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Thursday, April 23, 2009

Neonatal Thrombocytopenia: Evaluation and Management

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More: National Association of Neonatal Nurses 22nd Annual Conference

Selection from: Highlights of the National Association of Neonatal Nurses 22nd Annual Conference
Neonatal Thrombocytopenia: Evaluation and Management CE
Laura A. Stokowski, RN, MS

Thrombocytopenia in the Neonate: A Common Clinical Problem
A newborn infant, in apparent perfect health, is found to have a platelet count of 50,000/mcL on the first day of life. A preterm infant, born at 27 weeks of gestation, develops platelet counts as low as 30,000/mcL at 3 weeks of age. The platelet count of a term infant born of a mother with a history of idiopathic thrombocytopenia is 280,000/mcL at birth but falls to 80,000/mcL by the third day of life.

Do the infants in these familiar clinical scenarios have thrombocytopenia? Which infants require treatment? What is the best therapeutic approach? And what is likely to happen if no specific treatment is undertaken?

In his presentation, "Evaluation and Treatment of Thrombocytopenia in the NICU," at the National Association of Neonatal Nurses 22nd Annual Conference, Robert Christensen, MD, from the Department of Women and Newborns, Intermountain Healthcare, McKay-Dee Hospital Center, Ogden, Utah, addressed the often vexing clinical questions surrounding thrombocytopenia in the neonate.[1]

The fetal platelet count increases linearly with gestation from a mean of 187,000/mcL at 15 weeks to 274,000/mcL at 40 weeks. Normal platelet counts in preterm infants are in the identical range (150,000/mcL to 450,000/mcL) as that of adults. Thus, at any age, a platelet count less than 150,000/mcL is abnormally low, so by definition, all 3 infants in the preceding scenarios are thrombocytopenic. The clinical significance of platelet counts in the 100,000-150,000/mcL range is unclear. Although abnormal, these counts may not convey an increase in bleeding risk.

The incidence of thrombocytopenia varies by population. In the well newborn population, the incidence is less than 1%. In the neonatal intensive care unit (NICU), however, the incidence is much higher. Thrombocytopenia develops in 18% to 35% of NICU patients, and in 73% of extremely low birth weight (ELBW) infants.

Not all thrombocytopenia among NICU infants is of equal severity. About 75% of cases are considered mild (100,000-150,000/mcL) to moderately severe (50,000-100,000/mcL). The remaining 25% are severe (less than 50,000/mcL). Among ELBW infants, a high proportion is classified as severe.

Thrombocytopenias in the neonate can be classified according to underlying pathophysiologic cause and sometimes by kinetic mechanism resulting in a low platelet count (Table 1).

Table 1. Classification of Neonatal Thrombocytopenia
Kinetic Mechanisms
• Decreased platelet production
• Accelerated platelet destruction or sequestration
Pathophysiologic Categories
• Immune-mediated
• Infectious
• Genetic
• Drug-related
• Disseminated intravascular coagulation
• Miscellaneous

The major mechanism underlying neonatal thrombocytopenia, accounting for about 75% of cases, is impaired platelet production.[2] Increased platelet consumption and/or sequestration are the chief mechanisms in the remainder of cases. In some neonates, a combination of mechanisms (reduced platelet production and accelerated destruction) is responsible for the low platelet count.

Laboratory evaluations can provide clues to the kinetic mechanism of an infant's thrombocytopenia. Mean platelet volume (MPV) is a measure of the average size of circulating platelets. MPV is normal (7.5-9.5 fL) when thrombocytopenia is caused by reduced production, and elevated (> 10-12 fL) when caused by accelerated destruction. Larger platelets are evident when the bone marrow is stimulated to produce more immature platelets in response to increased platelet utilization. MPV is measured by automated analyzers and is reported along with the platelet count or can be obtained by calling the laboratory. The percentage of reticulated platelets (RPs) is another indicator of the kinetic mechanism. RPs are newly produced platelets that have a higher ribonucleic acid content than do older platelets.[3] RP% is low (< 2%) when platelet production is low, and high (> 10%) when platelets are being consumed at an accelerated rate.

Thrombopoietin (Tpo), a growth factor, is the primary regulator of platelet production in the neonate. Plasma Tpo may be useful in differentiating thrombocytopenia caused by low platelet production and accelerated platelet destruction. Made constitutively in the liver, Tpo is removed from the blood by binding to Tpo receptors on megakaryocyte progenitors, megakaryocytes, and platelets. When platelet production is abnormally low, fewer megakaryocytes are produced and plasma Tpo is high. Although still a research tool, measurement of plasma Tpo may provide valuable diagnostic information in infants with thrombocytopenia in the future.

Immune-Mediated Thrombocytopenia
Neonatal Alloimmune Thrombocytopenia. Neonatal alloimmune thrombocytopenia is a condition that affects 1 in 2000 live births. These otherwise healthy newborns present with petechiae and low platelet counts. The pathogenesis of neonatal alloimmune thrombocytopenia is analogous to Rh hemolytic disease of the newborn. Mothers of affected infants have normal platelet counts. The fetus carries an antigen (usually the HPA-1a) that is foreign to maternal platelets and sensitizes the mother. Transplacental antibodies produced by the mother in the second trimester destroy fetal platelets, resulting in thrombocytopenia. Unlike Rh disease, a first pregnancy can be affected. Intracranial hemorrhage, which can occur prior to birth, is found in about 10% to 15% of affected neonates.

Neonatal Autoimmune Thrombocytopenia. In autoimmune thrombocytopenia, the mother has idiopathic thrombocytopenia or systemic lupus erythematosus and is thrombocytopenic. Maternal antiplatelet antibodies cross the placenta and destroy fetal platelets. Because the neonate's platelet count falls to its nadir at 2-5 days of age, it is important to measure more than a single platelet count. Severe thrombocytopenia and intracranial hemorrhage in these neonates are rare.

Infection-Mediated Neonatal Thrombocytopenia
More than 80% of neonates with proven infections become thrombocytopenic. Bacterial, fungal, and viral infections have all been associated with neonatal thrombocytopenia.

Bacterial Infections. Bacterial infection causes endothelial damage, thus accelerating destruction of platelets and their removal by the reticuloendothelial system. At the time bacterial infection is diagnosed, 25% of neonates will already have low platelet counts. By 36-48 hours later, virtually all will be thrombocytopenic. It is commonly believed that thrombocytopenia associated with bacterial infection is caused by disseminated intravascular coagulation (DIC), but DIC is actually present in a minority of cases. The average duration of bacterial infection-mediated thrombocytopenia is 6 days.

Fungal Infections. The majority (75%) of neonates with fungal infection are thrombocytopenic at the time of diagnosis. Thrombocytopenia may be the most important clinical finding in neonates with Candida sepsis.

Viral Infections. Viral infections cause thrombocytopenia by a combination of reduced platelet production and accelerated platelet destruction. Thrombocytopenia is universal in TORCH infections. (TORCH, as an acronym, stands for toxoplasmosis, other [T pallidum, varicella-zoster virus, parvovirus B19], rubellavirus, cytomegalovirus (CMV), and herpes simplex virus. In particular, CMV is associated with severe thrombocytopenia. Coxsackievirus B and ECHO 11 not only cause severe thrombocytopenia but myocarditis and central nervous system involvement as well. Parvo B19 infection can cause anemia and hydrops. HIV does not generally cause thrombocytopenia in the neonate.

Genetic Neonatal Thrombocytopenia
A dysmorphic neonate with mild to moderate thrombocytopenia (50,000-150,000/mcL) most likely has a genetic syndrome associated with thrombocytopenia, such as trisomy 13, 18, 21, triploidy, or Turner's, Noonan's, Alport, or Wiskott-Aldrich syndromes. Some metabolic disorders, such as the organic acidemias isovaleric and methylmalonic acidemia, are also associated with neonatal thrombocytopenia.

Thrombocytopenic absent radius syndrome (TARS) is an autosomal recessive disorder in which radii are absent bilaterally but thumbs are present. Forearms are foreshortened and bowed. Thrombocytopenia is severe, and a third of babies also have congenital heart disease. Platelet counts of infants with TARS gradually decrease over the first year of life, resulting in early death from bleeding at 1 or 2 years of age.

Congenital amegakaryocytic thrombocytopenia is caused by a defect in the Tpo receptor. Severe thrombocytopenia with eventual pancytopenia usually leads to death from hemorrhage.

Drug-Related Thrombocytopenia
Few drugs have been proven to cause neonatal thrombocytopenia. Quinine taken during pregnancy is associated with maternal and neonatal thrombocytopenia. Heparin can cause thrombocytopenia in about 10% of adults, but this is probably rare in neonates.

Miscellaneous Causes of Neonatal Thrombocytopenia
Thrombocytopenia is common and often severe in infants with necrotizing enterocolitis (NEC). Platelet destruction occurs in the endothelium of vessels that supply blood to areas of bowel in the early stages of necrosis. Thrombocytopenia is also associated with intrauterine growth restriction and infants who are small for gestational age; the pathogenic mechanism is low platelet production.

Birth asphyxia is also associated with thrombocytopenia, although hypoxia alone does not appear to be sufficient to decrease platelets. Infants born of mothers with pregnancy-induced hypertension are often thrombocytopenic, but it is not severe or prolonged. Severe and prolonged thrombocytopenia can occur, however, as a result of thrombus formation along an intravascular catheter, in the renal vein, right atrium, or sagital sinus. Platelets adhere to the propagating clot, resulting in low circulating platelet count.

Evaluation and Management of Neonatal Thrombocytopenia
Diagnostic Evaluation
Supplementing the platelet count are indirect measures of platelet production or destruction such as mean platelet volume, reticulated platelet count, and plasma Tpo, if available. The length of time between transfusions (ie, how much time elapses after a platelet transfusion before the platelets drop again) indicates how quickly the platelets are being destroyed.

A bone marrow biopsy to quantify megakaryocytes is the only direct way to determine the true pathophysiologic mechanism. A biopsy showing few megakaryocytes confirms low platelet production, while the finding of many megakaryocytes signifies accelerated platelet destruction. This information can guide treatment of the thrombocytopenic infant.

In the United States, there are no guidelines for platelet transfusions in newborns. Experts suggest that platelets should be given when the degree of thrombocytopenia alone or in combination with other factors results in an unacceptable risk of hemorrhage.[2] Transfusion with 15 mL/kg (infant's body weight) of CMV-negative platelet suspension, prepared from a unit of whole blood or plasmapheresis, is the most common treatment for thrombocytopenia. In the absence of additional diagnostic data, indications for transfusion depend upon the infant's clinical condition and platelet count (Table 2).

Table 2. Indications for Platelet Transfusion in Neonates
Clinical Condition Platelet Count
Stable neonate < 25,000/mcL
Unstable neonate < 50,000/mcL
Neonate on ECMO < 100,000/mcL

ECMO = extracorporeal membrane oxygenation
A higher threshold is used for unstable infants because they are at greater risk of hemorrhage. Multiple platelet transfusions are usually necessary for infants with liver disease because of the failure of the hepatocyte to produce sufficient Tpo to stimulate platelet production in the bone marrow. Infants on extracorporeal membrane oxygenation also require daily transfusions to maintain hemostasis. Multiple platelet transfusions are associated with higher mortality rates, regardless of degree of illness.[4]

Intravenous immune globulin (IVIG), composed primarily of immunoglobulin (Ig)G with trace amounts of IgA and IgM, transiently increases platelet counts in some infants with thrombocytopenia. The mechanism of action of IVIG is not completely understood but is believed to involve blockade of platelet Fc receptors on reticuloendothelial cells and suppression of antibody production and binding. IVIG is the first-line treatment for neonates with neonatal autoiummune thrombocytopenia and may also be useful in neonatal alloiummune thrombocytopenia.

Severe and Prolonged Thrombocytopenia
Certain neonatal conditions are associated with severe and prolonged thrombocytopenia (Table 3). The mechanisms of thrombocytopenia associated with these conditions, along with platelet production indices, can be used to predict the patient's probable response to platelet transfusion.

Table 3. Severe and Prolonged Thrombocytopenia
Cause MPV RP% Mechanism
Alloimmune High High Immune reticulo-endothelial destruction
NEC/necrotic bowel High High Platelet adhesion to damaged epithelium
Fungal sepsis High High Platelet adhesion to damaged epithelium
Marrow failure Normal Low Impaired production
Liver disease Normal Low Impaired Tpo production

MPV = mean platelet volume; RP = reticulated platelets; NEC = necrotizing enterocolitis
Case Studies: Will These Infants Benefit From Platelet Transfusion?
The following case studies illustrate the considerations used to determine whether an infant with thrombocytopenia will benefit from platelet transfusion. Questions to ask about each case study are: (1) What is the kinetic mechanism causing the infant's thrombocytopenia; and (2) What do you predict will be the infant's response to a platelet transfusion?

Case 1. 27 weeks' gestation AGA (appropriate for gestational age) neonate who had normal platelet count at birth. Now 25 days old, recovering from NEC, still taking nothing by mouth and on antibiotics. Platelet count has been 30-40,000/mcL for 1 week. Mean platelet volume is 12 fL; reticulated platelets 10%.

Answer: The underlying cause of the thrombocytopenia in this situation is accelerated platelet usage or destruction. Platelets transfused into this infant are likely to have a short survival.
Case 2. 37 weeks' gestation nondysmorphic neonate whose platelet count has been < 50,000/mcL since birth. At 5 days of age, stools are hematest-positive and platelet count is 18,000/mcL. MPV is 7.3 fL; reticulated platelets 1%.

Answer: In this case, the underlying cause of low platelets is reduced platelet production. Transfused platelets will have a normal survival.
Neonatal thrombocytopenia is a clinical problem that can be either benign or serious, depending upon factors such as the underlying cause and the health of the neonate. By evaluating not only platelet counts but also indices of platelet production, the practitioner can gain a better understanding of the significance of the infant's thrombocytopenia and the appropriate therapy.



Christensen R. Evaluation and treatment of thrombocytopenia in the NICU. Program and abstracts of the National Association of Neonatal Nurses 22nd Annual Conference; November 8-11, 2006, Nashville, Tennessee.
Roberts I, Murray NA. Neonatal thrombocytopenia: causes and management. Arch Dis Child Fetal Neonatal Ed. 2003;88:F359-F364. Abstract
Sola MC. Evaluation and treatment of severe and prolonged thrombocytopenia in neonates. Clin Perinatol. 2004;31:1-14. Abstract
Christensen RD, Henry E, Wiedmeier SE, et al. Thrombocytopenia among extremely low birthweight neonates: data from a multihospital healthcare system. 2006;26:348-353.


Suggested Reading

Suggested Reading
Jones CW. Platelet disorders. NBIN 2004;4:181-190. Available at: http://www.medscape.com/viewarticle/497026. Accessed November 20, 2006.

Go to CE Test Questions »

Contents of: Highlights of the National Association of Neonatal Nurses 22nd Annual Conference

All sections of this activity are required for credit.
Safety in the NICU: Preventing Medical Errors
Laura A. Stokowski, RN, MS

Developmental Care in NICUs -- Getting It to the Bedside
Maureen O'Reilly, RNC, APNP

Neonatal Thrombocytopenia: Evaluation and Management
Laura A. Stokowski, RN, MS

The Loss of an Infant -- Universal Grief and Transcultural Education
Maureen O'Reilly, RNC, APNP

Keeping New Nurses -- Tools to Live By
Maureen O'Reilly, RNC, APNP
Go to CE Test Questions »
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