Blood and endocrine system diseases in children. Lesson 3. Topics: Hemorrhagic disease in children. Hemophilia, thrombocytopenia and thrombocytopathies children. Etiology Pathogenesis. Classification. Diagnostics. Differential diagnosis with other hemorrhagic conditions in children. Treatment. Emergency treatment of bleeding and hemorrhagic conditions requiring treatment. International Guidelines: Clinacal Practice guidelines: Henoch-Schonlein purpura http://www.rch.org.au/clinicalguide/guideline_index/HenochSchonlein_Purpura/ The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia http://www.bloodjournal.org/content/bloodjournal/117/16/4190.full.pdf GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA http://www.hemoacademy.cz/dokumenty/guidelines_mng.pdf Introduction: All hemorrhagic diatheses are divided into 3 groups, depending on the type and cause of hemorrhagic syndrome: vasopathies, thrombopathias, coagulopathies. IMMUNE THROMBOCYTOPENIC PURPURA (ITP) Autoantibodies against platelet surface Clinical presentation o Typically 1–4 weeks after a nonspecific viral infection o Most 1–4 years of age → sudden onset of petechiae and purpura with or without mucous membrane bleeding o Most resolve within 6 months o <1% with intracranial hemorrhage o 10–20% develop chronic ITP Labs o Platelets <20,000/mm3 o Platelet size normal to increased o Other cell lines normal o Bone marrow—normal to increased megakaryocytes Treatment o Transfusion contraindicated unless life-threatening bleeding (platelet antibodies will bind to transfused platelets as well) o No specific treatment if platelets >20,000 and no ongoing bleeding o If very low platelets, ongoing bleeding that is difficult to stop or life- threatening: Intravenous immunoglobulin for 1–2 days o If inadequate response, then prednisone o Splenectomy reserved for older child with severe disease Immune Thrombocytopenic Purpura (idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, primary thrombocytopenic purpura) Background: Immune thrombocytopenic purpura (ITP) is a clinical syndrome in which a decreased number of circulating platelets (thrombocytopenia) present as a bleeding tendency, easy bruising (purpura), or extravasation of blood from capillaries into skin and mucous membranes (petechiae). Pathophysiology: An abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes. Immunoglobulin-coated platelets induce receptor–mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because the immunoglobulin-coated platelets are destroyed by mononuclear macrophages in the red pulp. If bone marrow megakaryocytes are not able to increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Frequency: The annual incidence of chronic ITP has been estimated to be 1 in 10,000 Mortality/Morbidity: The most frequent cause of death in ITP is spontaneous or accidental, trauma-induced intracranial bleeding in patients whose platelet counts are less than 10,000 per µL. This situation occurs in 1-2% of cases. Sex: In children, the incidence is the same among males and females. Age: Children may be affected at any age, but the peak incidence occurs in children aged 3-5 years. Causes: 1. Postviral illness. In children, most cases of ITP are acute, and onset seems to occur within a few weeks of recovery from a viral illness. Thrombocytopenia is a recognized complication following Ebstein-Barr virus infection; varicella virus; cytomegalovirus; rubella virus; hepatitis A, B or C; or more typically, a vaguely defined, viral, upper respiratory infection or gastroenteritis. Transient thrombocytopenia often follows recent immunization with attenuated live-virus vaccines. 2. Human immunodeficiency virus (HIV). Thrombocytopenia may occur during the acute retroviral syndrome coincident with fever, rash, and sore throat. 3. Drug-induced thrombocytopenia. Persons who have been sensitized (by prior exposure) to quinidine or quinine may develop immune-mediated drug purpura within hours to days of subsequent exposure. ther drugs that have been associated with drug purpura include antibiotics (eg, cephalothins, rifampicin), gold salts, analgesics, neuroleptics, diuretics, antihypertensives, eptifibatide (Integrilin), and, more recently, abciximab (ReoPro), a chimeric monoclonal fragment antigen binding (Fab) antibody fragment directed against the platelet GPIIb/IIIa receptor. CLINICAL Physical: 1. Skin and mucous membranes. The presence of widespread petechiae and ecchymoses, oozing from a venepuncture site, gingival bleeding, or hemorrhagic bullae indicates that the patient is at risk for a serious bleeding complication (Fig. 1). If the patient's blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated (Fig. 2). Similarly, suction-type ECG leads may induce petechiae. 2. Abdomen. The spleen is palpable in less than 10% of children with ITP. In children with acute ITP, the presence of a readily palpable spleen is not typical. Fig. 1. Haemorrhagic rush in idiopathic thrombocytopenic purpura. Fig. 2. “Cuff” symptrom in thrombocytopenic purpura. Fig. 3. Petechiae and purpura from immune thrombocytopenic purpura Lab Studies: Complete blood count. The hallmark of ITP is isolated thrombocytopenia. Peripheral blood smear 1. The morphology of red cells and leukocytes is normal. 2. The morphology of platelets is typically normal, with varying numbers of large platelets. 3. Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood are evidence of pseudothrombocytopenia. Antiplatelet antibody. Assays for platelet antigen-specific antibodies, platelet-associated immunoglobulin, or other antiplatelet antibodies are available in some medical centers and certain mail-in reference laboratories. Imaging Studies: Computer-assisted tomographic (CT) scanning or magnetic resonance imaging (MRI) Use them promptly when the medical history or physical examination suggests serious internal bleeding. Procedures: The primary diagnostic evaluation is the bone marrow aspirate and biopsy. In ITP, a normal-to-increased number of megakaryocytes exist in the absence of other significant abnormalities. Spleen. No specific findings exist in the spleen. Medical Care: 1. The goal of medical care is to increase the platelet count to a safe level, permitting patients with ITP to live normal lives while awaiting spontaneous or treatment-induced remission. After 6 months, if the platelet count cannot be maintained at a safe level or it cannot be maintained at a safe level with medication without serious treatment-related toxicity, consider splenectomy. 2. Corticosteroids (oral prednisone, IV methylprednisolone) are the drugs of choice for initial management of ITP. 3. Intravenous immune globulin (IVIG) has been the drug of second choice for many years. However, recent studies indicate that for patients who are Rh(D) positive with ITP, intravenous Rho immune globulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG. 4. The limitation of using IV RhIG is the lack of efficacy in patients who are Rh(D) negative or splenectomized. Also, IV RhIG induces immune hemolysis in persons who are Rh(D) positive and should not be used when the hemoglobin concentration is less than 8.0 g/dL. Medical care in children 1. The initial treatment of ITP depends on whether the risk of severe hemorrhage, such as intracranial bleeding, is estimated to be low, moderate, or high. 2. Children whose platelet count is greater than 30,000/ L typically only have mild purpura, and the risk of a severe hemorrhage is low. They may be managed as outpatients without specific treatment. 3. Children whose platelet count is less than 20,000/ L may have more significant purpura and mucosal bleeding. Oral prednisone is conservative treatment, and the addition of IV RhIG for patients who are Rh(D) positive or IVIG for patients who are Rh(D) negative is a more aggressive treatment. 4. Children whose platelet count is less than 10,000/ L are likely to have a significant bleeding tendency and a high risk of serious hemorrhage. Initial treatment with IV methylprednisolone and either IV RhIG or IVIG is appropriate. 5. Platelet transfusions may be required for overt bleeding but are not recommended for prophylaxis. Chronic or treatment-resistant ITP 1. For those patients whose platelet counts do not or no longer respond to treatment with tolerable doses of corticosteroids, IV RhIG, IVIG, or splenectomy, other treatments are available. 2. Data supporting these options are based on relatively few case studies and response rates are comparatively lower. 3. Before concluding that a patient has failed both medical management and splenectomy, necessitating treatment with alternative options, perform an imaging study to ensure that the problem is not associated with the presence of an accessory spleen. 4. Among the medical treatment options in these circumstances are cyclophosphamide, azathioprine, and danazol. 5. Interventions of uncertain efficacy include vinblastine, vincristine, ascorbic acid, colchicine, or interferon-alpha, for which