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 Table of Contents  
Year : 2022  |  Volume : 7  |  Issue : 1  |  Page : 91-95

A case of late-onset vitamin K deficiency bleeding in an exclusively breastfed infant emphasizing the need for revision of vitamin K prophylaxis policy

1 Department of Immunohematology and Blood Transfusion, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
2 Department of Pediatrics, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India

Date of Submission05-Jan-2022
Date of Decision01-Feb-2022
Date of Acceptance21-Feb-2022
Date of Web Publication29-Apr-2022

Correspondence Address:
Dr. Aboobacker Mohamed Rafi
Department of Immunohematology and Blood Transfusion, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/gjtm.gjtm_2_22

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A 4-month-old male child presented with a history of seizure and vomiting. There was no history of fever, fall, or any other trauma. On examination, there was anisocoria, and anterior fontanelle was bulging and nonpulsating. Computerized tomography revealed an acute on chronic bilateral subdural hematoma (left > right) with a midline shift. He had no relevant past or family history suggestive of any bleeding disorder. Blood investigations revealed anemia with prolonged prothrombin time (PT)/international normalized ratio/and activated partial thromboplastin time (APTT). Mixing study was done and it showed a correction with pooled normal plasma. The possibility of coagulation factor deficiency was confirmed. Further, mixing studies and factor assays revealed normal levels of fibrinogen and Factor VIII, with a reduced level of Factor IX. Since both PT and APTT were prolonged and Factor IX level was low, a deficiency of Vitamin K-dependent coagulation factors was suspected. The child was immediately given intravenous Vitamin K injection. The diagnosis of Vitamin K deficiency bleeding (VKDB) was confirmed by protein induced by Vitamin K absence testing. Unfortunately, the child succumbed to the complications of the intracranial bleed.

Keywords: Intracranial bleed, protein induced by Vitamin K absence, Vitamin K

How to cite this article:
John SS, Jose E, Joseph B, Rafi AM. A case of late-onset vitamin K deficiency bleeding in an exclusively breastfed infant emphasizing the need for revision of vitamin K prophylaxis policy. Glob J Transfus Med 2022;7:91-5

How to cite this URL:
John SS, Jose E, Joseph B, Rafi AM. A case of late-onset vitamin K deficiency bleeding in an exclusively breastfed infant emphasizing the need for revision of vitamin K prophylaxis policy. Glob J Transfus Med [serial online] 2022 [cited 2022 Sep 26];7:91-5. Available from: https://www.gjtmonline.com/text.asp?2022/7/1/91/344331

  Introduction Top

Vitamin K, a fat-soluble vitamin, is required for the activation of coagulation factors (II, VII, IX, and X) and anticoagulant Proteins C and S. It plays a critical role as a cofactor of gamma-glutamyl carboxylase in the conversion of glutamic acid to gamma-carboxyglutamic acid residues in the N-terminus of Vitamin K-dependent procoagulant factors and Proteins C and S. Three forms of Vitamin K are known; Vitamin K1 (phylloquinone) is the major circulating form and is primarily provided by dietary sources. Vitamin K2 (menaquinones) is found in the diet and is also synthesized from the gut flora. The third form K3 (menadione) is a synthetic, water-soluble form that is no longer used medically because of its ability to produce hemolytic anemia.[1] Vitamin K deficiency is a rare condition in adult humans as it is available from various dietary sources. However, in newborn infants due to the low placental transfer of Vitamin K, immature gut flora, and low Vitamin K in breast milk, they are more prone to Vitamin K deficiency.[2] Vitamin K deficiency usually presents as bleeding in the newborn and is classified into three types depending mainly on the time of presentation since birth [Table 1].[3]
Table 1: Vitamin K deficiency bleeding classification

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The diagnosis of Vitamin K deficiency bleeding (VKDB) is commonly established when an infant presents with bleeding manifestations without any relevant family or past history of bleeding. It is supported by a prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT) in the presence of normal platelet count and fibrinogen level. The diagnosis is confirmed based on the increased levels of proteins induced by Vitamin K absence or antagonists (PIVKAs) and a rapid normalization of coagulation parameters, such as APTT and PT, after Vitamin K administration, or both.[4]

  Case Report Top

We report the case of a 4-month-old male child who presented to the emergency department with active seizures and vomiting. The child had no history of fever, fall, or trauma. On examination, there was anisocoria, and anterior fontanelle was bulging and nonpulsating. Bilateral deep tendon reflexes were absent with an extensor plantar reflex. A bruise (3 cm × 4 cm) was present over the left 11th rib. The child was started on antiepileptics which terminated the seizures and were then taken for an emergency computerized tomography (CT) scan which showed an acute on chronic subdural hematoma involving both the right and left fronto-temporo-parieto-occipital region with diffuse brain edema and a midline shift of 5 mm to the right [Figure 1]. The child was intubated as the pediatric Glasgow Coma Scale score was <8.
Figure 1: Plain axial computerized tomography scan of the head

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  • Acute on chronic subdural hematoma involving right fronto-temporo-parietal region (maximum thickness 5.7 mm) and left fronto-temporo-parieto-occipital region (maximum thickness 13 mm)
  • Extradural hematoma in the left frontal region
  • Midline shift of 5 mm to right
  • Hemorrhage in interhemispheric fissure and tentorium
  • Diffuse brain edema was noted.

He was born as a second child of a nonconsanguineous marriage by vacuum-assisted vaginal delivery at full term with a birth weight of 2.74 kg at another hospital. He was given prophylactic Vitamin K at birth and did not require any neonatal intensive care unit admission. Neonatal period was normal, and he had attained all the developmental milestones till age. There was no history suggestive of any bleeding diathesis or seizures in the child. No history of chronic antibiotic use in the child. There was no history of intake of any coumarin derivatives or Vitamin K antagonists by the mother during the antenatal period. There was no similar history in the elder sibling or in the family. There was no history of fetal loss or neonatal deaths in the family.

Laboratory evaluation

A basic blood workup was done which included hemogram, renal function testing, electrolytes, and coagulation screen [Table 2].
Table 2: Basic laboratory investigations

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Basic laboratory screening showed anemia with a prolonged PT/international normalized ratio (INR) and APTT with normal fibrinogen. Further evaluation in the form of mixing studies, factor assays, and rotational thromboelastometry (ROTEM) was done [Table 3].
Table 3: Coagulation testing

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Mixing study was done using pooled normal plasma (PNP), aged serum, and adsorbed plasma. There was a correction in PT and APTT with PNP and aged serum. Mixing study using adsorbed plasma showed no correction. Adsorbed plasma is prepared by using barium sulfate to remove the Vitamin K-dependent clotting factors in the plasma. It has been used in resource-limited settings to screen for coagulation factor deficiencies. Fibrinogen, Factor VIII, and IX assay were available. Factor IX assay showed a level of 5.5% with normal fibrinogen and Factor VIII values. ROTEM showed a prolonged CT with reduced amplitude in A5 in both EXTEM and FIBTEM [Figure 2].
Figure 2: ROTEM: Suggestive of coagulation factor deficiency

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With all these findings, a presumptive diagnosis of coagulation factor deficiency-most probably Vitamin K-depended factor deficiency was made. Other factor assays were not done as the test kits were not available in the institute.

Ultrasonogram of the abdomen and pelvis was done which detected no significant intraabdominal pathology, ruling out secondary causes of Vitamin K deficiency.

Blood sample was sent for testing PIVKA which is considered as a confirmatory test to diagnose Vitamin K deficiency. The results were conclusive to diagnose the same [Table 4]. Unfortunately, the child succumbed to the complications of the intracranial bleed.
Table 4: Protein induced by Vitamin K absence test

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  Discussion Top

VKDB, previously known as hemorrhagic disease of the newborn, is a well-known clinical entity for over a century. Vitamin K is required for the synthesis of coagulation factors that prevent and control bleeding. All neonates have low levels of Vitamin K owing to poor transport of Vitamin K across placenta, low Vitamin K content in breast milk, and because gut colonization that is critical for its synthesis takes a few days to establish.[6]

The American Academy of Pediatrics in 1961 has recommended that all neonates receive a single intramuscular dose of 0.5–1 mg of Vitamin K for the prevention of VKDB.[7] In continuation to that the National Health Mission, Government of India has issued the Standard Treatment Guidelines for VKDB and also regarding universal Vitamin K prophylaxis for all newborns delivered in health facilities at all levels including a subcenter.[8] However, as per reports, Vitamin K prophylaxis is not practiced uniformly in India.[9]

However, cases of VKDB in exclusively breastfed healthy newborns, despite intramuscular prophylaxis at birth, have been described, suggesting that prophylaxis with a single dose of intramuscular Vitamin K may be inadequate to prevent all cases of late VKDB.[10],[11],[12] An epidemiological study from Germany by von Kries indicated a failure rate (occurrence of late VKDB) of 0.25 per 100,000 infants who were given intramuscular Vitamin K after birth.

The late-onset VKDB occurs between 2 weeks and 6 months after birth, with an increased occurrence reported between 3 and 8 weeks after birth. It has an incidence of 4.4–72.0 per 100,000 live births in Asia and Europe [Table 5].[6]
Table 5: Incidence of late-onset Vitamin K deficiency bleeding in different countries

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The child in our case report was given Vitamin K prophylaxis and was exclusively breastfed and was confirmed to have a late-onset VKDB which is usually rare. The Italian Society of Neonatology since 2004 recommends an oral administration of Vitamin K in all exclusively breastfed newborns in the period from the 2nd to 14th weeks of age to prevent this late-onset VKDB.[13]

Classic VKDB is observed in infants who have not received prophylactic Vitamin K at birth, with an incidence ranging from 0.25 to 1.7 cases per 100 births. Infants who have this disease are often ill, have delayed feeding, or both.[6] Any infant presenting with bleeding should be treated with Vitamin K1; by slow intravenous (IV) injection to give the benefit of doubt and save the child. A single IV dose of 250–300 μg/kg body weight is commonly recommended, and a dose of 1–2 mg is assumed to be sufficient to completely manage Vitamin K deficiency in infants aged up to 6 months. For severe bleeding episodes, it may be necessary to administer blood products, such as fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC). An infusion of FFP (10–15 mL/kg) or PCC (50–100 units/kg) should be considered in severe cases and for very low birth weight infants who cannot sufficiently utilize Vitamin K due to immature liver function.[14]

The accurate measurement of Vitamin K status in humans is still a critical issue. Both indirect and direct analyses of blood levels of phylloquinone and menaquinones forms have been considered. Interference due to triglycerides is the major limitation for these tests. Recent advancements include liquid chromatography‒tandem mass spectrometry (LCMS/MS) detection, which assures higher specificity. The optimization and standardization of these methods require specialized laboratories.[15] In such a scenario, VKDB in a child can be suspected when there is a prolongation of APTT, PT-INR with a normal platelet, and fibrinogen levels. Immediate Vitamin K administration in these children could be lifesaving.

The conventional methods used to measure the Vitamin K deficiency based on the coagulation time lack sensitivity and specificity. Recently, the alterations in PIVKA have proven to be suitable biomarkers for detecting Vitamin K deficiency and its measurement exhibits an enhanced sensitivity and specificity in comparison to other conventional methods. PIVKAs are undercarboxylated precursor proteins of Vitamin K-dependent coagulation factors induced by Vitamin K deficiency. PIVKAs are released from the liver into the blood but lack calcium-binding activity and are thus inactive. Studies have shown that PIVKA levels correlate well with the severity of deficiency, and it could potentially be employed as an effective biomarker in the diagnosis of Vitamin K deficiency.[16]

  Conclusion Top

The National Health Mission, Government of India, recommends that all newborn infants should receive Vitamin K at birth as an intramuscular dose of 0.5–1 mg to prevent VKDB. Even though practices vary, there have been reports of late-onset VKDB even in children who have had prophylactic Vitamin K given. Certain countries have suggested a booster dose or adding oral prophylaxis as a possible approach to prevent Intra Cerebral Hemorrhage (ICH) due to late-onset VKDB. Based on such findings, we think that it will be necessary to review the present guidelines about VKDB prophylaxis to standardize timing and dosage in different clinical conditions. Evidence-based medicine has brought in the importance of correctly diagnosing such disorders. PIVKA-II testing could potentially be employed as an effective biomarker in the diagnosis of Vitamin K deficiency.

Ethical clearance and consent

The study has been done in accordance with the Declaration of Helsinki guidelines. The patient's identity has not been revealed anywhere in any form and this study has ethical clearance from the institution. Assent was obtained from the parents of this child.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Dowd P, Ham SW, Naganathan S, Hershline R. The mechanism of action of Vitamin K. Annu Rev Nutr 1995;15:419-40.  Back to cited text no. 1
Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev 2009;23:49-59.  Back to cited text no. 2
Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemost 1995;21:317-29.  Back to cited text no. 3
Lippi G, Franchini M. Vitamin K in neonates: Facts and myths. Blood Transfus 2011;9:4-9.  Back to cited text no. 4
Pagana KD, Pagana TJ, Pagana TN. Mosby's Diagnostic & Laboratory Test Reference. 14th ed. St. Louis, Mo: Elsevier; 2019.  Back to cited text no. 5
Araki S, Shirahata A. Vitamin K deficiency bleeding in infancy. Nutrients 2020;12:780.  Back to cited text no. 6
American Academy of Pediatrics. Committee on Nutrition. Vitamin K compounds and the water-soluble analougues: Use in therapy and prophylaxis in pediatrics. Pediatrics 1961;28:501-507.  Back to cited text no. 7
Pharos.nih.gov. 2022. Pharos: vitamin K deficiency hemorrhagic disease (4 associated targets). [online] Available at: https://pharos.nih.gov/diseases/Vitamin%20K%20deficiency%20hemorrhagic%20disease. [Last Accessed 01 February 2022].  Back to cited text no. 8
Pooni PA, Singh D, Singh H, Jain BK. Intracranial hemorrhage in late hemorrhagic disease of the newborn. Indian Pediatr 2003;40:243-8.  Back to cited text no. 9
Solves P, Altés A, Ginovart G, Demestre J, Fontcuberta J. Late hemorrhagic disease of the newborn as a cause of intracerebral bleeding. Ann Hematol 1997;75:65-6.  Back to cited text no. 10
Latini G, Quartulli L, De Mitri B, Del Vecchio A, Vecchio C. Intracranial hemorrhage associated with Vitamin K deficiency in a breastfed infant after intramuscular Vitamin K prophylaxis at birth. follow-up at 18 months. Acta Paediatr 2000;89:878-80.  Back to cited text no. 11
Ciantelli M, Bartalena L, Bernardini M, Biver P, Chesi F, Boldrini A, et al. Late Vitamin K deficiency bleeding after intramuscular prophylaxis at birth: A case report. J Perinatol 2009;29:168-9.  Back to cited text no. 12
Italian Society of Neonatology. Vitamin K Prophylaxis in Vitamin K deficiency hemorrhage. consensus conference. Siena: Italian Society of Neonatology;2004.  Back to cited text no. 13
Marchili MR, Santoro E, Marchesi A, Bianchi S, Rotondi Aufiero L, Villani A. Vitamin K deficiency: A case report and review of current guidelines. Ital J Pediatr 2018;44:36.  Back to cited text no. 14
Fusaro M, Gallieni M, Rizzo MA, Stucchi A, Delanaye P, Cavalier E, et al. Vitamin K plasma levels determination in human health. Clin Chem Lab Med 2017;55:789-99.  Back to cited text no. 15
Dong R, Wang N, Yang Y, Ma L, Du Q, Zhang W, 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.  Back to cited text no. 16


  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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