Randomized prospective trial comparing the native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant therapy

The dosage of the anticoagulant warfarin sodium is based upon the prolongation of the prothrombin time into an optimal therapeutic range. We have developed a new assay for the native prothrombin antigen that measures the fully gamma-carboxylated prothrombin using a radioimmunoassay. Based on preliminary data that indicated that the native prothrombin antigen predicted both bleeding and thrombotic complications more accurately than the prothrombin time in patients anticoagulated with warfarin sodium, we have performed a randomized prospective trial comparing the complication rate in warfarin-treated patients monitored with the native prothrombin antigen or the prothrombin time. Patients with indications for anticoagulation were randomized to be monitored by the native prothrombin antigen (therapeutic range, 12 to 24 micrograms/mL) or the prothrombin time index (therapeutic range, 1.5 to 2.0). Of the prothrombin time group (N = 80), seven (8.8%) had bleeding or thrombotic complications, with a complication rate of 9.5%/patient-year. In the native prothrombin antigen group (N = 76), one subject (1.3%) had a bleeding complication. The complication rate per patient-year was 1.5%. These results indicate an 85% reduction in the complication rate of the native prothrombin antigen group compared with the complication rate of the prothrombin time group. This difference is statistically significant by the Fisher exact test (P = .037) and by Kaplan Meier survival analysis (P = .040). This study suggests that the use of the native prothrombin antigen assay has the potential to decrease the complications associated with anticoagulation therapy with warfarin sodium.     

Comparison of plasma prothrombin and factor VII and urine prothrombin F1 concentrations in patients on long-term warfarin therapy and those in the initial phase

Control of warfarin anticoagulation during the initial phase of therapy is difficult and empirically based. Plasma and urine samples were obtained from normal controls, patients under stable anticoagulation, and patients in the initial phase of anticoagulation. Total plasma prothrombin, des-carboxy (non-adsorbable with barium chloride) prothrombin, and native (total minus non-adsorbable) prothrombin were quantitated using Echis carinatus venom activation. Functional plasma factor VII (VII) was measured using a one-stage clotting assay. Total and des-carboxy urine prothrombin F1 (F1) were measured by ELISA. All urine F1 in normals and both anticoagulated groups was adsorbed by barium chloride. Plasma des-carboxy prothrombin concentration was similar for the two anticoagulated groups and did not correlate with 1/INR. Native prothrombin correlated with 1/INR in both the stable (r = 0.76) and initial phase (r = 0.74) groups. For any given INR, the subjects on stable anticoagulation had lower native prothrombin concentrations than the initial phase patients. Functional factor VII concentration also correlated significantly with 1/INR in both the stable (r = 0.64) and initial phase (r = 0.76) patients. Unlike native prothrombin, VII concentrations did not vary between the two cohorts for any given INR. Previous studies indicate that native prothrombin is a superior predictor of both hemorrhagic and thromboembolic complications during warfarin therapy. Our findings indicate that VII, and not prothrombin, may be the predominant factor monitored by the INR. This further supports the need to reevaluate the usefulness of the INR in the monitoring of warfarin therapy during the initial phase. Am. J. Hematol. 57:193–199, 1998. © 1998 Wiley-Liss, Inc.     

Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions

PURPOSE: To determine the relation of bleeding to prothrombin times and important remediable lesions in outpatients treated with warfarin. PATIENTS AND METHODS: An inception cohort of 565 patients starting outpatient therapy with warfarin on discharge from a university hospital was assembled. Detailed records of outpatient prothrombin times were obtained for 103 of 130 case subjects with major or minor bleeding and for 117 control patients without bleeding. A nested case-control design was used to evaluate the association of bleeding with temporally related prothrombin times; odds ratios were estimated using multivariate logistic regression analysis to control for known predictors of major bleeding. The relation of bleeding to important remediable lesions was determined in all 130 cases of bleeding. RESULTS: For each 1.0 increase in the prothrombin time-to-control ratio, the odds ratio for major bleeding during the week after a prothrombin time measurement increased 80%; the odds ratio for minor bleeding increased 50%. These odds ratios were lower during the first month of therapy and higher thereafter. Bleeding was related to important remediable lesions in 49 of 130 cases (38%), but these lesions were unknown before bleeding in only 22 cases (17%). The mean prothrombin time rose sharply at the time of bleeding in patients without important remediable lesions, but not in patients with lesions. New, previously unknown lesions (including nine malignancies) were discovered in 20 of 59 case subjects (34%) with gastrointestinal bleeding or hematuria, but in only two of 71 case subjects (3%) with other bleeding (p less than 0.001). CONCLUSION: Our results provide a valid quantitative basis for estimating the odds of bleeding in relation to the prothrombin time and the yield of diagnostic evaluation in patients with bleeding.     

Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels.

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.     

Complications of warfarin therapy monitored by the international normalized ratio versus the prothrombin time ratio

The objective of our study was to determine the rates of bleeding complications and thromboembolic events in patients receiving oral anticoagulant therapy monitored with the prothrombin time (PT) ratio versus therapy monitored with the International Normalized Ratio (INR) using a retrospective time-series study design. Over 650 patients enrolled in a large anticoagulation clinic were studied during two time periods corresponding to the use of the PT ratio versus the INR to guide anticoagulant therapy, with over 400 patient-years of follow-up for each time period. The rate of bleeding complications using the PT ratio to guide therapy was 6.7% (1.2% major, 5.5% minor) per patient-year, compared with 2.9% (0% major, 2.9% minor) using the INR (p = 0.02). The rate of thromboembolic complications was 1.0% using the PT ratio, compared with 0.2% using the INR (p = NS). Therapy monitored with the INR required 19.8 visits per year, compared with 20.7 visits per year using the PT ratio. We conclude that the INR should be used to monitor oral anticoagulant therapy in an effort to reduce bleeding complications while maintaining an acceptable rate of thromboembolic events.     

Home prothrombin time monitoring after the initiation of warfarin therapy. A randomized, prospective study

STUDY OBJECTIVE: To evaluate the efficacy and accuracy of monitoring prothrombin times at home. DESIGN: Randomized, prospective cohort study. SETTING: Outpatients discharged from a university hospital or a community hospital. PATIENTS: Fifty patients started on warfarin for the first time who demonstrated an ability to use the monitor and who had not achieved a stable response to warfarin in the hospital. INTERVENTION: Oral anticoagulation therapy managed using a portable prothrombin time monitor compared with specialized anticoagulation clinic care. MEASUREMENTS AND MAIN RESULTS: In the 46 patients who completed the 8-week study, the median percentage of time that patients in the home-monitor group (n = 23) were within a range equal to the target prothrombin ratio +/- 0.3, but always above 1.25, was 93%, compared with 75% for patients in the clinic group (n = 23) (P = 0.003). There was no significant difference between groups in the percentage of time above the therapeutic range; however, the percentage of time that patients were subtherapeutic was significantly greater in the clinic group (P less than 0.001). There were no major thromboembolic or hemorrhagic complications in either group. Differences between home monitor measurements and corresponding clinical laboratory measurements using blood samples drawn within 4 hours of the home test were comparable to differences observed between measurements using two different clinical laboratory instruments. CONCLUSIONS: Use of a portable prothrombin time monitor by patients at home is feasible and provides accurate measurements. Patients doing home monitoring achieve superior anticoagulation control compared with those receiving standard anticoagulation clinic care.     

Warfarin therapy. The effect of heparin on prothrombin times

Sharp decreases in the prothrombin time after discontinuing heparin have been reported in patients undergoing oral anticoagulant therapy. Twenty-five patients receiving continuous intravenously administered heparin and orally or intravenously administered warfarin were studied. All patients had prothrombin times greater than 1.40 times control, and activated partial thromboplastin times 1.5 to three times control before discontinuing heparin therapy. Prothrombin times on the heparin infusion and four to six hours after it was discontinued were compared. The mean change in the prothrombin time was -1.60 s with a range of +0.8 to -5.5 s. Eight (32%) of 25 patients had a decrease of greater than 2 s. The decrease in prothrombin time correlated poorly with heparin dose or activated partial thromboplastin time in patients taking heparin. Since the change in prothrombin time is unpredictable, a repeated prothrombin time is recommended after stopping heparin therapy prior to discharging a patient.     

A retrospective analysis of the periprocedural management of oral anticoagulants in patients undergoing interventional radiology procedures

Limited evidence is available to guide periprocedural management of oral anticoagulants in the setting of interventional radiology (IR) procedures. For direct oral anticoagulants, therapy interruption (TI) is based on medication half-life and procedural bleeding risk. Periprocedural management of warfarin includes INR monitoring, and possible bridging with parenteral anticoagulants. It is unknown if these recommendations apply to IR procedures. To evaluate bleeding complications and thromboembolic events following periprocedural management of the factor Xa (FXa) inhibitors or warfarin in patients undergoing IR procedures. We performed a retrospective, observational study at NYU Langone Health (NYULH) of all adult patients who underwent an IR procedure from January 2015 to July 2017 and were receiving apixaban, rivaroxaban, or warfarin. Patients who were pregnant or who had a mechanical heart valve were excluded. At NYULH, TI is not required for FXa inhibitors, and an INR?<?3 is recommended for patients on warfarin undergoing low risk procedures. For moderate/high risk procedures, TI for 48 h or 72 h with reduced renal function, is recommended for FXa inhibitors, and an INR?<?1.5 is recommended for patients on warfarin. We evaluated 350 IR procedures, with a total of 174 low bleeding risk and 176 moderate/high bleeding risk. The 30-day major bleeding rate was 0.9%, clinically relevant non-major bleeding rate was 3%, minor bleeding rate was 1% and thromboembolic event rate was 1%. The periprocedural oral anticoagulation management strategy at NYULH appears safe given the low 30-day incidence of bleeding and thromboembolic events.     

Thromboembolism after treatment with 4-factor prothrombin complex concentrate or plasma for warfarin-related bleeding

Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49–1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.

     

Anticoagulation clinics and the monitoring of anticoagulant therapy

Patients attending an anticoagulation clinic were studied to delineate predisposing risk factors for bleeding and thromboembolic episodes. Seventy-three patients were observed for a total of 921.8 patient-treatment months. The mean duration of treatment was 12.6 months (range 3-36 months). No major bleed occurred (a bleed which caused discontinuation of therapy, hospitalization or death). Thirty-two patients had minor bleeding episodes (0.42 bleeds per patient-year of treatment). The average prothrombin time ratio during the third to the sixth month of therapy was predictive of the bleeding risk. There was no association between bleeding and age, sex, indication for anticoagulation therapy or associated illnesses. Four thromboembolic episodes occurred (0.05 per patient-year of treatment), 3 arterial and 1 venous. At the time of the one venous thromboembolic event the prothrombin time ratio was subtherapeutic. In all 3 patients with arterial thromboembolism the mean 3- to 6-month prothrombin time ratio was less than or equal to the lower limit of the recommended range of 1.6-2.5. In our study prothrombin time ratios of 1.3-1.5 for venous thromboembolic disease and 1.6-2.5 for arterial thromboembolic disease were not associated with thromboembolism or major bleeding. Anticoagulation clinics facilitate the close monitoring of patients on oral anticoagulant therapy.     

Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole

Despite the use of oral anticoagulation in patients with prosthetic heart valves, persistent thromboembolism over time warrants a search for improved methods of prevention. Thus, patients receiving 1 or more mechanical prosthetic heart valves were randomized to therapy with warfarin plus dipyridamole (400 mg/day) or warfarin plus aspirin (500 mg/day) on the basis of location and type of valve and surgeon, and followed up with a concurrent, nonrandomized control group taking warfarin alone. In 534 patients followed up 1,319 patient-years, excessive bleeding (necessitating blood transfusion or hospitalization) was noted in the warfarin plus aspirin group (23 of 170 [14%], or 6.0/100 patient-years) compared with warfarin plus dipyridamole (7 of 181 [4%], or 1.6/100 patient-years, p less than 0.001), or warfarin alone (9 of 183 [5%], or 1.8/100 patient-years, p less than 0.001). A trend was evident toward a reduction in thromboembolism in the warfarin plus dipyridamole group (2 of 181 [1%], or 0.5/100 patient-years) as compared with warfarin plus aspirin (7 of 170 [4%], or 1.8/100 patient-years), or warfarin alone (6 of 183 [4%], or 1.2/100 patient-years). Adequacy of anticoagulation (based on 12,720 prothrombin time determinations) was similar in all 3 groups with 65% of prothrombin times in the therapeutic range (1.5 less than or equal to prothrombin time/control less than or equal to 2.5), 30% too low, and 5% too high. Warfarin plus aspirin therapy resulted in excessive bleeding and is contraindicated. Longer follow-up study is needed to determine whether further separation of the incidence of thromboembolism can be detected.     

Prothrombin Habana: a new dysfunctional molecule of human prothrombin associated with a true prothrombin deficiency

A Cuban family with a new congenital dysprothrombinaemia is described. The propositus was a 5-year-old female who presented with umbilical bleeding after birth followed by easy bruising and bleeding tendency throughout her life. The main laboratory features of the defect included prolongation of prothrombin time and partial thromboplastin time. Prothrombin activity was less than 10% in several one- and two-stage systems. However, the staphylocoagulase-complexed prothrombin level and immunologic methods yielded levels of about 50%. The migration of the abnormal prothrombin was more anodic in single and bidimensional immunoelectrophoresis system and did not change by the addition of calcium. Family studies revealed that the father had approximately 50% prothrombin activity and antigen, whereas the mother had 45% prothrombin activity but about 100% prothrombin antigen. We suggest that the propositus is heterozygous for an abnormal prothrombin and heterozygous for true prothrombin deficiency.     

Retrospective study of rFVIIa, 4‐factor PCC,and a rFVIIa and 3‐factor PCC combination in improving bleeding outcomes in the warfarin and non‐warfarin patient

In case of severe bleeding, the physician must rapidly and effectively halt bleeding without the risk of thromboembolic complications. Despite widespread use, no study has directly compared recombinant activated factor VII (rFVIIa), the rFVIIa and 3‐factor prothrombin complex concentrate (PCC) combination (“combination”), and 4‐factor PCC on their effectiveness in improving patient outcomes. This study examined the medical records of 299 patients, 65.2% on warfarin prior to admission, who received these hemostatic agents and were admitted to an ICU or through the emergency department at Oregon Health & Science University. Mortality, length of stay, change in international normalized ratio (INR), plasma use, and number of thromboembolic complications were used to assess effectiveness. In patients receiving warfarin, the combination group had the greatest decrease in INR as well as lowest overall INR, but experienced a higher number of clotting complications, while the rFVIIa group used the most plasma. Non‐warfarin patients in the combination group had the shortest length of stay among survivors, but the rFVIIa group had the lowest mortality. Based on this data, it may be prudent to further study the use of rFVIIa in treating extreme bleeding in the non‐warfarin patient, while this study supports other data that 4‐factor PCC may be the most prudent for the warfarin patient. Am. J. Hematol. 91:705–708, 2016. © 2016 Wiley Periodicals, Inc.     

Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism.

There is no universally accepted approach to the initiation of systemic anticoagulant therapy. In an open, randomized study, two anticoagulant regimens that differed only in the timing of warfarin therapy after the start of heparin were compared. We randomized 119 patients with acute thromboembolic events to receive warfarin either within 48 hours of the start of heparin (early group, n = 63) or 96 hours or later after the start of heparin (late group, n = 56). Heparin was given as a 5000 IU bolus as a constant infusion titrated to maintain the activated partial thromboplastin time at 1.5 to 2 times control values. Warfarin was started at 10 mg daily for 3 days and the dose was titrated to maintain the prothrombin time at 1.2 to 1.5 times control values. There were no significant differences between the early and late warfarin groups with regard to age, sex, indication for anticoagulation, heparin dose, mean activated partial thromboplastin time during heparin, warfarin dose at discharge, length of warfarin therapy before discharge, bleeding, recurrent thromboembolic events, or mortality rates. Time to the start of warfarin after heparin was 31 hours and 108 hours in the early and late groups, respectively. Length of hospitalization, hospital costs, and the incidence of heparin-induced infusion phlebitis and thrombocytopenia were significantly less in the early group compared with the late group. Early initiation of warfarin after heparin is safer, less expensive, and as effective as the late initiation of warfarin.     

Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation.

BACKGROUND: Treatment with warfarin sodium is effective for stroke prevention in atrial fibrillation but many physicians hesitate to prescribe it to elderly patients presumably because of the associated risk for bleeding and the inconvenience of frequent blood tests for the patients. METHODS: In the Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK 2) Study, we studied the rate of bleeding events associated with the incidence of thromboembolic events in patients receiving warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; aspirin, 300 mg/d; or adjusted-dose warfarin therapy aiming at an international normalized ratio of the prothrombin time ratio (INR) of 2.0 to 3.0. The study was scheduled for 6 years from May 1, 1993, but owing to evidence of inefficiency of low-intensity therapy plus aspirin from another study it was prematurely terminated on October 2, 1996. Minor and major bleeding events were recorded prospectively. The rate of bleeding was calculated using the Kaplan-Meier method and risk factors were identified by the Cox proportional hazards model. RESULTS: Of 677 included patients, 130 (median age, 77 years; range, 67-89 years) experienced bleeding. One woman and 12 men experienced major bleeding. Four had intracranial bleeding: 2 cases were fatal and 2 were nonfatal. During treatment with mini-dose warfarin, warfarin plus aspirin, aspirin, and adjusted-dose warfarin, the annual rate of major bleeding was 0.8%, 0.3%, 1.4%, and 1.1%, respectively (P = .20). After 3 years of treatment the cumulative rate of any bleeding was 24.7%, 24.4%, 30.0%, and 41.1% (P = .003), respectively. Increasing INRvalue (P<.001) and prior myocardial infarction (P = .001) were independent risk factors for bleeding, whereas increasing age was not. CONCLUSIONS: Fixed mini-dose warfarin and aspirin alone or in combination were associated with both minor and major bleeding. The small number of major bleeding events in patients receiving adjusted-dose warfarin therapy as compared with those receiving less intensive antithrombotic treatments and the finding of no significant influence of age on the risk for bleeding indicate that even elderly patients with atrial fibrillation tolerate adjusted-dose warfarin therapy (INR, 2.0-3.0).     

Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.     

华法林对非瓣膜病心房颤动抗栓的安全性和有效性研究

目的观察华法林对非瓣膜病心房颤动(房颤)患者抗凝治疗的有效性和安全性。方法在18个中心进行阿司匹林(150～160 mg/d)与调整剂量华法林组随机对照研究中选取患者。华法林初始剂量2 mg/d,目标国际标准化比值(INR)2.0～3.0(年龄≥75岁者为1.6～2.5),常规门诊随访,分析该组患者终点事件和出血事件的发生及与抗凝强度的关系。结果共335例患者随机服用华法林,男204例(60.9%),年龄(62.6±10.3)岁,随访2～24个月(中位数19个月)。华法林平均剂量(3.19±0.69)mg。共进行 INR 测定3482人次,其中2378次 INR(占68.3%)维持2.0～3.0。用药期间发生主要终点事件10例(2.7%),次要终点事件19例(5.7%)。服用华法林期间总出血发生率为23例(6.9%),其中严重出血5例(1.5%),轻微出血18例(5.4%);发生血栓栓塞事件(缺血性卒中及体循环栓塞)19例(5.4%),其中15例(4.5%)患者发生事件时的 INR<2.0。多因素 logistic 回归显示,抗凝出血和血栓栓塞事件的独立危险因素均为年龄>75岁,前者收缩压≥160mm Hg,血肌酐升高,INR>3.0;后者有卒中病史,左室射血分数<0.40%和 INR<2.0。结论中国人非瓣膜病房颤患者应用华法林抗凝 INR 维持在2.0～3.0是安全有效的,但应避免 INR>3.0,以最大限度减少出血并发症,尤其应严密监测高龄、合并心力衰竭和肾功能异常的患者。     

A feasibility study of continuing dose-reduced warfarin for invasive procedures in patients with high thromboembolic risk

BACKGROUND: The management of perioperative anticoagulation therapy for patients having a high risk of thromboembolism who are receiving long-term oral anticoagulant therapy is uncertain. The prevalent approach is to discontinue oral anticoagulation therapy and initiate heparin therapy. Another potential strategy is to continue oral anticoagulation therapy with a temporary adjustment of warfarin intensity to a preoperative international normalized ratio (INR) of 1.5 to 2.0. Such moderate-dose anticoagulation therapy with warfarin has been shown to be hemostatically safe yet effective in the prevention of thromboembolism after hip or knee replacement. METHODS: Over an 11-year period (ie, 1993 to 2003), our hemostatic consultative service prospectively identified 100 consecutive patients for whom we continued warfarin therapy at adjusted doses during the perioperative period, targeting a goal for the INR of 1.5 to 2.0. Patients were assigned a score for venous thromboembolic risk as well as overall surgical risk using published instruments. Score assignment was based on what was deemed to be extremely high risk for thromboembolism in patients who were receiving long-term warfarin therapy. Although the patients were accrued prospectively, the final retrospective analysis was made after all patients were treated. RESULTS: The most common indication (62%) for high-risk assignment was a thromboembolic event within the past 6 months. The second most prevalent reason was prior postoperative venous thromboembolism (VTE) [11%]. Indications for long-term anticoagulation therapy were recent VTE (62%), inherited thrombophilia (7%), antiphospholipid syndrome (13%), mechanical heart valves (18%), and prior cerebrovascular accident (4%). The prevalence of inherited thrombophilia probably has been grossly underestimated, as neither factor V Leiden mutation nor prothrombin 20210 mutation had been described during the bulk of the accrual time. Most surgical procedures (58%) were significantly invasive (Johns Hopkins category 3 to 5). The mean INR values were 2.1 on the day prior to surgery (SD, 0.9594; range, 1.2 to 6.5; n = 65), 1.8 on the day of surgery (SD, 0.4899; range, 1.2 to 4.9; n = 75), and 1.8 on the first postoperative day (SD, 0.4436; range, 1.1 to 3.3; n = 70). Two patients had major bleeding, and four patients had minor bleeding. One patient developed deep venous thrombosis. Several weeks after surgery, one patient with a prosthetic heart valve died from an embolic stroke, which was associated with a failure to increase his anticoagulation to therapeutic levels. CONCLUSIONS: Moderate-intensity anticoagulant therapy with warfarin, targeting a goal INR of 1.5 to 2.0, appears to be a safe and feasible method for preventing thromboembolic complications in high-risk surgical patients who are receiving long-term oral anticoagulant therapy. This may be considered a reasonable method to afford thromboprophylaxis in highly selected patients who are occasionally seen in clinical practice. This observational study does not prove equality, let alone superiority, to other proposed methods of anticoagulation therapy.     

Effect of warfarin on arterial thrombogenesis: Problems of monitoring

Platelet reactivity to shear stress and collagen and dynamic overall coagulation were measured in vitro from nonanticoagulated blood of 137 patients on warfarin. One hundred five matched, healthy subjects served as controls. Platelet reactivity to both stimuli and contribution of platelets to plasmatic coagulation were significantly inhibited in patients on warfarin. No correlation was found between platelet reactivity and the coagulation status assessed by the international normalized prothrombin time ratio (INR). Despite similar INR, platelet reactivity showed great individual variation. In 98 patients who were followed up for 3 months, measurement of platelet reactivity to shear stress could discriminate between those who had either bleeding or thromboembolic episodes. These findings suggest that monitored platelet function would help in individualizing oral anticoagulant regimens and hence would increase the benefit of therapy without the risk of bleeding complications. © 1993 Wiley-Liss, Inc.     

Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.