Platelet Disorders

Platelet Disorders Majidvafaie MD

Platelets playa critical role in hemostasis. • When the vascular endothelium is disrupted, platelets adhere to the subendothelium and initiate primary hemostasis. • Excessive bleeding occurs if primary hemostasis is abnormal because platelets are either deficient in number or defective in function

The normal circulating platelet count for all ages ranges from 150,000 to 400,000/microL. • Circulating platelets constitute two thirds of total body platelets; the remaining platelets are located within the spleen. • The average life span of platelets is 7 to 10 days, although survival of transfused platelets in a thrombocytopenic recipient is reduced proportionately to the severity of the thrombocytopenia

Platelet characteristics • Size: 1–4 μm (younger platelets are larger). • Mean platelet volume (MPV): 8.9 6 1.5 μm3 • Distribution: one-third in the spleen, two-thirds in circulation • Average lifespan: 9–10 days.

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

Epidemiology • estimated about 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, although the age ranges from early in infancy to the elderly 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

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 remains undetermined

in chronic ITP most patients demonstrate antibodies against the platelet glycoprotein complexes, a11 b-B3 and GPIb • After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on splenic macrophages, ingesed, and destroyed.

Most common viruses have been described in association withITP, including Epstein-Barr virus and HIV • Epstein-Barr virus-related ITP is usually of short duration and follows the course of infectious mononucleosis • HIVassociated ITP is usually chronic • Helicobacter pylori or rarely following the MMR vaccine

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

Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 x 109/L) • 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

classification system • 1. No symptoms • 2. Mild symptoms: bruising and petechiae, occasional minor epistaxis,very little interference with daily living • 3. Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia • 4. Severe: bleeding episodes-menorrhagia, epistaxis, melena requiring transfusion or hospitalization, symptoms interfering seriously with the quality of life

The presence of abnormal findings such as hepatosplenomegaly,bone or joint pain, or remarkable lymphadenopathy suggests other diagnoses (leukemia). • 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

Outcome • Severe bleeding is rare (<3% of cases in 1 large international study). • 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.

Those who favor interventional therapy argue that the objective of early therapy is to raise the platelet count to >20 x 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%.

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

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

Indications for bone marrow aspiration/biopsy • an abnormal WBC count or differential • unexplained anemia • findings on history and physical examination suggestive of a bone marrow failure syndrome or malignancy

In adolescents with new-onset ITP, an ANA should be done to evaluate for SLE • HIV studies should be done in at-risk populations,especially sexually active teens • Platelet antibody testing is seldom useful in acute ITP

A direct antiglobulin test (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

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 due to previously unappreciated portal hypertension, and rarely, early aplastic processes, such as Fanconi anemia

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

Disorders that cause increased platelet destruction on a nonimmune basis are usually serious systemic illnesses with obvious clinical findings (e.g., hemolyticuremic syndrome [HUS], disseminated intravascular coagulation [D1C))

Isolated enlargement of the spleen suggests the potential for hypersplenism owing to either liver disease or portal vein thrombosis • Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, common variable immunodeficiency, or rarely lymphoma

. • Wiskott-Aldrich syndrome (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

Treatment • There are no data showing that treatment affects either short- or long-term 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 x 109/L, 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

Initial approaches • 1. 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 a coaster that ensues once interventional therapy is begun • This approach is far less costly, and side effects are minimal

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 x 109/L) in 95% of patients within 48 hr • IVIGappears to induce a response by downregulating Fc-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

For Rh positive patients, IV anti-D at a dose of 50-75 mcg/kg causes a rise in platelet count to >20 x 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 hemolysis have occurred in children and adults following infusion of IV anti-D

Corticosteroid therapy has been used for many years to treat acute and chronic ITP in adults and children. • Doses of prednisone of 1-4 mglkg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP

Whether bone marrow examination should be performed to rule out other causes of thrombocytopenia, especially acute lymphoblastic leukemia, before institution of prednisone therapy in acute ITP is controversial.

Corticosteroid therapy is usually continued for 2-3 wk or until a rise in platelet count to >20 x 109/L has been achieved, with a rapid taper to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis.

Each of these medications may be used to treat ITP exacerbations,which commonly occur several weeks after an initial course of therapy. • 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

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

The role of splenectomy in ITP should be reserved for 1 of 2 circumstances. • The older child (>4 yr) with severe ITP that has lasted >1 yr (chronic lTP) and whose symptoms are not easily controlled with therapy is a candidate for splenectomy

Splenectomy must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates acute lTP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of lVIG and corticosteroids.

Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms and the potential development of pulmonary hypertension in adulthood

Chronic Idiopathic Thrombocytopenic Purpura • Approximately 20% of patients who present with acute ITP have persistent thrombocytopenia for >12 mo and are said to have chronic ITP

a careful re-evaluation should be performed, especially for autoimmune disease, such as SLE; chronic infectious disorders, such as HIV; and non immune causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, X-linked thrombocytopenia, autoimmune Iymphoproliferative syndrome,CVIDS, autosomal macrothrombocytopenia, and WAS (also X-linked)

Platelet Disorders