S (2005). "Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia". Blood. 106 (2): 572–6. doi:10.1182/blood-2005-01-0243. PMC 1895171. PMID 15774614.
- ↑ Kuwana M (2014). "Helicobacter pylori-associated immune thrombocytopenia: clinical features and pathogenic mechanisms". World J Gastroenterol. 20 (3): 714–23. doi:10.3748/wjg.v20.i3.714. PMC 3921481. PMID 24574745.
- ↑ Wu KH, Peng CT, Li TC, Wan L, Tsai CH, Lan SJ; et al. (2005). "Interleukin 4, interleukin 6 and interleukin 10 polymorphisms in children with acute and chronic immune thrombocytopenic purpura". Br J Haematol. 128 (6): 849–52. doi:10.1111/j.1365-2141.2005.05385.x. PMID 15755291.
- ↑ Emmerich F, Bal G, Barakat A, Milz J, Mühle C, Martinez-Gamboa L; et al. (2007). "High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura". Br J Haematol. 136 (2): 309–14. doi:10.1111/j.1365-2141.2006.06431.x. PMID 17156395.
- ↑ Rocha AM, De Souza C, Rocha GA, De Melo FF, Saraiva IS, Clementino NC; et al. (2010). "IL1RN VNTR and IL2-330 polymorphic genes are independently associated with chronic immune thrombocytopenia". Br J Haematol. 150 (6): 679–84. doi:10.1111/j.1365-2141.2010.08318.x. PMID 20626741.
- ↑ 24.0 24.1 24.2 24.3 Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB; 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.
- ↑ 25.0 25.1 Stasi R, Stipa E, Masi M, Cecconi M, Scimò MT, Oliva F; et al. (1995). "Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura". Am J Med. 98 (5): 436–42. PMID 7733121.
- ↑ 26.0 26.1 McMillan R, Durette C (2004). "Long-term outcomes in adults with chronic ITP after splenectomy failure". Blood. 104 (4): 956–60. doi:10.1182/blood-2003-11-3908. PMID 15100149.
- ↑ Warrier R, Chauhan A (2012). "Management of immune thrombocytopenic purpura: an update". Ochsner J. 12 (3): 221–7. PMC 3448244. PMID 23049459.
- ↑ 28.0 28.1 Tarantino MD, Danese M, Klaassen RJ, Duryea J, Eisen M, Bussel J (2016). "Hospitalizations in pediatric patients with immune thrombocytopenia in the United States". Platelets. 27 (5): 472–8. doi:10.3109/09537104.2016.1143923. PMC 4926780. PMID 26941022.
- ↑ Vianelli N, Valdrè L, Fiacchini M, de Vivo A, Gugliotta L, Catani L; et al. (2001). "Long-term follow-up of idiopathic thrombocytopenic purpura in 310 patients". Haematologica. 86 (5): 504–9. PMID 11410414.
- ↑ Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T (1991). "High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura". Blood. 77 (1): 31–3. PMID 1984800.
- ↑ Altomare I, Cetin K, Wetten S, Wasser JS (2016). "Rate of bleeding-related episodes in adult patients with primary immune thrombocytopenia: a retrospective cohort study using a large administrative medical claims database in the US". Clin Epidemiol. 8: 231–9. doi:10.2147/CLEP.S105888. PMC 4920235. PMID 27382333.
- ↑ Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA; et al. (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.
- ↑ Gaines AR (2005). "Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0)(D) immune globulin intravenous administration for immune thrombocytopenic purpura". Blood. 106 (5): 1532–7. doi:10.1182/blood-2004-11-4303. PMID 15878975.