Late-onset vitamin K deficiency presenting as haemorrhagic shock and severe multi-system organ failure

Summary

Vitamin K is an essential dietary cofactor required for the synthesis of active forms of vitamin K-dependent procoagulant proteins. Vitamin K deficiency, particularly late-onset deficiency occurring between 1 week and 6 months of age, can cause a life-threatening bleeding disorder. An exclusively breastfed, full-term, 6-week-old infant male presented with severe haemorrhagic shock and multi-system organ failure related to caregiver refusal of intramuscular vitamin K after birth. Coagulation studies were normalised within 8 hours of intramuscular vitamin K administration. An increasing number of caregivers are refusing intramuscular vitamin K which has led to a rise in the incidence of vitamin K deficiency bleeding. Health policy organisations around the world emphasise the benefits of intramuscular vitamin K and risks of refusal, particularly in exclusively breastfed infants who are at higher risk due to low vitamin K levels in breast milk. This case highlights the multi-system severity of this life-threatening yet preventable disorder.

Background

Vitamin K, a fat-soluble vitamin, is a crucial co-enzyme activator for factors II (prothrombin), VII, IX, X, protein C and protein S; these four specific procoagulants participate in the coagulation cascade.¹ Newborns can easily develop vitamin K deficiency due to minimal hepatic stores at birth, low vitamin K content in breast milk, immature gut flora and poor placental transfer of vitamin K.² If vitamin K is not parenterally supplemented within the newborn period, the infant is at high risk for vitamin K deficiency bleeding (VKDB), previously known as haemorrhagic disease of the newborn.^{2 3} Late-onset VKDB occurs between 1 week and 6 months of age, with a peak incidence between 2 and 8 weeks of age.⁴

A rare yet potentially life-threatening bleeding disorder of early infancy, VKDB is commonly characterised by cutaneous bruising or bleeding from the gastrointestinal tract, umbilicus or circumcision site, mucosal surfaces and/or intracranial haemorrhage.³ There are several reports of significant rare and specific complications of VKDB, such as mediastinal masses due to thymic haemorrhage, intrathoracic bleeding, hemopericardium, intracranial bleeding, transient cholestasis and scrotal haematomas.5,12 However, there are no reports that describe severe, multi-system organ failure from VKDB.

Case presentation

An exclusively breastfed 6-week-old infant male presented to a community-based emergency department with poor feeding and progressive inconsolability over the previous 24 hours. He was born full term via spontaneous vaginal delivery to a mother with one previous uncomplicated pregnancy and delivery. Maternal screening laboratory results were unremarkable. She was not on medications that would predispose the infant to early VKBD. The infant passed newborn congenital heart disease and hearing screenings.

In the emergency department, he was hypothermic (35.5°C), tachycardic (156 beats per minute), tachypnoeic (52 breaths per minute) and hypertensive (120/71 mm Hg) with normal oxygen saturation (96%) in room air. Physical exam in the emergency department was also notable for retractions and ecchymoses on the left medial thigh. Point-of-care glucose was 16 mmol/L (289 mg/dL). Intraosseous access was secured, and the infant was transferred to our institution for further monitoring, evaluation and treatment for presumptive sepsis and hyperglycaemia.

On arrival at our paediatric intensive care unit (PICU), the infant was pale, lethargic, tachycardic and grunting with brief periods of apnoea and bradycardia. The pupils were midline, equal (3 mm) and reactive bilaterally. Anterior fontanelle was open, soft, flat and non-bulging. Bleeding from prior vascular access attempt sites was noted. Ultrasound-guided central vascular access was rapidly obtained, and the patient was intubated for impending cardiopulmonary failure.

Initial venous blood gas revealed a high anion-gap metabolic and respiratory acidosis: pH 6.94, pCO2 6.45 kPa (48.4 mm Hg), pO2 7.19 kPa (54 mm Hg), bicarbonate 8 mmol/L, base deficit negative 19 mmol/L, anion gap 22 mmol/L and an undetectable haemoglobin level with haematocrit less than 15%. A complete blood count confirmed the profound anaemia (haemoglobin 38 g/L). Other pertinent abnormal admission labs included lactate (13.5 mmol/L), pro-B-natriuretic peptide (4063 pg/mL), hyponatraemia (131 mmol/L), international normalised ratio (INR) > 9, prothrombin time (PT) > 70 s, activated partial thromboplastin time (aPTT) > 150 s, fibrinogen 288 mg/dL, white blood cell 25×10⁹/L, aspartate aminotransferase (AST) 132 U/L and alanine aminotransferase (ALT) 176 U/L. The chest radiograph showed enlarged thymic shadow and bilateral effusions (figure 1). CT of the head and chest revealed subarachnoid and intraventricular haemorrhages with ventriculomegaly (figure 2) and widened mediastinum with thymic haemorrhage (figure 3).

Figure 1. Initial chest radiograph. Enlarged thymus bordered laterally by red lines. Yellow arrows point to bilateral haemothoraces.

Figure 2. Head CT scan: subarachnoid haemorrhage circled in yellow and intraventricular haemorrhage circled in blue.

Figure 3. Chest CT: enlarged thymus due to haemorrhage circled in red. Yellow arrows point to bilateral haemothoraces.

Differential diagnosis

The presenting signs of hypothermia, tachycardia, tachypnoea, poor feeding and inconsolability raised concern for sepsis. The hyperglycaemia suggested a stress response to severe systemic disease, toxic ingestion, congenital diabetes mellitus or an inborn error of metabolism. The progressive shock, impending cardiorespiratory failure, encephalopathy, ecchymoses and clinical signs of coagulopathy on arrival to the PICU supported the differential diagnosis of septic shock but broadened it to include haemorrhagic shock possibly due to non-accidental trauma. Chest radiography obtained after endotracheal intubation revealed widened mediastinum and pleural effusions which could be attributable to an underlying haematologic/oncologic disease. Laboratory and further imaging alone were not diagnostic but supported severe systemic disease with multi-system organ failure. After multi-organ stabilisation, a review of the electronic medical record revealed that intramuscular vitamin K administration had been declined at birth. The history of intramuscular vitamin K refusal made late-onset VKDB the most likely aetiology of the haemorrhagic shock and subsequent multi-system organ failure.

Treatment

Within 2 hours of arrival, the infant received 1 mg intramuscular vitamin K empirically for profound coagulopathy of yet unclear aetiology. Once the initial INR resulted, an additional 4 mg intramuscular vitamin K and fresh frozen plasma 10 mL/kg were administered due to potential for ongoing bleeding apparent on imaging. The decision to give the additional vitamin K was extrapolated from dosing recommendations in biliary atresia and was made in consultation with paediatric pharmacy and paediatric haematology.¹³ The infant received packed red blood cells of 15 mL/kg divided into aliquots of 5 mL/kg, each administered over 3 hours, to mitigate risk of transfusion-associated circulatory overload.

Outcome and follow-up

Rapid and complete normalisation of coagulation parameters occurred within 8 hours of vitamin K administration: INR 1.3, PT 16.5 s and aPTT 31 s. The correction of coagulopathy along with organ-specific therapies was vital in the management of the infant’s severe multi-system organ failure. Acute hypoxemic and hypercarbic respiratory failure, subsequent paediatric acute respiratory distress syndrome and bilateral haemothoraces were managed with lung-protective mechanical ventilation. Targeted fluid and blood product resuscitation and sonographic measures of cardiac output were used to optimise end-organ perfusion in the expectant management of his hypoglycaemia, lactic acidosis, high anion-gap metabolic acidosis, shock liver and hyperbilirubinemia. His intracranial haemorrhage required the implementation of neuroprotective strategies (avoidance of hypercarbia, avoidance of hypoxia and hyperoxia, avoidance of hyperthermia, eunatraemia, euglycaemia), serial imaging and continuous electroencephalography. The risk of iatrogenic withdrawal/delirium due to continuous analgesic/sedation infusions to facilitate mechanical ventilation was mitigated using algorithmic sedation/delirium-prevention protocols. Blood, urine and respiratory cultures were obtained, and broad-spectrum antibiotics were administered for the treatment of presumptive sepsis. Lumbar puncture was deferred due to coagulopathy. Stress dose hydrocortisone was given for refractory septic shock and presumed secondary adrenal insufficiency. Following several days of these therapies, the infant was extubated on hospital day 5. The infant was then transferred out of the PICU on hospital day 6 and discharged home on hospital day 10. After hospital discharge, the infant was followed by paediatric haematology and paediatric neurosurgery. At 4 months of age, he was able to roll front to back, had resolving ventriculomegaly on head ultrasound and had no further lab abnormalities.

Discussion

Routine administration of intramuscular vitamin K was first recommended in the USA by the American Academy of Pediatrics (AAP) in 1961 to prevent all forms of VKDB. In 1985, Lane and Hathaway summarised three types of VKDB.¹⁴ Early-onset VKDB within the first 24 hours after birth is associated with intracranial haemorrhage in 25% of newborns.¹⁵ Classic VKDB typically occurs between days of life 2 to 7.¹⁵ Late-onset VKDB may present anytime from 1 week until 6 months with peak incidence at approximately 2 to 8 weeks.⁴ It commonly presents with vomiting and seizures and is associated with intracranial haemorrhage in up to 50% of patients.¹⁶ Late-onset VKDB is associated with high morbidity and mortality, often as high as 20%–50%.¹⁷ In the USA, without intramuscular vitamin K prophylaxis, classic VKDB is reported to occur in 0.25% to 1.7% of infants, and the median (IQR) burden of late-onset VKDB in the absence of any prophylaxis is 35 (10.5 to 80) per 100 000 live births among all low-, middle- and high-income countries.^{18 19}

Oral vitamin K administration became increasingly widespread following several reports that intramuscular vitamin K was associated with childhood cancers, although this link has been subsequently refuted by large epidemiological studies.¹⁸ Oral vitamin K administration appears to be effective in preventing classic VKDB. However, oral vitamin K has higher rates of failure in preventing late-onset VKDB, is not as effective as the one-time intramuscular shot and must be given repeatedly over several months.^{19 20} Accordingly, the WHO, Centers for Disease Control and AAP recommend a parenteral dose of vitamin K be administered to all newborns to prevent the life-threatening complications of VKDB. The PrevInfad workgroup from the Spanish Association of Primary Care Paediatrics, National Institute for Health and Care Excellence, European Society for Paediatric Gastroenterology Hepatology and Nutrition and Canadian Agency for Drugs and Technologies in Health include recommendations for oral vitamin K prophylaxis, often as second line to intramuscular vitamin K and with emphasis on the importance of completing prolonged administration course.²

In many countries, VKDB has been effectively eliminated through routine prophylaxis. However, in recent years, there has been an increase in caregiver refusal of intramuscular vitamin K administration at birth.^{21 22} Unsurprisingly, late-onset VKDB is re-emerging, putting more infants at risk of presenting with severe, multi-system organ failure and life-threatening complications. The diagnosis of VKDB should be considered in the broad differential of an infant presenting with subtle signs/symptoms (eg, pallor, poor feeding and lethargy) along with bruising, bleeding or in extremis. Obtaining a birth and immunisation history from caregivers and the electronic medical record is crucial. Laboratory studies in VKDB will invariably show increased aPTT, PT and INR values in the presence of normal platelet count and fibrinogen levels but are otherwise non-specific.²³ The diagnosis of VKDB can also be confirmed by increased biomarker levels of proteins induced by vitamin K absence or antagonism (PIVKA-II) which can be sent at the time of presentation or up to several days post hoc and provides irrefutable evidence of VKDB.24,28 Unfortunately, the PIVKA-II drawn on this patient was unable to be resulted by the processing laboratory. However, rapid normalisation of coagulation parameters with vitamin K replacement, as was evident in this case, is also consistent with VKDB diagnosis. Infants with suspected or confirmed VKDB should be treated with parenteral vitamin K. In cases of severe bleeding, the administration of prothrombin complex concentration is preferable to fresh frozen plasma due to speed of onset and small volume.²⁹

This report highlights the importance of the administration of vitamin K prophylaxis to all newborns. Due to increasing cases of caregiver refusal, VKDB is a re-emerging yet preventable life-threatening disease. Exclusively breastfed infants are at particularly high risk of VKDB, especially when caregivers have refused vitamin K prophylaxis because breast milk inherently contains relatively low levels of vitamin K.¹⁸ Therefore, healthcare providers must take a thorough history and consider VKDB on their differential when infants present with complex signs and symptoms of critical illness. They must be well-informed of the benefits of intramuscular vitamin K as well as the serious risks associated with caregiver refusal. Healthcare providers must continue preventative advocacy and provide informed consent and education while also focusing additional attention to caregivers who have declined prophylaxis, encouraging them to understand the life-threatening risks of refusal.

Learning points.

• Vitamin K deficiency bleeding (VKDB) is a life-threatening yet preventable disorder that causes severe critical illness in infants.

• Increasing caregiver refusal of vitamin K prophylaxis has led to increasing cases of VKDB.

• Due to low levels of vitamin K in breast milk, exclusively breastfed infants are at particularly higher risk of VKDB, especially when caregivers have refused vitamin K prophylaxis.

• Emergent treatment of suspected VKDB is parenteral vitamin K and, if severe, either four-factor prothrombin complex concentrate or fresh frozen plasma.

• Healthcare providers must provide ongoing education, advocacy and informed consent process for vitamin K administration in newborns.