Hemostatic markers in Japanese patients undergoing anticoagulant therapy under thrombo-test monitoring.

The objective of this study was to evaluate several molecular markers of hemostasis in 84 patients with hypercoagulable state, treated with warfarin under thrombo-test (TT) monitoring; TT was expressed as percent of control (TT%). In all patients, the average values of international normalized ratio (INR) of prothrombin time (PT;PT-INR) was 1.68+/-0.49; this increase in PT-INR was not, however, significant in patients under TT% monitoring. There were no thrombotic or severe bleeding complications in these patients during a period of 2 years. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were slightly increased, suggesting that anticoagulant therapy was not completely effective in our Japanese patients based on the values of TT%. Activated partial thromboplastin time, PT-INR, TT% and protein C activity were significantly correlated with the dose of warfarin; fibrinogen, activated thromboplastin, TAT, PPIC, D-dimer, sFM, protein S and thrombomodulin were not significantly correlated with the dose of warfarin. The PT-INR was negatively correlated with TT%, protein C and protein S, and the correlation between PT-INR and TT-INR was better than that between PT-INR and TT%. The range of TT% was not correlated with the plasma levels of TAT, PPIC, D-dimer or sFM, but the range of PT-INR was correlated with the plasma level of TAT, D-dimer and sFM. The percentage of TAT, D-dimer and sFM within normal range was significantly low in patients with high PT-INR. These finding showed that PT-INR is better than TT% for monitoring the anticoagulant therapy with warfarin, and that TT should be expressed as INR. The values of PT-INR should be more than 1.7 during the anticoagulant therapy with warfarin in Japanese patients with high risk of thrombosis.     

ISI/INR system in Japan: experience from simultaneous measurement of the same plasma at four different laboratories

In 1984, the Scientific and Standardization Committee (formerly ICTH) recommended the use of the International Sensitivity Index and International Normalized Ratio (ISI/INR) System for the monitoring of oral anticoagulant therapy. This system was introduced because the sensitivity of thromboplastin reagents used for the measurement of prothrombin time (PT) was widely different and comparison among hospitals employing different reagents was virtually impossible. In this study, we simultaneously measured the plasma from 7 patients with warfarin therapy at 4 different institutions for PT seconds, PT-INR, thrombotest (TT) seconds and TT-INR. The comparison between these laboratories revealed clinically important variances between the 4 laboratories even when PT was converted to PT-INR. Laboratory 1 and laboratory 3 were using the same thromboplastin reagents for the measurement of PT. The PT (seconds) in both laboratories showed similar numbers, but when they converted into INR, the variances were significant (maximum coefficient of variance 10.44). We investigated the reason why these differences occurred and found that the PT seconds (11.40) for normal control at laboratory 3 were somewhat larger than those of other laboratories. If we assume that PT-INR is identical to TT-INR, the estimated PT (second) for normal control at laboratory 3 can be calculated from TT-INR, and was found to be 10.56 +/- 0.10 seconds. This was nearly the same as the one that was used at laboratory 1. In conclusion, there still exist some difficulties that must be overcome before the ISI/INR system can be used reliably, and we suggest attention be given to the PT seconds used as normal control plasma.     

Relationship between prothrombin time international normalized ratio and thrombo test (%)]

OBJECTIVES: The optimal therapeutic range for laboratory evaluation of oral anticoagulant therapy is now defined by the prothrombin time international normalized ratio (PT-INR). However, the thrombo test (TT), an alternative method to measure intensity of anticoagulation, is also currently used throughout Japan. The relationship between PT-INR and TT (%) has yet to be clarified. This study investigated the relationship between PT-INR and TT (%). METHODS: The PT-INR and TT (%) were simultaneously measured of 505 consecutive samples from patients treated with warfarin in our hospital. Fourteen functions were used for regression analyses: a fractional function (Y = a/X + b), a square root function (Y = aX0.5 + b), a natural logarithmic function (Y = a.lnX + b), a power series function (Y = aXb), a quotient function (Y = abX), and polynomial functions [Y = anXn + an - 1Xn - 1 +......+ a1X1 + b, (1 < or = n < or = 9)]. The results were confirmed by the same methods in 383 samples and 296 samples from another two laboratories. RESULTS: The power series function showed the most significant (p < 0.0001) and highest adjusted R2 (0.858) correlation, with a regression formula of TT (%) = e4.48 (PT-INR)-2.09 in our laboratory. Using the same analyses, the power series function also showed the most significant and highest adjusted R2 in samples from the other two laboratories. CONCLUSIONS: This study showed that a power series function is the most appropriate for expressing the relationship between PT-INR and TT (%) among the 14 functions. The function between PT-INR and TT (%) is mainly derived from the relationship between TT (%) and TT (sec). Both internal validity and external validity confirmed the relationship between PT-INR and TT (%).     

Incidence of major bleeding complication of warfarin therapy in Japanese patients with atrial fibrillation.

BACKGROUND: During anticoagulation for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF), bleeding is the most serious complication. In Western countries, the incidences of major bleeding and intracranial hemorrhages with low-dose warfarin are known to occur at a rate of 0.4-1.3% and 0.2% per year, respectively. The purpose of this study was to investigate the incidence and risk factors for major bleeding related with warfarin therapy in Japanese patients with NVAF. METHODS AND RESULTS: From August 2004 to July 2005, 667 NVAF patients treated with warfarin for NVAF were followed-up. The target prothrombin time-international normalized ratio (PT-INR) value was set at 1.6-2.6 (low-dose warfarin). The exposure on warfarin was 503 patient-years (average PT-INR 2.00 +/-0.40). During the follow-up period, 12 major bleeding complications occurred (2.38% per patient-year), which included 3 intracranial hemorrhages (0.60% per patient-year). Among the patients' characteristics, average PT-INR > or =2.27 during the study was identified as an independent risk factor for major bleeding. CONCLUSIONS: The incidence of major bleeding and intracranial hemorrhages in Japanese NVAF patients with low-dose warfarin therapy was 2.38% and 0.60% per patient-year, respectively, which is higher than in Westerners.     

Pharmacogenetic distribution of warfarin and its clinical significance in Korean patients during initial anticoagulation therapy

During warfarin treatment, determining the optimal dose and maintaining the target PT-INR are challenging. Increasing evidence supports the theory that genotypic polymorphisms influence an individual’s warfarin dose requirement. In this study, we evaluated allele frequencies and effects of CYP2C9 and VKORC1 on warfarin response during initial anticoagulation therapy in Korean patients. We enrolled patients who had initiated warfarin therapy and undergone PT-INR testing at least three times within the first month of anticoagulation therapy. All the participating patients were tested for the detection of CYP2C9*3 (c.1075A>C) and VKORC1-1639G>A. A melting-curve analysis after real-time PCR was performed using CYP2C9*3 and VK1639 genotyping kits (Idaho Technology, US). A total of 37 patients were enrolled in this study. CYP2C9*1/*1 (87%) and VKORC1-1639AA genotypes (89%) were predominant in Korea. The CYP2C9*3 and VKORC1-1639G alleles were found in five (13%) and four patients (11%), respectively. Patients with the CYP2C9*3 allele received a lower warfarin dose (P = 0.018) and tended to show more rapid PT-INR increase than CYP2C9*1/*1 genotype. Patients with the VKORC1-1639G allele nonsignificantly received higher warfarin dose than those without. The CYP2C9*3 and VKORC1-1639G alleles influenced warfarin response during the first month of anticoagulation therapy. Considering these results, CYP2C9 and VKORC1 genotyping can be an useful tool to estimate initial warfarin dose and frequency of PT-INR monitoring during the first month of anticoagulation therapy.     

Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study

The combination of oral anticoagulants with dual antiplatelet therapy (DAT) in patients undergoing percutaneous coronary intervention with stent implantation (PCI-stenting) is subject to controversy due to the high risk of bleeding. In this multicenter retrospective parallel-group study, we compared the rate of adverse events in chronically anticoagulated patients who underwent PCI-stenting and were discharged on aspirin, clopidogrel and warfarin (triple antithrombotic therapy [TT] group) and were followed in Italian anticoagulation centers, with a parallel cohort of patients who underwent PCI-stenting and were discharged on DAT group. The primary endpoint was the incidence of major bleeding while the patients were in TT and DAT. A secondary endpoint was the occurrence of major ischemic adverse events (MACEs). The final cohort consisted of 229 TT patients and 231 DAT patients followed up for 6 and 7 months, respectively. There were 11 (4.8 %; 9.1 % patient/years) major bleeding events in the TT group (1 was fatal) as compared to 1 (0.4 %; 0.7 % patient/years) event in the DAT group (p = 0.003). Of the 28 (6.1 %) MACE recorded during the follow-up, 12 (5.2 %) occurred in the TT group and 16 (6.9 %) in the DAT group. In conclusion, despite close monitoring of anticoagulated patients in dedicated centers, the major bleeding incidence remains high among unselected patients undergoing PCI-stenting and treated with TT. Any efforts to minimize these events should be pursued.     

Warfarin after anterior myocardial infarction in current era of dual antiplatelet therapy: a randomized feasibility trial

In the current era of early revascularization and routine use of dual antiplatelet therapy, the incremental benefit of warfarin to reduce the incidence of left ventricular thrombus (LVT) in patients with impaired left ventricular ejection fraction post anterior ST-elevation myocardial infarction (aSTEMI), remains uncertain. The purpose of this study is to assess the feasibility of evaluating the added benefit and safety of triple therapy (TT-warfarin, ASA, and clopidogrel) versus dual therapy (DT-ASA and clopidogrel) in patients at risk of LVT post aSTEMI. Design: Open-label randomized controlled trial. Inclusion: aSTEMI, ejection fraction <40%, and no evidence of LVT. Exclusion: contraindication to, or alternate indication for anticoagulation. Intervention: TT versus DT. Follow-up: pre-discharge and 3 month echocardiogram. Outcomes: composite of death, MI, stroke, systemic embolizarion, LVT or major bleeding at three months. 295 patients with aSTEMI were screened: 27% of patients with LVEF < 40% had an LVT; 20/52 eligible patients were randomized to receive TT (n = 10) or DT (n = 10). Baseline characteristics: mean age 60 years, male gender 65%, diabetics 20%, and in hospital PCI 95%. There was no significant difference in the composite endpoint at 3 months (TT-20% with 1 LVT and 1 major bleed versus DT-10% with 1 MI). The incidence of definite or probable LVT in the screened population of patients post aSTEMI with an LVEF < 40% was 26.6% despite 94% having early revascularization. STEMI patients have a high incidence of LVT despite the routine use of early revascularization and dual antiplatelet therapy. More effective antithrombotic strategies merit evaluation in adequately powered randomized trials.     

Dose-related effect of statins in venous thrombosis risk reduction

Background

Atherosclerosis and venous thromboembolism share similar pathophysiology based on common inflammatory mediators. The dose-related effect of statin therapy in venous thromboembolism remains controversial. This study investigated whether the use of antiplatelet therapy and statins decrease the occurrence of venous thromboembolism in patients with atherosclerosis.

Methods

We conducted a retrospective cohort study reviewing 1795 consecutive patients with atherosclerosis admitted to a teaching hospital between 2005 and 2010. Patients who had been treated with anticoagulation therapy were excluded. Patients who either used statins for <2 months or never used them were allocated to the nonuser group.

Results

The final analysis included 1100 patients. The overall incidence of venous thromboembolism was 9.7%. Among statin users, 6.3% (54/861) developed venous thromboembolism, compared with 22.2% (53/239) in the nonuser group (hazard ratio [HR] 0.24; P <.001). After controlling for confounding factors, statin use was still associated with a lower risk of developing venous thromboembolism (HR 0.29; P <.001). High-dose statin use (average 50.9 mg/day) (HR 0.25; P <.001) lowered the risk of venous thromboembolism compared with standard-dose statins (average 22.2 mg/day) (HR 0.38; P <.001). Dual antiplatelet therapy with aspirin and clopidogrel decreased occurrence of venous thromboembolism (HR 0.19; P <.001). Interestingly, combined statins and antiplatelet therapy further reduced the occurrence of venous thromboembolism (HR 0.16; P <.001).

Conclusions

The use of statins and antiplatelet therapy is associated with a significant reduction in the occurrence of venous thromboembolism with a dose-related response of statins.     

老年非瓣膜病性心房纤颤患者抗血栓治疗现状分析

目的分析空军总医院老年非瓣膜病性心房纤颤（NVAF）患者抗血栓药物治疗现状及未抗凝治疗的原因。方法调查老年NVAF患者109例,对其病因、血栓栓塞危险因素、抗血栓药物应用情况及未应用华法林抗凝治疗原因进行分析。应用CHADS卒中风险评分表对NVAF患者进行血栓栓塞危险评估。结果91.6%患者接受了抗血栓治疗。符合抗凝治疗指征患者68例,仅38.2%接受了华法林治疗,57.4%进行了抗血小板治疗阿司匹林剂量为（87±15）mg/d,4.4%未进行任何抗血栓治疗。而其中NVAF呈阵发性者仅5.0%应用了华法林抗凝治疗。未抗凝治疗者54例,其中存在抗凝禁忌证12例（15.0%）;严重出血而停用1例（1.3%）,不能凝血监测2例（2.5%）;担心出血拒绝8例（10.0%）;阵发性心房纤颤未抗凝治疗20例（25.0%）;冠脉支架术后双重抗血小板治疗而未抗凝治疗3例（3.75%）;原因不明9例（11.3%）。结论老年NVAF患者抗血栓治疗中华法林应用率低,而且阵发性心房纤颤的华法林应用率更低,抗血小板治疗中阿司匹林剂量不足。     

药物洗脱支架植入术后心房颤动患者抗栓治疗方案疗效对比

目的对比不同抗栓治疗方案在接受药物洗脱支架（DES）植入的冠心病伴心房颤动患者中的作用。方法连续入选接受介入治疗置入DES,合并房颤病史或新诊断的房颤患者549名,根据患者出院后不同抗栓治疗方案分为三组：三联抗栓治疗组（华法林加双联抗血小板治疗,简称TT组,n=115）、双联抗血小板治疗组（简称DT组,n=347）和华法林加单一抗血小板治疗组（简称WS组,n=87）。随访12个月。初级终点为患者主要心脑血管不良事件（MACCE）,包括全因死亡、心肌梗死、靶血管重建、支架内血栓以及缺血性卒中。次级终点为安全性终点,包括TIMI主要及次要出血事件。结果与其他两组比较,TT组的MACCE发生率最低（7．1％、21．5％、17．3％,P〈0．01）。Cox回归分析显示,未服用华法林（HR=2．27;95％CI：1．39～3．70;P〈0．01）及CHASD2评分≥2（HR=2．49;95％CI：1．51～4．11;P〈0．01）是MACCE的独立预测因素。三组间TIMI主要出血发生率比较差异无显著性（3．6％、1．8％、2．5％,P〉0．05）,但TT组TIMI次要出血发生率明显增加（10．7％、4．9％、4．2％,P〈0．05）。Cox回归分析显示,年龄（HR=1．15;95％CI：1．07～1．22;P〈0．01）和既往消化道溃疡病史（HR=3．92;95％CI：2．09～7．37;P〈0．01）是出血事件的独立预测因子。结论对于接受DES的房颤患者,三联抗栓治疗的心脑血管保护作用最强,可明显降低主要心脑血管不良事件的发生率,但其总出血事件发生风险亦增加。     

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.     

Stroke prevention in atrial fibrillation

The only major and potentially fatal risk for patients with atrial fibrillation is the development of systemic thromboembolism. Stroke occurs five times more frequently in patients with atrial fibrillation than in comparable patients in sinus rhythm. The yearly incidence of stroke in atrial fibrillation largely depends on the underlying heart disease: from 0.5% in "lone" atrial fibrillation up to 20% in rheumatic heart valve disease. Oral anticoagulation with vitamin K antagonists dramatically reduces the stroke risk by two-thirds, but is a laborious and patient-unfriendly therapy. Oral direct thrombin blockers and oral factor Xa antagonists, both without therapy monitoring, may replace warfarin for this indication, but there are safety and efficacy issues to be resolved. Oral antiplatelet agents are effective, but clearly less than warfarin. Angiotensin receptor blockers are currently under investigation. Routine electrocardioversion for atrial fibrillation does not reduce the stroke risk, but promising techniques include electroablation of the left atrium and occlusion of the left atrial appendage.     

Two monitoring methods of oral anticoagulant therapy in patients with mechanical heart valve prothesis: a meta-analysis

Oral anticoagulant therapy (OAT) with warfarin has become the standard therapy for the patients with mechanical heart valve prothesis. The monitoring method of self-monitoring or self-management was promising to optimize the use of warfarin, but most of previous studies have included patients with various indications of OAT, which made it difficult to extrapolate the results to the specific patient population with mechanical heart valve prostheses. This study was intended to evaluate the new and traditional monitoring methods in patients with mechanical heart valve prostheses. Relevant literature finished before Dec. 2010 were searched through a number of digital databases. And then they were pooled by RevMan 4.2 and R 2.13.0 in three fields: rate within the target range, test frequency and occurrence rate of poor events. Five randomized control trials with a total of 2,219 patients were identified. Pooled estimates showed reductions in thromboembolic events (OR 0.52, 95% CI 0.35–0.77; P = 0.0012) and all-cause mortality (OR 0.50, 95% CI 0.29–0.86; P = 0.0115). No difference was noted in major and minor haemorrhage. All trials reported improvements in the mean proportion of international normalized ratios in range. Self-monitoring and self-management can improve the quality of OAT in the patients with mechanical heart valve prostheses. The patients spend more time within the therapeutic range resulting in decreases in thromboembolic events and mortality, with no increase in haemorrhage. However, self-monitoring and self-management was not feasible for all patients, and require identification and education of suitable candidates. The success of self-monitoring and self-management method depends on consistent, regular, and frequent testing.     

华法林对超高龄患者抗凝治疗价值研究

目的分析华法林抗凝治疗在80岁以上患者中临床应用的现状,评价其临床适应证、疗效及风险,探讨在超高龄患者中华法林的合理应用方法。方法回顾性分析2006年1月至2010年12月于北京大学第一医院心内科31例华法林抗凝治疗的80岁以上患者的临床资料,总结华法林的起始及维持剂量、国际标准比值(INR)监测及栓塞和出血事件的发生。结果 93.55%患者均属于被动抗栓治疗。70.97%的患者INR达2.0～3.0,70.97%的患者达标剂量<3 mg/d,41.94%的患者维持1.5 mg起始剂量。发生缺血性卒中2例,INR<2.0;出血事件2例,INR>2.5。结论 80岁以上超高龄患者的华法林抗凝治疗,1.5 mg/d的起始剂量安全有效;INR维持在2.0～2.5较为适宜。     

Anticoagulation therapy in children with mechanical prosthetic cardiac valves

From 1980 through 1984, 28 children younger than 19 years (mean 7.9) underwent cardiac valve replacement with 30 mechanical prostheses. Patients were followed for a total of 471 months (mean 15.7) and received either warfarin (mean 0.16 mg/kg/day) or acetylsalicylic acid and dipyridamole (mean 6.1 and 1.9 mg/kg/day, respectively) as thromboembolism prophylaxis. The frequency and incidence of thromboembolism and hemorrhage were compared. Warfarin-treated patients were at increased risk of hemorrhage (5 of 20 [25%], or 22 per 100 patient-years, vs 0 of 10 [0%], or 0 per 100 patient-years, p less than 0.05). Three of the 5 hemorrhagic episodes were mild, and in no case was hemorrhage life-threatening. Patients who did not receive warfarin had a greater risk of thromboembolism (2 of 10 [20%], or 12 per 100 patient-years, vs 0 of 20 [0%], or 0 per 100 patient-years, p less than 0.05). Both episodes of thromboembolism were life-threatening and necessitated emergency valve replacement. Although warfarin is associated with greater risk of hemorrhage than is acetylsalicylic acid and dipyridamole, warfarin is better than antiplatelet drugs in thromboembolism prophylaxis and is indicated for anticoagulation therapy in children with mechanical cardiac prostheses.     

The St. Jude valve prosthesis: analysis of the clinical results in 815 implants and the need for systemic anticoagulation

Between July 1979 and December 1984, 785 patients received 815 St. Jude Medical valve prostheses. Valve-related mortality in the follow-up period was due to thromboembolism in seven cases, anticoagulant-related hemorrhage in three and perivalvular leak in two. Freedom from valve-related death or reoperation at 3 years was 96.4% for aortic valve replacement and 98.3% for mitral valve replacement. The overall rate of thromboembolism was 2.6%/patient-year with warfarin, 9.2%/patient-year with antiplatelet medication and 15.6%/patient-year in patients with no anticoagulant therapy. One episode of thrombotic obstruction of a mitral valve, in a patient receiving no anticoagulant therapy, resulted in an occurrence rate of such obstruction of 0.22%/patient-year. Valve replacement with the St. Jude valve produced excellent clinical results, but long-term anticoagulation with warfarin was required to minimize thromboembolic complications. The use of antiplatelet agents alone provided inadequate protection.     

Bleeding complications to long-term oral anticoagulant therapy

Objective: To evaluate the incidence of bleeding complications in recent randomized trials on oral anticoagulant treatment for prevention of arterial thromboembolism.Data sources: International publications on studies of prevention of arterial thromboembolism by oral anticoagulant therapy.Study selection and data extraction: Randomized trials on oral anticoagulant therapy in patients with atrial fibrillation, recent myocardial infarction, and prosthetic heart valves were selected. For comparison older nonrandomized studies were studied.Background: Oral anticoagulant drugs are recommended for primary prevention of thromboembolic events in patients with chronic atrial fibrillation, recent myocardial infarction, and prosthetic heart valves. Still many physicians hesitate to prescribe anticoagulant drugs, presumably for fear of bleeding complications.Results: In six recent trials of warfarin in patients with atrial fibrillation, the highest annual incidence of fatal and major bleeding was 0.8% and 2.0%, respectively. In patients treated with warfarin after a recent myocardial infarction, the incidence of fatal and major bleeding was 0.2% and 0.5% per year, respectively. The annual incidence of fatal and major bleeding in patients with prosthetic heart valves on warfarin treatment was found to be 1.4% and 5.2%, respectively. The mean incidence of fatal and major bleeding in patients on warfarin in these eight trials was 0.5% and 1.7% per year, respectively. The mean incidence of fatal and major bleeds in patients on placebo was 0.1% and 0.7% per year, respectively. In three randomized trials evaluating aspirin versus warfarin, the respective mean incidences of fatal and major bleeding during aspirin treatment were 0.2% and 0.8% per year. A remarkable decrease in the incidence of major bleeding complications to oral anticoagulant therapy is revealed by these trials as compared to previous studies. Reasons for this decline may be less intensive anticoagulant regimes, better control of anticoagulant therapy due to the introduction of the international normalized ratio, and careful pretreatment evaluation of risk factors for bleeding. In all prospective trials of oral anticoagulation, the risk of bleeding was more than over-weighed by the beneficial effect on the incidence of stroke and peripheral thromboemboli.     

Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report

The Committee reviewed cardiac involvement in the antiphospholipid antibody syndrome. The Committee's recommendations are: Valve abnormalities: anticoagulation is recommended for symptomatic patients with valvulopathy. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients (recommended by 13/17 experts in an independent review). Committee members disagreed whether corticosteroid therapy is helpful, but agree that distinguishing among presumptive valvulitis (valve thickening on echocardiogram), valve deformity and vegetations is important, as treatment implications may differ. Occlusive arterial disease (angina, myocardial infarction): the Committee recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins). Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulation for those who have suffered thrombosis in the absence of atherosclerosis, but recognizes that developing data may support the use of antiplatelet agents instead. Intracardiac thrombi: the Committee recommends intensive warfarin anticoagulation, and consultation with cardiac surgeons when appropriate. Ventricular dysfunction: the Committee has no recommendations on this aspect of cardiac disease. Pulmonary hypertension: the Committee recommends intensive anticoagulation with warfarin and clinical trials of bosentan, epoprostenol and other new agents.     

Antiplatelet therapy following cardiac valve replacement-a comparative study of aspirin and ticlopidine

The antiplatelet agents, aspirin and ticlopidine, are widely used to prevent thromboembolism following cardiac valve replacement. To compare the clinical effects of each platelet inhibitor, a daily dose of ticlopidine 300 mg was given to 50 patients who underwent aortic valve or mitral valve replacement with an average age of 56.9 years over a mean 52.6 months after surgery. 50 more patients with an average age of 50.2 years were given a daily dose of aspirin 81 mg over a mean 51.3 months after surgery. Warfarin was given to maintain thrombotest values at 10 to 25% (PT-INR at 1.6-3.0). The incidence of thromboembolism was low in both groups; 1.0/100 patient years in the ticlopidine group and 1.9 in the aspirin group. Hemorrhagic complications, hematuria and ecchymosis, showed an incidence of 2.9 in the ticlopidine group and 2.3 in the aspirin group. Slight increases in GOT and GTP were observed in 4 and 18% of cases and elevated total cholesterol and neutral fat in 2 and 18% of cases. No adverse reactions were reported. With the exception of a significant decrease in ADP-induced platelet aggregation in patients who took ticlopidine, there were no significant differences observed between the two groups.     

Determination of plasma prothrombin level by Ca2+-dependent prothrombin activator (CA-1) during warfarin anticoagulation

BACKGROUND AND AIM OF THE STUDY: The carinactivase-1 (CA-1) test is a new method for monitoring plasma prothrombin levels during warfarin anticoagulation therapy. METHODS: A total of 192 patients were allocated to two groups. Group A patients (n = 42) were controls (no warfarin); group B patients (n = 150) received warfarin. A Ca2+-ion and Boc-Val-Pro-Arg-pNA (a chromogenic substrate for thrombin) were added to 10-fold diluted plasma, after which prothrombin was activated with CA-1. Prothrombin levels were determined by measuring the extent of p-nitoroaniline liberation. RESULTS: The mean prothrombin level was 112.8 +/- 20.0 microg/ml in group A (Gaussian distribution), and 53.3 +/- 19.6 microg/ml in group B. In group B, correlations were found between the CA-1 test and prothrombin levels measured by prothrombin time (PT; r = 0.61, p <0. 01), PT-INR (r = 0.61, p <0.01), Thrombotest (TT; r = 0.57, p <0.01) and Hepaplastin test (HPT; r = 0.69, p <0.01). CONCLUSION: The CA-1 test represents a viable method of monitoring the coagulation system. CA-1 recognized the Gla-domain of prothrombin, and activated prothrombin. The CA-1 test required only 10 microl of diluted blood plasma, and took approximately 30 min to complete. The CA-1 test also measures prothrombin levels, correlates excellently with other tests for coagulation, and compares well with currently available methods for determining the efficacy of warfarin.