Vitamin K2 (Menaquinone-7) supplementation does not affect vitamin K-dependent coagulation factors activity in healthy individuals.

BACKGROUND: Vitamin K has long been regarded as a procoagulant drug by physicians, and concerns have been raised with regard to its effects on hemostasis. Although many studies have shown that vitamin K supplementation is safe for thrombotic events, the effect of vitamin K supplementation on the activities of vitamin K dependent procoagulation factors in healthy individuals is not available. OBJECTIVES: This study aimed to investigate whether vitamin K2 supplementation at recommended doses affects the activity of vitamin K dependent procoagulation factors in healthy individuals without any anticoagulation treatment. DESIGN: Forty healthy volunteers between 25 and 40 years of age were recruited. Menaquinone-7 (MK-7) was administrated at 90 µg for 30 days. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and blood coagulation factors II, VII, IX, and X activities and Protein induced by vitamin K absence or antagonist-II (PIVKA-II) were measured on days 0 and 30 after MK-7 administration. RESULTS: PT, APTT, and TT showed no significant differences on day 30 when compared with baseline. The activities of coagulation factors II, VII, IX, and X on day 30 showed no significant differences with those at baseline. PIVKA-II levels were unchanged after 30 days of MK-7 supplementation. CONCLUSIONS: MK-7 supplementation at recommended dosage does not affect vitamin K-dependent coagulation factors' coagulation activity, and does not enhance the carboxylation of prothrombin in healthy individuals. This indicated that MK-7 administration does not alter hemostatic balance in healthy populations without anticoagulation treatment.

Heparin supplement counteracts the prohemostatic effect of prothrombin complex concentrate and factor IX concentrate: An in vitro evaluation.

INTRODUCTION: Coagulation factor concentrates like factor IX (FIX) and prothrombin complex concentrate (PCC) can contain anticoagulant substances that may hamper their procoagulant effectiveness in the treatment of hemophilia B or reversal of oral anticoagulation, as well as the laboratory assessment thereof. The aim of the present study was to evaluate the influence of anticoagulant heparin supplement on the prohemostatic potential of different PCCs and FIX concentrates. MATERIALS AND METHODS: Prohemostatic potential was evaluated in vitro employing PT/aPTT, thrombography (TGA) and thromboelastography (TEG) with FIX deficient plasma, vitamin K antagonist (VKA)-anticoagulated plasma and plasma anticoagulated with rivaroxaban. RESULTS: Most PCCs contained heparin, while heparin was detected in 1 out of 4 examined FIX concentrates. All heparin-containing clotting factor concentrates showed severely hampered prohemostatic effects when therapeutic doses were added to anticoagulated plasmas. Upon heparin removal, comparable prohemostatic effects were observed. Of importance is the notion that the anticoagulant effect of heparin was enhanced by rivaroxaban, resulting in a 7 fold increased PT sensitivity towards heparin in the presence of 500µg/L rivaroxaban. CONCLUSIONS: Compositional differences between clotting factor concentrates should be taken into account. Therapeutic levels of heparin may be co-infused when treating emergency bleeds with high prohemostatic drug doses, particularly those recommended in the reversal of non-VKA anticoagulants such as rivaroxaban by PCC. Given the relative short half-life of heparin compared to vitamin K-dependent clotting factors, an anticoagulant heparin effect shortly after concentrate infusion should be considered clinically and while interpreting laboratory coagulation parameters.

Elaborating European Pharmacopoeia monographs for biotherapeutic proteins using substances from a single source.

For more than twenty years, the European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic proteins have been elaborated using the multisource approach (Procedure 1), which has led to robust quality standards for many of the first-generation biotherapeutics. In 2008, the Ph. Eur. opened up the way towards an alternative mechanism for the elaboration of monographs (Procedure 4-BIO pilot phase), which is applied to substances still under patent protection, based on a close collaboration with the Innovator company, to ensure a harmonised global standard and strengthen the quality of the upcoming products. This article describes the lessons learned during the P4-BIO pilot phase and addresses the current thinking on monograph elaboration in the field of biotherapeutics. Case studies are described to illustrate the standardisation challenges associated with the complexity of biotherapeutics and of analytical procedures, as well as the approaches that help ensure expectations are met when setting monograph specifications and allow for compatibility with the development of biosimilars. Emphasis is put on monograph flexibility, notably by including tests that measure process-dependent microheterogeneity (e.g. glycosylation) in the Production section of the monograph. The European Pharmacopoeia successfully concluded the pilot phase of the P4-BIO during its 156th session on 22-23 November 2016.

[Intracranial hemorrhage in three haemophilic adults: A severe complication of hemophilia]. / Hémorragie intracérébrale chez trois adultes hémophiles : une complication sévère de l'hémophilie.

BACKGROUND: Intracranial hemorrhage (ICH) complications are uncommon at hemophilic patients. OBSERVATIONS: We report three cases of ICH occurring in hemophilic patients. Contributing factors were identified in two patients: hemophilia severity, presence of inhibitor, hepatitis C virus infection, and high blood pressure. No contributing factor was identified in the last patient. CONCLUSION: Rapid diagnosis of ICH is crucial in hemophilic patients. A search for contributing factors, both those specific to hemophilia, and those favoring ICH in the general population, is essential to optimize therapeutic care. Specific substitutive treatment for the deficient factor is a difficult management challenge.

Effects of soy consumption on oxidative stress, blood homocysteine, coagulation factors, and phosphorus in peritoneal dialysis patients.

OBJECTIVE: We studied the effects of soy consumption on oxidative stress, blood homocysteine, coagulation factors, and phosphorus in peritoneal dialysis patients. DESIGN: This was an unblinded, randomized clinical trial. SETTING: This study involved peritoneal dialysis centers in Tehran, Iran. PATIENTS: We included 40 peritoneal dialysis patients (20 males and 20 females). INTERVENTION: Peritoneal dialysis patients were randomly assigned to either a soy or control group. Patients in the soy group received 28 g/day textured soy flour (containing 14 g of soy protein) for 8 weeks, whereas patients in the control group received their usual diet, without any soy. MAIN OUTCOME MEASURES: Blood oxidized low-density lipoprotein (ox-LDL), homocysteine, phosphorus, fibrinogen concentrations, and the activities of coagulation factors VII, IX, and X were measured at baseline and at the end of week 8 of the study. RESULTS: The percentage of plasma coagulation factor IX activity decreased significantly by 17% in the soy group at the end of week 8 compared with baseline (P < .01), and the reduction was significant compared with the control group (P < .05). There were no significant differences between the two groups in mean changes of blood ox-LDL, homocysteine, phosphorus, fibrinogen concentrations, and the activities of coagulation factors VII and X. CONCLUSION: Soy consumption reduces plasma coagulation factor IX activity, which is a risk factor for thrombosis in peritoneal dialysis patients.

Anticoagulant modulation of blood cells and platelet reactivity by garlic oil in experimental diabetes mellitus.

Multiple blood cell types and metabolic pathways involved in the modulation of platelet reactivity were investigated in streptozotocin-induced diabetic rats treated with garlic oil. Platelet counts of diabetic rats treated with garlic oil were significantly (P<0.01) reduced as compared to diabetic control rats. Garlic oil also increased the leucocyte counts of diabetic rats as compared to diabetic control rats. The significant (P<0.001) decreases by garlic oil of plasma concentration factors, V, VII, VIII: C, IX and X in diabetic rats may be interpreted to mean that there was a modulation of factor VII similar to that brought about by thrombin on factors V and VIII: C. This reversal of hypercoagulation through integrated biochemical reaction is suggestive of multicellular modulation of platelet reactivity, erythrocytes and neutrophils and the functional interactions between plasma coagulation factors and platelet cofactors.

The risk of recurrent venous thromboembolism: the Austrian Study on Recurrent Venous Thromboembolism.

Venous thromboembolism (VTE) is a chronic disease. After withdrawal of oral anticoagulation at least a third of patients will experience a subsequent episode of venous thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The Austrian Study on Recurrent Venous Thromboembolism (AUREC) is a prospective cohort study aiming to investigate the overall rate of recurrent VTE, the predictive value of laboratory assays, the importance of acquired or congenital risk factors for thrombosis and the impact of extended or modified secondary thromboprophylaxis on the risk of recurrence among high-risk patients. So far, the AUREC investigators have identified subgroups of patients with a particular high risk of recurrence: patients with a history of venous thrombosis, elevated levels of coagulation factors VIII, IX and XI, pulmonary embolism or superficial venous thrombosis and a history of venous thrombosis and hyperhomocysteinemia. Patients with a history of venous thrombosis and mutations in genes encoding for coagulation factors (factor V Leiden, factor II, G20210A) do not have an enhanced risk of recurrence and, thus, do not qualify for extended secondary thromboprophylaxis. At present, interventional trials are in progress in patients with high factor VIII or hyperhomocysteinemia in order to investigate if these patient groups might benefit from extended oral anticoagulation or vitamin supplementation, respectively.

Effects of hydroxyapatite in combination with far-infrared rays on spontaneous mammary tumorigenesis in SHN mice.

We have found that the administration of a diet containing 5% hydroxyapatite (HAP) derived from pig and cattle bones, and exposure to far-infrared rays (FIR) markedly inhibited spontaneous mammary tumorigenesis in SHN mice. Thus, the effect of combined treatment with HAP and FIR on mammary tumorigenesis was examined. The significant inhibition of tumor development by individual treatment with HAP or FIR was not enhanced by combined treatment; instead, the decrease in the inhibitory effect of HAP with age was ameliorated. Associated with this, life span was elongated and a decline in ovarian function was prevented by HAP plus FIR. Normal and preneoplastic growth of mammary glands and plasma component levels were not significantly affected by any treatment. The findings indicate that HAP and FIR have characteristics common to most natural products; in combination with other agents, they have little additive effect, when each is highly active.

Age and human immunodeficiency virus infection in persons with hemophilia in California.

Thirteen hemophilia centers provide comprehensive care to approximately 90 percent of persons with hemophilia in California. For 1987, these centers reported patient human immunodeficiency virus (HIV) antibody status, age group, level of clotting factor deficiency, and hemophilia type on 1,438 persons with hemophilia A and B; HIV serologic status was known for 860 persons (59.8 percent) of whom 537 (62.4 percent) were HIV-antibody-positive. The HIV positivity rate increased with age after taking into account hemophilia type, clotting factor level and treatment center type. The three-year cumulative incidence of reported AIDS (acquired immunodeficiency syndrome) cases based on the number of HIV positive patients, was 11.6 percent. The cumulative incidence rate was 14.6 percent (54 of 370) for those patients over 20 years of age and 4.8 percent (8 of 167) for those under 21 years of age. Although a comparable distribution of the date of diagnoses of AIDS was seen by age group, there appeared to be a bimodal distribution in the rate of AIDS among the age groups, with the 6-12-year-olds and the 21 and older age groups showing higher incidence rates.

Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy.

Oral anticoagulants achieve an antithrombotic effect only several days after initiation of treatment. A rapid decline of the vitamin-K dependent natural anticoagulants (proteins C and S) during this period might result in a prothrombic phase. We addressed this question by measuring the rates of decline of these proteins, as well as the vitamin K dependent procoagulants, in two groups of patients: A "high dose group" (n = 7), who received a single 40 mg dose of warfarin, and a "low dose group" (n = 20), who received daily individually adjusted doses. In the high dose group an early and marked decline of factor VII:C and protein C antigen was observed, while levels of the other vitamin K dependent factors were still relatively high. In the low dose group, all these proteins declined more gradually. Mean +/- SD of protein C antigen level at 46 hr was 56 +/- 12% in the low dose group, and only 44 +/- 6% (p less than 0.05) in the high dose group. We conclude that during the initiation of warfarin therapy there is a transient prothrombotic phase, which is less marked in patients given daily adjusted doses.

Factor IX metal ion-dependent antigen assays for measurement of warfarin effect.

Factor IX metal ion-dependent antigen was assayed using monoclonal antibodies in 521 samples obtained after prothrombin time testing in patients treated with warfarin. Factor IX metal ion-dependent antigen was less than measured Factor IX clotting activity and less than total Factor IX antigen adsorbable to aluminium hydroxide, suggesting that the metal ion-dependent antigen assay measures a subpopulation of circulating Factor IX in patients treated with oral anticoagulants. There was a graded decrease of Factor IX metal ion-dependent antigen as prothrombin times increased in patient samples. In two hospitals, the median prothrombin times and Factor IX antigen levels were 19 and 20 seconds and 0.10 and 0.11 U/mL (kU/L), respectively. This study shows that immunoassays measure the biologic effect of warfarin and provide information that may supplement the prothrombin time test for patient monitoring. Factor IX metal ion-dependent antigen assays may be useful in efforts to standardize laboratory tests for warfarin effect.

Oral treatment of hemophilia A using traditional kanpo medicine, Huang-lien-chieh-tu-tang (plant extract).

Huang-lien-chieh-tu-tang (HLCT) extract was given orally to a patient with severe hemophilia A. The plasma concentration of factor VIII rose from less than 1 to 41% 1 h after oral administration of HLCT extract. APTT also decreased from 102.0 to 70.9 s. In vitro experiments, HLCT showed factor VIII, IX and X biological activity at concentrations around 0.08%. There was no factor-VIII-antigen-related activity in HLCT.