OVERVIEW: What every practitioner needs to know

Are you sure your patient has thrombocytopenia? What are the typical findings for this disease?

Neonatal thrombocytopenia is defined as a concentration of platelets in the blood falling below the “reference range” for gestational age. In adults, non-neonatal children, and term neonates, this lower reference range limit is 150,000/μL, and therefore thrombocytopenia is defined as a platelet count <150,000/μL.

However preterm infants have a range of platelet counts that includes lower values. At gestations below 32 weeks the reference range includes values down to 100,000/μL, and therefore thrombocytopenia in these preterm neonates is defined by a platelet count <100,000/μL. Counts among neonates <32 weeks gestation that fall in the range of 100,000 to 150,000/μL, were previously considered “mild thrombocytopenia”, but given new data on over 40,000 patients, counts in this range should now be considered normal.

Prevalence: Thrombocytopenia is distinctly uncommon among healthy term neonates, with a prevalence of about 1 case per 1000 live births. In contrast, thrombocytopenia is common among neonates admitted to a NICU. About 25% of NICU patients will have thrombocytopenia identified at some time during their NICU stay. Among extremely low birth weight neonates (<1 kg birth weight) thrombocytopenia is even more common; about 70% will have thrombocytopenia identified at some time during their hospital stay.

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What other disease/condition shares some of these symptoms?

Neonatal thrombocytopenia can be artifactual. Low platelet counts in neonates who have no clinical signs of platelet inadequacy (no petechiae, no bruising, no evidence of prolonged bleeding) should have the platelet count repeated, and verified by an examination of the blood film. Artifactual neonatal thrombocytopenia can result from platelet adherence to a poorly-bleeding heel-stick, or from clumping of platelets during or after the phlebotomy procedure.

What caused this disease to develop at this time?

Many conditions, diseases, and disorders in neonates can produce thrombocytopenia.

In apparently healthy term neonates with severe thrombocytopenia, alloimmune thrombocytopenia should be the prime consideration.

In term neonates who are ill with respiratory distress or hypotension, congenital infections (CMV or viral or bacterial sepsis) with or without DIC should receive prime consideration.

Among neonates with obvious congenital anomalies and severe thrombocytopenia, it is likely that thrombocytopenia is part of the syndrome. Moreover, it is likely that the kinetic variety of thrombocytopenia involves impaired platelet production. Examples include the trisomy syndromes and in association with specific orthopedic anomalies (TAR and CAMT with radio-ulnar synostosis).

In preterm infants, a variety of causes can be culpable. As a step toward arriving at the precise diagnosis, it is sometimes helpful to determine whether the thrombocytopenia in an ill preterm neonate is the result of decreased platelet production versus accelerated platelet destruction/usage.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In term healthy-appearing neonates with severe thrombocytopenia, identifying antiplatelet antibodies in the mother’s serum, which react against the father’s platelets, is helpful in coming to this diagnosis. Women who lack certain platelet antigens, which are present on their fetus’ platelets, can develop antibody to the offending antigen. These antibodies can cross the placenta and bind to fetal platelets resulting in fetal/neonatal thrombocytopenia.

Appropriate cultures for bacteria and CMV (urine).

Coagulation studies; PT, aPTT, fibrinogen.

Karyotype or other genetic studies when appropriate (particularly if trisomy 13, 18, 21 are suspected). Note: thrombocytopenia is very common in these syndromes, but it is usually not severe. Platelet counts <50,000/μL in a patient with what appears to be syndromic-associated thrombocytopenia should prompt examination for alternative causes. The exceptions are neonates with TAR (thrombocytopenia and absent radii) and CAMT (congenital amegakaryocytic thrombocytopenia), where thrombocytopenia can be very severe.

MPV (mean platelet volume) will be very low in Wiscott-Aldrich syndrome, generally normal in hyporegenerative thrombocytopenias, and generally elevated (>12 fL) in accelerated platelet turnover or loss (due to immune mechanisms, DIC, thrombi). The same pattern is seen in the Immature Platelet Fraction (IPF).

Severe/chronic cases of thrombocytopenia in neonates is sometimes the result of a combination of kinetic mechanisms (reduced production plus accelerated turnover). Neonatal liver disease can be associated with severe and prolonged thrombocytopenia. This variety is often the result of reduced platelet production (thrombopoietin is produced in the liver) AND accelerated platelet turnover (sometimes due to hypersplenism and/or DIC).

Would imaging studies be helpful? If so, which ones?

Imaging studies in neonates with thrombocytopenia are helpful in cases where the differential diagnosis includes a propagating thrombus. Neonates with an indwelling vascular catheter and thrombocytopenia (particularly those with a high MPV and no other apparent cause of the thrombocytopenia) might have ultrasound studies focusing on the catheter tip, and/or might have a “lineogram” with contrast material gently injected through the catheter, with examination for partial or complete vascular obstruction.

If you are able to confirm that the patient has thrombocytopenia, what treatment should be initiated?

Treatment depends on the condition of the neonate (actively bleeding, high risk for bleeding, low risk for bleeding) and the platelet count (or the platelet mass).

Thrombocytopenic hemorrhage

Platelet transfusion is the primary treatment available for neonatal thrombocytopenic hemorrhage. In general, a transfusion should be considered for any neonate with active bleeding (particuarly significant pulmonary or gastrointestinal hemorrhage, or bleeding/oozing from multiple IV sites or venipuncture sites) AND a platelet count <100,000/μL. The donor platelets should be transfused in a volume of 15 to 20 mL/kg body weight over a period of 1 to 3 hours (a one-hour infusion will generate a higher post-transfusion platelet count; a 3-hour infusion might be needed if you judge the patient cannot tolerate that volume of fluid rapidly).

We recommend neonates receive non-pooled and non-packed platelets. Pooling exposes neonates to addition donors and packing diminishes effective platelet plug formation of the donor platelets.

Thrombocytopenia with no hemorrhage

Over 90% of platelet transfusions given in NICUs in the United States are administered to neonates who do not have active bleeding. These transfusions are given as prophylaxis against bleeding. Additional study is needed to define which thrombocytopenic neonates should receive prophylactic platelet transfusions. Current recommendations for prophylactic platelet transfusions are based on; 1) condition of the patient and 2) either the platelet count (count-based guidelines) or the platelet mass (mass-based guidelines).

Guidelines for platelet transfusion of NICU patients.

Two sets of guidelines are shown in Table I; platelet count-based and platelet mass-based. The principal advantage of the mass-based guidelines is approximately 1/3 fewer platelet transfusions are administered, because neonates with large platelets who are transfused using the count-based guidelines are not transfused using the mass-based guidelines.

Table I.
Condition of the Patient Platelet Count (x103/µL) Platelet Mass*
ECMO, pre or post surgery, clinical bleeding 50 – 99 400 – 792
Unstable (but not bleeding) 20 – 49 160 – 399
Stable <20 <160

*Platelet mass = platelet count (x103/µL) X mean platelet volume (fL). For example, with a platelet count of 50,000/µL and a MPV of 10 fL, the platelet mass is 50 X 10 = 500.

Are there additional treatment options?

Thrombopoietin Mimetics – Recombinant thrombopoietin is not available in the United States as a pharmacological agent due to association with aplastic anemia, on the basis of antibody formation, in a few patients during clinical trials. Agonists of the thrombopoietin receptor (c-mpl) have been developed as a better alternative. Two have been FDA approved for specific indications among severely thrombocytopenic patients. No information on dosing nor indications for use have been developed for neonates, thus they are not recommended for use in neonates at this time.

Corticosteroids – These can be effective for older children with ITP, but are seldom used in neonates with thrombocytopenia.

What are the adverse effects associated with each treatment option?

Before platelet transfusion is ordered, careful consideration should be given to potential benefits and risks. For neonates with thrombocytopenic hemorrhage, platelet transfusions can be life-saving. However, benefits of prophylactic platelet transfusion are not well defined. Risks of platelet transfusions include bacterial infection (this risk is diminishing with employment of new microbial inactivation protocols in blood banks), hypotension, respiratory deterioration and increasing the area of necrosis (when given to a thrombocytopenic neonate who has necrotizing enterocolitis).

Several studies show a relationship between the number of platelet transfusions and mortality. Some of this can be explained by the fact that sicker neonates receive more platelet transfusions. However, sensitivity analyses indicate that some fo the explanation likely involves adverse effects of multiple platelet transfusions themselves as an independent risk factor.

Among neonates who received >20 platelet transfusions, almost all are due to acquired consumptive thrombocytopenia (associated with the use of ECMO or fungal sepsis, NEC, or bacterial sepsis). In one series 50% of these died and 100% of survivors developed chronic lung disease.

Among neonates that developed “severe thrombocytopenia” (two or more platelet counts <50,000μL) mortality rate did not correlate with the lowest platelet count, but was proportionate to the number of platelet transfusions.

What complications might you expect from the disease or treatment of the disease?

Severe thrombocytopenia can result in bleeding as a result of inadequate platelet plug formation. Generally, platelet-type hemorrhage consists of epistaxis, pulmonary hemorrhage, gastrointestinal hemorrhage, cutaneous hemorrhage (bruising and petechiae), and oozing from IV sites or incisions.

Are additional laboratory studies available; even some that are not widely available?

Platelet function can be assessed, in neonates, using the template bleeding time, the PFA100 closure time, thromboelastography, and whole blood impedance aggregometry. These tests are practical in neonates because they require very small volumes of blood for testing. However, these tests are not needed (not helpful) in thrombocytopenic neonates, particularly those with a platelet count <50,000/uL. The reason is that the test will be abnormal (prolonged) on the basis of thrombocytopenia. These tests, assessing platelet plug formation, are best reserved for neonates who have clinical bleeding issues (particularly petichiae and bruising) with a NORMAL platelet count. In such cases the tests can yield information regarding platelet function.

What is the evidence?

Baer. “Do platelet transfusion in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system”. J Perinatol. vol. 27. 2007. pp. 790-796. (Platelet transfusions can be life-saving, but they also carry risks. This study is one of several to identify a relationship between the number of platelet transfusions received and the mortality rate. However, this study goes further, assessing the likelihood that platelet transfusion are responsible for some fraction of the increased mortality rate. A sensitivity analysis suggests that when multiple platelet transfusions are administered in the NICU, the transfusions are themselves responsible for at least some fraction of the poor outcome.)

Baer. “Severe thrombocytopenia in the NICU”. Pediatrics. vol. 124. 2009. pp. e1095-1100. (Most studies of thrombocytopenia in the NICU involve patients with platelet counts <150,000/uL. The unique aspect of this one is that it focuses only on neonates with two or more platelet counts <50,000/uL, a level at which most authors use the term "severe neonatal thrombocytopenia".)

Dohner. “Very-high users of platelet transfusions in the NICU”. Transfusion. vol. 49. 2009. pp. 869-872. (What diagnoses are common among neonates that receive 20 or more platelet transfusions? Using data from a multihospital healthcare system, the most common associations are with ECMO use, NEC, and late-onset bacterial sepsis, with very few cases due to genetic hyporegenerative thrombocytopenias.)

Josephson. “Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey”. Pediatrics. vol. 123. 2009. pp. 278-285. (Neonatologists in Canada and the USA were asked, by electronic survey, about their platelet transfusion practices. Wide ranges in transfusion "triggers" were found, with little consistency regarding when platelet transfusion are to be administered.)

Wiedmeier. “Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system”. J Perinatol. vol. 29. 2009. pp. 130-136. (The aim of this study was to define the "reference range" of platelet counts, and mean platelet volume, during the neonatal period. As such, the figures of this paper can be used as a guide to the diagnosis of thrombocytosis and thrombocytopenia.)

Ongoing controversies regarding etiology, diagnosis, treatment

Recent surveys indicate, under similar circumstances, neonatologists in Europe are less likely to administer platelet transfusion than are neonatologists in the United States. Therefore, platelet transfusion rates (transfusions per 1000 NICU admissions) are, in general, lower in Europe than in the United States.

Some NICUs prefer to use “platelet mass”-based transfusion guidelines (see transfusion guidelines above) as opposed to “platelet count” -based guidelines. The advantage of mass-based is generally 1/3 fewer transfusions are given. The savings is derived from neonates with platelet counts that would qualify for a transfusion, yet the large size of their platelets (and there larger platelet mass) makes them not qualify for a platelet transfusion. Limited studies suggest that reducing platelet transfusion in this way is not associated with more clinical bleeding episodes, or more severe episodes, or worse outcomes.