Hypoprothrombinemia During Cefmetazole Treatment: A Case Report.

BACKGROUND Cefmetazole (CMZ), containing an N-methyl-tetrazole-thiol (NMTT) side chain, is a therapeutic option for diverticulitis in Japan. Cephems containing an NMTT, a methyl-thiadiazol, and a thiadiazolethiol side chain are known to induce coagulation disorders. CASE REPORT A 76-year-old woman developed hypoprothrombinemia after receiving oral levofloxacin (LVFX) 250 mg q24h for 2 days followed by intravenous CMZ 2 g q8h for sigmoid diverticulitis. On day 5 of CMZ administration (after 12 doses in total), black stool was observed. On the following day (after 14 doses), prothrombin time (PT) prolongation was noted; PT and international normalized ratio (INR) were 37.1 s and 2.47, respectively. We diagnosed the patient with hypoprothrombinemia because of vitamin K deficiency caused by markedly elevated protein levels induced by vitamin K absence or antagonist-II on day 6 of CMZ administration. Intravenous vitamin K administration and CMZ cessation rapidly restored PT and led to the disappearance of black stool. CONCLUSIONS The causes of vitamin K deficiency were considered to be an impaired vitamin K cycle due to CMZ and decreased vitamin K intake because of malnutrition. These findings are consistent with CMZ's reported adverse effects. Decreased vitamin K production due to alterations in the gut bacterial flora by LVFX and CMZ was also postulated as a cause. If a bleeding tendency is noted during diverticulitis treatment with NMTT-containing cephems, switching to intravenous quinolones or carbapenems is recommended. It remains unclear how this reaction can be avoided; however, prudent monitoring of bleeding signs and PT-INR is recommended.

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.

Experimental Model of Subclinical Vitamin K Deficiency.

INTRODUCTION: Vitamin K (VK) is a co-factor in the post-translational gamma glutamic carboxylation of Gla-proteins. VK-dependent coagulation factors are carboxylated in the liver by VK1. Osteocalcin and Matrix-Gla protein (MGP) are carboxylated in extrahepatic tissues by VK2. A model of VK deficiency would be suitable for studying extrahepatic Gla-proteins provided that severe bleeding is prevented. AIM: The aim of this work was to adapt an established protocol of vascular calcification by warfarin-induced inactivation of MGP as a calcification inhibitor, in an attempt to create a broader state of subclinical VK deficiency and to verify its safety. MATERIALS AND METHODS: Two consecutive experiments, each lasting 4 weeks, were required to modify the dosing schedule of warfa-rin and VK1 and to adapt it to the Wistar rats used. The original high doses of warfarin used initially had to be halved and the protective dose of VK1 to be doubled, in order to avoid treatment-induced hemorrhagic deaths. The second experiment aimed to confirm the efficacy and safety of the modified doses. To verify the VK deficiency, blood vessels were examined histologically for calcium deposits and serum osteocalcin levels were mea-sured. RESULTS: The original dosing schedule induced VK deficiency, manifested by arterial calcifications and dramatic changes in carboxyl-ated and uncarboxylated osteocalcin. The modified dosing regimen caused similar vascular calcification and no bleeding. CONCLUSION: The modified protocol of carefully balanced warfarin and VK1 doses is an effective and safe way to induce subclinical VK deficiency that can be implemented to investigate VK-dependent proteins like osteocalcin.

Switching from Warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation.

Use of chronic vitamin K antagonist (VKA) induces a long-term deficiency of vitamin K, which may cause arterial stiffness and bone-related disease. Switching from VKA to rivaroxaban could induce rapid sufficiency of vitamin K and improvement of arterial stiffness. The K2 SUMMIT-3 study is a multicenter, open-label, prospective, and randomized design. Patients with atrial fibrillation who have been taking VKA for more than 6 months but less than 10 years were randomly assigned to two groups; those switching from VKA to rivaroxaban and those continuing with VKA medication. The primary endpoint was the percentage difference of brachial-ankle pulse wave velocity (baPWV) in 3 months. A total of 77 patients were randomly assigned to receive rivaroxaban (n = 38) or VKA (n = 39). The average age was 74 ± 9 years. The duration for which VKA was prescribed prior to randomization was 90 ± 87 months.Abnormally high levels of Des-gamma carboxyprothrombin (PIVKA-II) or uncarboxylated osteocalcin (ucOC) indicating vitamin K insufficiency were observed in 100% or 82% of the patients at baseline but it reduced to 2% (p < 0.0001) or 55% (p = 0.01) at 3 months in the rivaroxaban group. To the contrary, theses data had no changes in the VKA group. The percentage difference in baPWV was - 1.4 ± 10.0% vs. 3.5 ± 14.7% in the rivaroxaban and the VKA groups, respectively. (p = 0.02). Switching from VKA to rivaroxaban resulted in rapid sufficiency of vitamin K and reduction of arterial stiffness in 3 months.

Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug-Bug Interaction?

Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.

Warfarin-induced vitamin K deficiency affects spermatogenesis in Sprague-Dawley rats.

Vitamin K is present in the testes though its actual function in male reproduction is poorly understood. This study investigated the harmful effect of extrahepatic vitamin K insufficiency on the testicular structure. Sprague-Dawley rats were fed with a diet containing warfarin for 2, 4 and 8 weeks; control animals received a standard diet without warfarin. It was found that extrahepatic vitamin K deficiency that is induced by warfarin results in histopathological features that range from delayed spermiation, presence of multinucleated giant cells in the seminiferous tubules, germ cells degeneration, asthenozoospermia, oligozoospermia and increase in the percentage of abnormal sperm morphology when compared to the controls. Data obtained from the two groups were analysed using the Student t test. It is concluded that warfarin-induced vitamin K deficiency has a negative impact on spermatogenesis.

Vitamin K for reversal of excessive vitamin K antagonist anticoagulation: a systematic review and meta-analysis.

Patients receiving vitamin K antagonists (VKAs) with an international normalized ratio (INR) between 4.5 and 10 are at increased risk of bleeding. We systematically reviewed the literature to evaluate the effectiveness and safety of administering vitamin K in patients receiving VKA therapy with INR between 4.5 and 10 and without bleeding. Medline, Embase, and Cochrane databases were searched for relevant randomized controlled trials in April 2018. Search strategy included terms vitamin K administration and VKA-related terms. Reference lists of relevant studies were reviewed, and experts in the field were contacted for relevant papers. Two investigators independently screened and collected data. Risk ratios (RRs) were calculated, and certainty of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Six studies (1074 participants) were included in the review and meta-analyses. Pooled estimates indicate a nonsignificant increased risk of mortality (RR = 1.42; 95% confidence interval [CI], 0.62-2.47), bleeding (RR = 2.24; 95% CI, 0.81-7.27), and thromboembolism (RR = 1.29; 95% CI, 0.35-4.78) for vitamin K administration, with moderate certainty of the evidence resulting from serious imprecision as CIs included potential for benefit and harm. Patients receiving vitamin K had a nonsignificant increase in the likelihood of reaching goal INR (1.95; 95% CI, 0.88-4.33), with very low certainty of the evidence resulting from serious risk of bias, inconsistency, and imprecision. Our findings indicate that patients on VKA therapy who have an INR between 4.5 and 10.0 without bleeding are not likely to benefit from vitamin K administration in addition to temporary VKA cessation.

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.

Gastrointestinal bleeding secondary to trimethoprim-sulfamethoxazole-induced vitamin K deficiency.

There is a well-known association between vitamin K deficiency and haemorrhagic events including gastrointestinal bleeding. There is also a well-known association between both poor dietary intake of vitamin K and chronic antibiotic use and the development of vitamin K deficiency. Although the medical literature notes that cephalosporin antibiotics have a propensity to cause vitamin K deficiency due to the molecular structure of the medications and their ability to suppress the synthesis of clotting factors, there are other antibiotics that have also been implicated in the development of vitamin K deficiency. There are very few reports of trimethoprim/sulfamethoxazole causing vitamin K deficiency and further leading to bleeding episodes. We present such a case and discuss the risk factors leading to such complications.

Diagnostic Error of a Patient with Combined Inherited Factor VII and Factor X Deficiency due to Accidental Ingestion of a Diphacinone Rodenticide.

BACKGROUND: To explore the characteristics of laboratory examination and confirm the diagnosis of a patient with combined inherited FVII and FX deficiency after he ingested diphacinone rodenticide accidentally. METHODS: The coagulant parameter screening tests and coagulation factor activities were tested many times in the patient due to accidental ingestion of a diphacinone rodenticide. After the patient was treated for more than one year, gene analysis of correlated coagulation factors was analyzed in the patient and other family members by DNA direct sequencing. 106 persons were selected as controls from routine health examinations. RESULTS: After the patient was admitted to hospital, routine coagulation screening tests revealed the prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) and low levels of vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) activity, which was 102.4 seconds, 88.5 seconds, 7%, 3%, 8%, and 2%, respectively. During more than one year of treatment, the value of PT and APTT still showed significantly prolonged activity and FVII and FX activity levels were about 5%. While FII and FIX activity levels were in the normal range after 12 weeks of treatment. Two homozygous mutations, g.11267C>T of F7 gene resulting in the substitution Arg277Cys and g.28139G>T of F10 gene leading to the substitution Val384Phe, were identified in the patient. The patient's parents and sister was heterozygous for Arg277Cys and Val384Phe mutations. FVII and FX antigen levels in the patient were 7% and 30%, respectively. CONCLUSIONS: There were many similarities in the characteristics of laboratory examination between combined inherited FVII and FX deficiency and acquired vitamin K deficiency. The best way to identify them was gene analysis.

High intra- and inter-individual variability of plasma vitamin K concentrations in patients with atrial fibrillation under warfarin therapy.

BACKGROUND/OBJECTIVES: Vitamin K intake is considered as a controllable contributor to warfarin sensitivity. It is restricted in warfarin-treated patients. However, little study has assessed the vitamin K status in warfarin-treated patients. We directly measured plasma vitamin K in warfarin-treated patients and evaluated its effect on anticoagulation. SUBJECTS/METHODS: A total of 302 plasma vitamin K concentrations were assessed using high-performance liquid chromatography for 203 outpatients with atrial fibrillation under warfarin treatment. Clinical and laboratory information including warfarin dosage, plasma warfarin concentrations, prothrombin time international normalized ratio (PT INR) and CYP2C9/VKORC1 genotypes was reviewed retrospectively. The anticoagulation stability (intra-individual variability, frequency of PT INR tests and complications) was investigated in 163 patients with long-term warfarin therapy. Plasma vitamin K was measured in 40 healthy subjects and in 40 patients before and after initial warfarin treatment. RESULTS: Vitamin K concentrations were significantly decreased after the initiation of warfarin treatment (before treatment: 1.72 ng/ml; after treatment: 0.59 ng/ml, P<0.05). There was a large inter-individual variability in vitamin K levels (0.2-4.2 ng/ml) in warfarin-treated patients. PT INR was more frequently checked in patients with low plasma vitamin K levels than in those with high vitamin K levels (9.5 times/year vs 7.5 times/year, P=0.029). Two patients with gross hematuria showed very low vitamin K levels (<0.4 ng/ml). CONCLUSIONS: We found high inter- and intra-individual variability in vitamin K concentration in warfarin-treated patients. Low vitamin K concentration in warfarin-treated patients suggested excessive dietary restriction. Plasma vitamin K measurement would be helpful for dietary control and anticoagulation stability.

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.

Deuterium-labeled phylloquinone fed to α-tocopherol-injected rats demonstrates sensitivity of low phylloquinone-containing tissues to menaquinone-4 depletion.

SCOPE: The influence of excess α-tocopherol (α-T) on tissue depletion of phylloquinone (PK) and menaquinone-4 (MK-4) was evaluated. METHODS AND RESULTS: Rats (n = 5 per group) were fed deuterium-labeled PK (2 µmol/kg diet) for 17 days, thereby labeling the conversion from deuterium-labeled PK to d4-MK-4. Then they were injected subcutaneously daily for the last 7 days with saline, vehicle, or α-T (100 mg/kg body weight). α-T injections (i) increased α-T concentrations by tenfold in liver, doubled them in plasma and most tissues, but they were unchanged in brain; (ii) increased the α-T metabolite, carboxyethyl hydroxychromanol (α-CEHC) concentrations: >25-fold in liver and kidney, tenfold in plasma and lung, and 50-fold in heart; brain contained detectable α-CEHC (0.26 ± 0.03 nmol/g) only in α-T-injected animals; and (iii) depleted most tissues' vitamin K. Compared with vehicle-injected rats, brains from α-T rats contained half the total vitamin K (10.3 ± 0.5 versus 21 ± 2 pmol/g, p = 0.0002) and one-third the d4-MK-4 (5.8 ± 0.5 versus 14.6 ± 1.7 pmol/g, p = 0.0002). Tissues with high PK concentrations (liver, 21-30 pmol/g and heart, 28-50 pmol/g) were resistant to K depletion. CONCLUSION: We propose that α-T-dependent vitamin K depletion is likely mediated at an intermediate step in MK-4 production; thus, tissues with high PK are unaffected.

Excess α-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats.

SCOPE: The effects of vitamin E on vitamin K metabolism were elucidated by comparing the effect of tocopherol intake on vitamin K concentrations in rats fed phylloquinone (PK) or menaquinone (MK)-4. METHODS AND RESULTS: Initially, the dietary effect of RRR-α-tocopherol, but not RRR-γ-tocopherol, in decreasing extrahepatic PK concentrations was confirmed. Subsequently, rats were fed a PK or MK-4-containing diet (0.75 mg/kg) with RRR-α-tocopherol (0, 10, 50, or 500 mg/kg) for 6 weeks. In rats fed PK, α-tocopherol consumption decreased PK in kidney, lung, heart, muscle, testis, and brain but not in serum and liver. However, in rats fed MK-4, α-tocopherol consumption did not decrease MK-4 in serum and tissues. Finally, vitamin K- and E-depleted rats were administered PK or MK-4 (0.2 mg) with RRR-α-tocopherol (0, 1, or 10 mg) by gavage. After PK administration, α-tocopherol was observed to decrease PK in kidney, adrenal gland, lung, testis, and brain but not in serum and liver, whereas, after MK-4 administration, α-tocopherol did not affect MK-4 in serum and tissues. CONCLUSION: Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.

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.

Serum undercarboxylated osteocalcin level increases with 48 weeks of teriparatide treatment in pre-treated elderly rheumatoid arthritis patients who use anti-resorptive drugs.

AIM: The serum undercarboxylated osteocalcin (ucOC) level, a biochemical bone marker of vitamin K insufficiency, is often affected by anti-osteoporosis drugs. There have been no reports regarding the relationship between ucOC and teriparatide. SUBJECTS AND METHODS: We conducted a prospective observational study of 26 female rheumatoid arthritis (RA) patients. The patients were divided into 3 groups: those who underwent a direct switch from anti-resorptive drugs to teriparatide (12 cases), those who started teriparatide without pre-treatment (5 cases), and the control patients (9 cases). The median age (interquartile range) of the patients in each group was 75 (67-77), 82 (78-84), and 69 (62-80) yr, respectively. All patients, except controls, received 48-week treatments of teriparatide. We analyzed the median 48-week changes from baseline of the serum ucOC levels with the Steel-Dwass method. RESULTS: The median change from baseline in the direct switch group was higher than that in other groups (p<0.05). CONCLUSIONS: The serum ucOC levels increased with treatment of teriparatide in elderly RA patients, especially when the patients received pre-treatment.