
==== Front
BMJ Case Rep
BMJ Case Rep
bmjcr
bcr
BMJ Case Reports
1757-790X
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39122381
10.1136/bcr-2024-261126
bcr-2024-261126
Case Report
Paediatrics
Late-onset vitamin K deficiency presenting as haemorrhagic shock and severe multi-system organ failure
https://twitter.com/JAzarMD
http://orcid.org/0000-0003-2209-9817
Azar Justin M 12justin.azar@gmail.com

Lambert Richard 12rllambert@geisinger.edu

Maffei Frank Anthony 12famaffei@geisinger.edu

Thomas Tessy A 12tathomas3@geisinger.edu

1 Janet Weis Children's Hospital, Danville, Pennsylvania, USA
2 Pediatrics, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, USA
None declared.

DrJustin MAzar; justin.azar@gmail.com
2024
8 8 2024
8 8 2024
17 8 e26112626 7 2024
Copyright © BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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.

Preventative pediatrics
Neonatal and paediatric intensive care
Routine care of the full-time infant
Infant health
Haematology (incl blood transfusion)
==== Body
pmcBackground

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.512 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.2428 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.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Consent obtained from parent(s)/guardian(s).
==== Refs
References

1 Mladěnka P Macáková K Kujovská Krčmová L et al Vitamin K - sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity Nutr Rev 2022 80 677 98 10.1093/nutrit/nuab061 34472618
2 Jullien S Vitamin K prophylaxis in newborns BMC Pediatr 2021 21 350 10.1186/s12887-021-02701-4 34496783
3 Townsend CW The haemorrhagic disease of the newborn Arch Pediatr 1894 11 559 65
4 Sutor AH Vitamin K deficiency bleeding in infants and children Semin Thromb Hemost 1995 21 317 29 10.1055/s-2007-1000653 8588159
5 Bruns LA Isbey S Tanverdi M et al Late-onset vitamin K deficiency presenting as scrotal bruising and mediastinal mass Pediatr Emerg Care 2019 35 e192 3 10.1097/PEC.0000000000001452 29538265
6 Lemaitre L Leclerc F Dubos JP et al Thymic hemorrhage: a cause of acute symptomatic mediastinal widening in an infant with late haemorrhagic disease. Sonographic findings Pediatr Radiol 1989 19 128 9 10.1007/BF02387903 2646584
7 Woolley MM Isaacs H Lindesmith G et al Spontaneous thymic hemorrhage in the neonate: report of two cases J Pediatr Surg 1974 9 231 3 10.1016/s0022-3468(74)80128-4 4825797
8 Wachs JA Desai SB Garica AR et al Neonatal thymic hemorrhage case study: thymic hematoma mimicking a mediastinal mass lesion in a neonate Pediatr Radiol 2023 53 s80 10.1007/s00247-023-05672-z
9 Brooks B DeSpain AW Sharron M Thymic hemorrhage presenting as an anterior mediastinal mass in an infant with vitamin K deficiency Crit Care Med 2018 46 271 10.1097/01.ccm.0000528588.93196.ee
10 Öztürk B Yaradilmiş RM Azapağasi E et al Attention to diseases that re-emerge due to refusal of vitamin K: an infant case Blood Coagul Fibrinolysis 2023 34 118 21 10.1097/MBC.0000000000001169 36719808
11 Bauer C Furthner D Grohmann E et al Vitamin K deficiency-induced spontaneous haemopericardium and cardiac tamponade in an infant with alpha-1 antitrypsin deficiency: a case report Eur Heart J Case Rep 2021 5 ytaa481 10.1093/ehjcr/ytaa481 33644648
12 Koopman LP Plötz FB Meuzelaar JJ et al Thymic cyst haemorrhages and transient cholestasis in a 4-week-old infant Eur J Pediatr 1998 157 236 8 10.1007/s004310050802 9537492
13 Shneider BL Magee JC Bezerra JA et al Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia Pediatrics 2012 130 e607 14 10.1542/peds.2011-1423 22891232
14 Lane PA Hathaway WE Vitamin K in infancy J Pediatr 1985 106 351 9 10.1016/s0022-3476(85)80656-9 3973772
15 Volpe JJ Intracranial hemorrhage in early infancy--renewed importance of vitamin K deficiency Pediatr Neurol 2014 50 545 6 10.1016/j.pediatrneurol.2014.02.017 24842253
16 Miyasaka M Nosaka S Sakai H et al Vitamin K deficiency bleeding with intracranial hemorrhage: focus on secondary form Emerg Radiol 2007 14 323 9 10.1007/s10140-007-0632-y 17786492
17 Loughnan PM McDougall PN Epidemiology of late onset haemorrhagic disease: a pooled data analysis J Paediatr Child Health 1993 29 177 81 10.1111/j.1440-1754.1993.tb00480.x 8517996
18 Committee on Fetus and Newborn Controversies concerning vitamin K and the newborn Pediatrics 2003 112 191 2 10.1542/peds.112.1.191 12837888
19 Sankar MJ Chandrasekaran A Kumar P et al Vitamin K prophylaxis for prevention of vitamin K deficiency bleeding: a systematic review J Perinatol 2016 36 S29 35 10.1038/jp.2016.30 27109090
20 Hand I Noble L Abrams SA Vitamin K and the newborn infant Pediatrics 2022 149 e2021056036 10.1542/peds.2021-056036 35190810
21 Sutor A von Kries R Cornelissen M et al Vitamin K deficiency bleeding (VKDB) in infancy. ISTH pediatric/perinatal subcommittee. International society on thrombosis and haemostasis. Thromb Haemost 1999 81 456 61 10.1055/s-0037-1614494 10102477
22 Shah SI Brumberg HL La Gamma EF Applying lessons from vaccination hesitancy to address birth dose vitamin K refusal: where has the trust gone? Semin Perinatol 2020 44 151242 10.1016/j.semperi.2020.151242 32291097
23 Yilmaz C Yuca SA Yilmaz N et al Intracranial hemorrhage due to vitamin K deficiency in infants: a clinical study Int J Neurosci 2009 119 2250 6 10.3109/00207450903170437 19916853
24 Clarke P Shearer MJ Vitamin K deficiency bleeding: the readiness is all Arch Dis Child 2007 92 741 3 10.1136/adc.2007.116962 17522165
25 Vasu V Mulla S Pandya A et al Late-onset vitamin K deficiency bleeding in an extremely preterm infant fed an exclusively human milk-based diet J Thromb Haemost 2024 22 466 9 10.1016/j.jtha.2023.10.029 37981048
26 Dituri F Buonocore G Pietravalle A et al PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants J Matern Fetal Neonatal Med 2012 25 1660 3 10.3109/14767058.2012.657273 22280352
27 Dong R Wang N Yang Y et al Review on vitamin K deficiency and its biomarkers: focus on the novel application of PIVKA-II in clinical practice Clin Lab 2018 64 413 24 10.7754/Clin.Lab.2017.171020 29739078
28 Motohara K Endo F Matsuda I Screening for late neonatal vitamin K deficiency by acarboxyprothrombin in dried blood spots Arch Dis Child 1987 62 370 5 10.1136/adc.62.4.370 3592727
29 New HV Berryman J Bolton-Maggs PHB et al Guidelines on transfusion for fetuses, neonates and older children Br J Haematol 2016 175 784 828 10.1111/bjh.14233 27861734
