Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.

BACKGROUND: Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. METHODS: A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. RESULTS: Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. CONCLUSION: Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.

α-Tocopherol Intake Decreases Phylloquinone Concentration in Bone but Does Not Affect Bone Metabolism in Rats.

Previous studies have shown that α-tocopherol intake lowers phylloquinone (PK) concentration in some extrahepatic tissues in rats. The study's aim was to clarify the effect of α-tocopherol intake on vitamin K concentration in bone, as well as the physiological action of vitamin K. Male Wistar rats were divided into 4 groups. Over a 3-mo period, the K-free group was fed a vitamin K-free diet with 50 mg RRR-α-tocopherol/kg, the E-free group was fed a diet containing 0.75 mg PK/kg without vitamin E, the control group was fed a diet containing 0.75 mg PK/kg with 50 mg RRR-α-tocopherol/kg, and the E-excess group was fed a diet containing 0.75 mg PK/kg with 500 mg RRR-α-tocopherol/kg. PK concentration in the liver was higher in E-excess rats than in E-free rats, was lower in the tibias of control rats than in those of E-free rats, and was lower in E-excess rats than in control rats. Menaquinone-4 (MK-4) concentration in the liver was higher in E-excess rats than in E-free and control rats. However, MK-4 concentrations in the tibias of E-free, control, and E-excess rats were almost the same. Blood coagulation activity was lower in K-free rats than in the other rats but was not affected by the level of α-tocopherol intake. Additionally, dietary intake of PK and α-tocopherol did not affect uncarboxylated-osteocalcin concentration in the serum, femur density, or expression of the genes related to bone resorption and formation in the femur. These results suggest that α-tocopherol intake decreases PK concentration in bone but does not affect bone metabolism in rats.

Early vitamin K deficiency bleeding in a neonate associated with maternal Crohn's disease.

We report herein a case of early vitamin K deficiency bleeding (VKDB) in a neonate associated with maternal Crohn's disease. A female neonate was born at 37 weeks' gestation and weighed 2778 g. She developed broad purpura on her back on day 1. Laboratory data showed anemia, prolonged coagulation time and elevated protein induced by vitamin K absence or antagonist-II. Early VKDB has not been reported in a neonate born from mother with active Crohn's disease. It is essential to give vitamin K selectively as soon as possible after birth to prevent early VKDB in neonates.

[Vitamin K deficiency bleeding: a case secondary to transient neonatal cholestasis]. / Maladie hémorragique par déficit en vitamine K : à propos d'un cas secondaire à une cholestase néonatale transitoire.

We report the case of late vitamin K deficiency bleeding (VLDB), with appropriate but insufficient prophylaxis, secondary to extrahepatic cholestasis. Late VKDB is rare today but serious, with a risk of intracranial hemorrhage in more than half of the cases. The diagnosis, causes and prevention of this disease are discussed.

Short bowel syndrome causing bleeding diathesis and profound vitamin deficiency in pregnancy.

BACKGROUND: Extensive bowel resection may lead to a state of inadequate nutrient absorption and malnutrition known as short bowel syndrome. Deficiencies in fat-soluble vitamins may occur from this condition, with sequelae such as a bleeding diathesis. Maternal vitamin deficiencies also have been associated with fetal anomalies. CASE: A young gravid patient with a history of neonatal bowel resection presented with bleeding diathesis. She subsequently was found to have profound vitamin deficiencies and delivered a newborn with multiple anomalies. CONCLUSION: Preconceptional counseling, nutritional status evaluation, and concomitant management with a gastroenterologist are essential to optimize pregnancy outcome for patients with a history of extensive bowel resection.

Intracranial hemorrhages and late hemorrhagic disease associated cholestatic liver disease.

Deficiency of vitamin K predisposes to early, classic or late hemorrhagic disease of the newborn (HDN); of which late HDN may be associated with serious and life-threatening intracranial hemorrhage. Late HDN is characterized intracranial bleeding in infants aged 1 week to 6 months due to severe vitamin K deficiency. Late HDN is still an important cause of mortality and morbidity in developing countries where vitamin K prophylaxis is not routinely practiced. Children with cholestatic liver disease are at risk for developing secondary vitamin K deficiency because of fat malabsorbtion and inadequate dietary intake. In this study, we described 11 infants with cholestatic liver disease with different etiologies exhibiting intracranial hemorrhage (ICH). Six patients underwent surgical evacuation of ICH, following the administration of vitamin K and/or fresh frozen plasma. The possibility of cholestatic liver disease should be considered in the treatment of ICH due to vitamin K deficiency.

Late vitamin K deficiency bleeding leading to a diagnosis of cystic fibrosis: a case report.

Vitamin K deficiency bleeding (VKDB) in infants still occurs despite worldwide use of prophylaxis. Clinical manifestations can be dramatic with over 50% of patients presenting with intracranial haemorrhage and a mortality rate of 20% in late vitamin K deficiency bleeding. Special attention should be given to infants with a high risk profile (preterm, breast feeding, cholestasis, malabsorption). A tentative diagnosis can be made observing quick normalisation of some easy-to-perform haemostatic parameters (PT, aPTT) after administration of vitamin K. Nowadays, VKDB can still be the first clinical sign of diseases causing malabsorption of fat-soluble vitamins. In this case report, VKDB led to the diagnosis of cystic fibrosis, the most common fatal autosomal recessive disease among Caucasian people.

Maternal-neonatal vitamin K deficiency secondary to maternal biliopancreatic diversion.

Bariatric surgery has become a common therapeutic approach for severe obesity, in case of unsuccessful behavioural and/or medical interventions. During the past years, the number of obese women who underwent bariatric surgery in childbearing age has progressively increased. We report a case of vitamin K deficiency, due to maternal biliopancreatic diversion, resulting in a symptomatic clinical presentation in the mother and in a hypocoagulable state in her neonate.

Hydrolysed formula is a risk factor for vitamin K deficiency in infants with unrecognised cholestasis.

OBJECTIVES: Vitamin K deficiency (VKD) may cause life-threatening haemorrhages, especially in breast-fed infants with unrecognised cholestasis. Interestingly, hypoallergenic formulas appear overrepresented in reported cases of VKD bleeding (VKDB) in formula-fed infants. We therefore assessed whether the risk of VKD in formula-fed infants with cholestasis is associated with hypoallergenic formulas. PATIENTS AND METHODS: Infants born in the Netherlands between January 1991 and December 2006 with cholestatic jaundice due to biliary atresia (BA) or to α-1-antitrypsin deficiency (A1ATD) were identified in the Netherlands Study Group for Biliary Atresia Registry and the A1ATD registry, respectively. The relative risk (RR) of VKDB in patients with BA or A1ATD was calculated for different formula types. The influence of prior or ongoing breast-feeding on the RR of VKDB was also assessed. RESULTS: A total of 179 infants with either BA (139) or A1ATD (40) were included. One hundred eighteen infants were formula fed; 8 presented with VKD. Six of these 8 infants (75%) received hypoallergenic formula (whey-based hydrolysate in 4). One infant on whey-based hydrolysed formula presented with VKDB. Risk factor analysis revealed that infants receiving hydrolysed, especially whey-based, formula, had a strongly increased risk of VKD (RR 25.0 [6.4-97.2], P < 0.001)) compared with infants receiving regular formula. Prior or ongoing breast-feeding was not significantly associated with VKD. CONCLUSIONS: Infants with cholestasis receiving (whey-based) hydrolysed formula are at increased risk of developing VKD, compared with infants receiving regular formula. Because VKD may lead to serious haemorrhages, infants receiving whey-based hydrolysed formulas may need additional vitamin K supplementation.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

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 the degree of cholestasis. Since alpha-1-antitrypsin deficiency (A1AD) induces a variable degree of cholestasis, we assessed the risk of VKD bleeding in infants with cholestatic jaundice due to A1AD. PATIENTS AND METHODS: Infants with a ZZ or SZ phenotype born in The Netherlands between January 1991 and December 2006 were identified from the databases of the five Dutch diagnostic centres for alpha-1-antitrypsin phenotyping and/or genotyping. We determined the risk of VKD bleeding upon diagnosis of A1AD in breastfed and formula fed infants and searched for correlations between serum levels of conjugated bilirubin and the risk of bleeding. RESULTS: A total of 40 infants with A1AD were studied. VKD bleeding was noted in 15/20 (75%) of breastfed infants, compared with 0/20 of formula fed infants with A1AD. The relative risk for VKD bleeding in breastfed versus formula fed infants was at least 15.8 (95% CI 2.3 to 108). Conjugated bilirubin levels at diagnosis did not correlate with the risk of VKD bleeding. CONCLUSIONS: The risk of VKD bleeding in breastfed infants with A1AD was high and did not correlate with serum level of conjugated bilirubin at diagnosis. A similar absolute risk was previously reported in breastfed infants with biliary atresia under the same prophylactic regimen. This confirms that-without adequate prophylaxis-the risk of VKD bleeding is uniformly high in exclusively breastfed infants with cholestatic jaundice, irrespective of underlying aetiology.

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. METHODS: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. RESULTS: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. RECOMMENDATIONS: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

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.

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.

Intracranial hemorrhage due to late hemorrhagic disease in two siblings.

Deficiency of vitamin K predisposes to early, classic or late hemorrhagic disease of the newborn (HDN); late HDN may be associated with serious and life-threatening intracranial hemorrhage. Late HDN is characterized by intracranial bleeding in infants aged 1 week to 6 months due to severe vitamin K deficiency, occurring particularly in exclusively breastfed infants. Late HDN is still an important cause of mortality and morbidity in developing countries where vitamin K prophylaxis is not routinely practiced. In this study, we report on two siblings with intracranial bleeding who were fully breastfed without a routine supplementation of vitamin K. Vitamin K should be given to all newborns as a single, intramuscular dose of 1 mg.

Is antenatal vitamin K prophylaxis needed for pregnant women taking anticonvulsants?

The objective of this cohort study of a consecutive sample of infants exposed during pregnancy to anticonvulsant drugs was to determine if the mother received late pregnancy prophylaxis with vitamin K, and if any infants had signs of hemorrhagic disease. The medical records of 204 neonates exposed to anticonvulsant drugs in utero and 77 unexposed control neonates were retrospectively reviewed. No hemorrhagic disease was observed, and the incidence of bleeding tendencies was not higher in infants exposed to these drugs compared with control infants, despite no prenatal vitamin K supplementation in all but 1 epileptic woman.