Normal or Increased Megakaryocytes in the Marrow Megakaryocyte Thrombocytopenia

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Neonatal Idiopathic (Autoimmune) Purpura: Passive Transfer of Platelet Antibody from Mother

Pregnant women with ITP are at a 50% risk for delivering thrombocytopenic infants, whether or not the mother is thrombocytopenic during pregnancy or at the time of delivery. This results from the transplacental passage of maternal IgG autoantibod-ies into the fetal circulation, with destruction of fetal platelets. Although self-limiting, neonatal ITP (NITP) may last for several weeks. Infants with severe thrombocytopenia (platelet counts <50,000/mm3) have a 1% risk for intracranial hemorrhage (ICH). The risk of severe neonatal thrombocytopenia appears higher if the mother has had a previously affected fetus. True maternal ITP must be distinguished from "gestational" thrombocytopenia. This is a common disorder, in which maternal thrombocytopenia is not severe (platelet counts >100,000/mm3) and infants are not at risk for thrombocytopenia.

Patients identified by the following criteria should be managed by a high-risk obstetric team:

• History of a previously affected infant

• Mother splenectomized for ITP

• Mother with thrombocytopenia (<100,000/mm3) in the current pregnancy. Treatment

The best approach to managing delivery in women with ITP remains controversial. There is no generally accepted noninvasive methods to identify neonates at risk. Percutaneous umbilical blood sampling and fetal scalp sampling are associated with risks. The benefits of cesarean section have not been proven to reduce the occurrence of intracranial hemorrhage.

1. Prenatal:

a. IVGG therapy, 1 g/kg/day administered weekly, is recommended for pregnant women who have a platelet count of <30,000/mm3 or bleeding during the third trimester. The role of IVGG therapy administered to the pregnant subject with ITP for the sole benefit of the fetus is more controversial.

b. The fetal platelet count may be determined by percutaneous umbilical vessel or scalp vein sampling.

c. Cesarean section is recommended when the fetal platelet count is less than 50,000/mm3.

2. Postnatal:

a. IVGG therapy, 1 g/kg/day for 2 days for platelet counts less than 50,000/mm3, is the treatment of choice for affected infants. A platelet count greater than 50,000/mm3 and a platelet count at least twice the pretreatment value 48 hours after completion of the IVGG infusion are indicators of a good response to therapy.

b. Ultrasound of the head should be performed to exclude the presence of intracranial hemorrhage and should be repeated at 1 month of age to identify hydrocephalus and/or intracranial bleeding as early as possible.

c. Corticosteroids are administered in the form of prednisone or methylpred-nisolone IV in a dose of 1-3 mg/kg/day. Corticosteroids should be reserved for those infants who are unresponsive or poorly responsive to IVGG therapy or for those in whom significant clinical bleeding is present (in these, combined therapy with IVGG should be considered).

d. Exchange transfusion is not always beneficial.

e. Random-donor platelet infusions are generally ineffective in infants with autoimmune thrombocytopenia.

f. In emergency situations (e.g., ICH), combination therapy with high-dose IVGG, corticosteroids, and random-donor platelets should be administered.

The nadir of the platelet count in infants with ITP often occurs a few days after delivery. It is, therefore, important that serial counts be obtained during the period of greatest risk for severe thrombocytopenia, the first week of life. The response to IVGG alone is 70% and to corticosteroids is 80%.

Neonatal Isoimmune (Alloimmune) Thrombocytopenic Purpura

Neonatal isoimmune (alloimmune) thrombocytopenic purpura (NATP) should be suspected in thrombocytopenic infants born to mothers with a normal platelet count, particularly if infants of successive pregnancies are affected. Immunization arises from fetomaternal passage of platelets in which there is incompatibility of fetal and maternal platelet antigens. The pathophysiology is similar to Rh disease. A number of platelet antigens have been implicated in NATP. The platelet antigenic system most commonly associated with NATP has been designated human platelet antigen (HPA-1a) or PlA1. Because these antibodies can interfere with normal platelet aggregation, a qualitative defect may be present in those platelets that are not yet destroyed by the antibody. This functional platelet defect may explain why the incidence of serious bleeding is higher in infants with NATP than in NITP infants.

Clinical Features

1. The incidence is 1-2 in 10,000. In 50% of cases, first-born offspring are affected, suggesting that antigenic exposure can occur during the early course of pregnancy (unlike Rh incompatibility, which occurs primarily at the time of delivery).

2. This type of neonatal thrombocytopenia accounts for most of the cases of fetal morbidity and mortality. Hemorrhagic manifestations are variable but tend to be more severe than in the passive transfer of a platelet antibody across the placenta (NITP).

3. Generalized petechiae may appear within minutes of birth and be followed by ecchymosis and even cephalhematomata. Intracranial hemorrhage can occur in utero and be detected on ultrasonography during apparently uncomplicated pregnancies. Death in utero may occur.

4. Bleeding from the umbilicus, skin puncture site, or gastrointestinal or renal tract may also occur.

5. Megakaryocytes are present in normal or increased numbers in the marrow. Reduced numbers of megakaryocytes indicate direct interaction of the antibody with these cells in certain instances.

6. Early jaundice occurs in 20% of cases.

Diagnosis

Laboratory confirmation is difficult* but important with reference to future pregnancies. A diagnosis of NATP is often inferential. The usual criteria include:

1. Congenital thrombocytopenia

2. Normal maternal platelet count and negative history of maternal ITP

3. No evidence of systemic disease, infection, malignancy, or hemangioma

4. Recovery of platelet count within 2-3 weeks

5. Increased megakaryocytes in bone marrow aspiration; however, a reduced number has been noted in a few instances.

Treatment

Active treatment of the infant

Treatment involves administering a maternal platelet concentrate suspended in normal plasma (mother's platelets lack the antigen responsible for isoimmunization). Maternal platelets should be (1) washed with normal plasma to remove antibodies more completely and (2) irradiated to eliminate the risk of graft versus host disease. In this way, platelets compatible with residual neonatal platelet antibody will be infused.

1. If the mother's platelets are not available, HPA-1a-negative platelets may be available from the blood bank. While antigen-negative platelets are being obtained and prepared for transfusion, random-donor platelets should be utilized for immediate therapy in infants with active bleeding. Random donor platelets are unlikely to be as effective as maternal platelets because

*The mother's and father's platelets should be typed for HPA1a and for other known alloantigens, if possible. A number of assays are utilized by platelet immunology laboratories, including fluorescence-activated flow cytometry, platelet suspension immunofluorescence, radioimmunoassays, antigen capture techniques such as monoclonal antibody immobilization of platelet antigens (MAIPA), immunoblotting, platelet lysis, and complement fixation. The mother's and infant's serum or plasma should be screened for the presence of antiplatelet antibody. The antibodies responsible for platelet destruction in NATP usually do not fix complement. Antibodies are usually absent from the newborn's plasma but often are found in high titer in the mother's. The most informative antibody assays are those that can detect platelet alloantibodies even in the presence of human leukocyte antigen (anti-HLA) antibodies. Maternal plasma should be studied with paternal or neonatal platelets as targets; maternal (antigen-negative) platelets and paternal plasma are appropriate negative controls. With some assay systems it may be possible to detect alloimmunization even if the precise antigen incompatibility is not known.

98% of the population has HPA1a-positive platelets. However, a transient increase in the platelet count may still occur with a half-life ranging from 1 to 24 hours.

2. IVGG in a dose of 1 g/kg daily for 1-3 days until the platelet count is between 50,000 and 100,000/mm3. After IVGG, the platelet count usually becomes normal within 1 week.

3. Corticosteroids, which reduce platelet destruction and increase vascular integrity, are also recommended.

4. Ultrasound of the newborn's brain should be carried out during the acute phase to detect intracranial hemorrhage. Careful follow-up of these infants is necessary for early detection of the presence of hydrocephalus, which may require shunting.

Antenatal management

Subsequent pregnancies of a mother who has had one infant with NATP are at high risk for recurrence and nearly all subsequent infants with antigen-positive platelets will be thrombocytopenic. The severity of antenatal and perinatal hemorrhage tends to increase in later pregnancies. The family should be advised of the risk of recurrence at the time the first infant is diagnosed. Antiplatelet antibody titers during pregnancy cannot be used to predict whether an individual fetus will be affected.

It is not possible to anticipate the first case of isoimmune purpura in a given family. However, once an index case has occurred, every effort should be made to obtain a determination of the platelet genotypes of the parents. For example, if the father is homozygous HPA1a positive and the mother a sensitized homozygous HPA1a negative, all subsequent infants will be heterozygous HPA1a positive and are likely to be affected. When this is known, the following maternal management is appropriate:

1. Determine fetal platelet count and allotype using blood obtained from percutaneous umbilical blood sampling after about 20 weeks' gestation.

2. Perform frequent ultrasound examination; however, fetal intracranial hemorrhage may not always be detected by ultrasound.

3. Administer prenatal IVGG therapy to the mother. IVGG 1 g/kg may be given weekly from midgestation until birth.

4. Recommend cesarean section for all pregnancies at risk for NATP.

5. Have washed maternal platelet concentrates available for immediate administration to the infant after birth.

Prognosis

The risk of intracranial hemorrhage is 15%.

Thrombocytopenia Associated with Erythroblastosis Fetalis or Exchange Transfusion

Severe cases of erythroblastosis frequently show petechiae and purpura in the first few hours after birth. This may be due to an isoimmune mechanism, or, when associated with hyperbilirubinemia, it may be an effect of bilirubin toxicity on platelet survival.

Thrombocytopenia may also occur following exchange transfusion because of the paucity of platelets in stored blood or from the shorter survival time of transfused platelets. The thrombocytopenia is transient.

Infection

Thrombocytopenia may occur in any form of sepsis (see Table 10-8). These infants are sick and have jaundice, pallor, purpura, and hepatosplenomegaly. The blood picture shows hemolytic anemia with increased normoblasts, reticulocytosis, and thrombocytopenia. Bone marrow biopsy usually shows normal numbers of megakaryocytes; however, in some cases, bone marrow aspiration has been reported as showing reduced numbers of megakaryocytes. The latter finding suggests that the paucity of megakaryocytes may be related to technical difficulties of marrow aspiration in this age group, although, in some cases, it may be a true finding and mirror the bone marrow biopsy findings.

The mechanism for thrombocytopenia includes the following:

1. Hypoplasia of megakaryocytes

2. Decreased platelet production

3. Increased platelet destruction due to splenomegaly and reticuloendothelial hyperactivity

Therapy is directed toward the underlying infection. Drug-Induced Thrombocytopenia in the Mother

Neonatal thrombocytopenia may be associated with drug-induced thrombocytopenia in the mother. In this situation, drug-hapten disease is responsible for both maternal and fetal disease (see Table 10-4). Thiazide diuretics have been incriminated as causing neonatal thrombocytopenia, but the mechanism appears to be different, because the maternal platelet count is normal and no antibodies have been demonstrated.

Disseminated Intravascular Coagulation

A number of conditions in the newborn may trigger DIC in which platelets along with other coagulation factors are consumed during the clotting process (Table 10-8).

Giant Hemangioma

Giant hemangioma coupled with thrombocytopenia probably represents a form of localized intravascular coagulation. The association of thrombocytopenic purpura with giant hemangioma is referred to as the Kasabach-Merritt syndrome. Platelet trapping has been demonstrated in giant hemangiomas, accompanied, in some instances, by evidence of the consumption of coagulation factors and an increase in fibrin degradation products.

Treatment

1. Transfusions of platelets and other coagulation factors have only transient effects but may hasten involution of the hemangioma. These modalities may be required because of active bleeding due to thrombocytopenia.

2. Corticosteroid therapy has little immediate effect, but may bring about involution of the hemangioma, especially in very young infants. However, tumor regression is probably a consequence of vascular thrombosis and infarction.

3. External compression of the hemangioma by firm bandaging, when possible, may reduce blood flow and platelet trapping.

4. Surgical excision, when possible, has corrected the thrombocytopenia.

5. Radiation therapy to reduce the size of the hemangioma should be considered when the hemorrhagic manifestations are severe.

6. Interferon a-2a has been shown to be effective. It inhibits angiogenesis, in part by inhibiting the proliferation of endothelial cells, smooth muscle cells, and fibroblasts that have been stimulated by fibroblast growth factor (FGF), decreasing collagen production and increasing endothelial prostacyclin production.

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Responses

  • andreas
    What could be the problem if very few megakaryocytes are shown in a bone marrow biopsy?
    7 months ago

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