Thrombocytopeni

2. Thrombocytopeni MajidVafaie associated professor of pediatric hematology and oncology

3. The normal platelet count is 150-450 × 109/L. • Thrombocytopenia refers to a reduction in platelet count to <150 × 109/L.

5. Causes of thrombocytopenia • decreased production on either a congenital or an acquired basis • sequestration of the platelets within an enlarged spleen or other organ • increased destruction of normally synthesized platelets on either an immune or nonimmune basis

6. Idiopathic (Autoimmune)Thrombocytopenic Purpura) • The most common cause of acute onset of thrombocytopenia in an otherwise well child is (autoimmune) idiopathic thrombocytopenic purpura (ITP)

7. EPIDEMIOLOGY • In a small number of children, estimated at 1 in 20,000, 1-4 wk after exposure to a common viral infection, an autoantibody directed against the platelet surface develops with resultant sudden onset of thrombocytopenia. • A recent history of viral illness is described in 50-65% of cases of childhood ITP • The peak age is 1-4 yr

8. In childhood, males and females are equally affected. • ITP seems to occur more often in late winter and spring after the peak season of viral respiratory illness.

10. PATHOGENESIS • Why some children develop the acute presentation of an autoimmune disease is unknown. • The exact antigenic target for most such antibodies in most cases of childhood acute ITP remain undetermined. • Although in chronic ITP, many patients demonstrate antibodies against the platelet glycoprotein complexes, αIIb-β3 and GPIb. • After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on splenic macrophages, ingested, and destroyed

11. Most common viruses have been described in association with ITP, including Epstein-Barr virus and HIV . • Epstein-Barr virus-related ITP is usually of short duration and follows the course of infectious mononucleosis. • HIV-associated ITP is usually chronic. • In some patients ITP appears to arise in children infected with Helicobacter pylori or rarely following vaccines

12. CLINICAL MANIFESTATIONS • The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of generalized petechiae and purpura. • The parents often state that the child was fine yesterday and now is covered with bruises and purple dots • There may be bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 × 109/L).

13. There is a history of a preceding viral infection 1-4 wk before the onset of thrombocytopenia • Findings on physical examination are normal, other than the finding of petechiae and purpura. • Splenomegaly, lymphadenopathy, bone pain, and pallor are rare.

16. An easy to use classification system has been proposed from the United Kingdom to characterize the severity of bleeding in ITP on the basis of symptoms and signs, but not platelet count

17. No symptoms • Mild symptoms: bruising and petechiae, occasional minor epistaxis, very little interference with daily living • Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia • Severe: bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion or hospitalization, symptoms interfering seriously with the quality of life

18. The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, remarkable lymphadenopathy other cytopenias, or congenital anomalies suggests other diagnoses (leukemia, syndromes). • When the onset is insidious, especially in an adolescent, chronic ITP or the possibility of a systemic illness, such as systemic lupus erythematosus (SLE), is more likely.

19. OUTCOME • Severe bleeding is rare (<3% of cases ) • In 70-80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo. • Therapy does not appear to affect the natural history of the illness • Fewer than 1% of patients develop an intracranial hemorrhage.

20. Those who favor interventional therapy argue that the objective of early therapy is to raise the platelet count to >20 × 109/L and prevent the rare development of intracranial hemorrhage. • There is no evidence that therapy prevents serious bleeding. • Approximately 20% of children who present with acute ITP go on to have chronic ITP. • The outcome/prognosis may be related more to age, as ITP in younger children is more likely to resolve whereas the development of chronic ITP in adolescents approaches 50%.

21. LABORATORY FINDINGS • Severe thrombocytopenia (platelet count <20 × 109/L) is common, and platelet size is normal or increased • In acute ITP, the hemoglobin value, WBC count, and differential count should be normal. • Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia.

22. Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes. • Some of the megakaryocytes may appear to be immature and are reflective of increased platelet turnover.

23. Indication of BMA • an abnormal WBC count or differential or unexplained anemia • findings on history and physical examination suggestive of a bone marrow failure syndrome or malignancy. • Other laboratory tests should be performed as indicated by the history and physical examination.

24. HIV studies should be done in at-risk populations, especially sexually active teens. • Platelet antibody testing is seldom useful in acute ITP. • A direct antiglobulintest (Coombs) should be done if there is unexplained anemia to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia) or before instituting therapy with IV anti-D

25. DIAGNOSIS/DIFFERENTIAL DIAGNOSIS • The well-appearing child with moderate to severe thrombocytopenia, an otherwise normal complete blood cell count (CBC), and normal findings on physical examination has a limited differential diagnosis • that includes exposure to medication that induces drug-dependent antibodies, splenic sequestration because of previously unappreciated portal hypertension, and, rarely, early aplastic processes, such as Fanconi anemia

26. Other than congenital thrombocytopenia syndromes such as TAR syndrome and MYH9-related thrombocytopenia, most marrow processes that interfere with platelet production eventually cause abnormal synthesis of (RBCs) and WBCs,and therefore manifest diverse abnormalities on the CBC

37. Disorders that cause increased platelet destruction on a nonimmune basis are usually serious systemic illnesses with obvious clinical findings ( [HUS], [DIC]) • Patients on heparin may develop heparin-induced thrombocytopenia. • Isolated enlargement of the spleen suggests the potential for hypersplenism owing to either liver disease or portal vein thrombosis

38. Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, common variable immunodeficiency, and, rarely, lymphoma • autoimmune lymphoproliferativesyndrome. • WAS; must be considered in young males found to have thrombocytopenia with small platelets, particularly if there is a history of eczema and recurrent infection

39. TREATMENT • There are no data showing that treatment affects either short- or longterm clinical outcome of ITP. • Many patients with new-onset ITP have mild symptoms, with findings limited to petechiae and purpura on the skin, despite severe thrombocytopenia. • Compared with untreated control subjects, treatment appears to be capable of inducing a more rapid rise in platelet count to the theoretically safe level of >20 × 109/L,

40. although there are no data indicating that early therapy prevents intracranial hemorrhage. • Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets. • Thus, platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present.

41. Initial approaches to the management of ITP include the following: • No therapy other than education and counseling of the family and patient for patients with minimal, mild, and moderate symptoms, as defined earlier. • This approach emphasizes the usually benign nature of ITP and avoids the therapeutic roller coaster that ensues once interventional therapy is begun. • This approach is far less costly, and side effects are minimal

43. Per the American Society of Hematology Guidelines: “A single dose of IVIG [intravenous immunoglobulin] (0.8-1.0 g/kg) or a • short course of corticosteroids should be used as first-line • treatment. • IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days induces a rapid rise in platelet count (usually >20 × 109/L) in 95% of patients within 48 hr. • IVIG appears to induce a response by downregulatingFc-mediated phagocytosis of antibody-coated platelets. • IVIG therapy is both expensive and time-consuming to administer. • after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis.

44. Prednisone. Corticosteroid therapy has been used for many years to treat acute and chronic ITP in adults and children. • Doses of prednisone of 1-4 mg/kg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP. • Corticosteroid therapy is usually continued for short course until a rise in platelet count to >20 × 109/L has been achieved to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis.

45. Intravenous anti-D therapy • For Rh-positive patients, IV anti-D at a dose of 50-75 μg/kg causes a rise in platelet count to >20 ×109/L in 80-90% of patients within 48-72 hr. • When given to Rh-positive individuals, IV anti-D induces mild hemolytic anemia. • RBC-antibody complexes bind to macrophage Fc receptors and interfere with platelet destruction, thereby causing a rise in platelet count. • IV anti-D is ineffective in Rh-negative patients. • Rare life-threatening episodes of intravascular hemolysishave occurred in children and adults following infusion of IV anti-D.

46. In the special case of intracranial hemorrhage, multiple modalities should be used, including platelet transfusion, IVIG, high-dose corticosteroids,and prompt consultation by neurosurgery and surgery.

47. There is no consensus regarding the management of acute childhood ITP, except that patients who are bleeding significantly (less than 5% of children with ITP) should be treated. • Intracranial hemorrhageremains rare, and there are no data showing that treatment actually reduces its incidence.

48. splenectomy • 1)The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are not easily controlled with therapy is a candidate for splenectomy. • 2Splenectomy must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids.

49. Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms, increased risk of thrombosis, and the potential development of pulmonary hypertension in adulthood. • As an alternative to splenectomy, rituximab has been used off-label in children to treat chronic ITP. • In 30-40% of children, rituximab has induced a partial or complete remission

50. In ITP, the spleen is the primary site of both antiplatelet antibody synthesis and platelet destruction. • Splenectomy is successful in inducing complete remission in 64-88% of children with chronic ITP. • This effect must be balanced against the lifelong risk of overwhelming postsplenectomy infection