Elsevier

Blood Reviews

Volume 23, Issue 2, March 2009, Pages 49-59
Blood Reviews

REVIEW
Vitamin K deficiency bleeding (VKDB) in early infancy

https://doi.org/10.1016/j.blre.2008.06.001Get rights and content

Summary

Vitamin K deficiency bleeding (VKDB) is a rare and potentially life-threatening bleeding disorder of early infancy. Vitamin K stores are low at birth; thereafter breast-fed infants are at risk because of low concentrations in human milk. Classical VKDB occurs in the first week of life, is related to delayed or inadequate feeding and is readily prevented by small doses of vitamin K at birth. Late VKDB peaks at 3–8 weeks, typically presents with intracranial haemorrhage often due to undiagnosed cholestasis with resultant malabsorption of vitamin K. Diagnosis can be difficult but PIVKA-II measurements can provide confirmation even several days post-treatment. Without vitamin K prophylaxis, the incidence of late VKDB in Europe is 4–7 cases per 105 births; it is higher in SE Asia where in rural, low-income areas some 0.1% of affected infants may suffer intracranial bleeding. Late VKDB is largely preventable with parenteral vitamin K providing the best protection. The efficacy of oral prophylaxis is related to the dose and frequency of administration. Most multi-dose oral regimens provide protection for all except a small reservoir of infants with undetected hepatobiliary disease. Targeted surveillance of high-risk groups (e.g. biliary atresia) offers a novel approach to assess efficacy of prophylaxis.

Introduction

The first description of a coagulopathy that had all the attributes of severe vitamin K (VK) deficiency is accredited to a Boston physician, Charles Townsend who in 1894 described 50 cases of a generalized bleeding tendency in neonates, which he thought sufficiently similar to classify as a single entity and which he named the Haemorrhagic Disease of the Newborn (HDN).1 Townsend noted that HDN could be differentiated from haemophilia by its much earlier time of presentation (usually on days 2 to 3), lack of family history and by its self-limiting time course. Commenting on the complete recovery of one particular 9-day old infant with presumed meningeal haemorrhage, considered by the first physician to be a ‘bleeder’ (haemophiliac) and a hopeless case, Townsend noted “The belief that the disease was self-limited, with careful artificial and wet nurse feeding, the mother’s supply proving a failure, was what saved the baby”. Thus Townsend made the first recorded link between the mother’s capacity to breast-feed and the haemostatic capacity of her newborn infant.1 The fascinating history of VKDB in infancy has been reviewed by Hathaway,2 a history that is littered with uncertainties and controversies on the extent of the problem and the role of VK prophylaxis in public health that still persist to the present day.

The name change from HDN to vitamin K deficiency bleeding (VKDB) was recommended by the ISTH Pediatric/Perinatal Subcommittee in 1999 to clarify that the etiological basis was solely due to VK-deficiency and to include those infants who develop VKDB beyond the usually defined 4-week neonatal period.3 Finally, the new name avoids any possible confusion of HDN with haemolytic disease of the newborn. Though VKDB is rare in most developed countries, the consequences for the few who develop it are potentially catastrophic with over 50% of infants with late VKDB (post 1-week) presenting with intracranial haemorrhage (ICH).4 For this reason nearly all developed countries have introduced prophylactic measures for its prevention. The inability to identify infants at risk has meant that prophylaxis is either given to all newborns or to those whose mothers intend to exclusively breast-feed them. Protection of breast-fed infants is important because VKDB is strongly associated with breast-feeding and is rare in formula-fed infants. A few countries such as the UK, Germany and the Netherlands have surveillance schemes in place to monitor the effectiveness of VK prophylaxis.

The classical role of VK is as an anti-haemorrhagic factor that is needed for the synthesis in the liver of functional forms of prothrombin (factor II) together with factors VII, IX and X.5 After secretion into the blood, these four VK-dependent proteins become available to take part in blood coagulation, the complex series of events that, once initiated, culminates in the conversion of fibrinogen to fibrin and the formation of a haemostatic plug. The biochemical role of VK is to act as a cofactor for the conversion of specific peptide-bound glutamate (Glu) residues to γ-carboxyglutamate (Gla) residues. Hence VK-dependent proteins are often known as Gla-proteins. Two other Gla-proteins, proteins C and S, have well-defined roles in the negative feedback control of coagulation. Put simply, a deficiency of VK is a failure to synthesize γ-carboxyglutamic acid. The consequences of VK-deficiency for haemostasis are an inability to synthesize functional molecules of factors II, VII, IX and X resulting in a hypocoagulable state. The haemostatic system has a considerable capacity to function adequately at low-factor concentrations but as deficiency progresses a point will be reached when the procoagulatory mechanisms fail and bleeding occurs. This point is highly individual and unpredictable.

Section snippets

Nutrition and physiology of vitamin K in the healthy infant

Naturally occurring compounds with VK activity have a common 2-methyl-1,4-naphthoquinone nucleus and a variable alkyl substituent at the 3 position. The VK found in the plant kingdom is phylloquinone (vitamin K1) whereas the multiple forms of VK synthesized by bacteria are menaquinones (vitamins K2). Phylloquinone has a phytyl side chain whereas menaquinones have multi-prenyl side chains, the number of prenyl units being indicated by a suffix (i.e. menaquinone-n, abbreviated MK-n). In the

Classification and etiology of VKDB

In 1985, Lane and Hathaway27 gave a detailed description of three patterns of VKDB (Table 2), which is still widely accepted and recognized by the Pediatric/Perinatal Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH).3 It has been customary to differentiate between idiopathic and secondary VKDB. In secondary VKDB there is an underlying cause, usually an undiagnosed disease such as a hereditary hepatobiliary/malabsorptive disease (e.g. biliary atresia,

Clinical presentation

Early VKDB is rare but frequently life threatening. Common sites/bleed types are the head (cephalhaematoma, intracranial or at site of scalp electrodes), intrathoracic, intra-abdominal or gastrointestinal tract.27 The severity may relate to maternal drugs that inhibit VK metabolism. Idiopathic cases are rarer and sometimes the separation of early and classical VKDB as separate entities seems unwarranted. In a hospital-based Ethiopian survey of VKDB during the first week of life, the mean age of

Incidence of classical VKDB

There is little accurate national data on the incidence of classical VKDB, even in industrialized countries. In a two-year prospective survey in the British Isles56 during 1988–1990 the incidence rate of 5.4 per 105 births for classical VKDB57 was similar to that of 4.4 per 105 births for late VKDB.57 Earlier studies had suggested a higher incidence for classical VKDB with Salomonsen6 reporting that the incidence of classical VKDB in Oslo during 1934–1939 was 0.8%. The later important and

The vitamin K and childhood cancer story

The events that led to the ‘vitamin K and childhood cancer’ scare are a typically British story. On August 2nd 1990 the Guardian newspaper reported on an epidemiological study of Jean Golding and colleagues into factors associated with childhood cancer and particularly on an unexpected association with VK, which in the investigators words, ‘fitted no prior hypothesis’.73 The Guardian was the only paper to give this report any prominence; the article itself being a fair synopsis of Golding’s

Global perspectives of VKDB

While VKDB and its prevention is still a significant concern in industrialized countries, it is a bigger problem in emerging countries. In many low-income countries the problem is unseen or overshadowed by more common and more visible deprivation and disease. One reason for the lack of information from developing countries is that bleeding in infancy can have different causes and VKDB can only be properly diagnosed by laboratory tests or, failing this, by showing that bleeding responds to VK.

Practice points

  • Late VKDB that presents as intracranial bleeding is often preceded by warning bleeds or bruising that should always be investigated by appropriate laboratory tests.

  • Accurate diagnosis of VKDB requires that gestational and/or post-natal age be taken into consideration when interpreting coagulation results (developmental haemostasis).

  • In cases of suspected VKDB confidence in diagnosis is greatly increased by use of specific tests of VK status (e.g. PIVKA-II) even post-VK or factor replacement.

Research agenda

  • Determine the bioavailability of low-dose oral drop regimens when taken with and without feeds.

  • Make further use of local and national registries of diseases associated with cholestasis (e.g. biliary atresia and α-1-antitrypsin deficiency, cystic fibrosis) to assess prophylactic efficacy of different oral VK regimens.

  • Incidence, causes, and prevention of VKDB in developing countries.

  • Metabolism and dietary requirements of VK in infants during the first six months of life.

  • Significance of gut

Conflict of interest statement

The author has previously received funding from F. Hoffmann-La-Roche Ltd., Basel, Switzerland for analytical work connected with the licensing of Konakion MM and a grant for the development of a PIVKA-II assay.

Acknowledgments

I would like to thank Dr. Paul Clarke, Norfolk and Norwich University Hospital for his thoughtful and incisive comments.

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