IMMUNE
THROMBOCYTOPENIA


ANSWER

Is there an increased risk of thrombosis in ITP patients with a COVID-19 infection?

There is no evidence that the risk of thrombosis is increased by raising platelet counts to hemostatic levels or exacerbated by any specific form of ITP management, even splenectomy and thrombopoietic agents which may be associated with thrombosis in non-COVID ITP settings.1

For more information on COVID-19 and ITP, visit COVID-19 and ITP: Frequently Asked Questions.

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Reference:

  1. American Society of Hematology, COVID-19 and ITP: Frequently Asked Questions. https://www.hematology.org/covid-19/covid-19-and-itp#:~:text=Severe%20COVID-19%20infection%20is,be%20associated%20with%20some%20excess. Accessed 1/22/21
ANSWER

Should ITP patients receive the COVID-19 vaccine?

The benefits of receiving the influenza vaccine and a SARS-CoV-2 vaccine outweigh the concern of a drop in platelet count.1

For more information on points to consider in the use of SARS-CoV-2 vaccines in immunocompromised and/or splenectomized patients, such as those with ITP, visit the ASH Vaccine FAQ.

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Reference:

  1. American Society of Hematology, COVID-19 and ITP: Frequently Asked Questions. https://www.hematology.org/covid-19/covid-19-and-itp#:~:text=Severe%20COVID-19%20infection%20is,be%20associated%20with%20some%20excess. Accessed 1/22/21
ANSWER

How was the autoimmune nature of ITP discovered?

The debate about the mechanism of thrombocytopenia in ITP was settled in 1951, when a hematology fellow decided to transfuse blood from a patient with ITP into himself. In what is now known as the Harrington Experiment, Harrington experienced a significant drop in platelet count shortly after transfusion, followed by a return to a normal platelet count within a week.3

See below for more information on the pathophysiology of ITP.

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References:

  1. Rodeghiero F et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503.
  2. Stasi, R., & Newland, A. C. ITP: a historical perspective. British Journal of Haematology. 2011; 153(4), 437–450. https://doi.org/10.1111/j.1365-2141.2010.08562.x
ANSWER

How is remission defined in ITP?

Response: Remission generally refers to the resolution of disease with normal or near-normal platelet counts. It can be induced by therapy or sometimes occurs spontaneously.4,5,6 Universal criteria for remission do not exist. The IWG focuses on 'complete response' to therapy and 'response' to therapy than remission per se. Remission is defined as achieving a platelet count of:

  • 50 x 109/L in the absence of therapy or any medication for ITP (concomitant or rescue) for at least 6 months in clinical studies4
  • >100,000 x 109/L off therapy by 12 months after diagnosis, by the American Society of Hematology Guidelines5
  • >30 x 109/L in the absence of treatment with no specific duration, by the International Consensus Report6

The International Working Group defines ‘complete response’ to therapy (platelet count >100 x 109/L) and ‘response’ to therapy (platelet count 30-100 x 109/L and at least doubling of the baseline count) rather than remission, per se.7

See below for more information on ITP remission.

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References:

  1. Newland A, Godeau B, Priego V, et al.. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 2016 Jan;172(2):262-73. doi: 10.1111/bjh.13827. Epub 2015 Nov 5. PMID: 26537623.
  2. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 Jan 28;4(2):252. PMID: 31794604; PMCID: PMC6963252.
  3. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812
  4. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393. doi:10.1182/blood-2008-07-162503
ANSWER

What are considerations for diagnosing ITP?

ITP is diagnosed by identifying a low platelet count on a complete blood count. However, patient history, physician examination, and evaluation of peripheral blood film are also assessed to exclude other causes of isolated thrombocytopenia. Other tests (i.e. bone marrow examination) may be beneficial to rule out other conditions (i.e. myelodysplastic syndrome). ITP may be classified as primary or secondary to other medical conditions present at diagnosis.6

See below for more information on diagnosis of ITP.

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Reference:

  1. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812
ANSWER

What are the different phases of ITP?

In 2009, the International Working Group (IWG) agreed on three distinct phases of the disease:
(1) the initial phase, “newly diagnosed ITP,” from the time of diagnosis up to 3 months; (2) “persistent,” between 3 and 12 months from diagnosis; and (3) “chronic phase,” now defined as a disease duration of more than 12 months.6

See below for more information on diagnosis of ITP.

Visit the RESOURCE CENTER for additional Medical Education

Reference:

  1. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812
ANSWER

What were the recommended changes to the management of ITP?

Several updates were made to the ASH guidelines and ICR recommendations to reflect advances in ITP management, including limiting corticosteroid usage, deferring splenectomy, and incorporating patient values for treatment selection.5,6

See below for more information on updated recommendations.

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References:

  1. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 Jan 28;4(2):252. PMID: 31794604; PMCID: PMC6963252.
  2. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812.

ITP Basics

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelet counts (< 100 x 109/L) and increased risk of bleeding.4

Primary ITP is an isolated thrombocytopenia that occurs in the absence of other identifiable causes of thrombocytopenia.4 Primary ITP is a diagnosis of exclusion that constitutes about 80% of diagnosed ITP patients.2

Secondary ITP is associated with other underlying immune disorders and constitutes about 20% of ITP cases.2 Secondary causes include autoimmune diseases (systemic lupus erythematosus [SLE], common variable immune deficiency [CVID]), infections (HIV, Hepatitis C, H. pylori), drug-induced thrombocytopenia (DITP) and, rarely, post-vaccination syndrome (e.g., measles, mumps and rubella vaccine [MMR]).4-6

Other non-immune related causes of thrombocytopenia may include: Chronic liver disease (CLD), hypersplenism, bone marrow suppression (for example, through chemotherapy), and pregnancy (gestational thrombocytopenia).4-7

Disease phases, based on disease duration from diagnosis, include:4

  • Newly diagnosed ITP lasts < 3 months following diagnosis

  • Persistent ITP lasts between 3 and 12 months after diagnosis

  • Chronic ITP lasts longer than 12 months

Severe ITP is defined by the presence of clinically relevant bleeding of sufficient magnitude to mandate treatment, regardless of disease phase. This includes bleeding symptoms at presentation that require treatment, or occurrence of new bleeding symptoms that require additional therapeutic intervention.4

Burden of Disease

Immune thrombocytopenia (ITP) affects all ages and genders, with the highest incidence in children (<18 years old) and the elderly (> 60 years).8,9

The incidence of ITP in adults is estimated to be 2.9–3.9 per 100,000 person-years.8,9 Adult ITP occurs most frequently later in life, with the median age of diagnosis being 56 years.10 In adults, ITP rarely resolves without treatment, with up to 90% of newly diagnosed cases progressing to later stages of disease.11

The incidence of pediatric ITP is 1.9–6.4 per 100,000 person-years.12 ITP is more likely to resolve spontaneously in children (up to 70% resolve within 6 months of diagnosis, and 80% within 12 months of diagnosis).9,13,14 Children with ITP can present at any age, but its incidence peaks between one and five years, with a highest peak in younger boys.9

Primary ITP is distinct from secondary ITP.

Graph

Figure 1. Estimated proportion of causes of ITP.2 Causes of secondary ITP include: SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; CVID, common variable immune deficiency; CLL, chronic lymphocytic leukemia; Evan’s syndrome; ALPS, autoimmune lymphoproliferative syndrome; HIV, human immunodeficiency virus; Hepatitis C; Helicobacter pylori; Post-vaccine; Miscellaneous systemic infection

Bleeding Risk

The main clinical burden of ITP for adult and pediatric patients is increased risk of bleeding, although presentation of these symptoms varies from patient to patient.4

In adult ITP, an inverse correlation has been shown between platelet counts and bleeding risk. Patients with platelet counts under 30 x 109/L are at increased risk of serious or life-threatening bleeding with the highest risk for those with counts under 10 x 109/L.7 A similar relationship has been shown in children with chronic ITP.15

Most patients with ITP will experience at least one bleeding- related event (BRE) per patient-year. Newly diagnosed, elderly and patients with prior bleeding events were at higher risk for bleeding.16

Severe bleeding

Severe bleeding (other than intracranial hemorrhage [ICH]) occurs in 9.6% of adults 14 and 20.2% of children with newly diagnosed or chronic ITP.14


Intracranial hemorrhage

Intracranial hemorrhage (ICH) is a rare but dangerous complication in ITP. The incidence of ICH is 1–1.8% in adults (37% presenting within the first 3 months after diagnosis),17,18 and 0.6% in pediatric ITP patients.18 Prior significant hemorrhage is a risk factor for ICH.17

Patients with ITP frequently require hospitalization to receive ITP treatments and to manage BREs,19 incurring substantial medical costs.20

Quality of Life

Adult patients with ITP may experience fear of BREs and fatigue (general, mental, physical), which may limit their daily activities.21-25 Quality of life of patients with ITP is similar to, or worse than, that of patients with other chronic conditions such as arthritis and diabetes.21

Diagnosis

A diagnosis of primary ITP relies on the exclusion of alternative etiologies of thrombocytopenia, as no robust clinical or laboratory parameters are available to establish a diagnosis.2,6 Diagnosis of ITP can be difficult due to its low incidence,26 and due to heterogeneity in immune system perturbations that may contribute to variable clinical presentation and responses to treatment.2

Major diagnostic concerns in patients with suspected ITP include:4,27

  • Distinguishing primary ITP from other non-immune causes of thrombocytopenia, which often have a similar presentation but may require different management approaches.

  • Determining whether ITP is primary or secondary to another underlying immune condition that might also benefit from treatment.

Clinical Manifestation

Presentation varies from patient to patient, from mild bruising tendency to major bleeding. Patients can present with:

Bleeding-icon
Bleeding:12,15,28
  • Mucocutaneous: skin (petechiae, purpura), oral cavity, gastrointestinal tract

  • Mucosal: conjunctival hemorrhage, epistaxis, menorrhagia, gingival, and gastrointestinal

  • Intracranial hemorrhage (ICH)

  • Internal bleeding

Fatigue
Fatigue27

Thrombosis
Thrombosis27

One third of all adult ITP patients are asymptomatic and diagnosed by chance during work-up for other medical issues.12,27

Goals of Adult ITP Treatment

The primary goal of treatment is to sustain platelet counts that are associated with adequate hemostasis, and reduce bleeding risk with minimal side effects. Treatments should be tailored to individual patients, taking into account the patient’s age, severity of illness, bleeding risk, comorbidities, lifestyle considerations, and careful evaluation of benefit/risk profile of each therapy.4 Treatment options may include the following (presented alphabetically, without signifying order of preference):29

Therapeutic Modalities

Reduce platelet destruction

Immunoglobulin (IVIg, Anti-D) Blocks Fcү receptors on macrophages to prevent their recognition of autoantibody-coated platelets.13,29
Corticosteroids Suppresses B and T cell-mediated autoantibody production, and impairs the ability of macrophages within the bone marrow to destroy platelets.13
Inhibition of B cells Targets CD20+ B cells to lower production of antiplatelet autoantibodies and block macrophage Fcү receptors.13,30
Nonspecific immunosuppression (e.g., azathioprine, cyclosporine) Nonspecifically inhibits T cells to interfere with immune activation.13
Splenectomy Removes the main site of platelet destruction (fewer macrophages are available to clear autoantibody-coated platelets).13
Syk inhibition Impairs the FcR signaling pathway involved in phagocytosis of autoantibody-coated platelets.32

Stimulate platelet production

Thrombopoietin receptor (TPO-R) agonists Bind TPO-R to stimulate platelet production, thereby raising platelet counts to outpace excess platelet destruction.31

Guideline Recommendations

ASH and ICR guidelines were updated in 2019 to reflect advances in management of adult and pediatric ITP patients. Listen to experts discuss the guidelines.

The Role of Thrombopoietin (TPO) in Normal Platelet Formation



Thrombopoietin (TPO)—a glycoprotein hormone produced constitutively by the liver—is the predominant regulator of platelet production. TPO acts by binding the thrombopoietin receptor (TPO-R) on megakaryocytes and their progenitors to stimulate development and platelet production.1,34

Although TPO is produced at a constant rate,1 its level within the body is inversely correlated with platelet counts in healthy people34 and is regulated primarily through platelet clearance in the spleen by macrophages.1

ITP Pathogenesis



Immune thrombocytopenia (ITP) is a highly complex autoimmune disease, triggered by immune system dysregulation. ITP results from autoantibody- and T cell-mediated platelet destruction and impaired platelet production.35,37

Due to the loss of platelet-bound TPO at all stages of the platelet life cycle, patients with ITP have functional TPO deficiency, with insufficient levels to overcome immune destruction of platelets.30,34

References

1 Cines DB, et al. La Press Medicale. 2014;43:e49-e59. 2 Cines DB, et al. Blood. 2009;113:6511-6521. 3 Audia S, et al. Blood. 2013;122:2477-2486. 4 Rodeghiero F, et al. Blood. 2009;113:2386-2393. 5 Mantadakis E, et al. J Pediatr. 2010;156:623-628. 6 Cines, et al. Semin Hematol. 2009;46(suppl 2):S2- S14. 7 Cines DB, et al. Ann Rev Med. 2005;56:425-442. 8 Schoonen WM, et al. Br J Haematol. 2009;145:235-244. 9 Moulis G, et al. Blood. 2014;124:3308-3315. 10 Fredericksen H, et al. Blood. 1999;94:909-913. 11 Stasi R, et al. Am J Med. 1995;98:436-442. 12 Terrell DR, et al. Am J Hematol. 2010;85:174-180. 13 Cines DB, Blanchette VS. N Engl J Med. 2002;346:995-1008. 14 Neunert C, et al. J Thromb Haemost. 2015;13:457-464. 15 Neunert C, et al. Pediatr Blood Cancer. 2009;53:652-654. 16 Altomare I, et al. Clin Epidemiol. 2016;8:231-239. 17 Melboucy-Belkhir, et al. Am J Hematol. 2016;91:E449-E501. 18 Kuhne T, et al. Haematologica. 2011;96:1831-1837. 19 Mahevas M, et al. Blood. 2016;128:1625- 1630. 20 An R, et al. Vasc Health Risk Manag. 2017;13:15-21. 21 George JN, et al. Br J Haematol. 2009;144:409-415. 22 Mathias SD, et al. Health Qual Life Outcomes. 2008;6:13. 23 Newton JL, et al. Eur J Haematol. 2011;86:420-429. 24 Effi cace F, et al. Am J Hematol. 2016;91:995-1001. 25 McMillan R, et al. Am J Hematol. 2008;83:150-154. 26 Matzdorff A, et al. Semin Hematol. 2013;50(suppl 1):S12-S17. 27 Kistenguri D, et al. Hematol Oncol Clin North Am. 2013;27:495-520. 28 Provan D, et al. Blood. 2010;115:168-186. 29 Matzdorff A, et al. Oncol Res Treat. 2018;41(suppl 5):1-30. 30 Houwerzijl EJ, et al. Blood. 2004;103:500-506. 31 Reff ME, et al. Blood. 1994;83:435-445. 32 Imbach P, et al. N Engl J Med. 2011;365:734-741. 33 Newland A, et al. Future Med. 2017;10:9-25. 34 Deutsch VR, et al. Br J Haematol. 2006;134:453-466. 35 Kuter DJ, et al. Hematol Oncol Clin North Am. 2009;23:1193-1211. 36 Grovovsky R, et al. Curr Opin Hematol. 2010;17:585-589. 37 Lambert MP, et al. Blood. 2017;129:2829-2835. 38 Semple JW, et al. Curr Opin Hematol. 2010;17:590-595. 39 Shan NN, et al. Haematologica. 2009;94:1603-1607.