Vitamin K Deficiency Bleeding Research Articles

Delayed vitamin K deficiency as a cause of bleeding: still a concern in the 21st century!

Delayed haemorrhage due to vitamin K deficiency in early infancy has rarely been the cause of acquired hemostatic disorders. We report here 11 cases of vitamin K deficiency bleeding (VKDB), despite receiving appropriate dosage of injectible vitamin K at birth. Bleeding symptoms ranged from excessive bleed from cuts to intracranial bleed. Tuberculosis, diarrhea with intermittent antibiotic therapy were some of the associated symptoms. Laboratory tests confirmed acquired bleeding diathesis due to vitamin K deficiency, which was corrected after adequate vitamin K supplementation. VKDB is not an uncommon phenomenon and should be considered in the differential diagnosis of a child with bleeding diathesis.

Vitamin K prophylaxis and vitamin K deficiency bleeding in the UK

<h3>Aim</h3> To correlate incidence, morbidity and mortality of vitamin K deficiency bleeding (VKDB) with changing practices in vitamin K (VK) prophylaxis in the UK—most recently the withdrawal of Konakion Neonatal in 2006, leaving Konakion MM as the only licenced preparation for prophylaxis in the UK. <h3>Method</h3> Since 1988 four 2-year studies of VKDB have been undertaken via the British Paediatric Surveillance Unit (BPSU), each with a contemporaneous survey of VK prophylaxis. The 2001–2002 survey preceded withdrawal of Konakion Neonatal, the 2006–2008 survey followed it. <h3>Results</h3> VKDB incidences in the two recent studies are not statistically different, but lower than previously. VK was recommended by all units in the two recent studies. In 1993–1994 only 38% of babies received intramuscular VK. By 2001–2002, 60% of units recommended intramuscular, most using Konakion Neonatal; by 2006–2008 72% of units recommended intramuscular, all using Konakion MM. In 1993–1994, 60% of babies were routinely offered oral prophylaxis, ending by day 7 in 25% of these. In 2001–2002 and 2006–2008 almost all used multiple-dose regimens extending to 28+ days in breastfed infants. Some parents withhold consent for any VK prophylaxis (50% of recent cases). The three cases of late VKDB associated with liver disease in 2006–2008 were jaundiced at presentation on day 23, 66 and 86; the first had oral, the others intramuscular VK. Long-term sequelae from intracranial haemorrhage are expected in one; another died of liver failure. Investigating prolonged jaundice was not routine in 10% of units responding (n=198 of total 236 units) <h3>Conclusions</h3> ▸ Most babies developing VKDB are breast-fed and have received no VK, usually because parents refuse it. Some 30% have unrecognised liver disease. ▸ Substituting Konakion MM for Konakion Neonatal has not been associated with a significant increase in VKDB incidence. ▸ Prophylaxis cannot alone prevent all cases. Early detection of liver disease by investigating prolonged jaundice identifies some of the most vulnerable babies before they bleed and may improve the prognosis of the underlying disease; all units should promote this practice.

Vitamin K deficiency bleeding: Early history and recent trends in the United Kingdom

At the start of the 20th century the mechanisms of haemostasis were virtually unknown. Townsend had coined the term ‘Haemorrhagic disease of the newborn’ in 1894 but it was not until the discovery of vitamin K (‘Koagulation vitamin’) by Dam and others in the 1930s that the condition became understood, allowing treatment and prophylaxis. Methods of prophylaxis (preparations used, doses and routes of administration), still widely debated, have varied with time and from one country to another. The formation of the British Paediatric Surveillance Unit in the 1980s has allowed a series of prospective population studies of Vitamin K deficiency bleeding (VKDB) in the United Kingdom (UK) and Ireland which, together with contemporaneous surveys of practices of vitamin K prophylaxis, have greatly improved our understanding of the condition and informed practices of prophylaxis. In the UK prophylaxis (by injection or by mouth) is now offered to every newborn baby and VKDB is very rare, most cases occurring in breastfed babies whose parents have refused prophylaxis; by contrast, in developing countries most babies do not receive prophylaxis and VKDB is probably a common (but poorly documented) cause of death and handicap in the early months of life. Vitamin K prophylaxis should be available to all newborn babies.

Case of toluene abuse

Haemorrhagic disease of the newborn (HDN) can be defined as vitamin K deficiency related bleeding. HDN is one of the most frequent bleeding disorders in infancy [1]. It is classified as early, classical and late - onset disease according to the time bleeding occurs. Early HDN is diagnosed when the bleeding begins in the first 24 hours of postnatal period. It is frequently seen in babies whose mothers are on antitubercular (isoniazid and/or rifampicin), or antiepileptic (such as phenytoin and phenobarbitol) drugs. Classical HDN occurs between 2-5 days of neonatal period and life-threatening bleeding is rare. Late-onset disease can be seen during infancy but predominantly at 4-8 weeks of life. Its incidence is 4-25/1,00,000 births in the western countries but as high as 25-80/1,00,000 in eastern countries [2]. Late haemorrhagic disease is diagnosed if bleeding occurring after the 7th day of life with normal platelet count, prolonged prothrombin time (PT) and partial thromboplastin time (PTT) associated with stopping of bleeding and PT/PTT returning to normal after giving vitamin K [3].

Risk factors, presentations and outcome of the haemorrhagic disease of newborn.

To determine the presentations, associated factors and acute outcome in the haemorrhagic disease of newborn. Cross-sectional analytical study. Paediatric Medicine Unit II, Nishtar Hospital, Multan, from June 2004 to May 2006. Fifty patients with haemorrhagic disease of newborn were studied. Age at onset of symptoms, gender, feeding pattern, place of delivery, site of bleeding and acute outcome of patients were noted. Chi-square test was applied to determine the significance of differences and relationship between variables and outcome. P-value of less than 0.05 was considered significant. The mean age at onset of symptoms was 51.65+/-39.49 days. Male to female ratio was 2.1:1 (p=0.047). Late onset disease (8 days to 6 months of life) was noted in 32 (72%) babies (p=0.094). Exclusive breastfeeding was noted in 45 (90%) babies (p<0.001). Thirty babies (60%) were delivered at homes (p=0.025), 13 (26%) at private clinics and 7 (14%) at government hospitals. Intracranial haemorrhage was noted in 26 (52%) babies, skin bleeding in 09 (18%) babies, gastrointestinal in 08 (16%), bleeding from injection site in 04 (8%), hematuria in 02 (4%) and bleeding from umbilicus in 01 (2%) baby. Forty babies recovered, whereas death occurred in 10 babies. The cause of death was intracranial haemorrhage in all babies (p=0.059) and all were of late onset disease (p=0.088). Haemorrhagic disease of newborn was common in male gender, breast-fed infants and spontaneous vaginal deliveries. Intracranial haemorrhage and late onset disease were the causes of mortality in all cases.

Vitamin K deficiency bleeding in cholestatic infants with alpha-1-antitrypsin deficiency

Objective:Exclusively breastfed infants with unrecognised cholestatic jaundice are at high risk of a vitamin K deficiency (VKD) bleeding. It is presently unknown whether (the size of) this risk depends on...

Late vitamin K deficiency bleeding after intramuscular prophylaxis at birth: a case report

We report the case of a 6-week-old female who presented an intracranial hemorrhage due to late vitamin K deficiency bleeding (VKDB). No other evident bleeding sites were present at the moment of diagnosis. Intramuscular vitamin K (1 mg) was administered at birth. She was exclusively breast-fed. No other risk factors for VKDB were detected. Low levels of vitamin K-dependent coagulation factors and their normalization after vitamin K administration confirmed the diagnosis of late VKDB. The present case suggests potential risks related to a single dose of intramuscular vitamin K at birth.

Vitamin K, an update for the paediatrician

This review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for gamma-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis. Newborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as "haemorrhagic disease of the newborn". Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (i.m.) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single i.m. administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 microg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease. Further work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.

Clinical trial for the prevention of late Vitamin K Deficiency Bleeding (VKDB): Preliminary results

Clinical trial for the prevention of late Vitamin K Deficiency Bleeding (VKDB): Preliminary results

Vitamin K deficiency bleeding (VKDB) in early infancy

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 10(5) 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.

The neonatal coagulation system and the vitamin K deficiency bleeding – a mini review

Coagulation factors do not cross the placental barrier but are synthesized independently by the conceptus. At birth, activities of the vitamin K dependent factors II, VII, IX, and X and the concentrations of the contact factors XI and XII are reduced to about 50% of normal adult values. The levels of the factors V, VIII, XIII, and fibrinogen are similar to adult values. Plasma concentrations of the naturally occurring anticoagulant proteins (antithrombin, protein C, and protein S) are significantly lower at birth than during the adult years. Plasminogen is reduced by approximately 50%. Platelet counts are within the normal range, regarding function, however, neonatal platelets seem to be hyporeactive. The von Willebrand factor contains large multimers and its concentration is increased. Properties and functions of vitamin K as well as requirement and plasma concentrations in newborns are reviewed. Regarding vitamin K deficiency bleeding (VKDB), the classical nomenclature is used: "early" (presenting within the first 24 h of life), "classical" (day 1-7 after birth), and "late" (8 days to 6 months). After the presentation of the history of vitamin K prophylaxis, vitamin K levels are described as can be expected after the administration of prophylactic doses at various routes. Subsequently, the actual schedule of vitamin K prophylaxis as recommended by the "Osterreichische Gesellschaft für Kinder- und Jugendheilkunde" is given as follows: i) the oral treatment of healthy full-term babies and orally fed preterm babies, ii) the parenteral treatment of small preterm and sick full-term babies, and iii) the treatment of mothers under medication with enzyme-inducing drugs with vitamin K during the last 15-30 days of pregnancy. The regimes of prophylactic vitamin K treatment of different countries are also given. Finally, the therapeutic use of vitamin K is addressed; the potential use of fresh-frozen plasma, prothrombin complex preparations, and recombinant factor VIIa is discussed.

Making Life Safe for Canaries

I can still remember the words written in red ink at the bottom of my essay: “You had a promising idea, but its development was disappointing.” Many think that we already know all we really need to know about the use of vitamin K, but I fear my old headmaster might have viewed things rather more critically. The speed with which people realized how vitamin K could be used to almost eliminate the risk of hemorrhagic disease of the newborn (HDN) was impressive. Indeed, the first article to describe clinical use appeared only 4 years after Danish biochemist Henrik Dam1 described his discovery in Nature in 1935. Use spread rapidly in Europe and America once a commercial product became available in the late 1940s, and when a single dose did not suffice to stop not just classic HDN but also intraventricular hemorrhage in the preterm infant, people started administering bigger doses. It did not take long after that for reports to appear that linked the use of the water-soluble analog menadione (the only preparation then commercially available) with an epidemic of severe jaundice and … Address correspondence to Edmund Hey, DM E-mail: shey{at}easynet.co.uk

Intracranial hemorrhages due to late-type vitamin K deficiency bleeding

Vitamin K deficiency bleeding (VKDB) represents a clinical picture characterized by bleedings due to insufficient levels of vitamin-K-dependent hemostatic factors. VKDB can be classified into three groups as early, classic, and late according to time of occurrence. Late-type VKDB has particular importance due to frequent intracranial hemorrhages that lead to high mortality and morbidity. In our study, we aimed to emphasize the importance of vitamin K prophylaxis in prevention of late-type VKDB. Data of 12 infants treated for intracranial hemorrhage due to late-type VKDB in Baskent University Hospitals between June 1998 and June 2005 have been analyzed. The ages of patients ranged between 25 and 90 days. Five were born in the hospital and seven were born at home. None of the infants born at home received vitamin K prophylaxis. Hemorrhages were classified as intraparenchymal in 58.33%, subarachnoid in 50.00%, subdural in 50.00%, intraventricular in 41.66%, and epidural in 8.33% according to cranial computerized tomography findings. Surgery was performed in seven cases (58.33%). A total of six patients died (50.00%). Three of the deaths were from the surgery-performed group. All newborns should receive vitamin K prophylaxis to prevent bleeding due to vitamin K deficiency. Symptoms of any predisposing disease and warning bleeds must be noticed early and additional doses of vitamin K should be administered, if required.

Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding

This article describes a 4-y-old girl with spontaneous, generalized bruising, abdominal distention, and signs of malnutrition. She had been treated previously with an antibiotic for diarrhea. Laboratory analyses showed the presence of iron-deficiency anemia, mild hypoalbuminemia, and considerably prolonged prothrombin time and activated thromboplastin time. Tests revealed that hemostasis improved after the patient received fresh frozen plasma. A coagulation profile showed a decrease in clotting factors II, VII, IX, and X. The patient was given intravenous vitamin K therapy (5 mg/d) for 3 d. All coagulation tests were normalized, and bruising started to disappear. Positive serology (immunoglobulin A antitissue transglutaminase and immunoglobulin A antiendomysial antibodies) and smallbowel mucosal histopathology confirmed the presence of celiac disease (CD). The girl recovered completely after she was put on a gluten-free diet. Vitamin K-deficiency bleeding is a rare complication that occurs almost exclusively in patients with typical CD manifestations. In addition to antibiotic therapy, treatment with other drugs that influence vitamin K resorption and metabolism may increase the risk of bleeding in patients with CD with hypoprothrombinemia.

Hemorrhagic disease of the newborn despite vitamin K prophylaxis at birth

Late hemorrhagic disease of the newborn (HDN) presents 0.5-6 months after birth with mucocutaneous and intracranial bleeding. We describe here two cases of late HDN in infants who received vitamin K. The first case is a previously healthy breastfed male who received one dose of oral vitamin K at birth and developed an intracranial hemorrhage 5 weeks later. He was treated with intravenous vitamin K and recombinant factor VIIa prior to emergent craniectomy. An unrelated infant presented at 5 months of age with diarrhea and easy bruising despite IM vitamin K at birth. These cases illustrate the morbidity associated with late HDN.

Vitamin K deficiency bleeding with intracranial hemorrhage: focus on secondary form

Non-accidental trauma is the leading cause of intracranial hemorrhage (ICH) in infancy. In contrast, ICH as a part of vitamin K deficiency bleeding (VKDB) secondary to hepatobiliary disease is rare, but encountered even in the era of vitamin K (VK) prophylaxis. During 43 months, six cases with ICH were diagnosed as an initial presentation of VKDB. Clinical features and imaging findings of them were retrospectively reviewed. All cases were breastfed and received oral VK prophylaxis. Liver dysfunction was found in five. Brain CT showed hemorrhage in subdural and subarachnoid space in six, parenchyma in three, and ventricle in one. Abdominal ultrasound was positive in four with final diagnoses of biliary atresia in two, neonatal hepatitis in one, and milk allergy in one. Two cases with negative ultrasound were diagnosed as idiopathic VKDB. In conclusion, ICH with secondary VKDB is rare, but important in infancy in the era of VK prophylaxis.

Vitamin K deficiency bleeding in Great Britain and Ireland: British Paediatric Surveillance Unit Surveys, 1993–94 and 2001–02

Objective:To conduct and report monitoring of vitamin K deficiency bleeding (VKDB) in Great Britain and Ireland following the 1988–90 survey (VKDB-90).Design:Two 2-year surveys conducted during 1993–4 (VKDB-94) and 2001–02 (VKDB-02).Setting:Data...

Neonatal vitamin K prophylaxis in Great Britain and Ireland: the impact of perceived risk and product licensing on effectiveness

Objective:To determine current use of vitamin K (VK) prophylaxis in newborns and review the efficacy and effectiveness of regimens used.Design:Efficacy and effectiveness calculated using current practice details, data from Southern...

Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline

Vitamin K prophylaxis is recommended to prevent the hazard of haemorrhage caused by vitamin K deficiency in newborns. The present Dutch guideline recommends 1 mg of vitamin K1 orally at birth, followed by a daily dose of 25 μg of vitamin K1 from 1 to 13 weeks of age for breastfed infants. Since the introduction of this prophylaxis, the incidence of vitamin K deficiency bleeding (VKDB) has decreased; however, late VKDB is still reported. From 1 January to 31 December 2005, a nationwide active surveillance was performed by the Netherlands Paediatric Surveillance Unit (NSCK) to study the current incidence and aetiology of late VKDB in infants. Six cases could be validated as late VKDB: all were breastfed, one fatal idiopathic intracranial haemorrhage at the age of 5 weeks and five bleedings secondary to an underlying cholestatic liver disease between the age of 3 and 7 weeks. The total incidence of late VKDB and idiopathic late VKDB was calculated to be 3.2 (95% CI: 1.2–6.9) and 0.5 (95% CI: 0–2.9) per 100,000 live births, respectively. With the current Dutch guideline, idiopathic late VKDB is rare but late VKDB secondary to cholestasis still occurs in breastfed infants. Doubling the daily dose of vitamin K1 to 50 μg, as is comparable to formula-feeding, may possibly prevent VKDB in this group. Further research, however, is needed to prove this hypothesis.

Polymorphisms of the Factor VII Gene Associated with the Low Activities of Vitamin K-Dependent Coagulation Factors in One-Month-Old Infants

Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.