Primary immune thrombocytopenia.pdf

Primary Immune Thrombocytopenia By: Amani Tahir Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder that affects both children and adults. Terminology:  Clinical Features: In children: ITP may follow a viral illness or immunizat...

Primary Immune Thrombocytopenia By: Amani Tahir Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder that affects both children and adults. Terminology:  Clinical Features: In children: ITP may follow a viral illness or immunization. The profound thrombocytopenia may be associated with extensive petechiae, purpura and bruises. There may also be bleeding from mucous membranes such as the nose or mouth. Despite the severity of the clinical features, most children need little treatment, and undergo spontaneous remission. Around15% will develop chronic ITP.  Clinical Features: In adults: There is generally no prodromal illness. ITP is often diagnosed by chance. Fatigue is one of the common, but often neglected, complaints of patients with primary ITP.  Clinical Features: The platelet count alone appears to be an unreliable predictor of outcome, and the clinical symptoms and signs of ITP are influenced by patient age, general health, comorbidities, medication and many other factors. There may be an acquired platelet dysfunction caused by antibody binding to glycoprotein (GP)IIb/IIIa may affect platelet aggregation, and anti-GPIb/IX autoantibodies can impair platelet adhesion to the subendothelial matrix, causing unexpectedly severe bleeding for the level of platelet count. Clinical Features: Other autoantibodies such as antiphospholipid antibodies occur in up to 30% of patients with ITP, and these may affect platelet and vascular function. In general, unlike the thrombocytopenia that accompanies bone marrow failure, serious bleeding is not common in patients with ITP. Pathophysiology: ITP in adults is a typical organ-specific autoimmune disease and, in common with other autoimmune diseases, There’s underproduction plus overdestruction of platelets. Antiplatelet Antibodies and their Antigenes: The autoantibodies involved in ITP are generally IgG, but IgA and IgM autoantibodies have been reported. Opsonized platelets are removed prematurely by the reticuloendothelial system. The autoantibodies may impair megakaryocyte growth and development, platelet release and may also induce apoptosis of megakaryocytes. The overall result of this is failure of platelet production.  several platelet antigens have been characterized. These include GPIIb/IIIa (αIIbβ3,the fibrinogen receptor) and GPIb/IX (the von Willebrand receptor), which appear to be the most frequently involved. Less commonly, GPIa/IIa, GPIV and GPV are involved. Some 40% of patients with chronic ITP have no detectible autoantibodies. They have a direct CD8+ T cell-mediated cytotoxicity that induces platelet destruction. The Role of Helicobacter Pylori in the development of ITP A number of studies have shown improvement in platelet counts in ITP patients positive for H. pylori following eradication of the bacterium Some studies have shown that there is a reduction in the level of antiplatelet antibodies in plasma following eradication of the bacterium. How H. pylori may initiate or perpetuate ITP is not known. Possibilities include molecular mimicry, where there is crossreactivity between the antibody, the bacterium and platelet antigens. Thrombopoietin Levels in ITP: Since thrombopoietin (TPO) is the principal growth factor involved in platelet production, it might be expected that TPO levels would be raised in patients with ITP.However,in ITP,levels of TPO are normal or only modestly elevated.The reason for this has been poorly understood. DIAGNOSIS  Despite significant advances in our understanding of ITP, the diagnosis remains one of exclusion in both paediatric and adult ITP.. History : A thorough history should be obtained, looking for diseases that might cause thrombocytopenia. The patient should be asked about bleeding during previous surgery or dentistry. The sites of bleeding should be determined.  Physical examination: A full physical examination should be normal, apart from the expected clinical signs associated with thrombocytopenia. In addition to the ‘dry purpura’ of ITP, there should be an examination of the mucous membranes, including the mouth and optic fundi looking for the presence of retinal haemorrhage. Enlargement of the liver, spleen or lymph nodes suggests an alternative diagnosis. Laboratory investigation: Laboratory investigation: FBC should confirm the isolated thrombocytopenia. There may be a degree of iron deficiency anaemia, but this should be in proportion to the clinical history. Platelet anisocytosis is a common finding as is large platelet forms, reflecting accelerated platelet production. As a result, along with the presence of platelet fragments associated with platelet destruction, platelet distribution width is increased.  There should be no abnormal white blood cells or red cell fragments in ITP. Although atypical lymphocytes and eosinophilia may occur in children with ITP. The observation of giant platelets should trigger consideration of inherited platelet disorders, which often are misdiagnosed as ITP. In children H. pylori infection is much lower and there is no need to screen for this.  The bone marrow in ITP generally shows normal development and maturation of all cell lines. Megakaryocyte numbers are typically normal or increased, although a decreased number of megakaryocytes does not rule out ITP. Marrow examination is unnecessary even in older patients or before splenectomy if the ITP presentation is typical Natural history of ITP: It is not clear which patients require treatment, whether treatment has any major beneficial effect on the patient, whether patients live longer or whether treatment alters the natural history of the disease. For the majority of patients, ITP is a fairly minor disorder. Serious bleeding is not common and clinical sequelae of the disease are generally absent in patients with platelet counts above 30 × 109/L.  In normal individuals, there is a correlation between the platelet count and bleeding. The lower the platelet count, the more likely is bleeding. In ITP this is not the case, and most patients with ITP show little bleeding until the platelet count drops below 20 × 10^9/L. One study showed that no grade 4 bleeding occurred in patients with platelets greater than 10 × 10^9/L.  ITP in adults typically is a chronic disease, the rate of spontaneous remission is reported as 9% and can occur even after 3 years in patients who present with severe thrombocytopenia. Although ITP is a benign disease, sideeffects of the therapies can cause serious morbidity and even mortality. Treatment for patients with ITP should be based on bleeding signs and symptoms and on the presence of factors that increase the bleeding risk. Possible side effects of the drugs and other treatments used in ITP should always be considere MANAGEMENT  The main aim of treatment is that to allow the patient to achieve a ‘safe’ platelet count. What constitutes a safe platelet count will vary from patient to patient. First-line therapies comprise corticosteroids, IVIg and anti-D. These three treatments work fairly quickly and their efficacy rates are high at around 70–80%. The disadvantage of these and most of the other treatments is that the platelet count generally drops once the treatment is stopped. These treatments are seldom curative, and must be considered palliative therapies. In addition, IVIg and anti-D are pooled blood products.  The disadvantage of these and most of the other treatments is that the platelet count generally drops once the treatment is stopped. These treatments are seldom curative, and must be considered palliative therapies. In addition, IVIg and anti-D are pooled blood products In children, the majority of cases require no medical treatment, and can be managed using a ‘watch-and- wait’ policy. Splenectomy: Splenectomy is a surgical second-line option for patients who have relapsed after treatment with a first-line drug. Many clinicians prefer to defer splenectomy until at least 12 months from diagnosis.  Responses are seen in about two-thirds of patients, who achieve a normal platelet count, and the response is often sustained with no additional therapy for at least 5 years. Even patients who do not have a complete response may still expect a partial or transient increase in platelet count. Around14% of patients do not respond and approximately 20% of responders will relapse months or years later. Postoperative complications of splenectomy Venous thromboembolism (VTE) may occur following splenectomy, particularly if the platelet count rises to 1000 × 10^9/L or more. ITP itself carries a small increased risk of VTE, although the exact level of risk is not known, but there may be an additive VTE effect in patients with ITP who undergo splenectomy. Splenectomized patients are at long-term risk for opportunistic postsplenectomy infection (OPSI) with encapsulated bacteria. Patients with refractory ITP: Refractory ITP is where the patient has undergone splenectomy which has failed or relapsed, and who has ‘severe’ ITP (clinically relevant bleeding) or a risk of bleeding. Some 20% or more of adult patients fall into this category.  Many adults with chronic refractory ITP are able to tolerate severe thrombocytopenia (platelet count as low as 10 × 109/L) Patients should be assessed for other possible causes of their thrombocytopenia, including drug-induced, infection, inherited thrombocytopenia and myelodysplastic syndromes. Instead of receiving further ineffective treatments, If any bleeding does occur, the patient can be treated with rescue therapy such as IVIg in combinationwith intravenous corticosteroids or cyclophosphamide, aimed at raising the platelet count rapidly. TPO receptor agonists(TRAS): Because of the relative lack of TPO seen in ITP, there is the potential to use exogenous TPO in order to stimulate the bone marrow to generate more platelets. Two TPO receptor agonists are now approved: called romiplostim, and the other, eltrombopag.  They do not involve immunosuppression and are not corticosteroid-based, they appear to offer many advantages over the drugs in current use. Their label indication is for patients who have failed splenectomy or in whom splenectomy is contraindicated. TRAs are currently not licensed for use in children.  ITP in Pregnancy: Thrombocytopenia occurs in 5% of pregnancies, but most of these cases are gestational rather than immune-mediated. Management of ITP in pregnancy: Treatment is largely based on the risk of maternal haemorrhage. Throughout the first two trimesters, treatment is initiated when the patient is symptomatic and/or when platelet counts fall below 20 × 109/L, or when it is necessary to produce an increase in platelet count to a level considered safe for procedures such as obstetric delivery or epidural anaesthesia.  The primary treatment options for maternal ITP are similar to those of other adult ITP patients, namely corticosteroids and IVIg. There is limited evidence for the use of intravenousanti-D, splenectomy and azathioprine. TRAs should not be used in pregnancy because ofpossible teratogenicity. Management of the neonate (of mothers with ITP) ITP in the neonate (from mothers with ITP) accounts for 3% of all cases of thrombocytopenia at delivery. The fetal or neonatal platelet count cannot be reliably predicted from the maternal platelet count.  After delivery, a cord blood platelet count should be determined in all cases. Intramuscular injections (such as vitamin K) in the fetus should be avoided until the platelet count is known. Those infants with subnormal counts should be observed clinically and haematologically, as the platelet count tends to fall further to a lowest point between days 2 and 5 after birth. Thank You!