Hematochezia Due to Panitumumab-induced Colitis with Vitamin K Deficiency.

Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be useful in treating either advanced or recurrent KRAS/NRAS/BRAF wild-type colorectal cancer. We herein report the case of a 60-year-old man with short bowel syndrome who developed hematochezia due to panitumumab-induced colitis with vitamin K deficiency during third-line chemotherapy. The cause of vitamin K deficiency was the lack of intravenous vitamin K supplementation following a change from central venous nutrition to peripheral venous nutrition. We advise clinicians to carefully check for colitis and manage the infusions of chemotherapy patients with short bowel syndrome.

Hypoprothrombinemia and severe perioperative haemorrhagic complications in cardiac surgery patients treated with high-dose cefazolin for infective endocarditis.

Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life-threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl-carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation.

Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.

OBJECTIVE: To determine prophylactic role of single dose of vitamin K in prevention of antibiotic induced hypoprothrombinemia. METHODS: This prospective comparative study included critically ill children in age group 2 mo to 12 y, admitted to a tertiary care hospital in India, likely to receive prolonged antibiotic therapy. One hundred twenty children, 60 in each group (A & B) were enrolled in the study. Patient allocation was done on alternate basis. Group A children received prophylactic vitamin K while group B did not. Baseline coagulation studies and other investigations were done in all children. Coagulation studies were repeated on day 10 and day 14 of antibiotic therapy and in between if required clinically. Children who developed deranged INR were given therapeutic vitamin K. If deranged INR returns to normal at 12 h of vitamin K administration then it indirectly confirms vitamin K deficiency. Analysis was done by fisher's t test and chi square test. RESULTS: In children on prolonged antibiotic therapy, vitamin K deficiency was a common problem (15%). It was common in male sex, severe grade of protein energy malnutrition (PEM), N-methylthiotetrazole (NMTT) group containing antibiotics use and duration of antibiotic more than 10 d. It was same in children whether they received or did not receive prophylactic vitamin K on day 1 of antibiotic therapy (95% CI; p value 0.79). CONCLUSIONS: Vitamin K deficiency is common problem in patients on prolonged antibiotic therapy. There is no role of single dose of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.

Acquired absolute vitamin K deficiency in a patient undergoing warfarin therapy.

We report a case of absolute vitamin K deficiency (VKD) diagnosed by measuring serum VK levels in an elderly woman undergoing warfarin therapy. A 78-year-old woman was admitted to our hospital because of dyspnea and sore throat diagnosed as pharyngitis 1 week before admission. On admission, the sore throat had exacerbated and dyspnea developed. She had history of atrial fibrillation, for which warfarin 1.5 mg/d was started approximately 10 years prior and her international normalized ratio (INR) had been maintained at an acceptable therapeutic level. Blood results revealed unmeasurable INR and abnormally prolonged activated partial thromboplastin time (APTT). She was diagnosed with adenoiditis and warfarin-related coagulopathy and administered intravenous VK (20 mg) and fresh frozen plasma (FFP; 4 U), which improved INR and APTT. Since the coagulopathy responded to intravenous VK administration, the patient was clinically diagnosed with warfarin-related relative VKD. Approximately 1 month later, she returned with complaints of sore throat. Blood results indicated abnormal INR (7.22) and APTT (N80.0 s). She was diagnosed with recurrent adenoiditis and VK deficient coagulopathy. The patient's serum VK levels were low (VK1 level, 0.13 ng/mL; VK2 levels, 0.85 ng/mL). Initial treatment of VK (20 mg) and FFP followed by intravenous VK (20 mg/d) for 6 days, her symptoms dissipated. Warfarin was suspected to have caused absolute VKD. Severe coagulopathy in patients undergoing warfarin therapy is primarily caused by, relative VKD. However, the possibility of warfarin-related absolute VKD should be suspected when INRis not sufficiently improved by intravenous VK administration.

Clinical decision-making for vitamin K-1 and K-2 deficiency and coronary artery calcification with warfarin therapy: are diet, factor Xa inhibitors or both the answer?

Coronary artery calcification is a recognised risk factor for ischaemic heart disease and mortality. Evidence is now strong that Mönckeberg's arteriosclerosis, a form of vascular calcification, can be attributable to vitamin K deficiency, but that vitamin K-2, especially the MK-4 form from foods like cheese can be protective. Warfarin blocks the recycling of hepatic and peripheral vitamin K leading to secondary vitamin K deficiency with adverse effects on vasculature, bone, kidneys, brain and other tissues and systems (inflammatory, immune function and neoplasia at least). There is individual susceptibility to vitamin K deficiency and warfarin sensitivity, partly explicable in terms of genetic polymorphisms, epigenetics, diet and pharmacotherapy. The emergence of extensive coronary calcification in a man with atrial fibrillation treated for a decade with warfarin is described by way of illustration and to raise the present clinical management conundrums. Finally, a putative set of recommendations is provided.

[Suspicious case of epidural hematoma due to coagulopathy caused by vitamin K deficiency associated with antibiotics].

We experienced a case of epidural hematoma caused by coagulopathy 3 days after surgery. A 72-year-old man, who had undergone a total gastrectomy, suffered from nausea and vomiting by ileus. He underwent repair of ileus under general anesthesia with thoracic epidural anesthesia. Three days after surgery, abnormal bleeding followed by disorder of prothrombin activity (PT) and activated partial thromboplastin time (aPTT) and paralysis due to thoracic epidural hematoma developed. It was suspected that these coagulopathies were the results of vitamin K deficiency. Vitamin K deficiency in this patient was considered to have been caused by cephem antibiotics containing N-methyl-thiotetrazole (NMTT) side chain and no oral intake of food for a few days preoperatively. The patient was treated with fresh frozen plasma and intravenous menatetrenon, which improved abnormal bleeding and disorder of PT and aPTT within 24hr. After a discussion with orthopedic consultants, we selected a conservative therapy rather than surgical removal of the hematoma. Thoracic epidural hematoma disappeared two months after surgery, but motor paralysis requiring rehabilitation remained. In conclusion, when patients have not eaten anything for a few days and antibiotics with an NMTT sidechain has been administered, care must be taken to prevent vitamin K deficiency and coagulopathy.

[Coagulation abnormalities after total hip prosthesis (THP), a rare cause: antibiotic prophylaxis]. / Anomalies de la coagulation après prothèse totale de hanche (PTH), une cause rare: l'antibioprophylaxie.

A 87-year-old patient developed coagulation abnormality following hip surgery related to the prophylactic use of cefamandole. Cefamandole as others cephalosporins with a methyl-tetrazol-thiol lateral chain interferes with the vitamin K regeneration cycle as do oral anticoagulants. Therefore, the use of others antibiotics or systematic vitamin K1 supplementation or single dose of cefamandole is recommended for patients with renal failure or with malnutrition. Vitamin K1 supplementation is a simple method resulting in complete resolution of the coagulation disorder.

Warfarin exposure and calcification of the arterial system in the rat.

There is evidence from knock-out mice that the extrahepatic vitamin K-dependent protein, matrix gla protein, is necessary to prevent arterial calcification. The aim of this study was to determine if a warfarin treatment regimen in rats, designed to cause extra-hepatic vitamin K deficiency, would also cause arterial calcification. Sprague-Dawley rats were treated from birth for 5-12 weeks with daily doses of warfarin and concurrent vitamin K1. This treatment causes an extrahepatic vitamin K deficiency without affecting the vitamin K-dependent blood clotting factors. At the end of treatment the rats were killed and the vascular system was examined for evidence of calcification. All treated animals showed extensive arterial calcification. The cerebral arteries and the veins and capillaries did not appear to be affected. It is likely that humans on long-term warfarin treatment have extrahepatic vitamin K deficiency and hence they are potentially at increased risk of developing arterial calcification.

Induction of coagulation effects by Wyeth-14,643 in Crl:CD BR rats.

A two-year mechanistic bioassay in male Crl:CD BR rats was initiated with 50 ppm Wyeth-14,643 (WY) to investigate the relationship between peroxisome proliferating compounds and Leydig cell adenoma formation. After 154 days, the survival rate in the WY group decreased below control levels. After 300 days, the dose was lowered to 25 ppm for the remainder of the study. Gross examination of WY-treated rats either found dead or euthanized in extremis revealed hemorrhages at several sites. To investigate this observation, blood was then collected on test day 281 from 10 randomly selected control and WY-treated rats and a clinical pathological examination was performed. The WY-treated rats had significantly decreased red blood cell count, hemoglobin, and hematocrit, and elevated platelet counts. In the WY-treated rats, prothrombin times in undiluted plasma were similar to the controls, but were markedly prolonged in 2 of 10 rats when the plasma samples were diluted to 25%. Subsequently, blood was collected prior to sacrificing WY-treated rats which were exhibiting clinical signs of anemia. These rats had prolonged prothrombin times, activated partial thromboplastin time, and thrombin clot time when compared to laboratory historical control data (116.7 vs 13.3, 116.4 vs 13.7, and 42.4 vs 25.7 seconds, respectively). In a subsequent, ongoing study, Vitamin K was added to control and WY-treated diets (100 ppm). No survival differences between control and WY-treated rats occurred through 260 days in this second study. These new data suggest that deaths in the WY-treated group in our initial study were due to a vitamin K deficiency. The role of increased serum estradiol, its effects on blood coagulation, and enhanced hepatic cell proliferation in the vitamin K-dependent coagulation processes warrant further investigation.

Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K.

Ten patients with maxillonasal hypoplasia (Binder "syndrome"), who were prenatally exposed to phenytoin (usually in combination with other anticonvulsants), were identified retrospectively. In addition to their facial anomalies, 6 of the patients were radiographed neonatally and showed punctate calcification, characteristic of chondrodysplasia punctata. Evidence is presented that the facial abnormalities seen in these children are due to anticonvulsant-induced vitamin K deficiency, causing abnormal development of the cartilaginous nasal septum. We propose that early vitamin K supplementation of at-risk pregnancies may prevent the development of maxillonasal hypoplasia, which in some patients is severely disfiguring and causes great emotional distress. Correction of this facial defect requires surgical and dental treatment over a long period of time.

Antenatal drugs affecting vitamin K status of the fetus and the newborn.

Coumarin derivatives and anticonvulsants administered during pregnancy enter the fetal circulation, interfering with the action of vitamin K. Vitamin K plays a crucial part in the gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors prothrombin, FVII, FIX, and FX. Other vitamin K-dependent proteins in the coagulation cascade are protein C and protein S. Vitamin K-dependent bone proteins are osteocalcin and gamma-carboxyglutamate matrix protein. Administration of coumarol derivatives results in under carboxylation of the vitamin K-dependent proteins. Anticoagulation therapy with warfarin is followed by an increased risk of embryopathy, which has been shown to be greatest between gestational weeks 6 and 12. Administration of warfarin is also followed by an increased risk both of fetal intraventricular hemorrhage, and of cerebral microbleedings, which may result in microencephaly and mental retardation. Treatment with coumarol derivatives should therefore be avoided during pregnancy, even in pregnant women with artificial heart valves, and replaced by heparin. Hemorrhage in the newborn related to the use of anticonvulsant drugs during pregnancy occurs very early within the first 24 hours, probably due to increased degradation of vitamin K. Transplacental administration of vitamin K has been shown to prevent neonatal hemorrhage induced by maternal anticonvulsant therapy. Prophylactic administration of vitamin K, especially by intramuscular injection, has been reported to be associated with an increased risk of childhood cancer. However, subsequent extensive studies have yielded no evidence of any relationship between prophylactic vitamin K administration and the occurrence of childhood cancer.

The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances.

Sprague-Dawley rats were given daily subcutaneous doses of sodium warfarin (100 mg/kg) and vitamin K1 (10 mg/kg) for up to 12 weeks, starting on the day after birth. This dosing regimen creates an extrahepatic vitamin K deficiency while preserving the vitamin K-dependent processes of the liver. Control rats received either vitamin K1 only or were untreated. All rats survived without any signs of hemorrhage. The warfarin-treated rats developed a marked maxillonasal hypoplasia associated with a 11-13% reduction in the length of the nasal bones compared with controls. The length of the posterior part of the skull was not significantly different from controls. In the warfarin-treated rats, the septal cartilage of the nasal septum showed large areas of calcification, not present in controls, and abnormal calcium bridges in the epiphyseal cartilages of the vertebrae and long bones. The ectopic calcification in the septal cartilage may have been the cause of the reduced longitudinal growth of the nasal septum and the associated maxillonasal hypoplasia. It is proposed that (1) the facial features of the human warfarin embryopathy are caused by reduced growth of the embryonic nasal septum, and (2) the septal growth retardation occurs because the warfarin-induced extrahepatic vitamin K deficiency prevents the normal formation of the vitamin K-dependent matrix gla protein in the embryo.

Effects of chronic beta-carotene supplementation on vitamin K status in adults.

Plasma vitamin K concentrations and prothrombin coagulation activity were determined in 26 normal adults who had received daily beta-carotene supplementation (0, 15, 30, or 60 mg) for six months. Neither plasma vitamin K nor coagulation activity were significantly decreased at any supplementation level. Thus, chronic beta-carotene supplementation, even at high daily doses, is not expected to result in clinical vitamin K deficiency. The data suggest separate mechanisms for intestinal absorption of beta-carotene and vitamin K.

Dioxins and furans in the mother and possible effects on the fetus and newborn breast-fed baby.

Due to pollution of the environment with PCBs, dioxins and furans these highly poisonous chemicals have accumulated in the adipose tissue of human beings. In breast milk of 14 mothers concentrations of dioxins and furans were found in milk fat, close to or in the range of the concentrations necessary to induce enzymes in "in vitro" rat liver cells (80-132 ppt). The hypothesis is that the above mentioned chemicals can be responsible for a vitamin K deficiency in the babies resulting in a bleeding analogous with phenobarbital. Both the pure TCDD content in milk fat and the content of dioxins and furans expressed as toxic equivalents (Nordic model) were higher in milk given to babies that presented a bleeding (4 out of 14). However, the sample size is too small for statistical analysis. No relation with age, parity, overweight, fish eating or smoking of the mother and dioxin content of her breast milk was seen in our small sample size.

The influence of cefotaxime on intestinal flora and bleeding diathesis in infants and neonates, compared with other beta-lactams.

Various second- and third-generation cephem antibiotics were administered to infants 2 years of age or less. Excluding Streptococcus faecalis, which is resistant to cephems, all of the intestinal bacteria decreased in number, and in many cases these were replaced by yeasts. A positive reaction for protein induced by vitamin K absence or antagonism (PIVKA II) occurred in 25 to 63% of the subjects administered cephems possessing a methylthiotetrazole group, but not in those dosed with cefotaxime or ceftazidime. The effects of cefotaxime and latamoxef (moxalactam) on platelet ADP aggregation were also investigated. When these drugs were administered to clinical patients, moxalactam showed stronger inhibition of aggregation than cefotaxime.