Increased hemostatic molecular markers in patients undergoing anticoagulant therapy

We evaluated several molecular markers of hemostasis in 92 patients with hypercoagulable states treated with anticoagulant therapy. In all patients, the average values of the international normalized ratio (INR) were 1.70 +/- 0.50; this increase in INR was not, however, significant in patients under thrombotest (TT) monitoring. There were no thrombotic or severe bleeding complications in these patients during a period of 27 months. 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 the TT. The INR was negatively correlated with TT, protein C, and protein S and particularly with TT between 10 and 80%. The range of TT was not correlated with the plasma level of TAT, PPIC, D-dimer, or sFM, but the range of 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 lower in patients with high INR. These findings show that INR is better than TT for the monitoring of warfarin therapy and that the therapeutic values of INR during the anticoagulant therapy should be > 1.7 in Japanese patients.     

Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy

Purpose  

Left atrial (LA) thrombus was sometimes found by transesophageal echocardiography (TEE) in non-valvular atrial fibrillation (AF), even in the setting of continuous warfarin therapy. A D-dimer cutoff level of 0.50 μg/mL appears to be a useful marker to rule out venous vein thrombosis. This study analyzed the clinical features of patients with LA thrombi who received anticoagulant therapy and whether the D-dimer test is useful to exclude LA thrombus.     

Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents

For more than 60 years, heparin and coumarin have been mainstays of anticoagulation therapy. They are widely available, inexpensive, effective, and have specific antidotes but are regarded as problematic because of their need for careful monitoring. In addition, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and is paradoxically prothrombotic in certain settings (ie, can precipitate "coumarin necrosis"). Heparin may require monitoring of its therapeutic effect and can also cause thrombosis (heparin-induced thrombocytopenia/thrombosis syndrome). These limitations have led to the development of new anticoagulants with the potential to replace current agents. These newer agents fall into 2 classes, based on whether they are antithrombin dependent (low-molecular-weight heparin, fondaparinux) or antithrombin independent (direct inhibitors of factor Xa and thrombin [factor IIa]). This paper addresses newer anticoagulants, reviewing their efficacy and limitations, and focuses on the risk of major bleeding that may complicate their use. In contrast to heparin and coumarin, none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. Available data on the efficacy and safety of current and experimental agents for anticoagulant reversal are reviewed, and a plan for management of anticoagulant-induced bleeding is presented.     

Decreased peripheral bone mineral content in patients under anticoagulant therapy with phenprocoumon

In experimental and clinical studies, conflicting results regarding the effect of oral anticoagulant therapy on bone metabolism have been reported. To measure a possible influence of long-term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin levels were performed with single photon absorptiometry in a total of 78 patients on anticoagulant treatment. We studied 43 women (mean age 66 years +/- 2 SEM) and 35 men (mean age 65 years +/- 2 SEM) with a median duration of phenprocoumon therapy of 1 year (1-9 years). In all patients, the medical history gave no symptoms of metabolic bone disease, or diseases or medications causing osteoporosis. Both in the male and female groups, mean peripheral BMC was significantly decreased (male: P less than 0.01, female: P less than 0.003) when compared with corresponding controls. Serum OC-levels measured in 16 patients were also significantly lower than those of the controls (P less than 0.02). Our data of decreased BMC and low serum OC-levels indicate reduced bone mass in patients on long-term anticoagulant therapy with phenprocoumon. This may imply an influence of anticoagulants on bone metabolism resulting in decreased bone formation.     

Progress in the monitoring of direct oral anticoagulant therapy

The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real-world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision-making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.     

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.     

Long-term anticoagulant therapy in patients with coronary artery disease.

Secondary prevention of coronary events in coronary artery disease (CAD) patients with aspirin is generally accepted because of ease of administration, predictable safety, and proven efficacy. The use of long-term anticoagulant therapy with heparins, vitamin-K antagonists (VKAs), or thrombin inhibitors is, however, more controversial. During the last 40 years, several trials have been conducted in order to evaluate the role of anticoagulant therapy in patients with CAD as a protection against subsequent death and thrombo-embolic complications. The conducted trials are heterogeneous in many ways, concerning comparative medications, patient populations, endpoints and follow-up, which makes a standardized recommendation on the basis of these studies difficult. This review is an overview of the largest and best studies on this topic and discusses the scientific background for a possible use of VKA or an alternative anticoagulant treatment in CAD patients, looking at both the beneficial effects and the risk of bleeding.     

Increased tissue-plasminogen activator (t-PA) levels in patients under oral anticoagulant therapy

Summary The fibrinolytic system was investigated in 30 patients under oral anticoagulant therapy, and in 23 control patients not receiving oral anticoagulants. Patients under oral anticoagulant therapy had significantly higher tissue-plasminogen activator (t-PA) antigen levels than patients in the control group. Mean t-PA levels before venous occlusion were 18.4 ng/ml in the anticoagulated patients vs. 7.9 ng/ml in the control patients (p<0.001). After venous occlusion for 10 minutes, t-PA levels were 45.0 ng/ml in the anticoagulated patients and 24.2 ng/ml in the control patients (p<0.01). Plasminogen activator inhibitor (PAI) capacity was not significantly different in the two groups before venous occlusion (VO) but differed slightly (p<0.05) after VO. The net decrease in euglobulin lysis time (ELT) after venous occlusion (= ELT before VO – ELT after VO), indicating the relative potency of the fibrinolytic activity in blood, was also significantly higher in the anticoagulated patients (median 240 min vs. 125 min, p<0.001). These data indicate that oral anticoagulant therapy increases the fibrinolytic activity in blood, and thus may have an additional therapeutic effect in addition to anticoagulation.     

Hemostatic molecular markers in nephrotic syndrome

Quantitative changes of hemostatic molecular markers were studied in patients with nephrotic syndrome. The plasma levels of fibrinopeptide A (FPA), thrombin-antithrombin III complex (TAT), products of thrombin activation, and fragment F1 + 2 (F1 + 2), a product of prothrombin activation, were measured by enzyme immunoassay in 21 patients with nephrotic syndrome and in 16 normal controls. The mean value of FPA was 17.5 ± 7.5 ng/ml (mean ± SD) in nephrotic patients and 4.5 ± 0.3 ng/ml in normal controls (P < 0.02); F1 + 2 concentration was 1.4 ± 0.3 ng/ml in nephrotic patients and 0.5 ± 0.1 ng/ml in normal controls (P < 0.001); TAT level was 1.0 ± 0.3 μg/l in nephrotic patients and 0.2 ± 0.1 μg/l in normal controls (P < 0.05). These data indicated intravascular hemostasis activation. Based on these results, we propose that low antithrombin III level in nephrotic patients may be due to both urinary loss and intravascular consumption. © 1993 Wiley-Liss, Inc.     

Long-term oral anticoagulant therapy in elderly patients

Forty-nine patients aged 65-89 years, treated for 6 months-6 years (mean 3.9 years) over a total of 195 patient years, were studied. The efficacy of anticoagulant control or the occurrence of complications or treatment failures did not vary with the age, sex, social status, mobility, visual acuity, domiciliary supervision of medication or the indication for anticoagulation. A significant correlation was observed between the concomitant drug therapy and anticoagulant control (P less than 0.001) but not with the occurrence of complications and treatment failures. Poor anticoagulant control was observed particularly in those receiving drugs known to potentiate warfarin effect and in whom more changes were made to their concomitant drug therapy. Five patients who experienced six non-fatal haemorrhages (two major and four minor) showed poor overall anticoagulant control from the outset (P less than 0.01). The treatment failure rate was 4%.     

重型肝炎人工肝血浆置换肝素应用的实时监测

重型肝炎有凝血机制的障碍，肝素的使用将进一步加重凝血功能的紊乱。目前国内人工肝治疗肝素用量大小不一，很多单位往往依据经验或血液透析的用量。肝素用量不足将导致管路凝血，影响治疗顺利进行，肝素用量过大将加重出血倾向，甚至带来严重后果。本研究通过实时监测人工肝血浆置换时患者凝血功能的变化状况并随时调整肝素的用量，保证了治疗的安全顺利进行，并为重型肝炎患者人工肝体外循环肝素的规范应用提供了依据。     

Need of more frequent International Normalized Ratio monitoring in elderly patients on long-term anticoagulant therapy after influenza vaccination.

Previous findings suggest the safety of influenza vaccination for patients on oral anticoagulant therapy (OAT). However, some studies reported a moderate reduction or increase of the anticoagulation. We assessed the effect of influenza vaccination on anticoagulation levels. Seventy-three patients on stable long-term OAT were recruited. Patients were compared with a control group of 72 patients observed during the same period. No differences in the anticoagulation levels were found in patients and in controls during the 3 months before and after the vaccination. However, in patients older than 70 years we observed a reduction of anticoagulation intensity achieved in the month after the vaccination, with a prolonged time spent below the therapeutic range (10% before and 27% after, P = 0.001), and this behaviour was still observed 3 months after vaccination. Influenza vaccination is safe in patients on OAT, but it is associated with a slight reduction in warfarin effect in the elderly, suggesting the need of more frequent International Normalized Ratio monitoring after vaccination in these subjects.     

Observance of antiplatelet therapy after stent implantation in patients under chronic oral anticoagulant treatment

PURPOSE: Patients undergoing coronary stenting must take dual antiplatelet therapy during a variable period. The combination of chronic oral anticoagulants (COA) with antiplatelet therapy has been related to an increased risk of hemorrhage. The aim of this study was to evaluate the level of the antiplatelet therapy observance in those patients and the incidence of adverse events after 1 year. METHODS: Patients with prior COA treatment with coronary lesions suitable for stenting were included. Clinical assessment was performed on admission, with follow-up at 1, 6, and 12 months. Antiplatelet and COA treatment, adverse cardiac events, and hemorrhagic episodes were registered. RESULTS: A total of 70 patients were included. Mean age was 70.5 +/- 8.7 years. The most common cause of COA was atrial fibrillation. Conventional stents were used in 40% and drug-eluting stents (DES) in 60%. Treatment at discharge was: ASA + clopidogrel + COA 64.2%, ASA + clopidogrel 25.4%, COA + clopidogrel 7.5%, and COA + ASA 3%. Observance of antiplatelet and COA therapy at 1-6-12 month follow-up after conventional stent was: COA 73.1-70.8-69.6%; ASA 92.3-75.4-65.2%; clopidogrel 92.3-62.5-43.5%. In patients receiving DES, it was: COA 76.9-78.9-80.6%, ASA 79.5-65.8-55.7%, and clopidogrel 94.9-84.2-61.1%. Dual antiplatelet therapy in patients with DES over these periods was taken in 79.5-51.4-27.8%, respectively. The incidence of adverse events was minor bleeding 11.4%, major bleeding 8.6%, myocardial infarction 4.3%, stent thrombosis 1.4%, and death 12.8%. CONCLUSIONS: There is a great variability in the treatment prescribed at discharge. Low observance with dual antiplatelet therapy has been detected in these patients, particularly after DES implantation, and they present a very high rate of complications in the follow-up.     

Hemostatic and thrombotic markers in patients with hemoglobin E/beta-thalassemia disease

Increased frequency of thrombosis has been observed in patients with hemoglobin E/beta-thalassemia (Hb E/beta-thal) disease, particularly those who have previously been splenectomized. We compared various hemostatic and thrombotic markers in blood from 15 Hb E/beta-thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin-antithrombin, beta2 thromboglobulin, C-reactive protein, tissue plasminogen activator antigen were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 were significantly higher in the S than in the NC group. Levels of plasminogen activator inhibitor-1 antigen were significantly higher in the S than in the NS group. Levels of protein C, protein S, antithrombin, and fibrinogen were significantly lower in the S and NS groups than in the NC group. Plasma lipoprotein(a) levels in the S and NS groups were not statistically different from NC. Our findings indicated that there is evidence of chronic low-grade coagulation and platelet activation, chronic low-grade inflammation, endothelial cell injury, impaired fibrinolysis, and decreased naturally occurring anticoagulants in splenectomized Hb E/beta-thal patients. These changes may account for the increased risk of thrombosis in these patients.