Platelet disorders

CLINICAL PRACTICE

Abstract The pathogenesis of suboptimal platelet function is multifactorial. Platelets do not function well if there are too many or too few platelets; also the platelets can be present in the appropriate quantity but be dysfunctional due to abnormal shape or size. This article will give a brief overview of normal platelet physiology and megakaryocytopoiesis and then discuss platelet dysfunction in the neonatal population. Knowledge regarding the varied causes of platelet dysfunction will lead to expedient identification and appropriate treatment for affected infants. © 2004 Elsevier Inc. All rights reserved.

From the Medical University of South Carolina, Charleston, SC. Address reprint requests to Carolyn W. Jones, MSN, RNC, NNP, 107 Dresden Drive, Goose Creek, SC 29445. © 2004 Elsevier Inc. All rights reserved. 1527-3369/04/0404-0000$30.00/0 doi:10.1053/j.nainr.2004.09.005

Platelet Disorders By Carolyn W. Jones, MSN, RNC, NNP

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he abnormalities of platelets are either one of two types: qualitative problems (the expected numbers of platelets are present, but they do not function appropriately) or quantitative problems (there are either too many or too few platelets). This article will begin with a review of normal platelet physiology and megakaryocytopoiesis and then discuss in detail the various quantitative and qualitative platelet abnormalities seen in the neonatal population.

Review of Normal Platelet Physiology and Megakaryocytopoisis

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latelets are not actually cells, but cytoplasmic fragments of large cells known as megakaryocytopoiesis. The platelets themselves are incapable of mitotic division since they lack a nucleus and have no DNA. Contained within the platelets are cytoplasmic granules which can release biochemical mediators when stimulated by an injury to a blood vessel.1 The disc-shaped platelets circulate in an inactive state as long as the endothelium lining of the blood vessels is intact and remain in circulation for about 10 days before being removed from circulation by the spleen.2 When the blood vessel is damaged, the blood is exposed to the subendothelial layer of the vessels. The platelets become spherical and extend pseudopods, which adhere to vessel walls and each other, and hemostasis is initiated in conjunction with coagulation factors.2 These events lead to the formation of a fibrin plug that stops bleeding from the injured vessel.3 The earliest blood cells develop from endothelial cells within the walls of the newly forming vessels of the cardiovascular system. These vessels begin forming within the walls of the yolk sac and allantois around the end of the third week of gestation. Blood formation begins in the embryo during the fifth week of gestation, occurring in various parts of the embryonic mesenchyme.4 Platelets are first noted in the fetal circulation by the fifth to sixth week of gestation.5 The transition to hepatic hematopoiesis may involve stem cell migration from the yolk sac to the liver.6 Megakaryocytes can be found in the liver/spleen tissue by 10 weeks’ gestation.7 Megakaryocytes were recognized as the source for platelets in the early 1900s, almost 100 years after platelets were first described.8 They make up 0.02 to 0.1% of the total nucleated bone marrow cells and are large in size.9 Neonatal megakaryocytes are smaller than adult megakaryocytes, and their size increases with advancing gestational age.10 The progenitors of megakaryocytes arise from pluripotent hematopoietic stem cells by a process that is not yet well understood. The burst forming unit–megakaryocyte (BFU–MK) is the earliest identifiable megakaryocyte progenitor. The later progenitor is the colony forming unit–megakaryocyte (CFU– BK). Both BFU–MK and CFU–MK can be quantified and have proliferative potential.11 CFU–MK are more plentiful in the bone marrow; BFU–MK are more plentiful in circulating peripheral blood.12 Interleukin 3 (IL-3) stimulates megakaryocytopoiesis progenitor cells. interleukin 6 (IL-6) and interleukin 11 Newborn and Infant Nursing Reviews, Vol 4, No 4 (December), 2004: pp 181–190

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(IL-11) act with IL-3 to stimulate CFU-MK proliferation. Interleukin 1 (IL-1), IL-6, IL-11, and leukemia-inhibiting factors are active in the latter stages of megakaryocyte maturation.13 Thrombopoietin (TPO), which stimulates all stages of megakaryocyte growth and development, was first described as a humoral regulator of platelet concentration in circulation by Kelemen and coworkers in 1958.14 Almost 36 years later, in 1994, TPO was purified and cloned by five independent research groups.15 TPO is thought to be the primary stimulant of megakaryocyte maturation.11 At the end of the maturation process, each megakaryocyte divides into a few thousand platelets.13

Qualitative Platelet Abnormalities

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ualitative platelet abnormalities are those in which the infant has a normal platelet count but is exhibiting signs of platelet type bleeding such as generalized petechiae, purpura, and mucous membrane bleeding. It is difficult to thoroughly assess general platelet function in the neonate due to difficulty in obtaining sufficient quantities of blood to conduct these types of studies.16 Bleeding times are useful in screening for qualitative disorders, since cessation of bleeding involves platelet adhesion, activation, and aggregation. Prolonged bleeding time doesn’t differentiate as to which platelet function is suboptimal but is suggestive of hereditary or acquired platelet dysfunction. Bleeding times are not useful in assessing platelet function if thrombocytopenia is present, since bleeding time is usually prolonged proportionally to the severity of thrombocytopenia.3 Hereditary Forms of Qualitative Platelet Dysfunction Genetic disorders are a rare cause of pathologic bleeding in the neonatal period; more often, their presentation is later in life. One type of hereditary platelet dysfunction that can present in the neonatal period is Glanzmann’s thrombasthenia. It is inherited in an autosomal recessive pattern. The platelets microscopically appear normal, the platelet count is normal, and the platelets adhere to exposed subendothelial proteins. There is, however, a failure of the platelets to aggregate in response to normal stimuli.17 Usually the patient will have a prolonged bleeding time with a normal PT and APTT. The platelets have either absent or reduced platelet glycoprotein (GP) IIb or IIIa, fibrinogen receptors needed for aggregation.18 There have been more than 20 different genetic defects of GPIIb and GPIIIa described. The traditional treatment for Glanzmann’s thrombasthenia is the transfusion of donor platelets and is reserved for serious hemorrhage or the need for surgery.3 A 2003 case report describes the use of recom-

binant factor VIIa in a child with Glanzmann’s thrombasthenia and may provide a therapeutic alternative to platelet transfusion in these patients.19 Another hereditary platelet dysfunction that has been documented in the neonatal period is Bernard-Soulier syndrome. As with Glanzmann’s thrombasthenia, it is also a deficiency of platelet surface glycoproteins (GPIb/IX) and is an autosomal recessive disorder. Characteristics include prolonged bleeding time, very large platelets, and thrombocytopenia (usually very mild). Presentation is usually in infancy or childhood and includes platelet-type bleeding (bruising, mucosal bleeding, and epistaxis). Bleeding occurs because affected patient’s platelets do not adhere to von Willebrand factor in the subendothelial matrix.20 Transfusions with platelets can cause antibody formation to the absent glycoprotein. A small study by Almeida and coworkers21 found variable efficacy in the use of recombinant factor VIIa for acute bleeding episodes in patients with Bernard-Soulier syndrome. There are several platelet function disorders relating to platelet secretion, which refers to the release of the contents of platelet granules, which occurs following platelet activation. Secretion disorders cause mild to moderate bleeding appearing as easy bruising and/or excessive postoperative losses. Included in this subset of disorders are Gray Platelet syndrome, Dense Granule deficiency, Chediak-Higashi syndrome (CHS), and Hermansky-Pudlak syndrome (HPS). The mode of inheritance of Gray Platelet syndrome is uncertain, but probably autosomal since males and females in the family can be affected. CHS and HPS are both autosomal recessive disorders. In addition to mild bleeding diatheses, CHS is also characterized by partial oculocutaneous albinism, frequent bacterial infections, giant lysosomes in leukocytes, progressive peripheral neuropathies, and cranial nerve abnormalities. The multisystem symptoms are due to the presence of abnormal granules in numerous cell types.20 The characteristics of HPS include oculocutaneous albinism, platelet storage pool deficiency, and ceroid lipofuscin deposition. In addition to bleeding diathesis, patients with HPS experience pulmonary fibrosis and colitis. It is most commonly seen in individuals of Puerto Rican descent.22 In a 1998 study of 49 patients with HPS by Gahl and coworkers,23 it was noted that all the patients had excessive bruising in infancy, but the diagnosis was not made until after the patients were walking. One also had neonatal nystagmus. On electron microscopy, there was a lack of platelet dense bodies. The patients had normal platelet counts, prothrombin times, and partial thromboplastin times.23 Current treatment is the use of platelet transfusions when needed postsurgically or for severe bleeding episodes.

Platelet Disorders

Acquired Forms of Qualitative Platelet Dysfunction Disorders of platelet function can be caused by pharmacologic agents given to the mother as well as the infant. Disease states occurring in an infant can disrupt normal platelet function, as can treatment modalities used in the neonatal intensive care unit. An example is aspirin (acetylsalicylic acid), which, when taken by the mother, crosses the placenta and can be detected in the fetal circulation. Salicylates cause irreversible inhibition of the cyclooxygenase enzyme (by forming a covalent complex with the cyclooxygenase enzyme) and increases bleeding time for the life of the affected platelets.3 Several studies24,25 have reported neonatal bleeding (cephalohematoma, gastrointestinal bleeding, and melena) among infants whose mothers received aspirin. A study by Stuart and coworkers26 reported neonatal bleeding episodes in infants whose mothers took aspirin within 5 days of delivery, but no bleeding in infants when the mother’s aspirin ingestion was greater than 6 days before delivery. Antiplatelet agents are rarely used in neonates, but aspirin is occasionally recommended (in very low doses) for the purpose of antithrombotic therapy after Blalock-Taussig shunts, endovascular stints, and some cerebrovascular events.27 Use of pharmacologic agents in the neonate can also cause platelet dysfunction. Indomethacin is commonly used as a treatment modality with patent ductus arteriosus (PDA) and also in early neonatal life as a prophylactic agent to prevent intraventricular hemorrhage. Indomethacin also interferes with cyclooxygenase function, but does not form a covalent complex with the enzyme; therefore its antiplatelet effects diminish when serum indomethacin levels fall. In a 1984 study by Corazza and coworkers,28 it was shown that bleeding times remain elevated for at least 48 hours after the completion of indomethacin treatment for PDA. Sola and Christensen3 recommend, if surgical ligation for a PDA must be performed soon after treatment with indomethacin and postoperative bleeding from a chest tube or at the surgical site is noted, platelet transfusion may be indicated despite a normal platelet count. Nitric oxide (NO) is another drug used in the neonatal population, which has the potential effect of reducing platelet function. Platelet function in adults has been documented to be decreased during NO therapy, likely due to increased cGMP. In infants, NO has been shown to inhibit aggregation of cord platelets and to inhibit platelet adhesion to endothelial cells.29 Extracorporeal membrane oxygenation (ECMO) is used in neonates for the treatment of persistent pulmonary hypertension, meconium aspiration, congenital diaphragmatic hernia, and other conditions when conventional ventilation and treatment is not successful. In a prospective

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study by Robinson and coworkers,30 abnormal platelet function and platelet counts were reported in patients receiving ECMO. They reported a 26% decrease in platelet counts and 50% decrease in platelet aggregation. The platelet count was improved with platelet transfusions, but not the platelet function. Platelet function was reported to be returned to normal 8 hours after ECMO was discontinued. Other treatments/conditions that cause platelet dysfunction in vitro include hyperbilirubinemia and phototherapy, although bleeding has not been reported in otherwise healthy infants with jaundice.3 Uremia and/or renal failure can also cause platelet dysfunction in the neonate. This is not completely understood, but may be due to excessive production of nitric oxide by endothelial cells and/or abnormalities of cyclooxygenase.31 White and de Alarcon32 describe a case of platelet spherocytosis in a 13-year-old patient who had a history of excessive bruising since infancy. There were no other relatives with a bleeding disorder. This very rare condition has not yet been described in a neonate.

Quantitative Platelet Abnormalities Thrombocytosis An elevated platelet count is not an uncommon finding in the neonatal population. Whether moderately elevated (platelet counts of 450,000 to 600,000) or more extreme (platelet count ⬎ 800,000), no adverse outcomes related to the thrombocytosis have been described.3 It has been observed that, at around 4 to 6 weeks of age, many preterm infants experience a moderately increased platelet count at around the same time as the nadir of anemia of prematurity.33 In initial studies in the use of recombinant erythropoietin (rEPO) in neonates, the elevation of hematocrit and reticulocytes was followed by a period of iron deficiency. An increase in platelet counts was observed at this time of iron deficiency and decreased ferritin levels. Iron deficiency is known to cause thrombocytosis in older children.34 Another study by Donato and coworkers35 demonstrated thrombocytosis (platelet count ⬎ 500,000) in 31% of infants during treatment with rEPO, with no difference noted if the rEPO was started early or late. No clinical manifestations of thrombocytosis were observed. In a large study of children with a mean age of 13 months, Vora and Lilleyman36 noted infection, iron deficiency, postoperative state, and postantineoplastic chemotherapy status as having possible associations with thrombocytosis. In another study, Chan and coworkers33 noted that most study infants having marked thrombocytosis (count of ⬎900,000) had infections, and none had com-

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plications. Early elevation of serum thrombopoietin levels is also related to subsequent thrombocytosis in low-birthweight preterm infants.37 Thrombocytosis has also been described in infants with Down’s syndrome, occurring from age 6 weeks to around 1 year.38 An elevation in the platelet count of infants with congenital adrenal hyperplasia (CAH) has also been noted. In a 1996 study by Gasparini and coworkers,39 patients with CAH were compared with age- and sex-matched healthy control infants. The patients with CAH were noted to have normal hemoglobin, hematocrit, and red blood cell counts while having significantly elevated white blood cell and platelet counts. Hemoconcentration due to dehydration and salt-wasting were ruled out as a cause since some blood counts remained normal. The exact mechanism is unknown, but is possibly due to a stress-related response of bone marrow precursors as can occur in sepsis. This thrombocytosis was noted to resolve within 4 weeks of treatment for CAH.39 Thrombocytosis is also seen in children with inflammatory conditions. An increased platelet count can be seen with gastroesophageal reflux disease (GERD). This is thought to occur due to a reaction of the esophageal mucosa to constant irritation of refluxing acidic gastric contents and could also be in part be due to recurrent bronchitis associated with GERD.13 Pharmacologic therapy used in neonates can also cause thrombocytosis. Van Reempts and coworkers40 noted thrombocytosis in 14% of 80 neonatal patients treated with ceftriaxone for suspected infection. Other drugs associated with neonatal thrombocytosis include aztreonam, imipenem-cilastatin, ceftizoxime, and ceftazidime.3 Maternal use of methadone is associated with thrombocytosis in the neonate, occurring at around 1 week of age and lasting up to 16 weeks. The mechanism of this is unknown.41 In a case report, Nako and coworkers42 reported an infant whose mother was on various nonnarcotic antischizophrenic medications (five different drugs) having a platelet count of 1,310,000 on day of life 15, which persisted for 3 months. Thrombocytopenia Thrombocytopenia is defined as a platelet count of less than 150,000 regardless of gestational age,43 and this definition is consistent for neonates, children, or adults.44 The incidence of neonatal thrombocytopenia varies greatly, depending on the patient population of interest. Two large studies report the occurrence of thrombocytopenia in all newborns to range from 0.7 to 0.9%, with these studies differing in whether infants of mothers with known thrombocytopenia were included and what value was used to define thrombocytopenia (100,000 versus 150,000).45,46

Among sick neonates, there is a much higher incidence of thrombocytopenia, reported at 18 to 35% among admissions to neonatal intensive care units.47 Thrombocytopenia in the neonate can be asymptomatic or can present with a variety of symptoms. Generalized superficial petechiae may be noted clustered on the head and/or upper chest after delivery (due to increased venous pressure) or at other sites in response to minor trauma or pressure.48 Melena, hematuria, blood-stained endotracheal secretions, and bleeding from previous puncture sites may also be noted.49,50 Another clinical sign of thrombocytopenia is evidence of previous significant bleeding, such as grade 3 to 4 intraventricular hemorrhage (IVH) or pulmonary hemorrhage.49 If an infant (or child, or adult) is thrombocytopenic, it is due to one of the following mechanisms (or possibly a combination): decreased platelet production, increased platelet destruction, or platelet sequestration.51 When evaluating an infant with thrombocytopenic purpura without coagulation abnormalities, the following factors regarding the infant should be considered: presence or absence of hepatosplenomegaly, congenital anomalies, and/or signs of sepsis. The mother should be evaluated for platelet count and appearance of her blood smear, history of hematologic and infectious diseases, complete drug history, and evidence of transmissible infection. The family should also be evaluated for presence of parental consanguinity and/or hematologic disease in family members.2 Decreased Platelet Production Pregnancy-induced Hypertension (PIH) and Intrauterine Growth Restriction (IUGR).

The pathogenesis of PIH and IUGR related thrombocytopenia in the neonate possess some similarities. The thrombocytopenia that occurs with both disorders is thought to be due to placental insufficiency and/or fetal hypoxia. Impaired megakaryocytopoiesis and platelet production are noted, with megakaryocytes and their precursor and progenitor cells noted to be decreased.52 In addition, levels of megakaryocytopoietic cytokine TPO are elevated.53 At birth, the platelet count of the neonate is usually low to normal (150,000 to 200,000) or borderline thrombocytopenic (100,000 to 150,000).49 The platelet count falls, with nadir reached at day 4 to 5, and usually recovers to greater than 150,000 by day 7 to 10.53 In the absence of other pathologic conditions causing platelet consumption, a precipitous decrease in the infant’s platelet count is not common, and the nadir is rarely below 50,000. In most cases, the platelet count does not fall low enough for significant risk of hemorrhage. Daily platelet counts

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are recommended to monitor the nadir; usually no treatment is required.49 Chromosomal Abnormalities. Some chromosomal abnormalities are noted to present with thrombocytopenia. Of infants with trisomy 18, 87% are thrombocytopenic; 54% of infants with trisomy 13 have thrombocytopenia as a presenting symptom, as do 31% of infants with Turner’s syndrome.54 Although some infants with trisomy 21 are thrombocytophilic, isolated thrombocytopenia occurs as well. In a study of 25 neonates with trisomy 21, 28% had platelet counts of ⬍100,000; all resolved within 2 to 3 weeks of life.55 In Noonan syndrome, a rare autosomal dominant disorder presenting with facial anomalies, congenital heart disease, skeletal abnormalities, and genital malformations, an association with myleoproliferative disorders (such as essential thrombocytopenia) has been observed.56 Alport’s syndrome, a genetic disorder associated with nephritis and nerve deafness, can present with thrombocytopenia and large platelets.57 Thromobcytopenia with absent radius syndrome (TAR) is another genetic disorder in which the low platelet count is due to decreased production of platelets; the inheritance pattern of this disorder is unclear.58 All infants with TAR present with thrombocytopenia and bilateral absence of the radii (but with both thumbs present). Other abnormalities often present, including congenital heart disease, renal problems, and abnormalities of the lower limbs. The thrombocytopenia is symptomatic within the first 4 months of life in 90% of patients, often resulting in gastrointestinal or intracerebral bleeding.58 The etiology of the thrombocytopenia is unknown; bone marrow samples show decreased, absent, or immature megakaryocytes.59 A study by Letestu and coworkers60 demonstrated an association with dysmegakaryocytopoiesis characterized by a blockage at an early stage of differentiation. Another study by Ballmaier and coworkers61 showed elevated serum TPO levels in patients with TAR, which excludes a TPO production defect as a cause of the thrombocytopenia associated with TAR. The defective megakaryocytopoiesis/thrombocytopoiesis in TAR is probably a lack of response to TPO in the signal transduction pathway.61 Platelet transfusion therapy is recommended for platelet counts of 10,000 to 20,000. Limiting donor exposure and leukoreduction of platelet concentrate are preferred. Congenital amegakaryocytic thrombocytopenia (CAT) is a rare bone marrow failure syndrome characterized by absence or a decreased number of megakaryocytes.62 Xlinked and autosomal recessive patterns of inheritance have been documented. Bone marrow transplant is currently the only curative option.63 In Fanconi anemia, there is decreased production of platelets due to bone marrow failure. These patients are pancytopenic and have various congenital anomalies (most commonly musculoskeletal

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and genitourinary). The anomalies are present at birth, but pancytopenia may not be noted until later in childhood.2 Increased Platelet Destruction Platelet destruction in the neonate can be from an immune response to antibodies in the neonatal circulation. In the following sections, autoimmune and alloimmune thrombocytopenia will be discussed, as well as immunemediated thrombocytopenia caused by drug interactions and thrombocytopenia caused by other disease states in the neonate. Autoimmune and Alloimmune Thrombocytopenia Alloimmune thrombocytopenia [neonatal alloimmune thrombocytopenia (NAIT)] and autoimmune thrombocytopenia have both similarities and differences. Both alloimmune and autoimmune thrombocytopenia are a result of extravascular platelet destruction by antiplatelet antibodies. In both types, IgG antiplatelet antibodies are produced in the mother and cross the placenta, where they then coat the infant’s platelets. This causes the monocytic–phagocytic system to remove the infant’s platelets from circulation, thus shortening the life span of the infant’s platelets to only a few hours.64 Isolated thrombocytopenia then occurs, with the biggest risk to the infant being significant hemorrhage (especially intracranial hemorrhage). The duration of these types of thrombocytopenia in the fetus is weeks to a few months.65 Autoimmune thrombocytopenia occurs in infants of mothers with an autoimmune disease such as idiopathic thrombocytopenia purpura (ITP) or systemic lupus erythematosus (SLE). Thrombocytopenia occurs in approximately 10% of cases in which the mother has ITP or SLE, and intracranial hemorrhage occurs in approximately 1% of infants of mothers with ITP or SLE.66 Immunoglobulin binds to the mother and infant’s platelets, and maternal antiplatelet autoantibodies cause destruction of platelets in the infant and the mother.67 Therefore, the mother as well as the infant are thrombocytopenic. Antiplatelet antibodies do not show specificity (they have broad reactivity with all platelets). Levels of platelet associated IgG are elevated on both the infant’s and the mother’s platelets.68 The severity of the maternal disease and maternal platelet count can usually predict the neonatal platelet count.69 Thrombocytopenia usually lasts 1 to 2 months in the infant, with spontaneous recovery the usual course.70 Burrows and Kelton71 reported in 1990 that when a mother is known to have autoimmune disease, the neonate should have a platelet count done on the cord blood and then daily platelet counts for up to the first week. They further state

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that the infant usually reaches the lowest point during this time and a spontaneous increase is seen by day 7. The course of the first infant delivered from a mother with active ITP usually predicts the course of the next sibling.65 A study by Christiaens and coworkers72 showed that the subsequent infants of mothers with ITP did not have severe thrombocytopenia (platelet count ⬍ 50,000) if the first sibling’s platelets remained greater than 50,000. In addition, if severe thrombocytopenia was experienced by a previous infant; this is predictive of thrombocytopenia complicating the current pregnancy.69 IgG antibodies are transferred via breast milk, so the question has been raised regarding the effect of breastfeeding on the neonatal platelet count. James Bussel reports one neonate in whom severe neonatal thrombocytopenia resolved only with the cessation of breastfeeding. His practice is to monitor the platelet count of breastfed infants of mothers with ITP, and document a return to normal of the infant’s platelet count.65 If severe thrombocytopenia is present, intravenous immunoglobulin (IVIG) may be given to the affected neonate.73 A study published by Ovali and coworkers70 in 1998 compared different treatments of thrombocytopenic infants of mothers with ITP. The infants received IVIG, and, if unresponsive, were given steroids. The majority did not have satisfactory results with IVIG alone, and the success of treatment may have been due to combined treatment. Further study was recommended. Neonatal alloimmune thrombocytopenia occurs secondary to maternal antiplatelet antibodies, which are able to cross the placenta at 14 weeks’ gestation.74 The mother develops immunity to antigens inherited from the father and located on fetal platelets. If the father is homozygous for a specific platelet antigen, that antigen is passed to the fetus; if the father is heterozygous for the antigen, there is a chance that the fetus won’t inherit the antigen.75 IgG antibodies are transferred from the mother to the fetus via the placenta. Maternal IgG antibodies react with antigens on fetal platelets, and the fetal platelets, which are now coated with IgG, are phagocytized by macrophages and destroyed.76 These mothers had no history of bleeding and a normal platelet count.11 The most common antigen is the HPA 1a, occurring in 1 in 350 white pregnancies.77 Less commonly occurring antigens are Bak, anti-Yuk, anti-Pen, anti-DUZO, and anti-Pl.11 The reported incidence in the United States is ⬃2,500 infants.78 Severe outcomes in infants with NAIT are reported to occur in 1 per 1,000 to 2,000 pregnancies per year.79 It is also thought that subclinical cases of NAIT can occur in which the infant inherits paternal platelet antigen that causes maternal antiplatelet antibody formation, but the antibodies don’t have enough potency to cause throm-

bocytopenia in the infant. In addition, some women don’t form HPA antibodies despite exposure.75 The fetal thrombocytopenia that occurs with NAIT can be severe and can have early onset. Fetal platelet alloantigens can be fully expressed by 16 to 18 weeks’ gestation,80 and significant fetal thrombocytopenia has been documented at less than 20 weeks’ gestation.74 The major risk to the fetus/neonate is intracranial hemorrhage (ICH) due to severe thrombocytopenia, with death occurring in 10% of affected infants, and neurologic sequelae in 20%.81 NAIT causes more ICH than any other hemostatic disorder in the newborn period.82 These complications occur in otherwise well newborns and fetuses. The recurrence rate of NAIT is 100% among platelet antibody–positive siblings, and subsequent siblings are usually equally or more severely affected. In addition, the mother’s female relatives are also at risk, and testing should be considered before the birth of their first child.83 As previously mentioned, the mother is usually well with a normal platelet count and does not have a history of ITP or other autoimmune diseases. The affected infant’s CBC is usually otherwise normal.83 In addition to a low platelet count, the infant’s platelets may also have subnormal functioning.84 Since routine maternal prenatal screening does not include platelet autoantibodies, maternal platelet immunization is not usually detected until the birth of an affected child. The usual presentation is a term infant of a healthy mother with purpura and/or petechiae within a few hours of life and severe thrombocytopenia without other signs of disseminated intravascular coagulopathy (DIC) or sepsis. When given a random donor platelet transfusion, the infant’s platelet count usually does not improve or only improves transiently (for a few hours at most).83 Transfusion of maternal or matched platelets is considered the optimal treatment for rapidly increasing the platelet count in infants with severe thrombocytopenia. When using maternal platelets, donor screening for transmissible infections must still be performed, and this delays the availability of maternal platelets. Also, the platelets are usually “washed” to remove maternal plasma, which may contain antibody from the platelets. The washing process can damage the platelets and decrease their function.64 IVIG (with or without the use of steroids) can be used in the infant to increase the platelet count,64,83 but an increase in the platelet count is not usually seen for 24 to 72 hours.64 Antenatal treatment can include administration of IVIG and prednisone to the mother as well as platelet transfusions for the fetus.84 Difficulties exist related to routine prenatal screening for NAIT. Approximately 20% of women do not have detectable circulating antibodies, so the maternal antibody level is not useful for predicting fetal thrombocytopenia.85 The fetal platelet count can be directly measured via fetal

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blood samples obtained by percutaneous umbilical vessel blood sampling (PUBS). The risks of PUBS include fetal loss from hemorrhage, preterm delivery, cardiac arrhythmias, and an increase in antibody levels due to fetomaternal hemorrhage.86 The risk of fetal loss is ⬃1% per procedure and greater than 5% when serial transfusions are done.87 It is possible to perform platelet antigen typing by DNA-based platelet typing. This confirms serologic typing, distinguishes heterozygotes from homozygotes, allows diagnosis of the fetus without fetal blood sampling, and provides the diagnosis of uncommon platelet antigen types.82 This type of testing is very expensive and not practical for routine use. Respiratory Distress Syndrome (RDS) Autopsies performed on infants with RDS show microthrombi of the pulmonary vessels.88 In infants with RDS, there is an increased amount of fibrin deposited in the vessels and alveoli of the lungs. This may lead to the release of procoagulants and activation of the coagulation system and therefore increased platelet consumption.89 In addition, animal models show mild thrombocytopenia in animals ventilated in the absence of lung disease.90 Infections Infants with infections are noted to have thrombocytopenia, even in the absence of DIC. Three possible causes for this have been suggested and include direct effects by the organism or its toxic products, immune-mediated injury, and adhesion of the platelets to the subendothelial layer of injured blood vessels.2 Not all infants with a bacterial infection are thrombocytopenic at the onset of the infection, but many develop thrombocytopenia during the course of the illness.91 Murray and coworkers92 describe the course of thrombocytopenia with sepsis and/or necrotizing enterocolitis (NEC) as being predictable, with the platelet count decreasing precipitously (nadir reached by 24 to 48 hours). The thrombocytopenia can be severe, with platelet counts often ⬍50,000. Careful monitoring is recommended to follow the platelet nadir so that transfusions can be given as needed. Although these patients often require platelet transfusions, the recovery can occur over 5 to 7 days as the sepsis/NEC improves.92 Thrombocytopenia is also noted in congenital infections and is likely due to both accelerated destruction of platelets and diminished production of platelets. Reticuloendothelial hyperactivity and splenomegaly often accompany congenital viral infections and could lead to accelerated removal of platelets from circulation. Vacuolization of megakaryocytes has also been reported and

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would decrease production of platelets.93 Congenital viral infections that cause thrombocytopenia in the neonate include all TORCH infections, coxsackie virus B, Epstein Barr, mumps, adenovirus, and echovirus.93–95 Fungal infections are also noted to cause thrombocytopenia in the neonate. A study by Padovani and coworkers96 demonstrated 73% of infants with fungal sepsis presented with thrombocytopenia. Another study by McDonnell and Isaac97 recommends empirical antifungal treatment while awaiting culture results in clinically septic extremely low-birth-weight infants. Malassezia furfur can occur in infants receiving intravenous lipids and also features severe thrombocytopenia.98 Disseminated Intravascular Coagulation Disseminated intravascular coagulation occurs when an underlying disease process is complicated by increased tissue factor activity, cytokine release, and excess thrombin production. This causes a consumptive coagulopathy.99 Thrombocytopenia is noted in addition to other abnormalities of various clotting factors.100 This coagulation activation can be triggered by acidosis, poor perfusion, or endotoxins and is noted in infants with sepsis, RDS, meconium aspiration syndrome (MAS), and amniotic fluid aspiration.44 Kasabach Merritt Syndrome Giant hemangiomas associated with consumptive coagulopathy are known as Kasabach Merritt Syndrome. These vascular tumors can reside in the internal organs, head or neck area, or the extremities. The infant’s platelets are trapped within the hemangioma, and the associated thrombocytopenia is often severe with onset within the first 3 months of life.101 Laboratory findings in the infant will include an acute decrease in the platelet count, prolongation of PT, PTT, hypofibrinogenemia, increased fibrin degradation products. Giant platelets and red blood cell fragments are common on blood smear.102 Most lesions can be successfully treated with steroids or alpha interferon. If these treatments are not successful, the hemangioma may require surgery, embolization, or radiation.103 Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome is a rare, sex-linked recessive disorder. Clinical findings include chronic thrombocytopenic purpura, atopic dermatitis, and an increased incidence of recurrent infections. Also noted is an increased incidence of malignancy (especially lymphoma).2 The infant’s platelets are noted to be decreased in size and also have decreased aggregation and decreased survival time.

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Splenic sequestration may occur. Normal megakaryocytes are noted in the bone marrow.89 The general prognosis is poor, but a bone marrow transplant from a hapto-identical sibling has been successful. Some success has also been noted with a bone marrow transplant from hapto-identical parents and matched, unrelated donors.104

Asphyxia Perinatal hypoxia has been associated with severe and prolonged thrombocytopenia. DIC is often present due to tissue damage leading to increased tissue factor, triggering the coagulation cascade. However, some infants have a decreased platelet count without DIC or persisting beyond the resolution of DIC. The decreased platelet count is thought to be due to direct deleterious effects of hypoxia on the megakaryocyte progenitors.105

Thrombosis Indwelling catheters such as umbilical artery and venous catheters can lead to neonatal thromboses, which consume platelets and cause thrombocytopenia in the infant. The thrombus can be asymptomatic but can cause significant impairment of organ function where the thrombus impedes blood flow.89 Thrombus development is also seen with homozygous protein C deficiency.106 Several case reports describe the successful treatment of the thrombocytopenia occurring with homozygous protein C deficiency with heparin or other anticoagulants.106 –108

Maternal Pharmacologic Agents Thrombocytopenia as a result of maternal–fetal drug interaction is thought to be caused by immune mediated platelet destruction. This has been noted with the maternal use of quinidine as well as some anticonvulsants (carboamazopine, phenytoin, and valproic acid).89 Thrombocytopenia has also been noted with the maternal use of thiazides, but it is unclear whether the pharmacologic agents or the maternal hypertension was associated with the neonatal thrombocytopenia.109 The use of heparin in the neonate as a treatment for thrombolic complications has also been associated with thrombocytopenia in the newborn.110 In vitro studies have also described thrombocytopenia as a possible adverse effect with ampicillin and furosemide; however, no clinical correlation is reported.3

Conclusion

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he causes of platelet dysfunction in the neonate are varied. Knowledge of various types of platelet dysfunction in the neonatal population will lead to timely identification of an infant’s individual disorder. With a systematic approach, the pathophysiology of the dysfunction can be determined so that appropriate treatment options can be offered.

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