Oral contraceptives and hormonal replacement therapy cause an imbalance in coagulation and fibrinolysis which may explain the increased risk of venous thromboembolism.
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Blood Coagulation↗
Biomedical subjects
H R Büller
Publications and source records attributed to H R Büller.
Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease.
It is unknown whether the variation in severity of cardiovascular disease (CVD), seen in patients with familial hypercholesterolemia (FH), is reflected in the intima-media thickness (IMT) of carotid and femoral arteries. We measured IMT in both these arteries in 248 consecutive patients with FH, attending our Lipid Clinic. One hundred and six patients were classified as having CVD, while the remaining FH subjects had no clinical evidence of CVD. IMT measurements of 20 prespecified carotid and femoral arterial wall segments of the FH groups with and without CVD were compared. All IMTs in both groups were severely thickened with respect to normal controls. Furthermore, the highest IMTs and the largest absolute differences were observed in the common femoral artery (1.23 +/- 0.46 mm vs 1.10 +/- 0.51 mm; P = 0.006). In subjects with CVD, the distributions of IMT within tertiles for both arterial segments were opposite to those found in FH patients without CVD, (P < 0.05, for both segments). The mean IMT of, in particular, the common femoral artery is thicker in FH individuals with CVD compared with those without. Some FH patients have abnormal IMT of the femoral artery, whereas in others the carotid artery is more affected. Therefore, in FH patients, combined assessment of the carotid and femoral arterial walls provides a more accurate estimation of total atherosclerotic burden in FH.
Adult↗
In vivo treatment of rats with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) does not affect experimentally induced colon carcinoma metastasis.
Recent randomized trials have suggested that treatment with low molecular weight heparin (LMWH) improves survival of cancer patients with venous thromboembolism, as compared to treatment with unfractionated heparin (UFH). Experimental studies have shown that UFH has activities besides its anticoagulant function which may affect progression of malignancy, including stimulation of new blood vessel formation. In contrast, LMWH has been suggested to inhibit angiogenesis. In the present study, we compared quantitatively the effects of treatment with UFH, LMWH or placebo on the development of experimentally induced colon carcinoma metastases in rat liver and on tumor-associated angiogenesis. It is shown that UFH and LMWH in therapeutic dosages neither affect development of metastases nor tumor blood vessel formation in this animal model. These results indicate that heparins do not affect colon cancer metastasis in liver. Further studies in other animal models are required to establish the mechanisms by which heparins potentially affect cancer.
Animals↗
Incidence of venous thromboembolism in families with inherited thrombophilia.
The risk of spontaneous or risk-period related venous thromboembolism in family members of symptomatic carriers of antithrombin (AT), protein C (PC) or protein S (PS) defects, as well as of the Factor V Leiden mutation is still undefined. We performed a retrospective cohort study in family members (n = 793) of unselected patients with a documented venous thromboembolism and one of these deficiencies to make an estimate of this risk. The annual incidences of total and spontaneous venous thromboembolic events in carriers of AT, PC or PS defects (n = 181) were 1.01% and 0.40%, respectively, as compared to 0.10% and 0.04% in non-carriers, respectively (relative risks both 10.6). In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5). Additional risk factors (immobilisation, surgery and trauma: oral contraceptive use; and pregnancy/ post-partum) increased the risk of thrombosis in carriers of AT, PC and PS defects as compared to non-carriers (relative risks 8.3, 6.4 and 8.2, respectively). Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of Factor V Leiden to 3.3-fold and 4.2-fold, respectively, whereas other risk factors had only a minor effect. These data lend some support to the practice of screening family members of symptomatic carriers of a AT, PC and PS deficiency. For family members of symptomatic carriers of Factor V Leiden, screening does not seem to be justified except for women in fertile age.
Adolescent↗
Is the prevalence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different?
INTRODUCTION: Previous investigations have suggested a lower prevalence of the factor V Leiden mutation in patients with pulmonary embolism, as compared to patients with deep leg vein thrombosis. METHODS: We studied unselected patients with pulmonary embolism, in whom we also assessed the presence of deep vein thrombosis by ultrasonography. We assessed the prevalence of heterozygosity for the factor V Leiden mutation and compared the outcome of patients with a normal ultrasound (primary pulmonary embolism) to those with an abnormal ultrasound (combined form of venous thromboembolism). Furthermore, we performed a literature search to identify all articles regarding the prevalence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and a combined form of venous thromboembolism. We calculated a (common) odds ratio for these 3 manifestations of venous thromboembolism, including the current findings. RESULTS: In 92 patients with proven pulmonary embolism, 25 (27%) had also an abnormal ultrasound. In these patients, the prevalence of the factor V Leiden mutation was 24% (95% CI 9%-45%), whereas the mutation was present in 5 of 67 patients with primary pulmonary embolism (7%; 95% CI 2%-16%). The literature analysis indicated the common odds ratio for the presence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and the combined form of venous thromboembolism to be 7.9 (95% CI 5-12), 3.5 (95% CI 2-6) and 6.8 (95% CI 3-14), respectively. CONCLUSION: In patients with primary pulmonary embolism the prevalence of the factor V Leiden mutation appears to be half of that reported in patients with primary deep vein thrombosis. The mechanism remains unclear.
Adult↗
Redundancy of single diagnostic test evaluation.
Diagnostic research and diagnostic practice frequently do not cohere. Studies commonly evaluate whether a single test discriminates between disease presence and absence, whereas in practice a test is always judged in the context of other information. This study illustrates drawbacks of single-test evaluation and discusses principles of diagnostic research. We used data on 140 patients suspected of pulmonary embolism who had an inconclusive ventilation-perfusion lung scan. We evaluated three tests: partial pressure of oxygen in arterial blood (PaO2), x-ray film of the thorax, and leg ultrasound. On the basis of single-test evaluations, ultrasound was most informative. Given a prior probability of 0.27, it had a much better combination of positive and negative predictive value (0.71 and 0.21, respectively) relative to thorax x-ray (0.33 and 0.11) and PaO2 (0.35 and 0.27). The combination of positive and negative likelihood ratio was also more promising for ultrasound (7.3 and 0.7) than for thorax x-ray (1.3 and 0.3) and PaO2 (1.3 and 0.9). As the tests are always performed after the history and physical, we judged their added value using multivariable logistic modeling with receiver operating characteristic (ROC) analyses. The ROC areas of the model, including history and physical, with additional PaO2, thorax x-ray, or ultrasound, were 0.75, 0.77, 0.81, and 0.81, respectively, which indicated similar added value of thorax x-ray and ultrasound. Application of the models to patient subgroups also yielded added predictive value for thorax x-ray film. Thus, the results of single-test evaluations may be very misleading. As no diagnosis is based on one test, single-test evaluations have limited value in diagnostic research and only have relevance in the context of screening and the initial phase of test development. Diagnostic research should always apply an approach of constructing, extending, and validating diagnostic models in agreement with routine clinical work-up using logistic regression analyses.
Analysis of Variance↗
Prevention of deep vein thrombosis after hip replacement--comparison between two low-molecular heparins, tinzaparin and enoxaparin.
Consecutive patients undergoing total hip replacement in 43 centres were randomly assigned to receive blindly either enoxaparin (40 mg) or tinzaparin (4,500 anti-Factor IU Xa), as once daily subcutaneous injections. The first injection was administered 12 h preoperatively. Efficacy was assessed by bilateral venography performed 12-14 days postoperatively. Efficacy and safety were blindly and centrally adjudicated. Among the 499 patients included, 440 had a venogram. The total incidence of DVTs was 44 (20.1%) of the 219 patients of the enoxaparin group and 48 (21.7%) of the 221 patients of the tinzaparin group. The upper limit of the 80% confidence interval of the difference between the two treatment groups was less than 5.0%. Therefore according to the protocol's specifications equivalence was shown. Proximal DVTs occurred in 10.5% of the enoxaparin group (23 patients) and in 9.5% (21 patients) of the tinzaparin group. No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died. The LMWH tinzaparin appears clinically to be as effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis after total hip replacement, at the doses used and under the conditions of this study.
Adult↗
Safety of low-molecular-weight heparin in pregnancy: a systematic review.
Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.
Anticoagulants↗
Antithrombotic drugs in the primary medical management of intermittent claudication: a meta-analysis.
BACKGROUND: There is no consensus on the efficacy of the antithrombotic drugs available for patients with intermittent claudication. METHODS: A Medline and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). Mortality, cerebro- or cardiovascular events, amputations, arterial occlusions or number of revascularization procedures performed in the lower limbs, pain-free and total walking distance, ankle brachial index and calf blood flow, were the main outcomes considered. When feasible, end of treatment results, either continuous or binary, were combined with appropriate statistical methods. RESULTS: Mortality was significantly decreased by ticlopidine compared to placebo (common odds ratio 0.68, 95% C.I., 0.49 - 0.95); clopidogrel decreased vascular events in comparison to aspirin (odds ratio 0.76, 95% C.I., 0.63 - 0.92) in level 1 studies. Arterial occlusions and the number of revascularization procedures performed were statistically significantly decreased by aspirin and ticlopidine, respectively. A small but statistically significant improvement in pain-free walking distance was determined by picotamide, indobufen, low molecular weight heparins, sulodexide and defibrotide, in small studies. CONCLUSIONS: Clopidogrel and ticlopidine do reduce clinically important events in patients with intermittent claudication and could be added to the primary medical treatment of these patients. The use of aspirin in these patients cannot be based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis, where it has documented efficacy. Other antithrombotic drugs were not properly evaluated in patients with intermittent claudication.
Fibrinolytic Agents↗
Lipoprotein(a) concentrations in women with a history of severe preeclampsia--a case control study.
A high concentration of lipoprotein(a) is associated with atherosclerotic disease. Atheroma may develop in spiral arteries in both preeclamptic and normal pregnancies, but they are much more common in preeclampsia, particularly in the decidual segments. We hypothesized that a high concentration of lipoprotein(a) is associated with the development of preeclampsia. We studied 40 women with a history of severe preeclampsia, 35 women with a history of preeclampsia and the (H)ELLP syndrome and 67 controls with a normal obstetric history. Lipoprotein(a) levels were measured at least 10 weeks post partum in the second half of a normal menstrual cycle. None of the women in the study or the control group were pregnant or used oral contraceptives. Lipoprotein(a) levels over the 90th percentile of the lipoprotein(a) distribution of our control group (420 mg/l) were defined as abnormal. There was a statistically significant higher prevalence of abnormal levels of lipoprotein(a) in women with a history of severe preeclampsia (33%) in comparison with women with a history of preeclampsia and (H)ELLP syndrome (9%) and with the control group (10%). We found that a history of severe preeclampsia and spontaneous abortion was associated with elevated lipoprotein(a) levels as a post-hoc finding. Whether spontaneous abortion and high levels of lipoprotein(a) are related remains to be demonstrated.
Adult↗
Comparison of three methods to assess therapeutic quality control of treatment with vitamin K antagonists.
During treatment with vitamin K antagonists, International Normalized Ratios (INR) are determined periodically to maintain a therapeutic level of anticoagulation. We evaluated two existing methods for therapeutic quality control (linear interpolation and equidivision), with regard to their validity and reproducibility. In addition, we proposed and evaluated a (hybrid) method that takes into account potential effects of dosage modifications when INRs are far out of the target range. Validity was assessed by deleting intermediary INR results and estimating this INR based on the two surrounding INRs with each of the three methods. The estimated INRs were then compared with the observed INR. Reproducibility of time spent in an INR range was evaluated for each of the three methods by deleting at random increasing proportions of INRs and comparing these estimates with the situation without deletions. We found that estimates of time spent in INR categories obtained with equidivision were most reproducible, but least valid. The hybrid method showed slightly higher validity and reproducibility in comparison with linear interpolation. Since these differences were small, linear interpolation is preferable to the hybrid method, since the calculations involved are easier.
Fibrinolytic Agents↗
Long-term treatment of venous thromboembolic disease.
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Decision Support Techniques↗
Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread.
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Anticoagulants↗
The use of a rapid D-dimer blood test in the diagnostic work-up for pulmonary embolism: a management study.
BACKGROUND: D-dimer assays have a potential to rule out pulmonary embolism in case of a normal test result. We studied the clinical utility of incorporating the SimpliRED D-dimer test result and clinical probability in the routine diagnostic work-up of patients with suspected acute pulmonary embolism. METHODS: In a prospective management study 245 consecutive patients, hospitalised as well as outpatients, were included. A SimpliRED D-dimer test and perfusion/(ventilation) scintigraphy were obtained in all patients, whereas clinical probability was determined in the subgroup of patients with a non-diagnostic scan and normal D-dimer result. A diagnostic algorithm determined the necessity for further testing and decisions about treatment. All patients were followed up for 3 months. RESULTS: In 54 patients (22%) with a normal lung scan and 50 patients (21%) with a high probability lung scan, antithrombotic therapy was withheld or started respectively, irrespective of the D-dimer result. A non-diagnostic lung scan was found in 137 (56%) patients, of whom 70 patients had an abnormal D-dimer test, in whom further testing was ordered. Of the remaining 67 patients with a non-diagnostic lung scan and normal D-dimer test 8 patients had a high clinical probability, and the subsequent ultrasonography and pulmonary angiography yielded pulmonary emboli in 1 patient. In the remaining 66 patients, pulmonary embolism was considered to be absent and antithrombotic treatment was stopped/withheld. During follow-up of these patients only one patient experienced a possible venous thromboembolic event (failure rate 1,5%; 95% CI 0-8%). The SimpliRED D-dimer was normal in 6 of 61 patients with proven pulmonary embolism (sensitivity 90%; 95% CI 80-96%). CONCLUSION: Our findings suggest that it is safe to withhold anticoagulant therapy in those patients with a non-diagnostic lung scan, a normal SimpliRED D-dimer test result, and without a high clinical probability. This results in a substantial decreased need for ultrasonography and pulmonary angiography. The SimpliRED should not be used in isolation to exclude pulmonary embolism.
Adult↗
The effects of unfractionated heparin on survival in patients with malignancy--a systematic review.
Clinical and experimental studies have suggested that unfractionated heparin (UFH) effects malignancy progression. We reviewed all published clinical reports concerning the effects of UFH, as compared to no treatment on survival of cancer patients. Studies were classified on methodological strength and subdivided as to whether therapeutic or prophylactic dosages of UFH were used. Mortality rates after 3 years were extracted or calculated. One randomized study that evaluated the use of UFH in therapeutic dosages in patients with small cell lung carcinoma reported on an improved survival (odds ratio (OR) 0.64; 95% confidence interval (CI): 0.25 to 1.62). A detrimental effect was observed in 2 randomized studies which investigated the effects of intraportal UFH treatment in a prophylactic dose after surgery for gastrointestinal cancer (OR 1.66; 95% CI: 1.02 to 2.71). In contrast, level 2 studies in which either therapeutic or prophylactic dosages of UFH on mortality of patients with gastrointestinal cancer were evaluated, showed OR of 0.58 (95% CI; 0.11-3.13) and 0.65 (95% CI 0.51 to 0.84), respectively. We conclude that there is no convincing evidence of either positively or negatively effects of UFH on survival of patients with malignancy.
Humans↗
Low-molecular weight heparins in venous and arterial thrombotic disease.
INTRODUCTION: Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolism, myocardial infarction, unstable coronary syndromes and ischemic stroke. METHODS: A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated. RESULTS: Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively. CONCLUSION: Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.
Fibrinolytic Agents↗
A prospective clinical study on the feasibility and safety of a combined noninvasive/pulmonary angiography strategy in patients with suspected pulmonary embolism: an interim analysis.
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Angiography↗
Requirements for appropriate evaluation of diagnostic tests in suspected pulmonary embolism.
In contrast to the development of new drugs, strict guidelines for the development of new diagnostic methods do not exist. A diagnostic test can be made available without proper evaluation of its clinical utility, which can lead to its premature introduction and inappropriate use. In this review suggestions are made regarding the criteria that should be met during the various phases of development of new diagnostic techniques. It is suggested that a new diagnostic test should only be implemented in routine clinical use after all phases of development have been properly performed with good results. Several diagnostic tests for pulmonary embolism (pulmonary angiography, ventilation-perfusion scintigraphy, D-dimer assays, and spiral computed tomography), and the studies evaluating them, are thereafter reviewed. It is concluded that present pulmonary angiography and ventilation-perfusion scintigraphy are the only properly evaluated diagnostic tests for pulmonary embolism. Although new developments, such as D-dimer assays and the spiral computed tomographic scan are certainly promising, further studies are needed to determine their real value and safety in the diagnostic work-up of patients suspected of pulmonary embolism.
Angiography↗