Thrombotic, thrombocytopenic purpura (ADAMTS-13 deficiency): a rare neonatal presentation

Introduction

This is a rare case of a neonate presenting with a large cerebral infarction due to congenital ADAMTS-13 deficiency. The most common presentation in the newborn period is with jaundice requiring exchange transfusion. This case highlights the need to consider this diagnosis in the presence of anaemia, jaundice and thrombosis or bleeding in a neonate.

Presentation of the case

The baby boy was born at 34 weeks’ gestation. His mother was 25 years old and had a history of two early miscarriages and one termination of pregnancy. The parents were consanguineous and of Pakistani origin. His mother had received one course of steroids. The baby was delivered by forceps due to abnormal cardiotocography (CTG). His arterial cord pH was 7.17.

At birth, he was pale, had poor respiratory effort and his heart rate was <60 beats per min (bpm). He was intubated, ventilated and given cardiac massage. By 7 min of age, his heart rate was 120 bpm and remained above 100 bpm. His peripheral oxygen saturations were 50% despite 100% fractional inspired oxygen (FiO₂) and high ventilator support.

On admission to the newborn intensive care unit, he was commenced on high frequency oscillatory ventilation (HFOV) and 100% FiO₂. Nitric oxide did not improve his oxygen requirements. His FiO₂ decreased to 30% after commencing inotropes and HFOV. On day 2 he was extubated onto continuous positive airway pressure (CPAP) and by day 4 was breathing in ambient oxygen.

Intravenous antibiotics commenced at birth for possible sepsis were stopped after 48 h as blood cultures were negative. His highest CRP was 7 mg/L; screening for toxoplasmosis, rubella, cytomegalovirus and herpes simplex infection were negative. On admission, he was noted to be pale with haemoglobin of 90 g/L. His platelet count was 62×10⁹/L and his clotting was abnormal (PT 22.7 s; APTT 140.7 s). He was treated with two 15 mL/kg packed red cell transfusions, 15 mL/kg platelet transfusion and 10 mL/kg fresh frozen plasma (FFP). On examination, he was noted to have a petechial rash and hepatomegaly. He required a further 15 mL/kg top up blood transfusion on days 2 and 22 for anaemia. The blood film was reported as showing possible haemolysis.

On admission, he had a severe lactic acidosis (23 mmol/L). This was resolved by day 2. A metabolic screen, including blood ammonia, plasma amino acids, serum acylcarnitine, serum ferritin and urinary organic acid concentrations was normal. At 12 h of age, he developed hyperbilirubinemia (highest bilirubin was 189 μmol/L on day 1) requiring double phototherapy and this resolved by day 2. Direct antiglobulin (Coombs) test (DAT) and Kleihauer test were negative.

He developed seizure activity on day 1 that was treated with a loading dose of phenobarbitone. Cranial ultrasound scans on days 1 and 5 showed a likely area of left cerebral infarction with possible associated intracranial haemorrhage. Computed tomography of the head on day 6 showed a large left cerebral infarction involving temporal, occipital and parietal lobes with midline shift to the right and associated left basal ganglia and thalamic changes. Additionally, there was a right cerebral infarction involving the occipital lobe (Figure 1).

Figure 1

Image of computed tomography of the head showing infarct (arrow points to infarct).

He was discharged home from the neonatal unit on day 28. At 9 months of corrected age, he presented to the Accident and Emergency Department with temperature, vomiting and diarrhoea. He was noted to be pale with a petechial rash. His bloods showed haemoglobin of 54 g/L, platelet count of 15×10⁹/L and normal white cell count. Blood film showed marked microangiopathic anaemia with fragmented red cells, nucleated red cells and spherocytes, suggesting a diagnosis of thrombotic thrombocytopenic purpura probably due to congenital ADAMTS-13 deficiency. His blood results normalised with platelets, FFP and blood transfusion. His bloods confirmed a marked reduction in ADAMTS-13 activity at 9% (normal 60–100%, <10% severe deficiency) in the absence of any antibodies to ADAMTS-13. He currently receives regular two weekly FFP infusions.

Discussion

ADAMTS-13 is a von Willebrand factor (vWF) cleaving protease. In congenital ADAMTS-13 deficiency or Upshaw-Schulman syndrome [or congenital thrombotic thrombocytopenic purpura (TTP)] there is a tendency for increased coagulation due to the presence of ultra-large, uncleaved vWF multimers [2, 3]. Red blood cells flowing through the microscopic clots are subjected to shear stress, which damages their membranes, leading to intravascular haemolysis and schistocyte formation [5]. The reduced blood flow from thrombosis results in end organ damage, notably to the kidney and brain.

ADAMTS-13 maps to the 9^th chromosome and is an autosomal recessive condition [6]. The condition often presents with the pentad of microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, fever, renal and neurological dysfunction [1], however, TTP should be considered in any patient with MAHA and thrombocytopenia [2]. In neonates, it usually presents with hyperbilirubinemia often requiring exchange transfusion [1]. The treatment for ADAMTS-13 deficiency is FFP infusions 2–3 weekly in severe cases [4]. FFP is best used preventatively rather than as rescue therapy [4]. TTP has also been treated with intermediate purity factor VIII concentrate BPL 8Y that is derived from pooled plasma and contains ADAMTS-13. Using 8Y has the potential advantage that this much smaller volume can be delivered by parents or carers at home without the need for regular hospital attendance [7]. The baby in our case did not develop the classic severe jaundice, possibly because he had received FFP on day 1.

The pathogenesis of ADAMTS-13 leads to TTP as a result of microvascular thrombosis. Large vessel arterial thrombosis has been described in patients with acquired TTP who have auto-antibodies against ADAMTS-13, but to our knowledge, stroke has not been described in neonates [3]. The severity of the deficiency and the degree of prematurity may account for the early presentation. ADAMTS-13 deficiency should be considered in a baby with a microangiopathic haemolytic anaemia, jaundice and thrombocytopenia with negative DAT [1, 8]. Neonatal thrombosis as demonstrated by this case should also lead to consideration of a diagnosis of ADAMTS-13 deficiency. Treatment with FFP infusion will normalise the abnormalities and prevent further renal and neurological damage.