Vitamin K deficiency embryopathy: A phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism

Menger, H.; Lin, Angela E.; Toriello, Helga V.; Bernert, Günter; Spranger, Jürgen W.

doi:10.1002/(sici)1096-8628(19971017)72:2<129::aid-ajmg2>3.0.co;2-q

Cited by 83 publications

(32 citation statements)

References 8 publications

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“…Hence, vitamin K is an important regulator of bone and cartilage mineralization. Vitamin K also regulates growth plate cartilage calcification, as revealed by effects of vitamin K antagonism by warfarin (6)(7)(8)(9)(10). Genetic deficiencies of MGP in humans and mice have been linked to skeletal abnormalities, including premature epiphyseal calcification and shortening of long limb bones, reflecting endochondral bone formation (11)(12)(13)(14).…”

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Low vitamin K status is associated with osteoarthritis in the hand and knee

Neogi

Booth

Zhang

et al. 2006

Arthritis & Rheumatism

146

101

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Objective. Poor intake of vitamin K is common. Insufficient vitamin K can result in abnormal cartilage and bone mineralization. Furthermore, osteophyte growth, seen in osteoarthritis (OA), may be a vitamin K-dependent process. We undertook this study to determine whether vitamin K deficiency is associated with radiographic features of OA.Methods. We conducted an analysis among 672 participants (mean age 65.6 years, 358 women) in the Framingham Offspring Study, a population-based prospective observational cohort. Levels of plasma phylloquinone (the primary form of vitamin K) had previously been measured in these participants, for whom we also had bilateral hand and knee radiographs. The main outcomes were 1) prevalence ratios (PRs) of OA, osteophytes, and joint space narrowing (JSN) per quartile of plasma phylloquinone level for each joint, adjusting for correlated joints using generalized estimating equations, and 2) adjusted mean number of joints with each feature per quartile of plasma phylloquinone level. Analyses were conducted in hands and knees separately and adjusted for age, sex, body mass index, total energy intake, plasma vitamin D, and femoral neck bone mineral density.Results. The PRs for OA, osteophytes, and JSN and adjusted mean number of joints with all 3 features in the hand decreased significantly with increasing plasma phylloquinone levels (P < 0.03 for all). For example, as plasma phylloquinone levels rose, the PR for hand OA decreased from 1.0 to 0.7 (P ‫؍‬ 0.005). For the knee, only the PR for osteophytes and the adjusted mean number of knee joints with osteophytes decreased significantly with increasing plasma phylloquinone levels (PR decreased from 1.0 to 0.6, P ‫؍‬ 0.01).Conclusion. These observational data support the hypothesis of an association between low plasma levels of vitamin K and increased prevalence of OA manifestations in the hand and knee.

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confidence: 99%

Low vitamin K status is associated with osteoarthritis in the hand and knee

Neogi

Booth

Zhang

et al. 2006

Arthritis & Rheumatism

146

101

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“…However, if maternal plasma vitamin K concentrations are decreased during pregnancy, fetal vitamin K deficiency can result. 16 Furthermore, because the quantity of vitamin K able to cross the placenta is limited by the slow placental transfer rate, the fetus cannot compensate for periods of prolonged maternal deficiency, even if maternal vitamin K concentrations return to normal. 16 Hypovitaminosis K has been reported in babies of patients suffering from diseases that cause vitamin K malabsorption.…”

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confidence: 99%

“…16 Furthermore, because the quantity of vitamin K able to cross the placenta is limited by the slow placental transfer rate, the fetus cannot compensate for periods of prolonged maternal deficiency, even if maternal vitamin K concentrations return to normal. 16 Hypovitaminosis K has been reported in babies of patients suffering from diseases that cause vitamin K malabsorption. 16 In a study of such cases, two of three patients did not show other clinical evidence of vitamin K deficiency.…”

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confidence: 99%

Brodifacoum Toxicosis in Two Neonatal Puppies

Munday¹,

Thompson²

2003

Vet Pathol

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Abstract. Eight out of a litter of 13 puppies were either born dead or died within 48 hours of birth. Three puppies that died shortly after birth were necropsied. Two puppies had hemorrhage in the thoracic and peritoneal cavities, intestinal serosa, and meninges. The third puppy was smaller than the other two puppies but did not have detectable hemorrhage. Brodifacoum, a second-generation coumarin anticoagulant, was detected in livers from the two puppies with hemorrhage. The dam did not have clinical signs of coagulopathy before or subsequent to whelping. The owners were confident that the dog had not been exposed to rodenticide for at least 4 weeks before whelping. A presumptive diagnosis of in utero brodifacoum toxicity was made. To the authors' knowledge this is the first time a second-generation coumarin anticoagulant has been detected in the liver of a newborn animal. This case is also unique because the dam was unaffected, suggesting that fetuses are more susceptible to brodifacoum toxicity than adult animals.Key words: Anticoagulant; brodifacoum; canine; coagulopathy; coumarin; transplacental; vitamin K.A 1-year-old Great Pyrenees bitch that was housed at a breeding kennel gave birth to 13 puppies after 63 days of gestation. Whelping was observed and was considered normal. However, two puppies were born dead, three died within 6 hours, and three died between 6 and 48 hours of birth. Four of the six puppies that died postpartum had variable hemoptysis or epistaxis before death. Two puppies were reported to have died suddenly without previous clinical signs of disease. The birth weight of the eight puppies that were born dead or died was 280 Ϯ 107 g (mean Ϯ 1 SD), whereas the birth weight of the five puppies that survived was 502 Ϯ 57 g (mean Ϯ 1 SD).The three puppies that were born alive but died within 6 hours of birth were necropsied. The abdominal cavities of two puppies (puppy Nos. 1 and 2) each contained approximately 40 ml of uncoagulated blood. Both puppies also had approximately 15 ml of uncoagulated blood within the thoracic cavity. However, one (puppy No. 3) did not have visible hemorrhage. Representative tissue samples from all three puppies were fixed in 10% buffered formalin and routinely processed for histologic examination. Histologic examination of tissues from puppy Nos. 1 and 2 revealed microscopic hemorrhage within the intestinal serosa and meninges. No significant lesions were observed by histologic examination of tissues from puppy No. 3. No histologic evidence of any infectious process was present in tissues from any of the puppies. Aerobic cultures of lung, liver, small intestine, and kidney from all three puppies did not yield pathogenic bacteria. Direct fluorescent antibody (American Bioresearch, Seivierville, TN) examination of kidney, lung, and liver did not reveal canine herpes virus antigen in any of the puppies.Liver samples from all three puppies were analyzed by high performance liquid chromatography (HPLC) for warfarin, bromadiolone, and brodifacoum. 17 Briefly, liver samp...

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“…For example, if a given toxicity occurs prior to or immediately after implantation, it may result in spontaneous loss of the embryo. If the exposure to a drug happens during morphogenesis and organogenesis (i.e., before the developmental milestones are reached), cardiovascular, skeletal, or other anatomical malformations can occur (Table 1) (Menger et al, 1997, van Driel et al, 2002. Functional deficit is often associated with physical malformations such as renal failure and fetal hypotension, in the case of administration of angiotensin converting enzyme inhibitors during the second and third trimesters of pregnancy, or central nervous system and heart and lung dysfunction associated with fetal exposure to warfarin (van Driel et al, 2002).…”

Section: Mammalian Pregnancy and Embryofetal Developmentmentioning

confidence: 99%

Nonclinical aspects of venous thrombosis in pregnancy

Struble

Harrouk

DeFelice

et al. 2015

Birth Defects Research Pt C

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Pregnancy is a hypercoagulable state which carries an excess risk of maternal venous thrombosis. Endothelial injury, alterations in blood flow and activation of the coagulation pathway are proposed to contribute to the hypercoagulability. The risk for thrombosis may be accentuated by certain drugs and device implants that directly or indirectly affect the coagulation pathway. To help ensure that these interventions do not result in adverse maternal or fetal outcomes during pregnancy, gravid experimental animals can be exposed to such treatments at various stages of gestation and over a dosage range that would identify hazards and inform risk assessment. Circulating soluble biomarkers can also be evaluated for enhancing the assessment of any increased risk of venous thrombosis during pregnancy. In addition to traditional in vivo animal testing, efforts are under way to incorporate reliable non-animal methods in the assessment of embryofetal toxicity and thrombogenic effects. This review summarizes hemostatic balance during pregnancy in animal species, embryofetal development, biomarkers of venous thrombosis, and alterations caused by drug-induced venous thrombosis.

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Vitamin K deficiency embryopathy: A phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism

Cited by 83 publications

References 8 publications

Low vitamin K status is associated with osteoarthritis in the hand and knee

Low vitamin K status is associated with osteoarthritis in the hand and knee

Brodifacoum Toxicosis in Two Neonatal Puppies

Nonclinical aspects of venous thrombosis in pregnancy

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