The authors reported previously that an administration of hemostatic drugs including VK has no significant roles on the prevention of hemorrhage during immediate postoperative period. In this ...article, we studied the effect, of VK on the prevention of hemorrhage in postoperative patients treated with antibiotics. For this purpose, we measured prothrombin time (PT), Factor II (F-II), Factor, VII (F-VII), protein C, PIVKA II (P-II) and plasma level of VK in two groups of patients with or without VK administration. In the group of patients with VK administration 120mg/day of VK2 were given intravenously everyday. The patients of both groups were fasted and treated with antibiotics for two weeks after the operation. In the group without VK administration, PT was prolonged and F-II levels were decreased from the seventh postoperative day. Although F-VII and PC levels were decreased on the first postoperative day and returned subsequently on the seventh day, no significant difference was observed between the levels of two groups. P-II levels were significantly increased in the group without VK administration, whereas no significant changes was observed in the group with VK administration. The plasma level of VK1 decreased in both groups, but the level of, VK2, especiall MK-4, was high in the group with VK administration. These results indicate that patients treated with antibiotics during postoperative fasting period may have a VK deficiency from the seventh day. Although no bleeding disorders were observed, an administration of VK is recommended for these patients.
Since the biological role of vitamin K (VK) in the synthesis of blood clotting factors was established, hypothrombinemia in humans and animals has frequently been investigated in relation to VK ...metabolism. The minimum dose of VK to restore normal plasma clotting factor levels, and its effective duration, were examined in VK-deficient male rats. The prothrombin time (PT) in rats kept on an ordinary diet containing about 500ng/g of VK1 was 10.6±0.4sec. The PT in rats fed a VK-deficient diet, containing 32ng/g of VK1, for 7 days was 13.5±0.2sec. When rats were maintained on the VK-deficient diet. a slight but constant VK deficiency was seen from day 7 to day 15. These animals were given single subcutaneous injections of various doses of VK1 on day 7. The PT, APTT, factor VII, prothrombin and fibrinogen levels, as well as plasma and liver PIVKA-II levels were determined 1, 2, 4, and 8 days after the VK1 injection. For rats on a VK-deficient diet, the minimum effective dose of VK1 was 3μg/kg by subcutaneous injection and its effect lasted for 2 days. When 100μg/kg of VK1, was injected, the effect lasted for almost 8 days. VK synthesized in the large intestine did not seem to be utilized in these rats to prevent the development of hypothrombinemia.
Daily vitamin (vit.) K administration (50mg i.v. for 20 days) was performed in patients with vit. K deficiency and hepatocellular carcinoma (HCC) with positive PIVKA-II levels. The half-life of ...PIVKA-II was 60 hours in either of those patients. In HCC patients with one-shot vit. K administration (10mg i.v.), PIVKA-II decreased and its reduction rate and slope of decline were identical to those in vit. K deficiency patients for the first 2-3 days, but PIVKA-II increased thereafter reaching the level before one-shot vit. K about 10 days later. Thus it was suggested that PIVKA-II in HCC patients has the same vit. K sensitivity as that in vit. K deficiency patients. In HCC patients with effective therapy (resection or TAE), the reduction rate and slope of PIVKA-II decline were the same as those in vit. K deficiency patients who were given vit. K. However, in patients in whom therapy failed, the reduction rate and slope of PIVKA-II decline were not identical to those in vit. K deficiency patients. Thus it seems useful to follow HCC patients with PIVKA-II measurement after therapy for its half-life and reduction rate.
Recently, a bleeding tendency during the administration of antibiotics has been given attention. We studied the effects of flomoxef sodium (FMOX), a new class of oxacephem antibiotic, on platelet ...function and blood coagulation. The subjects were 12 cases of respiratory tract infections. FMOX was administered by drip infusion at a dose of 2 g /day for 7 days. And the following parameters were measured before and after the administration: platelet count, bleeding time, platelet adhesiveness, platelet aggregation activity, platelet ATP release activity, prothrombin time, active partial thromboplastin time, serum fibrinogen, fibrin degradation products, thrombo test, hepaplastin test, clotting factors II·VII·IX·X, PIVKA-II As a result of this study, there was no deterioration in the platelet function and blood coagulation tests. In 2 cases, however, PIVKA-II was positive. We could not prove any vitamin K deficiency in other parameters and the patients had, normal prothrombin values. We thought on this study that the significance of PIVKA-II is a feature issue. We concluded that FMOX is a safe antibiotic regarding platelet function and blood coagulation at a dose of 2 g /day for 7 days.
We studied 152 apparently healthy newborns below 30 days of age on crossed immunoelectrophoresis of prothrombin using capillary blood samples, in order to find out the frequency of mild vitamin K ...deficiency in healthy infants. About 70% of the newborns at 0 to 3 days of age, 47% of the newborns at 4 to 5 days of age and 28.6% of the newborns at 6 to 9 days of age had PIVKA-II on crossed immunoelectrophoresis. Sixty six infants at one month of age included 28 breast fed infants and 38 either mixed or bottle fed infants. About 14% of these infants had a small amount of PIVKA-II. Although the frequency of mild vitamin K deficiency was very high at birth and quickly decreased to 28.6% by 6 to 9 days after birth, about 14% of apparently healthy infants at one month of age remained mildly deficient from vitamin K, no matter what the type of feeding may be. Through a large scale screening test using Normotest, 16 infants at one month of age were picked up for their value of less than 50% of normal. Among these 16 infants, 87.6% of them were demonstrated to have PIVKA-II and sigificantly larger amount of PIVKA-II than in one month old infants in group D. There was negative correlation between the amount of PIVKA-II and the value of Normotest in these infants. In conclusion, 70% of newborns at birth are deficient from vitamin K and this deficient state is alleviated gradually and spontaneously with age. However, about 14% of one month old infants are still mildly deficient from vitamin K, no matter what the type of feeding may be.
By using the methop of enzyme immunoassay, plasma abnormal prothrombin (protein induced by vitamin K absence or antagonist-II: PIVKA-II) was measured in patients with hepatobiliary diseases. In 21 ...(60%) of 35 patients with hepatocellular carcinoma (HCC), plasma PIVKA-II levels were increased (>0.10 arbitary unit/ml). After curative resection of HCC, plasma PIVKA-II levels decreased to within normal ranges. Therefore, plasma PIVKA-II determination was very useful in the detection and monitoring of therapy for HCC patients. Plasma PIVKA-II levels were also increased in both postoperative patients receiving antibiotics containing N-methltetrazolethiol without vitamin K, and patients with external biliary drainage.
A vitamin K deficiency- associated bleeding tendency during antibiotic therapy has recently become a serious problem, especially with the use of the new cephems. Broad spectrum antibiotics such as ...the cephems of the 2nd and 3rd generation may cause a marked change in the intestinal bacterial flora, leading to vitamin K deficiency in some patients. The changes of the intestinal bacterial flora and blood coagulation system including protein induced by vitamin K absence or antagonist (PIVKA II), an abnormal prothrombin which is demonstrated in patients with vitamin K deficiency, were investigated in children during antibiotic therapy. The influences of oral food intake and diarrhea, and the differences classified by antibiotics and age were also investigated. Among the 160 patients, 37 patients (23%) showed the existence of PIVKA II and 24 patiens (15%) showed an abnormal prothrombin time (PT), activated partial thromboplastin time (APTT), hepaplastin test (HPT), and thrombotest (TT). Bleeding tendencies were noted in 11 patients (7%). PIVKA II became positive within 7 days after the initiation of antibiotics in 71% of the 37 patients, and returned negative with vitamin K administration. PIVKA II was infrequently demonstrated in infants and frequently demonstrated in patients with sepsis, intrauterine infection, and central nervous system infection. None of patients with urinary tract infection were positive for PIVKA II. As for the relationship between the detection rate of PIVKA II and the antibiotics used, PIVKA II was frequently demonstrated in patients treated with latamoxef (LMOX), cefmetazole (CMZ), and cefoperazone (CPZ). None of the patients treated with cefotaxime (CTX), ceftazidime (CAZ), and ampicillin (ABPC) were positive for PIVKA II. LMOX, CMZ and CPZ have a 1-methyl-1-H-tetrazole-5-yl-thiomethyl group at position 3 of dihydrothiazine nucleus, and further investigation about the influences of this group to the vitamin K assosiated blood coagulation system is necessary. The change of the intestinal bacterial flora was investigated for 124 of the 160 patients, and 83 of those (67%) showed a decrease of the intestinal bacterial flora. Twenty-three of the 83 patients (28%) were positive for PIVKA II. In 23 patients who had both a decrease of the intestinal bacterial flora and a decrease of oral food intake with or without diarrhea, 15 patients showed positive PIVKA II, a detection rate of 65%. This suggests that insufficient oral intake of vitamin K and the decrease of the intestinal bacterial flora play important roles in the etiology of the vitamin K deficiency during antibiotic therapy. A careful monitoring of the blood coagulation system, including PIVKA II, is necessary for patients receiving antibiotic therapy with broad spectrum agents such at the new cephems, and prophylactic use of vitamin K is indicated in newborn infants and patients with poor oral intake.
8 young infants aged 14 days to 5 months with vitamin K-dependent factor deficiency were studied with special reference to prothrombin activity and antigen level. Among them, 3 infants had congenital ...bile duct atresia and 5 were breast-fed babies with severe hemorrhagic tendency of unknown cause. In the patients with both congenital bile duct atresia and breast feeding the ratio of prothrombin activity to prothrombin antigen was lower than 0.1. Furthermore, the arc of prothrombin antigen in these patients demonstrated a faster anodal shift than did normal prothrombin antigen on crossed immunoelectrophoresis. This abnormal prothrombin antigen was not consumed after recalcification of patient plasma, and absorbed poorly on BaSO4. In addition, the abnormal prothrombin antigen disappeared from the patient plasma within a few days after parenteral administration of vitamin K. These results suggest that this abnormal prothrombin is PIVKA-II.
Normotest (sample volume: 25 micronl) and Thrombotest were performed in parallel on 150 consecutive capillary blood samples from patients on long term oral anticoagulant therapy. The ratio of ...Normotest to Thrombotest decreased from 2.50 at a Thrombotest level of 5-5.5% to 1.95 at a Thrombotest level of 13-13.5%, indicating that the effects of PIVKA were more pronounced at lower levels of coagulation activity. The influence of varying sensitivity of the thromboplastin reagents to PIVKA is discussed. The therapeutic range of Thrombotest (5-10%) corresponded to a Normotest level of 12-20%.
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