Long haul flights and deep vein thrombosis: who is at risk?
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Aircraft↗
Biomedical subjects
H R Büller
Publications and source records attributed to H R Büller.
Short- and long-acting synthetic pentasaccharides.
Inhibition of activated coagulation factor X (FXa) is an attractive target for antithrombotic treatment strategies, because of the central position of FXa in the coagulation cascade. Most of the now available anticoagulant drugs have inhibitory effects not only on FXa, but also on thrombin. With the development of pentasaccharides, a new class of antithrombotic agents has emerged that acts by specific inhibition of FXa and lacks activity against FIIa. Fondaparinux, the first synthetic short-acting pentasaccharide, has been evaluated, in a large phase II and III clinical programme concerning prophylaxis and treatment of venous thromboembolism and also in phase II studies in patients with acute coronary syndromes. Idraparinux, the long-acting pentasaccharide, has been studied in a dose-finding study in patients with established deep-vein thrombosis and phase III studies are now planned in patients with venous thromboembolism and in patients with atrial fibrillation.
Acute Disease↗
The use of specific antidotes as a response to bleeding complications during anticoagulant therapy for venous thromboembolism.
When a bleeding complication occurs during therapy with heparin or vitamin K antagonists, there is an option to give a specific antidote. Several new anticoagulants have been developed that are likely to have some risk of bleeding complications, for which no specific antidotes are available. Interestingly, it is unknown how often the use of an antidote is necessary in clinical practice. We investigated 1877 patients treated for venous thromboembolism included in three large clinical trials, of which 181 (9.6%) had a total of 225 adjudicated bleeding episodes; 46 hemorrhages being designated as major. Some form of antidote was given to 26 (14.4%) patients with a hemorrhage. Of the patients with at least one major hemorrhage, 19 (41.3%) received an antidote. Vitamin K was given to 23 (1.2%) patients, one (0.05%) patient received protamin sulfate and seven (0.4%) patients received fresh frozen plasma. The use of antidotes was comparable for initial and long-term treatment. Antidotes were statistically significantly more frequently given in Canada as compared to other participating countries. Vitamin K was more frequently given in case of a higher international normalized ratio value. Although antidotes against anticoagulant treatment are widely available, our analysis shows that in only a very small number of patients a direct, or slow-acting antidote to reverse the anticoagulant effect was used.
Aged↗
Does the location of deep venous thrombosis of the leg determine the risk of the post-thrombotic syndrome?
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Adult↗
Screening of high factor VIII levels is not recommended in patients with recently diagnosed pulmonary embolism.
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Acute-Phase Reaction↗
Individualized duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model.
BACKGROUND: The optimal duration of oral anticoagulant therapy for patients with a first episode of deep vein thrombosis (DVT) is still a matter of debate. However, according to the ACCP consensus strategy a limited stratification in treatment duration is advocated, i.e. 3 months for patients with a transient risk factor and 1 year or longer for patients with recurrent disease or a consistent risk factor such as thrombophilia or cancer. This consensus strategy is founded on the mean optimal duration of therapy obtained in large cohorts of patients and is mainly based on the risk of recurrent venous thromboembolism (VTE), with only minimal consideration for the patient's bleeding risk. OBJECTIVE: The aim of this study is to optimize the anticoagulant treatment strategy with vitamin K antagonists for the individual patient with DVT. METHODS: Based on an extensive literature study, a mathematical model was constructed to balance the risk of recurrent VTE against the risk of major hemorrhagic complications. The following parameters are incorporated in the model: baseline estimates and risk factors for recurrent VTE and bleeding, clinical course of DVT, and efficacy of treatment with vitamin K antagonists. With the use of these parameters, the risk for a recurrent VTE and a bleeding episode can be calculated for the individual patient. The optimal duration of anticoagulant therapy can be defined as the timepoint at which the benefit of treatment (prevention of VTE) is counterbalanced by its risk (bleeding). RESULTS/CONCLUSIONS: How long a patient should receive anticoagulant treatment is a matter of balancing the benefits and risks of treatment. The model shows that the optimal treatment duration varies greatly from patient to patient according to the patient's unique bleeding and recurrence risk.
Adult↗
High rate of skin complications due to low-molecular-weight heparins in pregnant women.
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Anticoagulants↗
[Adverse cardiovascular effects of postmenopausal hormone replacement therapy].
The views on the effects of postmenopausal hormone-replacement therapy (HRT) on cardiovascular disease have moved from one end of the spectrum to the other over the past decades. The presumed beneficial effects of HRT on arterial cardiovascular disease were based on observational findings and have led to the widespread use of these agents. However, recent large-scale randomised, placebo-controlled trials have demonstrated that HRT in women with a history of arterial diseases initially increases the risk of recurrent disease, while offering no benefit in the long term. Healthy postmenopausal women on HRT have an increased risk of arterial cardiovascular events compared with those taking placebo (relative risk 1.29; 95% CI: 1.02-1.63). Finally, the risk of venous thrombosis and pulmonary embolism is increased with the use of HRT. These results demonstrate that bias and confounding can play an important role in observational research and underscore the importance of randomised, placebo-controlled trials when studying the efficacy of drugs.
Cardiovascular Diseases↗
[Diagnostic workup for indicating the presence of pulmonary embolism: still not optimal].
Despite numerous studies, which have documented that only 25-30% of patients presenting with suspected pulmonary embolism actually have emboli, the tendency to overdiagnose and overtreat this disease remains. Findings from the study by Kamphuisen et al. (2002:2083-7) in consecutive patients with suspected pulmonary embolism (non-diagnostic ventilation perfusion scan) in a general training hospital, confirm that with an optimal collaboration between pulmonologists, internists, radiologists and nuclear specialists, who follow a previously agreed diagnostic work-up, the proportion of patients without a proper confirmation or exclusion of pulmonary embolism can be minimized. However, a more promising solution to the problem might be the implementation of a strategy consisting of anamnestic features, measurement of the D-dimer concentration in plasma, and spiral CT.
Angiography↗
Administration of low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma.
A retrospective analysis of the relation between time interval from prophylactic administration of low molecular weight heparin (LMWH) to delivery and the occurrence of wound haematoma was performed in all women, who had a caesarean section in 1998. After administration of LMWH within 2 hours of surgery, the percentage of women with a wound haematoma was significantly larger (12% vs 3%). Multivariate regression analysis, including other risk factors for wound haematoma, indicated administration of LMWH within 2 hours prior to delivery as the only statistically significant factor, which influenced the development of wound haematoma (odds ratio = 5.3, 95% CI = 1.2-22.8).
Anticoagulants↗
Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.
BACKGROUND: It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results- We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G-455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P=0.12 and OR 0.89, 95% CI 0.59 to 1.35, P=0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, P=0.02). Homozygosity for the fibrinogen -455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P=0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P=0.04). CONCLUSIONS: Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.
Humans↗
Decreased circulating levels of von Willebrand factor after intravenous administration of a rapidly degradable hydroxyethyl starch (HES 200/0.5/6) in healthy human subjects.
OBJECTIVE: Impairment of haemostasis has been described with slowly degradable medium molecular weight hydroxyethyl starch (MMW-HES), whereas rapidly degradable MMW-HES is generally considered to have no important effects on blood coagulation. This study was undertaken to investigate the effects of a rapidly degradable MMW-HES plasma substitute on primary haemostasis and blood coagulation in human subjects. DESIGN: Randomised, cross-over study. SETTING: Research unit of a university hospital. PARTICIPANTS: Nine healthy, adult male volunteers. INTERVENTIONS: A 60-min intravenous infusion of 1 l HES 200/0.5/6 (HAES-steril 6%) or 4% albumin (control). MEASUREMENT AND RESULTS: The infusion of HES resulted in decreased circulating levels of von Willebrand factor antigen (from 85+/-8% to 59+/-6% after HES vs from 80+/-7% to 69+/-8% after albumin, p<0.05) and ristocetin cofactor activity (from 93+/-4 to 67+/-4% after HES vs from 79+/-5 to 75+/-5% after albumin, p<0.01). This was associated with an impairment of in vitro platelet function as determined with the PFA-100 platelet function analyser (closure time with collagen/epinephrine from 120+/-7 to 159+/-14 s after HES vs from 121+/-7 to 137+/-10 s after albumin, p<0.05; with collagen/ADP from 88+/-3 to 116+/-9 s and from 103+/-4 to 114+/-7 s after HES and albumin, respectively, p=0.01). CONCLUSIONS: The infusion of 1 l of HES 200/0.5/6 in healthy human subjects results in moderately decreased plasma levels of von Willebrand factor associated with impairment of platelet function.
Adult↗
A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.
BACKGROUND: The factor V Leiden mutation is a common genetic defect associated with an increased risk for venous thromboembolism. The clinical implications for asymptomatic carriers of this mutation and, consequently, the usefulness of screening families in which a proband has both the mutation and venous thromboembolism are unclear. OBJECTIVE: To determine the incidence of venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation. DESIGN: Prospective cohort study. SETTING: University hospitals in the Netherlands. PARTICIPANTS: 470 asymptomatic carriers of the factor V Leiden mutation (234 men, 236 women; mean age, 43 years [range, 15 to 88 years]), 12 of whom were homozygous. Carriers were identified by screening the first-degree relatives (>15 years of age) of 247 symptomatic probands. MEASUREMENTS: Objectively diagnosed episodes of venous thromboembolism and the relationship between incidence and exposure to high-risk situations. RESULTS: Nine venous thromboembolic events were observed in 1564 observation-years, resulting in an annual incidence of 0.58% (95% CI, 0.26% to 1.10%). The incidence of spontaneous venous thromboembolism was 0.26% (CI, 0.07% to 0.65%) per year; 3.5% (CI, 0.1% to 17.8%) per episode of surgery, trauma, or immobilization; 0.0% (CI, 0.0% to 19.5%) per pregnancy; 1.8% (CI, 0.4% to 5.2%) per year of oral contraceptive use; and 2.9% (CI, 0.8% to 15.3%) per year of use of hormone replacement therapy. CONCLUSIONS: The absolute annual incidence of spontaneous venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation is low and does not justify routine screening of the families of symptomatic patients.
Adolescent↗
[No indication for thrombophilia screening in patients with idiopathic venous thromboembolism and their relatives].
In 70% to 80% of patients with venous thromboembolism, a thrombophilic defect can be identified. The most important defects are: antibodies to phospholipids or lupus anticoagulants, mutation of factor V Leiden, prothrombin mutation, mild hyperhomocysteinaemia, and increased factor VIII levels. Deficiencies of antithrombin, protein C or protein S are rare. Whether or not screening for thrombophilia in patients with idiopathic venous thromboembolism is justified, depends on the potential benefits for the patients, or their relatives. At present, patients with a thrombophilic defect do not appear to have a much higher risk for recurrent venous thromboembolism, than patients with thrombosis but without a defect. The absolute risks of venous thromboembolism in asymptomatic relatives with a thrombophilic defect are too low to justify initiating a general policy of family screening. In conclusion, a conservative approach towards thrombophilia screening in idiopathic venous thromboembolism is warranted.
Diagnosis, Differential↗
Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects.
BACKGROUND: In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study. METHODS AND RESULTS: Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. CONCLUSIONS: During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.
Adult↗
[Effects of second and third generation oral contraceptives on hemostasis].
Use of oral contraceptives induce changes in haemostatic parameters: changes occur in the procoagulant, anticoagulant, and fibrinolytic systems. The increased risk of venous thromboembolism with use of third, as compared with second generation oral contraceptives, found in epidemiological studies, has stimulated new research in haemostatic changes induced by both generations of oral contraceptives. A randomized crossover study showed that use of the third generation pill caused a greater increase of factor VII and prothrombin and a more pronounced decrease of factor V than the second generation pill. Acquired resistance to activated protein C (APC) was induced more strongly by preparations of the third than by those of the second generation. The concentration of protein S decreased markedly exclusively during use of the third generation pill, while it did not change during use of the second generation pill. The oral contraception-related effects on the anticoagulant system strongly resemble those of some forms of hereditary thrombophilia. If a woman with hereditary APC resistance (caused by factor V Leiden) uses oral contraceptives as well, and especially when she uses those of the third generation, she is subject to a considerable increase of the risk of venous thrombosis and becomes even more resistant to the anticoagulant action of protein C. In view of the epidemiological backgrounds of the difference in risk of thrombosis between second and third generation contraceptives, the second generation pill is recommended as the first choice for oral contraception.
Activated Protein C Resistance↗
The diagnosis of deep venous thrombosis using laser Doppler skin perfusion measurements.
Compression ultrasonography (CUS) falls short in the diagnosis of deep venous thrombosis in asymptomatic patients and thrombi limited to the calf veins. Alternatively, laser Doppler fluxmetry (LDF) may be useful for this purpose, as it can measure the peripheral vasoconstriction response upon an increase in venous pressure, which is hypothetically preactivated upon venous damming by a thrombus. We investigated the merits of LDF in the diagnosis of DVT. In 81 outpatients, referred with clinically suspected unilateral DVT, skin perfusion in the symptomatic and contralateral legs was measured in the big toe by measuring resting flux (RF) before and during an increase in venous pressure by inflating an ankle cuff to 50 mm Hg. The percentage of LDF reduction (LDFr) was used as a parameter to detect DVT and compared with an independent gold standard (a combination of CUS, D-dimer testing, and 3-month clinical follow-up). The prevalence of DVT was 31%. LDFr in symptomatic legs with DVT [24%; interquartile range (IQR) 8-44%] was significantly (P < 0.001) lower than in symptomatic legs without DVT (60%; IQR 44-70%). Assessment of the diagnostic accuracy of LDF yielded an area under the ROC curve of 0.79. The optimum cutoff value resulted in a sensitivity and a specificity of 80 and 72%, respectively. LDFr is reduced in legs with DVT, supporting the hypothesis of preactivation of the peripheral vasoconstriction response. The diagnostic value of LDF measurements is not likely to surpass that of CUS in symptomatic patients, but may be of additional use in situations where CUS is less sensitive.
Aged↗
The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden.
The risk of venous thromboembolism (VTE) is increased in pregnancy and during the post-partum period. The absolute risk for pregnancy-related VTE in heterozygous women with the factor V Leiden mutation is approximately 2%, but studies on this risk for homozygous women show conflicting results. In a retrospective family study, we found that the risk of pregnancy-related VTE in women with a symptomatic first-degree relative was 17% per pregnancy (95%CI 4.7-37.4). Anticoagulant prophylaxis during the post-partum period appears to be indicated in asymptomatic homozygous women from symptomatic kindred, whereas this could be decided on an individual basis during pregnancy.
Factor V↗