Platelet Disorders Majid vafaie 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): 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 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 mcg/kg causes a rise in platelet count to >20 x 109/L in 80-90% of patients within 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)

The presence of co-existing H. pylori infection should be explored and, if found, treated. Therapy should be aimed at controlling symptoms and preventing serious bleeding.

In lTP, the spleen is the primary site of both anti platelet 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

This decision is often affected by lifestyle issues as well as the ease with which the child can be managed using medical therapy, such as lVlG, corticosteroids, IV anti-D Rituximab, a chimeric monoclonal anti-B cell antibody, effectively induces a remission in % of children with chronic lTP

Two new effective agents that act to stimulate thrombopoiesis, romiplastin and eltrombopag have been approved by the Federal Drug Administration to treat adults with chronic lTP. There are no data regarding either drug's safety or efficacy in children.

THROMBOCYTOPENIA IN THE NEWBORN Neonatal Alloimmune Thrombocytopenia (NAIT) Neonatal Autoimmune Thrombocytopenia

Neonatal thrombocytopenia is relatively common, occurring in 1–3% of healthy term infants and in 20–30% of sick neonates Thrombocytopenia in sick neonates is often due to underlying illness such as sepsis, DIC or respiratory distress syndrome or due to maternal factors such as pregnancy-induced hypertension and gestational diabetes and intrauterine growth retardation (IUGR)

NAIT NAITis the most common cause of severe thrombocytopenia in the newborn It occurs in approximately 1 in 1,000 births. NAIT typically resolves in 2–4 weeks First-born infants are often affected and subsequent affected pregnancies are more severe and therefore require antenatal treatment

Neonatal alloimmune thrombocytopenia can be thought of as a platelet analog of Rh incompatibility It differs from Rh incompatibility because 50% of cases are first-born infants, suggesting the antigenic exposure occurs early in pregnancy unlike in Rh which occurs primarily at the time of delivery

The most common antigen involved is P1A1 (HPA-1a) which accounts for approximately 75% of cases A further 10–20% of cases are due to maternal sensitization to HPA-5b

Clinical Features Typically infants are otherwise-healthy full- term babies, generalized petechiae within minutes of birth,ecchymosis cephalhematomata Bleeding from the umbilicus, skin puncture site, or gastrointestinal or renal tract ICH (up to 10–20%) Death in utero may occur

Early jaundice occurs in 20% of cases. Platelet count is very low at birth, usually,50,000/mm3

Treatment random donor platelet transfusion 10–20 ml/kg IVIG 1 g/kg/day for 1–3 days depending on response with the goal platelet count being above 30–50,000/mm3 Methylprednisolone (1 mg IV) every 8 hours with IVIG until the IVIG is stopped. No tapering of the steroid is necessary

Head ultrasound is mandatory for the thrombocytopenic neonate If there are any abnormal neurological findings, a CT or MRI should be done If ICH is present in NAIT on ultrasound, the target platelet count should be greater than 100,000/mm3 and a head CT or MRI should be performed to better define the hemorrhage. Ultrasound should be repeated at one month to identify early hydrocephaly

Management of Subsequent Pregnancies If a previous sibling has been identified, the likelihood of the next fetus being affected depends on the father’s platelet typing. If the father is homozygous for the antigen responsible (as is the case in 75% of men with HPA-1A) then essentially all later fetuses will be affected

If the father is heterozygous, or if typing is unavailable or uncertain,amniocentesis or (if necessary) fetal blood sampling could determine fetal platelet type due to the invasive nature and potential to cause fetal bleeding, it is recommended to avoid fetal blood sampling to evaluate platelet count whenever possible

Instead mothers with a previously affected neonate without ICH should be started on a combination of weekly IVIG at 1 gram per kilogram per week and prednisone at 0.5 mg per kilogram per day starting at 20 weeks gestation until birth

Previous child with ICH in the secon trimester: Start treatment at 12 weeks gestation with IVIG 2 g/kg/week with or without prednisone 0.5–1 mg/kg/day (added at 20–26 weeks)

Previous child with ICH during third trimester: Start treatment at 12 weeks gestation with IVIG 1 g/kg/week; with or without increasing dose of IVIG to 2 g/kg at week 20; with or without prednisone at 0.5–1 mg/kg/day (at 28 weeks).

Neonatal Autoimmune Thrombocytopenia Neonatal autoimmune thrombocytopenia is due to a passive transfer of autoantibodies from mothers with isolated ITP (it may be seen in association with other conditions such as maternal SLE, hypothyroidism and lymphoproliferative states).

Neonates born to mothers who have autoimmune thrombocytopenia are typically well after an uncomplicated delivery. To distinguish this entity from neonatal alloimmune thrombocytopenia,maternal history must be obtained and the maternal platelet count determined.

GTP Gestational thrombocytopenia (GTP) occurs in 5–10% of pregnancies, but maternal thrombocytopenia by definition is mild (70– 100,000/mm3) in GTP GTP is not associated with neonatal thrombocytopenia The platelet count in the mother swiftly returns to normal after delivery

Neonatal thrombocytopenia in infants born to mothers with autoimmune thrombocytopenia is usually less severe than that seen in alloimmune thrombocytopenia only 10–15% of newborns have a platelet count less that 50,000/mm Neonatal passive ITP is also associated with a lower bleeding rate than in NAIT ICH only occurs rarely

The platelet count may often be near-normal at delivery, but then falls to a clinically significant nadir over the next 1–3 days

Treatment Treatment is required when the infant’s platelet count falls below 30,000/mm3 or if significant bleeding is present. The regimen is the same as for NAIT, using IVIG, IV methylprednisolone and random donor platelet transfusion if indicated. The duration of neonatal thrombocytopenia is usually about 3 weeks Unlike NAIT, there is no benefit to the fetus from maternal treatment during pregnancy