Immune Thrombocytopenia (ITP)


Immune thrombocytopenia (ITP) is an autoimmune disorder of the blood characterized by decreased platelet counts. Autoantibodies produced by the immune system attack antigens on the surface membranes of platelets, which are sequestered in the spleen and targeted by macrophages to undergo phagocytosis.1 As a result, the life span of the platelets is shortened, and the number of functional platelets circulating in the blood is decreased.

Changing Terminology of ITP

Originally, this disorder was called idiopathic thrombocytopenic purpura because the cause of the condition was unknown at the time. The disease terminology changed to immune thrombocytopenia once scientists had determined the etiology of the disease — namely, dysregulation of the immune system.2 The term purpura has also been deleted from the name because approximately one-third of patients with a diagnosis of thrombocytopenia do not experience active bleeding.2

Etiology of ITP

Autoantibody Formation

In ITP, the immune system produces abnormal autoantibodies, usually immunoglobulin G (IgG) autoantibodies, that target and bind to glycoproteins on platelet surface membranes.3 These glycoproteins trigger the production of autoantibodies, but the exact reason why this immune response occurs is still unclear.14 Approximately 75% of the autoantibodies target glycoprotein IIb/IIIa or glycoprotein Ib/IX complexes on platelet surface membranes; the remaining 25% may target other epitopes, such as glycoprotein V, glycoprotein IV, and the glycoprotein Ia/IIa complex.14,15 

Platelet Destruction

Mononuclear macrophages then target the platelet-autoantibody complex for Fc receptor-mediated phagocytosis, which most frequently occurs in the spleen following sequestration of the “abnormal” platelets.3 Dendritic cells also target the platelet-autoantibody complex for phagocytosis.4

Splenic Involvement

The spleen is the primary site of ITP pathogenesis because:

  • Autoantibodies against platelets form in the white pulp of the spleen; and
  • Mononuclear macrophages in the red pulp of the spleen destroy the autoantibody-covered platelets.3

Scientists have suggested that the immune system of an individual in whom ITP develops is predisposed to the formation of autoantibodies against platelets. Studies have shown that people with ITP commonly have decreased levels of regulatory T cells called CD4+ T helper cells. These cells play a critical role in suppressing immune reactions and the differentiation of B cells into autoantibody-secreting plasma cells, 4,5 

Impaired Platelet Production 

Additionally, cytotoxic CD8+ T cells target the megakaryocytes responsible for platelet production within the bone marrow, impairing their ability to produce platelets at a normal rate.4 The inability of megakaryocytes in the bone marrow to increase platelet production to compensate for the lack of functional circulating platelets further compounds the premature destruction of platelets by macrophages. This combination of factors results in thrombocytopenia and increases the risk for bleeding that results in purpura.3 

Types of ITP

The 2 main types of ITP are primary and secondary. Primary ITP occurs in isolation from other diseases or treatments. Currently, the underlying root cause of primary ITP is not clearly understood.4

Secondary ITP occurs as a result of or in the context of other diseases or treatments, so the underlying trigger of each case is easier to define. Underlying triggers of secondary ITP include other autoimmune disorders, lymphoproliferative disorders, infections (eg, with viruses), certain medications, and blood transfusions. Comorbidities, environmental exposures, and treatments are responsible for approximately 20% of all cases of ITP.4 

Scientists report that secondary ITP in children is rare, accounting for approximately 2.4% of pediatric cases. Between 18% and 38% of patients with ITP are adults who have specific comorbidities or are taking certain medications that increase the likelihood for the development of secondary ITP.6 

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Comorbidities of ITP

Autoimmune Conditions

Systemic autoimmune conditions, such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Evans syndrome, rheumatoid arthritis, Hashimoto thyroiditis or other autoimmune thyroid diseases, Sjӧgren syndrome, and autoimmune hepatitis, may trigger the development of ITP as a comorbid autoimmune condition.6-8 Patients with systemic autoimmune conditions are also at increased risk for the development of B-cell lymphomas, and B-cell lymphomas can increase the risk for secondary ITP.6,7 

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Malignancies

ITP may develop in patients with paraneoplastic syndromes, such as adenocarcinoma, chronic lymphocytic leukemia, large granular T-lymphocyte lymphocytic leukemia, and lymphomas.6-8 Lymphoproliferative diseases are generally accepted causes of thrombocytopenia. Research shows that tumor cells can produce antiplatelet antibodies and may also promote autoimmune responses via antigen mimicry.6,9-11

Some researchers have pointed out that an autoimmune condition such as ITP can paradoxically occur concomitantly with cancer because the response of the immune system to tumor cells is often suppressed while its response to normal, healthy tissues is overactive.6

Immunodeficiencies

ITP can occur in immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection or other primary and secondary immunodeficiency conditions.6,7

The common thread behind the 3 conditions that induce secondary ITP is dysregulation of the immune system and the regulatory mechanisms that enable the identification of self and non-self.6

Environmental Triggers of ITP

Infections

Certain infections, particularly in children, correlate with the onset of secondary ITP, including infections with bacteria such as Helicobacter pylori or with viruses such as cytomegalovirus, HIV, Epstein-Barr virus, hepatitis C virus (HCV), and COVID-19 virus.4,8,12 

One hypothesis suggests that strong immune responses elicited by acute viral, chronic viral, or bacterial infections may promote the production of antibodies that cross-react with platelet antigens or immune complexes that bind to platelet Fc-gamma receptors. Cross-reactivity leads to the production of autoantibodies against both platelet receptors and viral proteins. HCV and HIV may infect megakaryocytic cells, contributing to impaired platelet production and reduced thrombopoietin production.4,8 

HCV resulting in portal hypertension may increase the splenic sequestration of platelets, prompting their premature destruction by mononuclear macrophages.8

Vaccines

An acute, severe onset of secondary ITP has occurred in children following vaccination for measles, mumps, and rubella (MMR).8 In addition to MMR reactions, surveillance for adverse vaccine reactions has reported the onset of secondary ITP following vaccinations for COVID-19; diphtheria, tetanus, and pertussis (DTP); diphtheria, tetanus, and acellular pertussis (DTaP); hepatitis A; and varicella, particularly in children.8,12,13 ITP less commonly occurs following vaccination against hepatitis B virus, pneumococcus, Haemophilus influenzae type B, and varicella-zoster virus.8

Drug-Mediated ITP

In addition to vaccines, specific medications are a potential iatrogenic cause of ITP. Drug-induced ITP may occur in patients taking medications that include acetazolamide, aspirin, aminosalicylic acid, carbamazepine, cephalothin, digitoxin, phenytoin, meprobamate, methyldopa, quinidine, rifampin, and sulfamethazine.7 Additionally, heparin and platelet inhibitors such as abciximab, tirofiban, and eptifibatide can trigger drug-induced thrombocytopenia.8

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Transfusion-Induced ITP

Rarely, secondary ITP can occur following blood transfusions, usually in women with acute hemorrhage who have had multiple children and received multiple transfusions. These instances are also confined primarily to the 1% of White individuals who are homozygous for the HPA1b allele on glycoprotein IIIa.8

Genetic Predisposition

Polymorphisms causing variations in genes affecting Fc-gamma receptor pathways may contribute to a predisposition for the development of ITP.4 Single-nucleotide polymorphisms (SNPs) in immunity-related genes, particularly those encoding specific cytokines or chemokines including interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-alpha, tumor growth factor (TGF)-beta, and interferon (IFN)-gamma, correlate with ITP pathogenesis.4

A CD4+ Th0/Th1 cytokine profile with lower numbers of regulatory T-cells and higher levels of IFN-γ and IL-2 is usually observed in patients with primary ITP.16

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References

  1. Kessler CM. Immune thrombocytopenia (ITP): practice essentials. Medscape. Updated January 7, 2021. Accessed October 13, 2022.
  2. Kessler CM. Immune thrombocytopenia (ITP): background. Medscape. Updated January 7, 2021. Accessed October 13, 2022.
  3. Kessler CM. Immune thrombocytopenia (ITP): pathophysiology. Medscape. Updated January 7, 2021. Accessed October 13, 2022.
  4. Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG. Emerging concepts in immune thrombocytopenia.  Front Immunol. 2018;9:880. doi:10.3389/fimmu.2018.00880
  5. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T Cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135. doi:10.1155/2012/925135
  6. Schifferli A, Cavalli F, Godeau B, et al. Understanding immune thrombocytopenia: looking out of the box. Front Med (Lausanne). 2021;8:613192. doi:10.3389/fmed.2021.613192
  7. Justiz Vaillant AA, Gupta N. ITP-immune thrombocytopenic purpura. StatPearls [Internet]. Updated July 8, 2022. Accessed October 13, 2022.
  8. Cines DB, Liebman H, Stasi R. Pathobiology of secondary immune thrombocytopenia. Semin Hematol. 2009;46:S2-S14. doi:10.1053/j.seminhematol.2008.12.005
  9. Nobuoka A, Sakamaki S, Kogawa K, et al. A case of malignant lymphoma producing autoantibody against platelet glycoprotein Ib. Int J Hematol. 1999;70(3):200-206.
  10. Vial G, Rivière E, Raymond AA, et al. Antigenic mimicry in paraneoplastic immune thrombocytopenia. Front Immunol. 2019;10:523. doi:10.3389/fimmu.2019.00523
  11. Benvenuto M, Mattera R, Masuelli L, et al. The crossroads between cancer immunity and autoimmunity: antibodies to self antigens. Front Biosci (Landmark Ed). 2017;22(8):1289-1329. doi:10.2741/4545
  12. David P, Dotan A, Mahroum N, Shoenfeld Y. Immune thrombocytopenic purpura (ITP) triggered by COVID-19 infection and vaccination. Isr Med Assoc J. 2021;23(6):378-380. 
  13. Cecinati V, Principi N, Brescia L, Giordano P, Esposito S. Vaccine administration and the development of immune thrombocytopenic purpura in children. Hum Vaccin Immunother. 2013;9(5):1158-1162. doi:10.4161/hv.23601
  14. Kessler CM. Immune thrombocytopenia (ITP): etiology. Medscape. Updated January 7, 2021. Accessed October 13, 2022.
  15. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13):995-1008. doi:10.1056/NEJMra010501
  16. Onisâi M, Vlădăreanu AM, Spînu A, Găman M, Bumbea H. Idiopathic thrombocytopenic purpura (ITP) – new era for an old disease. Rom J Intern Med. 2019;57(4):273-283. doi:10.2478/rjim-2019-0014

Reviewed by Harshi Dhingra, MD, on 10/16/2022.

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