Multivariate relationships between international normalized ratio and vitamin K-dependent coagulation-derived parameters in normal healthy donors and oral anticoagulant therapy patients

Background and objectives  

International Normalized Ratio (INR) is a world-wide routinely used factor in the monitoring of oral anticoagulation treatment (OAT). However, it was reported that other factors, e. g. factor II, may even better reflect therapeutic efficacy of OAT and, therefore, may be potentialy useful for OAT monitoring. The primary purpose of this study was to characterize the associations of INR with other vitamin K-dependent plasma proteins in a heterogenous group of individuals, including healthy donors, patients on OAT and patients not receiving OAT. The study aimed also at establishing the influence of co-morbid conditions (incl. accompanying diseases) and co-medications (incl. different intensity of OAT) on INR.     

Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy

OBJECTIVES: To determine the safety and efficacy of intravenously administered phytonadione (vitamin K1) in patients on routine oral warfarin anticoagulation. PATIENTS AND METHODS: This retrospective cohort study comprised adults who were taking warfarin, were not bleeding, and received intravenous phytonadione anticoagulation therapy before a diagnostic or therapeutic procedure between September 1, 1994, and March 31, 1996. The main outcome measures were adverse reactions to intravenously administered phytonadione, prothrombin-international normalized ratio time values, the incidence of bleeding and thrombosis after the procedure, and the time between the procedure and return to anticoagulation after resumption of warfarin treatment. RESULTS: Two (1.9%) of the 105 patients studied had suspected adverse reactions to intravenous phytonadione (dyspnea and chest tightness during infusion in both). For the 82 patients who underwent a procedure, the median time from phytonadione to procedure onset was 27 hours (range, 0.7-147 hours), which was significantly less for patients receiving an initial phytonadione dose of more than 1 mg (P=.009). None had thromboembolism after surgery, although 2 (2.4%) of the 82 patients had procedure-associated major bleeding. For the 60 patients resuming warfarin therapy after a procedure, the median time to return to therapeutic anticoagulation was 4.1 days (range, 0.8-31.7 days) and was unaffected by the phytonadione dosage. CONCLUSIONS: Intravenous phytonadione appears to be safe and is effective for semiurgent correction of long-term oral anticoagulation therapy before surgery. In small doses, it does not prolong the patient's time to return to therapeutic anticoagulation.     

获得性维生素K依赖性凝血因子缺乏症45例临床分析

目的 探讨获得性维生素K依赖性凝血因子缺乏症的病因、临床特点、治疗疗效.方法 回顾性分析45例患者的病因和临床表现.均给予静脉滴注维生素K110～40 mg/d,部分临床出血症状严重患者辅以输注新鲜冰冻血浆或凝血酶原复合物,维持治疗1～3个月.采用Stago自动血凝分析仪检测治疗前后凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)变化,部分有条件者检测治疗前后Ⅱ、Ⅶ、Ⅸ、Ⅹ因子活性变化.结果 45例患者中未发现明显病因19例(42.2%,19/45),常见原因为抗凝血灭鼠剂中毒11例(42.3%,11/26).临床以多部位出血为主要表现,出血部位依次为黏膜出血(77.8%,35/45)和肉眼血尿(46.7%,21/45),应用维生素K1治疗后,PT、APTT显著缩短[PT:(110.35±35.36)、(13.48±2.17)s,t=19.10,P＜0.01;APTT:(98.91±48.98)、(33.25±6.95)s,t=6.19,P＜0.01],凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ活性显著增高[Ⅱ:C:(17.48±10.93)%、(70.12±21.31)%,t=12.13,P＜0.01;Ⅶ:C:(10.23±5.68)%、(92.76±29.15)%,t=14.43,P＜0.01;Ⅸ:C:(11.98±4.69)%、(88.64±40.21)%,t=13.27,P＜0.01;Ⅹ:C:(12.93±7.48)%、(63.97±20.11)%,t=9.74,P＜0.01].结论 维生素K依赖性凝血因子缺乏症患者病史隐匿、容易误诊,检测PT、APTT对其诊断及疗效监测具有一定价值.应用维生素K1 10～40 mg/d静脉滴注治疗安全有效.     

Studies on a family with combined functional deficiencies of vitamin K-dependent coagulation factors.

Two siblings with m ild hemorrhagic symptoms had combined functional deficiencies of vitamin K-dependent clotting factors. Prothrombin (0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) were most severely affected. Antigenic amounts of affected coagulation factors were normal and normal generation of thrombin activity occurred in the patients' plasmas after treatment with nonophysiologic activators that do not require calcium for prothrombin activation. Hepatobilary disease, malabsorptive disorders, and plasma warfarin were not present. Both parents had normal levels of all coagulation factors. The patients' plasmas contained prothrombin that reacted both with antibody directed against des-gamma-carboxyprothrombin and native prothrombin. Crossed immunoelectrophoresis of patients' plasmas and studies of partially purified patient prothrombin suggested the presence of a relatively homogeneous species of dysfunctional prothrombin, distinct from the heterologous species found in the plasma of warfarin-treated persons. These studies are most consistent with a posttranslational defect in hepatic carboxylation of vitamin K-dependent factors. This kindred uniquely possesses an autosomal recessive disorder of vitamin K-dependent factor formation that causes production of an apparently homogeneous species of dysfunctional prothrombin; the functional deficiencies in clotting factors are totally corrected by oral or parenteral administration of vitamin K1.     

Plasma protein S in disseminated intravascular coagulation, liver disease, collagen disease, diabetes mellitus, and under oral anticoagulant therapy

Plasma levels of protein S (PS) antigen, both total and free fractions, were measured together with C4b-binding protein (C4bp) and protein C (PC) antigen in 39 patients with disseminated intravascular coagulation (DIC), 34 with liver disease, 17 with collagen disease, 17 with diabetes mellitus, and 51 under stabilized warfarin treatment. In patients with DIC, mean concentrations of total PS and free PS were normal, while PC was reduced and C4bp were elevated. Total PS, free PS, C4bp and PC were all decreased in liver disease, elevated in diabetes mellitus, and normal in collagen disease. In warfarin-treated patients, total PS, free PS and PC were moderately decreased, but the decrease in C4bp was minimal. The concentration of PS correlated positively with PC in liver disease, diabetes mellitus, and during oral anticoagulation, but did not in DIC. These results indicate that PS and PC behave similarly when liver synthetic function is principally affected, but in contrast to PC, PS is hardly consumed during intravascular coagulation.     

Treatment of vitamin K-dependent coagulation factor deficiency and subarachnoid hemorrhage

BACKGROUND:

In adults, vitamin K-dependent coagulation factor deficiency (VKCFD) increases in the recent years. We treated a VKCFD patient with subarachnoid hemorrhage, with favorable outcomes.

METHODS:

A 19-year-old male student with VKCFD was treated at our hospital. The initial treatment was injection of a large dose of vitamin K and fresh plasma, and then with oral high dose of vitamin K4.

RESULTS:

At 4 weeks after admission, the focus of hemorrhage subsided, neurological examination was normal, and the patient was discharged.

CONCLUSIONS:

VKCFD is rare and its diagnosis should be based on the history of the patient and the results of laboratory examinations. A large dose of vitamin K is the first choice of treatment.KEY WORDS: Vitamin K-dependent coagulation factor deficiency, Subarachnoid hemorrhage, Diagnosis     

Vitamin K-dependent coagulation factors and fibrinogen levels in FFP remain stable upon repeated freezing and thawing

BACKGROUND: FFP is considered adequate for transfusion up to 24 hours after thawing and is currently used most often to replace deficient clotting factors, such as in warfarin overdose. We set to examine the levels of vitamin K-dependent factors (i.e., prothrombin, FVII, F IX, FX), as well as fibrinogen, upon twice freezing and thawing of FFP. If factor levels in refrozen FFP remain within normal limits, this component can possibly be transfused, thus avoiding wastage of precious blood components. STUDY DESIGN AND METHODS: Twenty units of FFP, five units of each blood group A, B, AB, and O, were thawed, and aliquots were taken for measurement of coagulation factors. The plasma units were then kept for 24 hours at 4 degrees C, at which point a second aliquot was taken, The remaining FFP units were refrozen and kept at -80 degrees C for 1 week. The above procedure was then repeated. Coagulation-factor activity and fibrinogen level were measured by the coagulation analyzer. RESULTS: The mean levels of prothrombin, FVII, F IX, FX, and fibrinogen of each blood group (A, B, AB, and O) were calculated for each of four time points and found not statistically different (p > 0.05). Therefore, the rest of the analysis was done for all 20 FFP units as one group. The mean +/- SD levels of each coagulation factor at each time point demonstrated that all levels were within normal limits of all factors measured and that for none of the factors was there a significant decay of activity. CONCLUSIONS: The levels of prothrombin, FVII, F IX, FX, and fibrinogen remain stable and adequate for transfusion in twice-thawed-and-refrozen FFP. This component can be safely used for transfusion as a source of vitamin K-dependent clotting factors and fibrinogen.     

The effect of oral anticoagulant therapy on aptt results from a bedside coagulation monitor

Objective. The Ciba Corning 512 coagulation monitor (CC512) can be used to monitor heparin therapy by performing an activated partial thromboplastin time (APTT) at the patient’s bedside. This study was designed to compare the CC512 results to results using the laboratory system. The relative sensitivities of both systems to the effect of oral anticoagulant therapy also was investigated.Methods. Activated partial thromboplastin times were performed with both the CC512 and laboratory system on 74 specimens from patients receiving IV heparin therapy, and on 14 specimens from patients on warfarin only. Heparin assays were performed on 43 of the specimens from the heparinized patients.Results. When a patient was receiving heparin only, the APTT results of the CC512 proved to be similar to existing laboratory methods. The CC512 APTT results of patients on warfarin only were markedly prolonged, whereas the laboratory APTTs were only slightly affected.Conclusion. The CC512 results were comparable to the laboratory system. However, the CC512 APTT was more sensitive to the effect of warfarin than the laboratory APTT system used in this study. CC512 APTT results on a patient receiving both oral and intravenous anticoagulation could be misleading. The authors wish to thank D.M. O’Brien and the nursing staff of the Coronary Care Unit for providing CC512 data and laboratory specimens, and I. Smith for the preparation of graphics. We also wish to thank Australian Diagnostics Corporation, which provided consumables.     

妊娠合并获得性维生素K依赖性凝血因子缺乏症一例报告及文献复习

目的探讨妊娠合并获得性维生素K依赖性凝血因子缺乏症(ADVKCF)的临床特点及诊治方法。方法报告一例妊娠合并ADVKCF患者的诊治经过,以"获得性维生素K依赖性凝血因子缺乏症""超级华法林(鼠药)中毒""妊娠"的中英文为检索词分别在PubMed、Embase、Web of Science、CNKI和万方数据知识服务平台检索国内外相关病例,总结妊娠合并ADVKCF的临床特点、治疗方案及母儿结局。结果该文报道1例妊娠合并ADVKCF患者,因皮肤淤斑及胎死宫内入院,被诊断为妊娠合并ADVKCF,排胎同时予输注血制品、补充维生素K等治疗后,病情好转出院。笔者共检索到国内外相关病例5例,患者首发症状主要表现为肉眼血尿、口腔黏膜出血。5例患者的凝血酶原时间及活化部分凝血时间均明显延长,有1例出现胎死宫内,2例新生儿死亡。结论妊娠合并ADVKCF非常罕见,易因凝血指标异常与其不同程度的出血表现误诊为DIC,多合并不良的妊娠结局,对该类患者尽早诊断、及时治疗或可改善预后。     

Polymorphisms of the factor VII gene associated with the low activities of vitamin K-dependent coagulation factors in one-month-old infants

Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.     

The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.

Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins and in defining vitamin K nutriture have led to a substantial revision in our understanding of vitamin K physiology. The only unequivocal function for vitamin K is as a cofactor for the carboxylation of VKD proteins which renders them active. While vitamin K was originally associated only with hepatic VKD proteins that participate in hemostasis, VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet and their contribution to hepatic vs. non-hepatic tissue. New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional hemostasis, the undercarboxylation of at least one non-hemostatic protein is frequently observed in the general population. The advances in defining VKD protein function and vitamin K nutriture are described, as is the potential impact of VKD proteins on atherosclerosis. Many of the VKD proteins contribute to atherogenesis. Recent studies suggest involvement in arterial calcification, which may be influenced by dietary levels of vitamin K and by anticoagulant drugs such as warfarin that antagonize vitamin K action.     

MODS抗凝治疗中凝血因子X检测的意义

目的探讨多器官功能障碍综合症(MODS)患者在低分子量肝素抗凝治疗过程中凝血因子X和凝血参数监测的意义.方法采用ACL 200血凝仪连续监测(0,1h,24h,48h,96h)MODS患者血浆凝血因子X活性、凝血酶原时间(PT)、部分凝血活酶时间(APTT)的变化,分别将使用低分子量肝素抗凝后1h,24h,48h,96h血浆凝血因子X活性、PT、APTT与用药前比较.结果使用低分子量肝素抗凝治疗后1h,PT、APTT均延长,凝血因子X活性明显下降;低分子量肝素维持量(第24h,48h,96h)时,凝血因子X活性各测定值之间无显著性差异(P＞0.05),但与用药前比较,具有非常显著性差异(P＜0.01),而PT、APTT与用药前比较无显著性差异.结论在低分子量肝素抗凝治疗过程中,监测凝血因子X和凝血参数非常必要,且监测凝血因子X较监测PT、APTT更为有用.检测血浆凝血因子X活性是监测MODS患者低分子量肝素抗凝治疗过程中十分有用的方法.     

MODS抗凝治疗中凝血因子X检测的意义

目的探讨多器官功能障碍综合症(MODS)患者在低分子量肝素抗凝治疗过程中凝血因子X和凝血参数监测的意义.方法采用ACL 200血凝仪连续监测(0,1h,24h,48h,96h)MODS患者血浆凝血因子X活性、凝血酶原时间(PT)、部分凝血活酶时间(APTT)的变化,分别将使用低分子量肝素抗凝后1h,24h,48h,96h血浆凝血因子X活性、PT、APTT与用药前比较.结果使用低分子量肝素抗凝治疗后1h,PT、APTT均延长,凝血因子X活性明显下降;低分子量肝素维持量(第24h,48h,96h)时,凝血因子X活性各测定值之间无显著性差异(P＞0.05),但与用药前比较,具有非常显著性差异(P＜0.01),而PT、APTT与用药前比较无显著性差异.结论在低分子量肝素抗凝治疗过程中,监测凝血因子X和凝血参数非常必要,且监测凝血因子X较监测PT、APTT更为有用.检测血浆凝血因子X活性是监测MODS患者低分子量肝素抗凝治疗过程中十分有用的方法.     

机械瓣膜替换术后抗凝血浆蛋白C含量改变的意义

目的　探讨机械瓣膜替换术后口服华法令者,血浆蛋白C,PC)的改变以及与其他凝血因子改变的关系。方法　采用酶联免疫吸附法测定PC含量,采用经典一期法测定凝血因子X∶C、凝血酶原时间并计算国际正常化比值(INR)。　结果　正常对照组(n=45),口服华法令组(n=78)PC含量分别为(5.00±0.64)mg/L、(2.54±2.18)mg/L,两者差异有极显著性(P＜0.001)。服药时间1～6个月、7～24个月、25～132个月者PC含量分别为(4.02±3.60)mg/L、(2.52±1.56)mg/L、(2.40±1.66)mg/L。PC含量改变与因子X、凝血酶原时间(PT)、INR间无明显相关性。　结论　机械瓣膜替换术后口服华法令者血浆蛋白C含量减低,并与服药时间长短有关,蛋白C的改变存在较大的个体差异。在抗凝治疗初期,对蛋白C含量的监测有着特别重要的意义。