Thrombocytopenic Neonate - Approach to the Evaluation and Management of a
|Next review: 01/04/2024|
|Approved By: Trust Clinical Guidelines Group|
|Copyright© Leeds Teaching Hospitals NHS Trust 2021|
This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
Approach to the Evaluation and Management of a Thrombocytopenic Neonate
3. Management of Thrombocytopenia
Appendix 1: The Natural History of Specific Conditions
Appendix 2: History Taking and Examination of a Thrombocytopenic Neonate
Appendix 3: Evidence for the use of platelet transfusions in non-immune thrombocytopenia
Appendix 4: Responsibility for Guideline Developments/Peer Review
- Platelet count below 150 X109/L is below normal at any gestational age.
- In a well term infant with a platelet count below 50 X109/L and no other identifiable cause then a diagnosis of neonatal alloimmune thrombocytopenia should be assumed until proven otherwise.
- Thrombocytopenia within the first three days of life in a premature infant is usually an indicator of a poor intra-uterine environment.
- Falling platelets in a premature infant after the first three days of life is usually an indicator of developing sepsis particularly fungal sepsis.
- Maintaining platelet count above 25 X109/L is generally thought to be safe practice.
- Thrombocytopenia is the second commonest haematological abnormality in the neonatal period.
- The majority of cases present at birth or within the first 72hours of life.
- Thrombocytopenia is defined as a platelet count less than 150X109/L.
- Mild Thrombocytopenia: 50 - 150X109/L
- Severe thrombocytopenia: < 50X109/L
- Premature infants have a slightly lower count than term infants but it usually remains generally within the normal range.
- A count below 150X109/L is thus abnormal at any gestational age.
- There are two major mechanisms that lead to thrombocytopenia:
- Decreased platelet production
- Increased platelet destruction
In many infants both mechanisms can be responsible. Information regarding the natural history of common conditions is contained in appendix 1.
- A term well infant less than 72 hours old with bruising, petechiae and a platelet count below 50X109/L with no obvious cause should be assumed to be due to neonatal alloimmune or autoimmune thrombocytopenia until proven otherwise.
The approach generally used now is based upon the age of presentation, Early (<72hours of age) and Late (>72hours of age).
TABLE 1: Classification of Neonatal Thrombocytopenia
The most common are highlighted.
LATE OR EARLY ONSET
Neonatal autoimmune thrombocytopenia
Congenital Infection(CMV,HSV toxoplasmosis, rubella,HIV)
Thrombosis (renal vein,sagittal sinus, line-associated)
Metabolic (Proprionic academia, methylmalonic academia) DIC
Inherited(Wiskott-Aldrich-Syndrome,TAR, Fanconi’s anaemia, Amegakaryocytic thrombocytopenia, X-linked thrombocytopenia’s)
DIC (Disseminated intravascular coagulation); CMV (Cytomegalovirus); HSV (Herpes Simplex Virus); TAR (thrombocytopenia with absent radii); IUGR (intrauterine growth retardation); PET (pre-eclampsia)
2.1 General Evaluation of a thrombocytopenic Neonate
- The main aims are to:-
- Identify or exclude life-threatening conditions such as overwhelming sepsis and neonatal alloimmune thrombocytopenia.
- Identify those conditions that have implications for the neonate’s future progress.
- Not to over-investigate self-limiting conditions.
- The first step in the evaluation of thrombocytopenia is to check that it is not spurious.
- The need to consult with a haematologist is usually where there is an:
- Unexplained pattern of thrombocytopenia
- Known cause but unexpected severe or prolonged thrombocytopenia
- Appendix 2 contains a list of important factors to include in the history and examination of a thrombocytopenic neonate.
TORCH: Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes/HIV
LP: Lumbar puncture, US: Ultrasound, LFTs: Liver Function Tests
3.1 Treatment of Non-Immune Mediated Thrombocytopenia
- The first steps are to treat the haemostatic consequences of the low platelet count and then the underlying cause. The only treatment at present are platelet transfusions, see corresponding guidelines.
- Maintain platelet count above 50X109L for clinically unstable infants and above 25X109/L for stable neonates by platelet transfusions.
- See Appendix 3 for the evidence regarding the use of platelet transfusions
3.2 Treatment of Immune Mediated Thrombocytopenias
3.2.1 NEONATAL ALLOIMMUNE THROMBOCYTOPENIA
- This condition should be considered separately as there is a relatively higher risk of haemorrhage at the equivalent platelet count. Treatment should only be initiated following discussion with a haematologist. For further information about this condition, see Appendix 1.
- The indications for transfusion with HPA compatible platelets are:
- Platelet count less than 25X109/L in stable neonates
- Platelet count less than 50X109/L with evidence of minor bleeding
- Platelet count less than 50X109/L with history of an affected sibling with intracranial haemorrhage
- Platelet count less than 100X109/L with evidence of severe bleeding
- If the infant received in-utero transfusions then irradiated platelets should be used.
- If compatible platelets are not available then either give washed and irradiated maternal platelets or random donor platelets with high dose intravenous immunoglobulin. The processes involved in ordering, prescribing and giving immunoglobulins can be found on (link to Pharmacy website)
- The platelet count should be maintained above 25X109/L for the first week of life or for as long as there is evidence of ongoing haemorrhage.
- A cranial ultrasound should be performed on all thrombocytopenic infants.
- In a history of an affected sibling then obtain a platelet count on cord blood and at 24 and 48hours of age, then again at 4days and then at one week. If count remains normal at one week then no further monitoring is required.
3.2.2 NEONATAL AUTOIMMUNE THROMBOCYTOPENIA
- In maternal autoimmune disease then obtain a cord blood count at birth and then again at 24hours of age. If there is evidence of thrombocytopenia then the platelet count should be repeated daily until an increase is seen and then as clinically indicated.
- The indications for treatment are:-
- Platelet count less than 50X109/L with evidence of haemorrhage
- Platelet count less than 25X109/L in stable neonates
- Intravenous immunoglobulins are given, either 1g/kg/day for 2days or 0.5g/kg/day for 4 days.
- If there is no response in the platelet count after two days then prednisolone (2mg/kg/day) can be given with or without further immunoglobulins.
- A platelet transfusion should only be given as an emergency measure in the presence of life threatening haemorrhage.
|Target patient group:||Neonates in NICU, Post-natal and Labour wards|
|Target professional group(s):||Secondary Care Doctors
- Sola M C, Del Vecchio A, Rimsza L M. Evaluation and treatment of thrombocytopenia in the NICU. Clinics in Perinatology. Sept 2000;27(3):655-679
- Sola M C. Evaluation and treatment of severe and prolonged thrombocytopenia in neonates. Clinics in Perinatology. March 2004;31(1):1-14
- Roberts I, Murray N A. Neonatal thrombocytopenia: New insights into pathogenesis and implications for clinical management. Current Opinion in Pediatrics. 2001;13:16-21
- Roberts I, Murray N A. Neonatal thrombocytopenia: Causes and management. Arch. Dis Child Fetal Ed. 2003;88:F359-364
- Roberts I, Murray N A. Thrombocytopenia in the newborn. Current Opinion in Pediatrics. Feb 2003;15(1):17-23
- Sola-Visner M, Saxonhouse M A, Brown R E. Neonatal thrombocytopenia: What we do and don’t know. Early Human Development. Aug 2008;84(8):499-506
- Roberts I, Murray N A. Management of thrombocytopenia in neonates. British Journal of Haematology. June 1999;105(4-11):864- 870
- Chalmers E A. Neonatal coagulation problems. Arch. Dis. Child Fetal Ed. 2004;89:F475-478
- Christenson R D. Advances and controversies in neonatal ICU platelet transfusion practice. Advances in paediatrics. 2008;55:255- 269
- Thrombocytopenia. Neonatal Handbook, Newborn Emergency Transport Service
- Groves A, Kuschel C. Neonatal thrombocytopenia. Newborn Service Clinical Guideline
- Bustani P. Thrombocytopenia(neonatal) Guideline. Jessops Hospital for Women. Sheffield
- Roberts I, Murray N. Neonatal thrombocytopenia. Seminars in fetal & neonatal medicine (2008) 13, 256e264
- Holzhauer S, Zieger B. Diagnosis and management of neonatal thrombocytopenia. Seminars in Fetal & Neonatal Medicine 16 (2011) 305-310
- British Committee for Standards in Haematology. New HV, Berryman J, Bolton-Maggs PH, et al. Guidelines on transfusion for fetuses, neonates and older children. British Journal of Haematology. 2016 Dec;175(5):784-828. DOI: 10.1111/bjh.14233.
- Curley A, Stanworth SJ, Willoughby K, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med 2019; 380:242
- Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, et al. Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood 2019; 134:2354.
Trust Clinical Guidelines Group
LHP version 1.0
NEONATAL ALLOIMMUNE THROMBOCYTOPENIA:
This condition affects 1 in 1000 pregnancies. A platelet antigen is inherited from the father which is not present on the mother’s platelets. This antigen then appears on the fetal platelets, the mother produces antibodies against it and these cross the placenta to cause destruction of neonatal and fetal platelets. The mother has a normal platelet count. 40-50% of cases occur in the first pregnancy and 75- 90% of subsequent pregnancies are affected. The antibodies also affect the haemostatic function of the platelets hence there is a higher associated risk of haemorrhage.
The antigen system commonly involved is the Human Platelet Antigen (HPAs) and around sixteen different forms are known at present, with some being associated with more severe disease such as 1a and 3b. The commonest in Caucasians is HPA-1a, which accounts for 80-90% of cases whilst HPA-5a (associated with less severe disease) accounts for 10-15%. In Asians, the HPA-4 system is more commonly involved.
Severe thrombocytopenia is seen at birth and the count continues to fall over the first few days. A recovery in the count is finally seen over 1-4weeks, although up to 12weeks has been reported. The affected neonate is usually otherwise healthy with or without evidence of bleeding such as a widespread petechial rash or signs of gastrointestinal bleeding.
If untreated, 10-30% of neonates will develop an intracranial haemorrhage with half of these occurring in utero. The mortality from this in both neonatal and fetal cases is between 6-13%. In the survivors, a quarter will suffer long-term neurodevelopment sequelae. The occurrence of an antenatal ICH in a previous sibling is a strong predictive factor for the severity of disease in further pregnancies. Hence a cranial ultrasound is required in any diagnosed case with or without evidence of neurological involvement.
NEONATAL AUTOIMMUNE THROMBOCYTOPENIA:
This is caused by the transplacental passage of maternal antiplatelet antibodies which are directed against both the maternal and fetal platelets. Both the mother and the neonate will have low platelet counts.
The three main maternal conditions leading to this are:
- Maternal Idiopathic Thrombocytopenia Purpura – Can present de novo during pregnancy. Mother’s platelet count can be normal due to compensatory increased thrombocytosis or splenectomy. Accounts for 13-64% of neonatal thrombocytopenia and 5-10% of the severe cases.
- Systemic Lupus Erythematosus
- Gestational or Incidental thrombocytopenia – A mother with no history of autoimmune disease presents with mild decrease in platelet count during pregnancy which resolves after delivery. The neonate has a very low risk of developing thrombocytopenia.
The platelet count reaches a nadir at around 2-5days after birth and can go below 50X109/L. The affected neonate appears well and there is a very low risk of significant bleeding. Less than 1% develop an intracranial haemorrhage although in the moderate to severe cases this does increase to 3%.
PERINATAL AND CONGENITAL INFECTION:
There is usually evidence of a systemic infection, hence whether term or preterm the neonate appears sick. 80% of neonates who have proven infection have a platelet count below 150X109/L whilst 55-65% will have a count below 100x109/L.
Around a quarter of infants will have a falling platelet count at the time of diagnosis whilst in the vast majority the count will then fall within the next 36-48hours. The count tends to stay low for around 6days before increasing again. Thrombocytopenia can occur in the absence of disseminated intravascular coagulation although if the count drops below 50x109/L then DIC is more likely to co-exist.
Congenital viral infections can also lead to thrombocytopenia. Coxsackievirus B and echovirus both cause a thrombocytopenia in association with fulminant hepatitis and liver failure, respiratory failure, myocarditis and CNS involvement. Parvovirus B19 causes fetal hydrops with anaemia, splenomegaly and thrombocytopenia.
There is usually a history of maternal diabetes, pregnancy induced hypertension, IUGR, pre-eclampsia or fetal hypoxia. Premature infants are more at risk of developing associated thrombocytopenia.
They present at birth or in the first few days of life with an initial low to normal platelet count which then starts to fall. The count reaches a nadir by day 2-4 then has resolved by day 7-10. The thrombocytopenia is usually mild to moderate although in severe PIH and IUGR the
count can fall to below 50X109/L and take longer to recover, (>21days).
There is usually an associated high haematocrit and low neutrophil count. 75-90% of neonates with maternal PIH will have an associated neutropenia. These infants are usually clinically stable with no coagulapathy and have a very low risk of haemorrhage.
LATE ONSET SEPSIS AND NECROTISING ENTEROCOLITIS:
80-90% of patients with NEC develop thrombocytopenia as one of the presenting signs. A quarter of VLBW infants develop at least one episode of sepsis and 50% will develop thrombocytopenia in association with this.
The usual cause is line infection by either CONS or gram negative rods. Fungal infection is also a major cause of late onset thrombocytopenia in ELBW and VLBW infants. 73% will present initially with thrombocytopenia and in Candida infection falling platelets is the most consistent early laboratory finding.
In both conditions there is a typical pattern to the thrombocytopenia. The platelets start to fall with the emergence of the early signs of sepsis/NEC and this fall progresses rapidly with the nadir reached by 24-48hours from onset. The thrombocytopenia is severe and requires repeated platelet transfusions until the sepsis or NEC is controlled. There is then a slow recovery in the platelet count.
When investigating the cause of thrombocytopenia in a neonate the following factors have to be considered:-
1). Maternal History:
- Maternal platelet count
- History of autoimmune disorders
- History of previously affected sibling or other family members with thrombocytopenia – TAR, Fanconi’s anaemia are both inherited in an autosomal recessive manner.
2). Antenatal History
- Medications during pregnancy – An immune-mediated drug reaction can cause thrombocytopenia in both mother and fetus due to cross-reactivity of antibodies. This is seen with thiazide diuretics, hydralazine, tolbutamide and indomethacin. Aspirin can also affect the fetal and neonatal platelet count.
- Evidence of placental insufficiency – pre-eclampsia, maternal diabetes
- Any incidence of flu-like or viral-like illnesses in mother during pregnancy might suggest CMV infection
- Any indication of active herpes infection during pregnancy
3). Perinatal History
- Any evidence of asphyxia
- History of chorionamnionitis or PROM
- Indomethacin and nitric oxide are known to induce platelet dysfunction and hence convey a higher risk of haemorrhage in the presence of thrombocytopenia.
5). Response to transfusions
- The platelet life span in neonates is thought to be similar to adults and in conditions where the underlying mechanism is platelet consumption the life span is shortened from around 5.5 days to just under 3 days.
- The need for transfusions every 1-2 days suggests that platelets are being consumed whilst a weekly requirement suggests decreased platelet production.
- Birth weight – If small then suggestive of congenital CMV infection or IUGR
- Microcephaly – Seen in CMV infection and Fanconi’s anaemia
- Signs of sepsis and or NEC
- Presence of central lines – May suggest either line sepsis or thrombosis as the cause
- Dysmorphic features suggestive of a syndrome
- Abdominal mass which would suggest renal vein thrombosis
- Forearm and or thumb abnormalities – In TAR the thumb and digits are always present. In Fanconi’s anaemia abnormalities of the thumb are usually seen.
- Inability to rotate the forearm which indicates proximal radio-ulnar synostosis which is associated with congenital amegkaryocytosis
- Haemangiomas – Kassabach – Merritt
- Evidence of bleeding – Suggests severe thrombocytopenia or associated DIC
- Heart murmur – One third of neonates with TAR have associated congenital heart defects, mainly Tetrology of Fallot or ASDs
It is known that thrombocytopenia is a risk factor for significant haemorrhage, mainly intracranial haemorrhage, mortality and an adverse neurological outcome. It has been shown that thrombocytopenic neonates who had received platelet transfusions were 10 times more likely to die than neonates who had not. It is unknown whether thrombocytopenia contributes directly to these poor outcomes or is simply a marker of the severity of the causative condition. Most episodes of significant haemorrhage occur in the first few days of life whilst most episodes of severe thrombocytopenia occur after this period. The risk of haemorrhage is higher when the underlying mechanism is decreased platelet production not platelet consumption as is seen in late onset sepsis.
Until recently, there was very little evidence to identify a safe threshold at which the platelet count can be allowed to fall to before requiring a transfusion. There are no neonatal trials that have shown a reduced rate in haemorrhage or improvement in outcome in neonates with non-immune mediated thrombocytopenia treated with transfusions.
The majority of platelet transfusions undertaken on a neonatal unit are prophylactic to non-bleeding neonates with platelet counts below 50X109/L. One randomised controlled trial looking at platelet transfusions showed that maintaining a normal platelet count (>150X109/L) by transfusions in moderate thrombocytopenia inferred no benefit compared to maintaining platelet counts above 50X109/L. Two randomised control trials published in 2019 have demonstrated that a threshold level of <25X109/L appears safe for clinically stable preterm neonates on NICU. There is less new evidence on safe thresholds for term babies, however The British Committee for Standards in Haematology have published guidelines recommending a threshold of <25X109/L for asymptomatic stable term neonates on NICU but acknowledge the paucity of trials in this area.
Based on the current evidence the following recommendations are made for transfusion thresholds in non-immune thrombocytopenia:
25 – 49
Do not transfuse if clinically stable.
50 – 99
Do Not Transfuse
Do Not Transfuse
Do not Transfuse
Major haemorrhage: Significant intraventricular haemorrhage, pulmonary haemorrhage
Minor bleeding: Petechiae, puncture site oozing or blood stained endotracheal secretions
Responsibility for Guideline Developments/Peer Review
1. This guideline was developed by Dr Sarah McCullough and updated by Dr Alyce Hayes. A draft version was then circulated around the neonatal consultants and alterations made based on their comments and suggestions. Fellow registrars and ANNPS were also invited to read and appraise these initial draft versions. Dr Michael Richards, Consultant Haematologist, then reviewed it and a final version produced based on his recommendations. This final version was then presented to the neonatal consultants at Leeds General Infirmary for their final approval.
1.1 The use of immunoglobulins in the guidelines has been reviewed by the pharmacist, Katherine Stirling. Its use for the purposes stated in this guideline has already been approved by pre-existing pharmacy guidelines. A link to these guidelines will be included in the relevant section of the guideline.
Evidence Base/Formulation of Recommendation
2. A thorough literature search was undertaken to collect the relevant information. The main focus of this guideline was on the management and evaluation of a thrombocytopenic neonate rather than on the treatment. Hence the majority of the information is from review articles rather than randomized controlled trials. A guideline already exists for the treatment of thrombocytopenia and a link to this will be included in the relevant section.
Risk Benefits and Cost Benefits
3. The benefits of this guideline are:
- To provide a consistent and structured approach to a thrombocytopenic neonate
- To inform and educate medical professionals involved in the care of thrombocytopenic neonates
- To ensure that the appropriate investigations are performed on the appropriate patients at the appropriate time
- That specialist advice is sought when most appropriate
3.1 The implementation of this guideline should not cause any harm and should in fact prevent neonates undergoing unnecessary investigations whilst identifying those who require further evaluation and treatment.
3.2 The guideline should also result in earlier identification of at risk infants and ensure that the appropriate treatment is initiated.
3.3 By preventing unnecessary investigations this should result in reducing costs.
3.4 No extra procedures or measures will need to be introduced.
3.5 There should be no additional costs in implementing this guideline as all of the investigations and procedures mentioned in the guideline are already part of routine care. This guideline hence just provides a better coordination of this care. Thus the costs of this guideline can be met by the existing budget.
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