IMMUNE THROMBOCYTOPENIA (ITP)

• ACRONYMS

• ASH - American Society of Hematology
• ITP - Immune thrombocytopenia (formerly "idiopathic thrombocytopenic purpura")
• IVIG - Intravenous immunoglobulin
• TPO-RA - Thrombopoietin receptor agonists

---

• DEFINITIONS

• Platelet count units - platelet counts can be expressed in several ways. A normal platelet count is 140,000 - 400,000 platelets/μL of blood. Labs usually express platelet counts as thousands (140 - 400) and list the unit as Thousands/μL or "K/μL" which also stands for Thousands/μL.
• Thrombocytopenia - peripheral platelet count < 100,000/μL
• Primary ITP - peripheral platelet count < 100,000/μL in the absence of other causes or disorders (see causes of thrombocytopenia) associated with thrombocytopenia. Primary ITP is a diagnosis of exclusion.
• Secondary ITP - peripheral platelet count < 100,000/μL in the presence of a condition known to be associated with ITP
• Newly diagnosed ITP - ITP diagnosed within 3 months
• Persistent ITP - between 3 - 12 months from the diagnosis of ITP
• Chronic ITP - ITP lasting more than 12 months
• Severe ITP - ITP with bleeding that requires treatment [7]

---

• CAUSES OF THROMBOCYTOPENIA

• Overview
• A broad range of conditions can cause thrombocytopenia. The table below lists some of the more recognized causes. If none of these conditions explain the thrombocytopenia, then primary ITP should be considered

---

• DRUGS THAT HAVE BEEN ASSOCIATED WITH THROMBOCYTOPENIA

• Abciximab (Reopro®)
• Acetaminophen (Tylenol®)
• Alemtuzumab (Lemtrada®)
• Azathioprine (Imuran®)
• Carbamazepine (Tegretol®)
• Chemotherapeutic drugs
• Colchicine
• Eptifibatide
• Exenatide (Byetta® Bydureon®)
• Gold salts
• Heparin - see HIT syndrome
• Interferon beta
• Mercaptopurine (6-MP)
• Methotrexate
• Natalizumab (Tysabri®)
• NSAIDs
• Penicillin
• Pegylated interferon
• Procainamide
• Quinidine
• Quinine
• Rifampicin
• Sarilumab (Kevzara®)
• Sulfonamide antibiotics
• Ticlopidine (Ticlid®)
• Tirofiban (Aggrastat®)
• Tocilizumab (Actemra®)
• Valproic acid
• Vancomycin [1,2,6]

---

• EPIDEMIOLOGY

• The estimated annual incidence of ITP is 2 - 4 cases per 100,000 people with half of the cases occurring in children
• The disease has a very different clinical course in children and adults. In children, the condition typically develops abruptly after an infection and resolves spontaneously over the next six months in 80% of cases. Boys and girls are affected equally, and the peak incidence is between 5 and 6 years of age.
• In adults, the condition typically has an insidious onset and is chronic in up to 70% of individuals. The incidence has a bimodal distribution with the first peak occurring between the ages of 20 - 30 years and the second larger peak occurring after the age of 60. Women are affected slightly more during the first peak, and the sexes are affected equally during the second. [3,4,5,10]

---

• RISK FACTORS

• Age
• Adults - bimodal distribution with first peak between 20 - 30 years, and second larger peak after 60 years
• Children - peak incidence between 5 - 6 years
• Female sex - females are affected more up until age 60, then equal
• MMR vaccine - 0.87 to 4 cases per 100,000 doses
• Infections
• H pylori
• Hepatitis C
• Cytomegalovirus (CMV)
• Parvovirus
• Varicella zoster
• HIV
• Cancers
• Chronic lymphocytic leukemia (CLL)
• Hodgkin’s disease
• non-Hodgkin’s lymphomas
• Large granulocytic leukemia (LGL)
• Immune disorders
• Common variable immunodeficiency
• IgA deficiency
• Evans syndrome
• Antiphospholipid syndrome
• Systemic lupus erythematosus
• Post-organ transplantation
• Family history - possible risk factor [1,2,3,4]

---

• SYMPTOMS

• Overview
• Symptoms of ITP are highly-dependent upon the severity of the disease. In general, bleeding is uncommon when the platelet count is > 30,000/μL, so many patients are asymptomatic.


• Symptoms of ITP may include the following
• Bleeding - epistaxis, menorrhagia, gingival and gastrointestinal bleeding
• Purpura - bruising of the skin; typically occurs on the extremities (dry purpura) or on the oral mucosa (wet purpura)
• Petechiae - pinpoint microvascular hemorrhages that do not blanch (note: hemangiomas do blanch); typically occur on the hands and feet; more common when platelet count is < 15,000/μL
• Intracranial hemorrhage - rare and serious complication that almost always occurs at a platelet count < 10,000/μL
• Thrombosis - paradoxically, ITP has been associated with an increased risk of thrombosis; etiology unclear, but may be related to presence of antiphospholipid antibodies
• Fatigue - nonspecific symptom that may be present in up to 40% of patients

---

• PATHOLOGY

• The exact cause of ITP is unknown. Proposed mechanisms include the following:
• Platelet antibodies - the development of platelet antibodies (most commonly to glycoprotein IIb/IIIa) leads to accelerated clearance of platelets in the spleen. Platelet antibodies are not detected in up to 50% of patients with ITP, so they do not fully explain the condition.
• Impaired platelet production - platelet production by megakaryocytes in the bone marrow is often suppressed in ITP. The mechanism by which this occurs is not completely understood.
• Antibody-independent autoimmunity - destruction of platelets by cytotoxic T-cells has been demonstrated
• T-cell dysfunction - abnormal T-cell distributions and loss of regulatory T-cells is another potential mechanism

---

• DIAGNOSIS

• Overview
• No professional guidelines have been published that provide diagnostic criteria for ITP, nor is there a single "gold standard" test that establishes a diagnosis
• Primary or "stand-alone" ITP should be considered in patients who have a platelet count of < 100,000/μL in the absence of other conditions associated with thrombocytopenia (see causes of thrombocytopenia)
• Secondary ITP is an immune-mediated thrombocytopenia that occurs in the presence of a specific condition, infection, or drug that has been associated with thrombocytopenia. Since the pathology behind immune thrombocytopenia is not completely understood, distinguishing a true autoimmune-mediated thrombocytopenia from other pathologies can be difficult, and the presence of a true secondary ITP may be hard to discern.

• Routine labs
• Platelet count - platelet count < 100,000/μL
• CBC - in ITP, erythrocytes and leukocytes are typically normal in count and morphology. If patient has experienced significant bleeding, anemia may be present
• Peripheral smear - a peripheral smear should be performed to exclude other causes of thrombocytopenia like hematological cancers and thrombotic thrombocytopenic purpura (TTP). In TTP, signs of red blood cell destruction (e.g. schistocytes) will be present. [1,2,5]

• Other labs
• Antiplatelet antibody assays
• Specific antigen tests - tests for antibodies that are bound to platelet-specific glycoproteins llb/llla, lb/IX, or la/lla. Test has a sensitivity of around 53% and a specificity around 72%. Because of the low sensitivity, the test is generally not recommended as part of the routine workup.
• Nonspecific antigen tests - also called platelet-associated immunoglobulin G (PAIgG assay). The test has a sensitivity of around 91% and a specificity around 27%.
• Blood type - if Anti-Rh(D) immunoglobulin is being considered for treatment, blood typing is indicated. Anti-Rh(D) is only effective in Rh(D) positive individuals.
• Direct antiglobulin test (direct Coombs test) - if anemia is present, may help distinguish autoimmune hemolytic anemia from other conditions
• Reticulocyte count - if anemia is present, reticulocyte count may help decipher if anemia is from red blood cell destruction (ex. TTP) or poor production
• Bone marrow biopsy - bone marrow biopsy may be useful to exclude other myelodysplastic disorders in select patients. The American Society of Hematology does not recommend bone marrow biopsy in children and adults with typical ITP.
• Antiphospholipid antibodies - found in up to 40% of adults with ITP
• Antinuclear antibodies (ANA) - lupus is associated with ITP. A positive ANA test may be a predictor of chronic ITP in childhood.
• TSH (thyrotropin) receptor antibody and thyroid function tests - up to 14% of chronic ITP patients will develop hyperthyroidism at some point. Hypothyroidism also is prevalent. [1,2,5,8]

• Associated disease testing
• H pylori testing - H pylori testing may be useful in adults but is not routinely recommended in children. In the U.S., treatment of H pylori generally does not improve ITP.
• Hepatitis C testing - hepatitis C infection is present in up to 20% of patients with ITP. The American Society of Hematology recommends all adults with ITP be tested for hepatitis C.
• HIV testing - The American Society of Hematology recommends all adults with ITP be tested for HIV.
• Quantitative antibody testing (IgG, IgA, IgM) - ITP is associated immunodeficiencies including common variable immunodeficiency (CVID) and IgA deficiency [1,5]

---

• PROGNOSIS

• Children
• ITP resolves spontaneously in 80% of children, usually within 6 months
• Only 3% of children with ITP have clinically significant bleeding such as severe epistaxis or GI bleeding
• Children > 10 years old are more likely to develop chronic ITP [4,5]

• Adults
• In adults, spontaneous remission of primary ITP is much less likely than in children, with only 9 - 28% of adults achieving remission without splenectomy [4]
• Despite the low remission rate, the prognosis is generally favorable. In one study, 134 patients with primary ITP were followed for 10 years. Eighty-five percent of patients achieved platelet counts > 30,000/μL while off of all therapies and had an overall mortality equal to the general population. Nine percent of patients had refractory disease, and their overall mortality was higher than the general population. [9]

---

• TREATMENT

• References [4,5,10,13]

American Society of Hematology 2019 ITP Treatment Recommendations for Children
First-line treatment No bleeding or minor bleeding (skin manifestation such as petechiae and bruising) Observation is recommended Non-life-threatening mucosal bleeding and/or diminished health-related quality of life Corticosteroids (preferred) Dosing: Prednisone 2 - 4 mg/kg/day (maximum 120 mg/day) for 5 - 7 days Effective in up to 75% of patients Platelet count responds in 2 - 7 days Intravenous immunoglobulin (IVIG) Dosing: single dose of 0.8 - 1 g/kg OR 0.4 grams/kg/day for 2 - 5 days Effective in > 80% of patients Platelet count responds in 1 - 2 days. IVIG may be more beneficial in patients with active serious bleeding and in those with very low platelet counts (<10,000). One-third of patients will fall below acceptable platelet count 2 - 6 weeks after treatment Anti-Rh(D) immunoglobulin (WinRho®) Dosing: 50 - 75 μg/kg IV Only for use in Rh(D) positive, non-splenectomized patients. Anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets. Avoid in patients with decreased hemoglobin and/or autoimmune hemolysis 50 - 77% of patients will respond and platelet count responds in ≥ 50% within 24 hours Platelet count responds in 2 - 7 days
Second-line treatment Thrombopoietin receptor agonists (first-line) Thrombopoietin receptor agonists (TPO-RAs) stimulate megakaryocyte proliferation and differentiation. Side effects include possible increased risk of thromboembolism, increased bone marrow reticulin, rebound thrombocytopenia upon discontinuation, and hepatotoxicity (eltrombopag). Response is typically seen in 1 - 2 weeks. Romiplostim (Nplate®) - romiplostim is a weekly SQ injection. In one trial, 88% of children treated with romiplostim achieved a platelet count ≥ 50,000. [PMID 21502541] Eltrombopag (Promacta®) - eltrombopag is a once daily tablet. In trials, around 40% of children treated with eltrombopag achieved a durable platelet response of ≥ 50,000. Rituximab (second-line) Dosing: 100 mg/week for 4 weeks OR 375 mg/m2/week for 4 weeks Response rate is highly variable (30 - 80%) Platelet count responds within a few weeks Splenectomy (third-line) Effective in 60 - 70% of patients Platelet response seen in 24 hours and 80% of responders maintain response over 4 years Increases risk of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae infections (see asplenic patients for more)
MMR-associated ITP Children with a history of ITP who are unimmunized - should receive first scheduled MMR vaccine Children with either nonvaccine or vaccine-related ITP who have received their first dose of MMR vaccine - check vaccine titer. If immune (90 - 95% of children), do not give another MMR vaccine. If not immune, give MMR at recommended age. [4]

• References [4,5,10,13]

American Society of Hematology 2019 ITP Treatment Recommendations for Adults
Whom to treat Newly diagnosed ITP in adults who are asymptomatic or have minor mucocutaneous bleeding Platelet count < 30,000/μL - corticosteroids are favored over observation Platelet count ≥ 30,000/μL - observation is favored over corticosteroids
First-line treatment Corticosteroids (course ≤ 6 weeks) Dosing: prednisone 0.5 - 2 mg/kg then taper✝ OR dexamethasone 40 mg/day for 4 days Effective in 70 - 80% of patients Platelet count responds in several days to several weeks. Sustained response after discontinuation only seen in 30 - 50% of patients. Repeated cycles are often necessary. ✝In the FLIGHT study detailed below, the following dosing was used: Prednisolone 1 mg/kg for 4 days followed by 40 mg daily for 2 weeks, 20 mg daily for 2 weeks, 10 mg daily for 2 weeks, 5 mg daily for 2 weeks, and 5 mg every other day for the final 2 weeks If corticosteroid-dependent or unresponsive for ≥ 3 months, proceed to second-line treatment
Second-line treatments Thrombopoietin receptor agonists Thrombopoietin receptor agonists (TPO-RAs) stimulate megakaryocyte proliferation and differentiation. Side effects include possible increased risk of thromboembolism, increased bone marrow reticulin, rebound thrombocytopenia upon discontinuation, and hepatotoxicity (eltrombopag). Response is typically seen in 1 - 2 weeks. Avatrombopag was not included in the recommendation because it was relatively new at the time the guidelines were published. Romiplostim (Nplate®) - romiplostim is a weekly SQ injection. In one trial, 38% of splenectomized patients and 61% of nonsplenectomized patients achieved a durable platelet response with romiplostim [PMID 18242413] Eltrombopag (Promacta®) - eltrombopag is a once daily tablet. In one trial, 73% of ITP patients achieved a platelet count ≥ 50,000 with eltrombopag. [PMID 19231632] Avatrombopag (Doptelet®) - avatrombopag is a once daily tablet. In one small trial, avatrombopag was superior to placebo for cumulative number of weeks with platelet count ≥ 50,000. [PMID 30191972] Rituximab Dosing: 100 mg/week for 4 weeks OR 375 mg/m2/week for 4 weeks Response seen in 60% of patients with long-term response achieved in 18 - 35%. Median time to response is 5.5 weeks. In one study, rituximab was no better than placebo in preventing treatment failure (defined as splenectomy or meeting criteria for splenectomy) in patients with corticosteroid-resistant ITP. [PMID 25662413] Splenectomy If possible, splenectomy should be delayed for at least 1 year after diagnosis because of the potential for spontaneous remission in the first year Response rate is 80% with two-thirds of patients achieving a lasting response. Response seen in 1 - 24 days. Increases risk of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae infections (see asplenic patients for more)
Other treatments (not addressed in 2019 guidelines) Corticosteroids + IVIG IVIG dosing: 1 gram/kg given as a one-time dose and repeated if necessary Effective in up to 80% of patients Platelet count responds in 1 - 4 days. Effect of IVIG typically lasts 1 - 2 weeks. Anti-Rh(D) immunoglobulin (WinRho®) Dosing: 50 - 75 μg/kg IV Only for use in Rh(D) positive, non-splenectomized patients. Anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets. Avoid in patients with decreased hemoglobin and/or autoimmune hemolysis Up to 80% of patients will respond Platelet count responds in 4 - 5 days and effect typically lasts 3 - 4 weeks Fostamatinib (Tavalisse™) Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptors. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets. Major side effects of fostamatinib include hypertension, neutropenia, diarrhea, and hepatotoxicity Fostamatinib is a tablet that is taken twice daily In one trial, 18% of ITP patients treated with fostamatinib achieved a durable platelet count ≥ 50,000 compared to 2% of placebo-treated patients. [PMID 29696684]
Special cases Pregnancy - treatment with corticosteroids or IVIG is recommended Hepatitis C-associated ITP - if treatment is required, IVIG is recommended; hepatitis C infection should be treated

---

• STUDIES

• STUDY
  FLIGHT study - Mycophenolate + Steroids vs Steroids Only for ITP, NEJM (2021) [PubMed abstract]
• Design: Randomized, open-label trial (N=120 | length = median 1.2 years) in patients > 16 years old with primary or secondary ITP (mean platelet count 7×10⁹/L)
• Treatment: Mycophenolate + Steroids vs Steroids only. Prednisolone dosing was 1 mg/kg for 4 days followed by 40 mg daily for 2 weeks, 20 mg daily for 2 weeks, 10 mg daily for 2 weeks, 5 mg daily for 2 weeks, and 5 mg every other day for the final 2 weeks. Dexamethasone could be used as an alternative. Mycophenolate was titrated up to 1000 mg twice daily for 6 months, then tapered if possible.
• Primary outcome: Treatment failure, defined as a platelet count of less than 30×10⁹/L and initiation of a second-line treatment, assessed in a time-to-event analysis
• Results:
• Primary outcome: Mycophenolate + Steroids - 22%, Steroids only - 44% (p=0.008)
• Platelet count > 100X10⁹/L: Mycophenolate + Steroids - 92%, Steroids only - 64% (p<0.001)
• Findings: The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life.

---

• BIBLIOGRAPHY

• 1 - PMID 23714309 - Hematol Oncol Clin North Am review
• 2 - PMID 21632906 - Cleveland Clinic review
• 3 - PMID 11919310 - NEJM review
• 4 - PMID 21325604 - ASH 2011 GL for ITP
• 5 - PMID 19846889 - BSH GL 2010
• 6 - PMID 17687133 - Drug-induced ITP
• 7 - PMID 19005182 - ITP standardization
• 8 - LabCorp website
• 9 - PMID 11313240 - Morbidity and mortality in adults with idiopathic thrombocytopenic purpura, Blood, 2001
• 10 - PMID 31483965 - Immune Thrombocytopenia, NEJM (2019)
• 11 - PMID 15497100 - Platelet Dysfunction in Renal Failure, Semin Thromb Hemost (2004)
• 12 - PMID 25222481 - Management of Thrombocytopenia in Advanced Liver Disease, Can J Gastroenterol Hepatol, (2014)
• 13 - PMID 31794604 - American Society of Hematology 2019 Guidelines for Immune Thrombocytopenia, Blood Adv (2019)