Immune mediated disorder in which platelets are opsonized by antibodies and are prematurely destroyed by the reticuloendothelial system.
Now referred to as immune thrombocytopenia with removal of idiopathic and purpura terminology.
It is a disputed of increased immune platelet destruction and inefficient thrombopoiesis.
IgG antiplatelet, antibodies, accelerate plate with clearance and reduce platelet production.
Primary immune thrombocytopenia, it is an isolated event, whereas in secondary immune thrombocytopenia, the condition is associated with other disorders such SLE or HIV infection.
Designated as newly diagnosed, within the past three months, persistent, lasting between three and 12 months, or chronic meaning ITP has lasted longer than 12 months.
Incidence about 66 cases of ITP, idiopathic thrombocytopenic purpura, per million persons per year.
Incidence ranges from 2-4 cases per hundred thousand person-years with two peaks, one between 20 and 30 years of age with a slight female predominance and a larger one after 60 years of age with equal sex distribution.
Prevalence 7.2 per 100,000 per year in children and 9.5 per 100,000 in North America.
More than 1 million cases globally worldwide.
Only 5% of patients present with severe bleeding.
Bleeding with hospitalization admission within five years after diagnosis in approximately 15% of patients.
Patients with ITP often report fatigue and impaired quality-of-life.
ITP occurs commonly and women of childbearing age.
The risk of venous thromboembolism is twice as high among patients with ITP than among the general population.
The prevalence rate is increased in the elderly.
One third of elderly patients are diagnosed with ITP by chance during a blood screen, incidentally.
Patients with chronic ITP face up to a 50% increase in morbidity/mortality vs non-ITP patients.
Chronic ITP affects 2/3 of patients for the rest of of their lives.
Antiplatelet autoantibody against glycoproteins in the platelet membrane.
The most common antiplatelet antibodies are specific for GPIIb/IIIa or GP alpha.
Platelets coated with GPIIb antibodies a cleared by Fc-mediated mechanisms.
Platetelets coated with GBIbalpha antibodies undergo both Fc clearance and desialylation.
It is thought that antibody-coated platelets are prematurely destroyed in the spleen and liver, or both through interaction with Fcy receptors.
Autoantibodies can use complement mediated or desialytation induced destruction of platelets, as well as inhibit megakaryocyte function.
In up to 50% of patients antiplatelet antibodies are not detected, suggesting alternative possibilities or mechanisms of platelet destruction.
The presence or absence of antiplatelet antibodies does not correlate with outcomes.
Abnormalities in T cells could drive the autoimmune process and CD 8 cells may be involved.
Other mechanisms of platelet destruction involve activation of helper T cells and cytotoxic T cells.
Platelet turnover normal or decreased in most patients, probably due to autoantibody impairment of megakaryocyte production and maturation.
ITP is defined as a platelet count below 100,000 per cubic millimeter with other processes being ruled out.
Platelet production may be impaired in ITP because platelet antibodies can damage megakaryocytes as well as platelets.
The peripheral blood smear in ITP shows no other abnormalities, such as schistocytes or dysplastic changes, although some patients have large platelets.
No diagnostic test exist, as antiplatelet antibody detected in only 50-60% of cases and bone marrow examination is not diagnostic.
Bone marrow examination is performed only in cases with other hematologic abnormalities and in patients who do not have adequate response to treatment.
Associated with bone marrow decrease in the number of megakaryocytes and an inhibition of megakaryocye maturation.
Antibodies damage megakaryocytes, preventing them from releasing platelets.
While platelet destruction is the main factor for thrombocytopenia, impaired production is also involved.
Thrombopoietin bound to platelets is destroyed.
Endogenous is bound by platelets resulting in a lowered level in the blood and less available to stimulate platelet production by the megakaryocytes in the bone marrow.
Autoantibodies bound to megakaryocytes cause some apoptosis and loss of megakaryocytes decrease production of platelets.
Endogenous thrombopoietin is lost when bound to apoptotic megakaryocytes.
Thrombopoietin is the humeral regulator of platelet production, and it is produced mainly in the liver, binds and activates specific thrombopoietin receptors on the membrane of the megakaryocyte and induces cytoplasmic signaling for platelet production.
Thrombopoietin receptor agonists such as elthrombopag, avatrombopag, and romiplsotim have a initial response to thrombocytopenia within 1 to 2 weeks and ongoing treatment is usually required to achieve a maintenance effect.
Approximately 10 to 30% of patients can discontinue treatment after receiving thrombopoietin receptor agonists for many months or years and the disease can remain in remission although late relapses may occur.
Thrombopoietin-receptor agonists are now second line treatments, completing with splenectomy and rituximab therapy.
Fc region of IgG antibodies on platelet surface binds to the Fc-? receptors of macrophages, triggering phagocytosis of the antibody coated platelet by the macrophage.
Sensitization of platelets by immunoglobulin IgG and IgM antibodies react with antigenic sites, which are usually glycoprotein IIb/IIIa.
The autoantibodies are usually IgG, and when attached to platelet membranes may bind complement and cause accelerated platelet destruction via phagocytes by reticuloendothelial cells in the liver and spleen.
Lifespan of platelets in the presence of high affinity IgG platelet antibody is only a few hours, compared to the normal survival of 10 days.
Most of macrophages that ingest antibody coated platelets reside in the spleen and liver but can be located at other sites.
Thrombopoietin plasma levels are not elevated in ITP patients as compared to patients with thrombocytopenia of other causes.
Approximately 20,000 new cases per year in the U.S., with about 200,000 total cases.
More common in women than men, 1.7:1.0.
A female predominance occurs after childhood, until approximately age 50 to 60, and than similar incidence between sexes in older individuals.
Median age 56 years.
Occurs most commonly between the ages of 18 and 40 years.
Incidence in older people over the age of 60 years more than twice that of people younger than 60 years.
5% lifetime risk of fatal hemorrhage.
Low platelet counts, exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or anticoagulants, and female sex are associated with increased risk for bleeding events in adults with immune thrombocytopenia (ITP).
For patients over the age of 60 years have a predicted fatality rate as high as 48% and a 76% 2 year risk os a major nonfatal hemorrhage (Cohen).
Platelet count 30 x 10 to the 9th/L commonly accepted as threshold for the occurrence of major bleeding.
Bleeding in ITP is rare in individuals with a platelet count of more than 50,000 per cubic millimeter.
Bleeding is generally confined to patients with platelet count of less than 10-20,000 per cubic millimeter.
Bleeding risk at one year is 2.5 times higher among patients with platelet counts between 25,000 and 50,000, and seven times in those accounts below 25,000 per cubic millimeter.
Treatment decisions are influenced by other risk factors: older age, history of bleeding, concomitant use of anticoagulants and platelet inhibitors, the presence of corxistent conditions such as renal impairment, and the risk of trauma from daily activities.
It is recommended patients who are receiving anticoagulant, antiplatelet agents should retrieve treatment to maintain platelet counts at 50,000 per cubic mL.
Low platelet counts, exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or anticoagulants, and female sex are associated with increased risk for bleeding events in adults with immune thrombocytopenia (ITP), according to new research.
Patients with persistently low platelet counts has a risk of fatal hemorrhage ranging from 0.45 per year for patients younger than 40 years and 13% per year for patients 60 years and older.
In children it is an acute self-limited disease often following a viral infection or immunization.
In adults usual of insidious onset with no preceding illness and has a chronic course.
An immune dysregulation leads to the production of autoantibodies or immune complexes that accelerate peripheral platelet destruction by binding to platelets and causing platelet phagocytosis, along with T-cell and possibly complement mediated lysis.
Chronic ITP may persist indefinitely in adults, but as many as half of improvable 1 to 2 years with treatment.
The long-term outlook for chronic ITP in adults is favorable, for the majority of patients.
Resolution by 6 months in adults is rare.
Patients may be asymptomatic, have mild bruising or mucosal bleeding or have severe hemorrhage including intracranial bleeding.
A diagnosis based on exclusion of other conditions.
In general, performance of a bone marrow examination no longer recommended for diagnosis.
Assays for platelet antibodies no longer recommended as the tests are not sensitive or specific enough for diagnosis.
Diagnosis the American Society of Hematology guidelines requires a complete history and physical examination, complete blood count, review of the peripheral blood smear and exclusion of other causes of thrombocytopenia.
History of the patients family of inherited thrombocytopenic or autoimmune disorders must be sought.
Additional evaluation includes possible viral serologies, anti-phospholipid antibodies, anti-nuclear antibodies, thyroid function tests, Coombs test, H pylori testing, a DIC panel, test for bleeding disorders such as von Willebrand disease, and quantitative immunoglobulins.
Clinically the findings are limited to possible bleeding manifestations otherwise the examination should be normal.
The peripheral blood smear may show large platelets.
Diagnosis based on three criteria: isolated thrombocytopenia with an otherwise normal hemogram, absence of hepatosplenomegaly or lymphadenopathy and a substantial response in platelet count with specific therapy such as corticosteroids, intravenous immunoglobulins or ant-D immunoglobulin.
The peripheral blood smear may show large platelets.
Childhood ITP is most frequently diagnosed between the ages of one and six years.
Nearly 10% of cases of ITP in children are identified in the first year of life.
80-90% of children have spontaneous remission within 2-8 weeks.
In approximately 20% of children with ITP the disease becomes chronic and lasts beyond 6 months.
Acute ITP in children equally common among boys and girls.
Peak incidence in children 2-4 years.
Serious morbidity and mortality in children is rare, approximately 1%.
Adults rarely have spontaneous remission.
Both spontaneous and treatment induced remission can occur many years after diagnosis.
Many adults have mild and asymptomatic disease that remains stable and requires no treatment.
Algorithms for treatment are not available and therefore management differs among experts.
Most treatments aimed at interfering with antibody mediated platelet destruction by inhibiting the function of macrophage Fc receptors, decreasing antiplatelet antibody production, or both.
About 10% of adult patients develop severe thrombocytopenia requiring treatment at 3-7 year follow-up.
Treatment goals are to provide a platelet count that prevents major bleeding episodes while minimizing any adverse effects.
Death from hemorrhage in ITP is rare, but does occur.
Risk of fatal hemorrhage between 0.0162-0.0389 per patient-year at risk with a platelet count <30×10 to 9th/L.
Treatment data suggest that treatment itself is associated dangerous associated ITP itself and that many patients are overtreated.
Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists.
Strategies that avoid medication side effects are favored.
In adults with newly diagnosed ITP and a platelet count of <30 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the guideline panels suggests corticosteroids rather than management with observation.
For patients with a platelet count at the lower end of this threshold, for those with additional comorbidities, anticoagulant or antiplatelet medications, or upcoming procedures, and for elderly patients (>60 years old), treatment with corticosteroids s appropriate.
In adults with newly diagnosed ITP and a platelet count of <20 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, outpatient or in patient care is acceptable.
In adults with newly diagnosed ITP, the guideline panels recommends against a prolonged course (>6 weeks including treatment and taper) of prednisone and in favor of a short course (≤6 weeks).
In adults with newly diagnosed ITP, the guideline suggests either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid for initial therapy.
Dexamethasone may be preferred over prednisone.
In adults with newly diagnosed ITP guidelines suggests corticosteroids alone rather than rituximab and corticosteroids for initial therapy.
In adults with ITP for ≥3 months who are corticosteroid-dependent or unresponsive to corticosteroids and are going to be treated with a thrombopoietin receptor agonist (TPO-RA), the ASH guideline panel suggests either eltrombopag or romiplostim.
In adults with ITP lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests either splenectomy or a TPO-RA.
In adults with ITP lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests rituximab rather than
In adults with ITP lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests a TPO-RA rather than rituximab.
Each of these second-line treatments may be effective therapy and therefore the choice of treatment should be individualized based on duration of ITP, frequency of bleeding episodes requiring hospitalization or rescue medication, comorbidities, age of the patient, medication adherence, medical and social support networks, patient values and preferences, cost, and availability.
Splenectomy should be delayed for at least 1 year after diagnosis because of the potential for spontaneous remission in the first year.
Patients who value avoidance of long-term medication may prefer splenectomy or rituximab.
Patients who wish to avoid surgery may prefer a TPO-RA or rituximab.
Patients should have appropriate immunizations prior to splenectomy and receive counseling regarding antibiotic prophylaxis following splenectomy.
In children with newly diagnosed ITP and a platelet count of <20 × 109/L who have no or mild bleeding only, the ASH guideline panel suggests against admission to the hospital and in favor of management as an outpatient.
In children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel suggests observation rather than corticosteroid management.
In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished quality of life, the ASH guideline panel recommends against courses of corticosteroids longer than 7 days and in favor of courses 7 days or shorter.
In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding corticosteroids are suggested rather than anti-D immunoglobulin.
In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished quality of life, the ASH guideline panel suggests corticosteroids rather than IVIG
Management of children with ITP who do not have a response to first-line treatment: Second-line therapies: splenectomy, TPO-RA, and rituximab.
The ASH guideline suggests the use of TPO-RAs rather than rituximab, or splenectomy.
Description of the health problem ITP is an acquired autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production.
ITP has an incidence of 2 to 5 per 100 000 and can be an isolated primary condition or it may be secondary to other conditions.
ITP is a heterogeneous disorder with variable clinical symptoms and remains a diagnosis of exclusion of other causes of thrombocytopenia.
The likelihood of a spontaneous remission from ITP is age related, with 1-year remission rates of 74% in children <1 year of age, 67% in those between 1 and 6 years of age, and 62% in those 10 to 20 years of age.
Natural history data in adults, are reported that 20% to 45% of patients achieving complete remission by 6 months; identifying spontaneous remissions beyond 6 months is more difficult secondary to the use of disease-modifying therapies.
The clinical course of ITP may also be different depending on whether it is primary ITP, occurs in the setting of additional autoimmune cytopenias (Evans syndrome), is the manifestation of a primary immunodeficiency, or is associated with an underlying autoimmune condition or infection (secondary ITP).
In the latter, the treatment of ITP is often directed at management of the underlying condition.
Bleeding events are often unpredictable.
Even in the setting of severe thrombocytopenia, may not exhibit bleeding beyond bruising and petechiae.
Serious mucosal bleeding may occur, including menorrhagia, epistaxis, gastrointestinal hemorrhage, hematuria, or, rarely, intracranial hemorrhage (ICH).
ICH has been reported in 1.4% of adults and 0.1% to 0.4% of children with ITP.
Severe bleeding is reported in 9.5% of adults and 20.2% of children.
Adults with ITP have a 1.3- to 2.2-fold higher mortality than the general population due to cardiovascular disease, infection, and bleeding.
ITP has a significant impact on the quality of life, related to restrictions on activities, anxiety due to the risk of bleeding, and the burden of treatment and monitoring.
Fatigue is common and reported in 22% to 45% of patients with ITP.
Patients at platelet counts of 30×109/L or greater whether on treatment or not have a long-term mortality rate identical or slightly higher than the general population.
If patients do not respond by six weeks they are less likely to achieve a significant response beyond the time.
Spontaneous major bleeding in adults with ITP <5% with platelets counts of greater than 10x 109/L and occurs in about 40% of individuals with a platelet count <10x 109/L.
Corticosteroids, and typically prednisone, effective in 50-80% of cases.
When corticosteroids are reduced or stopped remission is sustained in only 10-30% of cases.
Regimens that utilize dexamethasone may have higher rates of sustained remission.
Splenectomy is traditionally the second line treatment if patients do not respond to steroids or do not have a sustained response with low doses of steroids.
Complete or partial remission occurs in more than two thirds of patients following splenectomy, with a 15-25% relapse rate.
Following splenectomy approximately 2/3 of patients had a good response that lasts for at least five years, and additional therapy is not needed.
Splenectomy removes the major site of platelet destruction and also a site of platelet antibody production.
In a review of 130 articles, splenectomy for ITP resulted in complete remission in 2/3 of patients and parial response in 20% of patients, with few recurrences making it the most effective treatment (Kojouri K et al).
Splenectomy is now reserved as a third line therapy with a 78% response rate in 10 years, in part owing to the frequency of postoperative intraabdominal venous thrombosis after laparoscopic surgery.
The most common pharmacological treatments include corticosteroids, intravenous immunoglobulins (IGIV) and Rho (D) immune globulin (anti-D).
IVIG in combination with corticosteroids provides a faster response.
Second line agents include monoclonal anti-CD 20 antibody rituximab, Thrombopoietin receptor agonist eltrombopag, avattrombopag, romiplastin and of the spleen tyrosine kinase (SYK) inhibitor fostaimatinib.
Sustained remissions with intravenous immune globulins or Rho(D) are uncommon.
IVIG raises the platelet count within 1-4 days and 80% of patients, but its effect lasts only one-two weeks.
IVIG is indicated with serious active bleeding in those with very low platelet counts, less than 10,000 per cubic millimeter, who are at increased risk of serious bleeding.
IVIG is effective therapy in some patients, acting through saturating Fc receptors and preventing clearance of antibody coated platelets.
Concomitant use of glucocorticoids with IVIG can be associated with a more sustained response than with IVIG alone.
For acute or chronic ITP no evidence exists that treatment with corticosteroids, IGIV or anti-D decrease mortality or morbidity.
Anti-D transiently increases platelet counts in about half of unsplenectomized adult patients, lasting 2-3 weeks.
Anti-D has comparable efficacy rates of 70%, to IVIG.
Anti-D should not be used in Rh-negative patients, which make up about 18% of the population.
Anti-D lowers hemoglobin levels and should be used with caution in patients with anemia.
Anti-D has risks of hemolysis, acute renal failure and DIC.
Anti-D not effective in patients who have had a splenectomy.
Rituximab has an overall response rate of 25-50% and they may be durable.
Rituximab an anti-CD20 antibody reduces platelet reduction via immunoglobulin producing B cell depletion.
Rituximab has an overall 60% response rate in ITP, however only 20% of patients achieve long-term relationship.
The long-term responses to rituximab in patients with ITP has been reported to be a modest 21% at five years.
Patients treated with rituximab have impaired responses to immunizations with pneumococcal and H flu type B vaccines.
Rituximab and alemtuzumab are antibodies against CD20 and CD52, respectively.
In patients with de novo immune thrombocytopenic purpura, adding rituximab to corticosteroids appears to delay, but not prevent, relapse.
Caucasian patients with relapsed iTTP had significantly longer relapse-free survival (RFS), compared with African American patients.
Rituximab added to corticosteroids, results in 5-year RFS for Caucasian patients with relapsed disease improves dramatically.
In patients with steroid refractory ITP maintaining a long-term platelet response without continues treatment recommends the use of splenectomy before the use of rituximab.
In the corticosteroids plus rituximab group, rates of 1-year and 3-year RFS were significantly higher compared with patients who received corticosteroids alone.
There is no difference at five years (0.60 for corticosteroids plus rituximab vs. 0.56 for corticosteroids alone).
African American patients have a higher risk of relapse, compared with Caucasian patients
Among Caucasian patients, the addition of rituximab significantly improved RFS, compared with corticosteroids alone, but no significant difference in African American patients.
Anti-CD 38 monoclonal antibody targeted therapy rapidly boosts platelet levels by inhibiting antibody dependent cell mediated cytotoxicity on platelets and maintains efficacy by clearing plasma cells.
Estimated 5-year RFS was about 50% and 40% in African American patients with de novo iTTP and relapsed iTTP, respectively, regardless of treatment with rituximab.
For Caucasian patients with de novo ITP the 5-year RFS was approximately 80%.
Eltrombopag is indicated for the treatment of thrombocytopenia in adults and pediatric patients with chronic ITP who have had an insufficient response to corticosteroids. immunuglobulins, or splenectomy.
The use of Thrombopoietin receptor agonists have moved into a more upfront setting in recent years.
Other agents that may induce responses include azathioprine, cyclophosphamide, danazol, vinca alkaloids, dapsone, and mycophenolate mofetil.
Mycophenolate mofetil in combination with glucocorticoids results in a better response as measured by platelet count recovery and fewer treatment failures than glucocorticoids alone.
Most cells have two pathways for supplying purines to support DNA synthesis and cellular function: a de novo synthesis and salvage of nucleotides from DNA turnover.
Mycophenolate starves the cells of purines, particularly guanosine, by inhibiting inosine 5’phosphate dehydrogenase, enzyme that generates guanosine 5’ monophosphate from -5’ monophosphate.
The inadequate supply of guanosine inhibits both B and T cells.
Azathioprine, cyclophosphamide, and vincristine are agents that block signal transduction in lymphoid cells, such as the spleen tyrosine kinase inhibitor fostamatanib.
Rilzabrutinib, an oral BTK inhibitor has rapid and durable clinical activity in ITP.
Mortality rate due to bleeding for patients with severe ITP is 0.4-1.6% for patients followed for 5-10 years.
Treatment recommended for children with platelet counts <10,000 cell/mm3 and minor purpura should be glucocorticoids or intravenous immunoglobulins (IVIg).
Regardless of platelet count in children with life threatening bleeding initial treatment with intravenous immunoglobulins is recommended.
In children significantly fewer days are required to achieve platelet counts of greater than 50,000 cells/mm3 with intravenous immunoglobulins (IVIg) (median 4 days) than with glucocorticoids (2-13 days).
Although 60-80% of patients with ITP have initial response to glucocorticoids, only 30-50% of adults have a sustained response after treatment.
A substantial number of patients are affected by fatigue as an intrinsic process and it may be appropriate to treat such patients even with minimal or no bleeding symptoms, if they are substantially affected by this.
This process may be associated with thrombophilia, suggesting a simultaneous pro-thrombotic process as well as a hemorrhagic one, indicating that an optimal platelet count treatment goal may be 50 to 100,000 mL instead of greater than 150,000 mL.
In a 52-week study randomly assigning 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, received standard care or weekly subcutaneous injections of romiplostim: the rate of platelet response in the treatment group was 2.3 times that of standard care group (Kuter DJ et al).
In the above ITP study patients receiving romiplostim had a significant lower incidence of treatment failure of 11% compared to those receiving standard of care, 30%.
In the above ITP study splenectomy was also performed less frequently in patients receiving romiplostim,9%, versus 36% in those receiving standard of care.
In the above ITP study the romiplostim group had a lower rate of bleeding events, blood transfusions, and great improvement in quality of life than the standard of care group.
In the above ITP study serious adverse events in patients receiving romiplostim was 23% compared to 37% in patients receiving standard of care.
With serious active bleeding specific measures of management include the withdrawal of anticoagulant, an anti-platelet agents and treatment with platelet transfusions, glucocorticoids, IV immune globulin, or all of these measures.
Platelet transfusions can limit bleeding but have only a transit effect for a few hours, and should be given with combination IVIG and glucocorticoids and repeat transfusions.
In life-threatening situations antifibrinolytic treatments with tranexaamic acid can help stop bleeding, particularly for mucous membranes and menorrhagia can be treated with hormonal therapy.
IVIG is commonly used to raise platelet count in patients with ITP prior to surgery.
But eltrombopag, an oral thrombopoietin receptor agonist, may be a good alternative.
The trial enrolled patients with ITP and a platelet count of <100×109/L before major surgery or <50×109/L before minor surgery.
Patients were randomized to receive daily eltrombopag starting 3 weeks before surgery or IVIG 1 week before surgery.
Ultimately, 30 (78.9%) patients who received eltrombopag achieved perioperative platelet count targets compared with 22 (61.1%) who received IVIG.