Jan Beyer

Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis.

Noninvasive diagnosis of deep vein thrombosis (DVT) is based on ultrasound examination of the leg veins, usually restricted to only compression of the proximal veins (CUS). Patients with negative CUS findings require a second examination or a combination with other tests, which impairs clinical efficiency. In this prospective outcome study, 1646 consecutive patients with clinically suspected DVT were examined once by a standardized protocol of complete compression ultrasound comprising all proximal and distal veins (CCUS) as the only diagnostic test. The examination was equivocal in 15 patients (1% technical failure rate). Another 366 patients (22%) were tested positive for proximal DVT, distal DVT, muscle vein thrombosis, or phlebitis. Of 1265 patients in whom CCUS findings were negative, 242 met exclusion criteria for follow-up (age <18, life expectancy <3 months, other reasons for anticoagulation, postthrombotic lesions of the leg veins, or lack of informed consent). During the 3 months of follow-up, three of 1023 patients with negative CCUS findings experienced a symptomatic venous thromboembolic event (0.3% [95% CI 0.1%-0.8%]). We conclude that the CCUS protocol has a low technical failure rate and is safe with respect to excluding DVT, thereby reducing the diagnostic workup of patients with suspected DVT to a single ultrasound examination.

Ultrasound screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS study

Summary.  Background: Venography is currently used to assess the incidence of deep vein thrombosis (DVT) in dose‐finding and confirmatory trials of new antithrombotic agents. Centrally adjudicated, complete compression ultrasound (CCUS) could be a non‐invasive alternative to venography. Objectives: A substudy of two, similarly designed, phase IIb trials of a novel, oral anticoagulant for the prevention of venous thromboembolism after elective hip or knee arthroplasty was undertaken to validate CCUS against venography. Patients/Methods: Patients received study drugs until mandatory, bilateral venography was performed 7 ± 2 days after surgery. CCUS was performed within 24 h after venography by sonographers blinded to the venography result. Sonographers were trained and certified for the standardized examination and documentation procedure. Venograms and sonograms were adjudicated centrally at different sites by two independent readers; discrepancies between readers were resolved by consensus. Results: A total of 1104 matching pairs of evaluable venograms and sonograms were obtained from the participants of the two trials (n = 1435): 19% of venograms and 20% of sonograms were not evaluable. The observed frequency of any DVT was 18.9% with venography and 11.5% with CCUS. Sensitivity of CCUS compared with venography was 31.1% for any DVT (95% confidence interval 23.4, 38.9), 21.0% (2.7, 39.4) for proximal DVT, and 30.8% (23.1, 38.6) for distal DVT. The figures for specificity were 93.0% (91.0, 95.1), 98.7% (98.0, 99.5), and 93.3% (91.5, 95.3), respectively. Conclusions: Based on these results, centrally adjudicated CCUS will be unable to replace venography for DVT screening early after major orthopaedic surgery in studies evaluating anticoagulant drugs.

Bridging anticoagulation for patients on long-term vitamin-K-antagonists. A prospective 1 year registry of 311 episodes.

there are no reports on the use of real-time fluorescence monitoring in LD-PCR. A combination of two real-time PCRs allowed detection and discrimination of inversion-positive individuals, inversion-negative individuals and carrier women (see Fig. 1 for details). For validation purposes a total of 30 samples of known genotype were analyzed with this new longdistance real-time PCR (LD real-time PCR) and full concordance was observed. In addition, LD real-time PCR aliquots subjected to agarose gel electrophoresis again gave results that were in total agreement with the expected genotypes. In summary, we report new LD-PCR parameters for FVIII intron 22 inversion detection, which circumvent the complications that have appeared as the manufacturer introduced modifications in the kit originally used by Liu et al. [2] Moreover, and importantly, we describe an innovative singlestepmethod for convenient intron 22 inversion detectionwithin one working day. LD real-time PCR in combination with SYBR Green I chemistry is a simple, fast automated technique that obviates the lengthy electrophoretic processes with extremely fragile low-percentage agarose gels used in LD-PCR. To our knowledge, this is the fastest method described for amplification and specific detection of very large PCR products and could be adapted to other LD-PCR diagnostic applications [7–9].

Incidence, risk profile and morphological pattern of venous thromboembolism after prostate cancer surgery

Summary.  Background: Venous thromboembolism (VTE) is the most common non‐surgical complication after major pelvic surgery. Little is known about the risk factors or the time of development of postoperative venous thrombosis. Methods: A cohort of 523 consecutive patients undergoing radical prostatectomy with lymphadenectomy was prospectively assessed by complete compression ultrasound at days −1, +8 and +21. Results: Complete data were available in 415 patients, while four patients had VTE before surgery and were excluded from the analysis. In the remaining 411 patients, 71 VTE events were found in 69 patients (16.8%). Most were limited to calf muscle veins (56.5%), followed by deep calf vein thrombosis (23.2%), proximal deep vein thrombosis (DVT, 14.5%) and pulmonary embolism (PE, 5.8%). Of the 14 patients with proximal DVT/PE, 11 patients (78.6%) developed VTE between days 8 and 21. Risk factors for VTE were a personal history of VTE (OR 3.0), pelvic lymphoceles (LCs) impairing venous flow (OR 2.8) and necessity of more than two units of red blood cells (OR 2.6). Conclusion: Venous thromboembolism is common after radical prostatectomy. A significant proportion develops after day 8, suggesting that prolonged heparin prophylaxis should be considered. Since LCs with venous flow reduction result in higher rates of VTE, hemodynamically relevant lymphoceles should be surgically treated.

Eligibility for home treatment of deep vein thrombosis : prospective study

Low molecular weight heparin is safe and effective for the treatment of deep vein thrombosis.1 We have recently shown in a randomised study that immobilisation is not necessary.2 The results challenge the traditional notion that these patients must be treated in hospital. For selected patients, outpatient treatment has been shown to be safe and effective. 3 4 We determined the proportion of patients who still require admission to hospital and why. Between 1 November 1998 and 15 August 1999 all patients presenting to the vascular diagnostics unit of the University Hospital Dresden, Germany, as outpatients with acute deep vein thrombosis in the leg were prospectively evaluated regarding eligibilty for home treatment. We defined acute deep vein thrombosis as non-compressible deep veins on ultrasonography (UM9 …

Influence of Cyclosporin A on human gingival keratinocytes in vitro

PURPOSE Gingival hyperplasia is a well known side effect of Cyclosporine A therapy. The aetiology of this is not totally understood and there is debate whether it is hyperplasia of the gingival epithelium or of the submucosal connective tissue, or both, and what roles play factors like age and gender of the patients, duration and dosage of the drug. MATERIAL AND METHODS The influence of different Cyclosporine A concentrations (10(-6) g/ml; 5 x 10(-7) g/ml; 10(-9) g/ml) and of no medication (controls) on growth and proliferation of cultured human gingival keratinocytes was investigated after a culture period of 3, 6 and 9 days. Cell proliferation was assessed by counting anti Ki-67 stained nuclei, cell growth by counting total number of nuclei and by the EZ4U-assay. RESULTS There was no significant correlation of the cell proliferation rate and cellular growth with either gender (p > 0.568) or duration of medication (p > 0.876); but Cyclosporine A concentration showed a highly significant influence on cellular growth (p = 0.0001). Inhibition of cell growth was dependent on drug dosage, but a low concentration of 10(-9) g/ml even stimulated cell growth. CONCLUSIONS There is evidence that Cyclosporine A in low concentrations (10(-9) g/ml as applied in long-term therapy) stimulates gingival keratinocyte growth and therefore might be related to hyperplasia of the gingiva. However, high Cyclosporine A concentrations may inhibit cell growths and factors like gender of the patient did not show any influence in-vitro.

International registry on splanchnic vein thrombosis: Description of the study population

Primary immune thrombocytopenia (ITP) is characterized by isolated thrombocytopenia. The mechanisms leading to a low platelet count include antibody-mediated destruction of platelets and suppression of megakaryocyte and platelet development. The causes of loss of tolerance and autoantibody production are unknown and it is likely that both genetic and environmental factors are involved. Platelet-specific autoantibodies are directed against a restricted number of ‘dominant’ epitopes of GPIIbIIIa, less frequently of GPIbIX or other platelet glycoproteins. There is evidence to suggest that these autoantibodies are produced from a limited number of clonal B cells by antigen-driven selection. Abnormalities of T cells certainly play a role in causing or perpetuating ITP. Chronic ITP is characterized by a Th1 profile and an impaired T-regulatory cell function, both of which are reversed upon successful treatment. Furthermore, cytotoxic T cells have been shown to cause platelet destruction in vitro and can probably suppress megakaryopoiesis. Chronic infections such as HIV, HCV and Helicobacter pylorican present with isolated thrombocytopenia and therefore mimic ITP. Antibodies cross-reacting with platelet antigens have been identified in thrombocytopenia associated with these infections, supporting a role for molecular mimicry in the development of this disorder. Disclosure of Interest: Honararia for participation on advisory boards and as a speaker at medical education events supported by GlaxoSmithKline, Amgen and RocheThe antiphospholipid syndrome (APS) is an autoimmune disease associated with the presence of antiphospholipid antibodies (APL) and the occurrence of thrombosis and pregnancy complications. One of the assays to detect APL is based on the prolongation of phospho-lipid dependent coagulation assays caused by these antibodies; lupus anticoagulant (LAC). To prevent thrombotic complications, APS patients use long-term anticoagulant treatment that could interfere with LAC determination. Rivaroxaban is a new direct factor Xa inhibitor. In this study we assessed whether rivaroxaban interferes with the detection of LAC. We tested normal pooled plasma (NPP), LAC-positive plasma of SLE patients and LAC-negative plasma from SLE patients. These plasmas were spiked with rivaroxaban. LAC ratios were determined by measuring the LAC-dependent and -independent coagulation times (dRVVT screen/dRVVT confirm, aPTT low and high phospho-lipids, taipan venom and ecarin times). Taipan venom and ecarin are snake venoms that directly activate prothrombin. The taipan venom time is LAC sensitive, whereas the ecarin time is not. Rivaroxaban added to plasma of healthy individuals prolonged the dRVVT LAC ratio, leading to a false positive lupus anticoagulant signal. Rivaroxaban had no influence on the aPTT LAC ratio of normal plasma, but slightly increased the ratio in plasma of SLE patients. For some plasmas negative for LAC, the presence of rivar-oxaban lead to a false positive LAC signal in the aPTT. We observed that the ratio of the taipan venom time over ecarin time remained uninfluenced by the presence of rivaroxaban, both in the absence or presence of antiphospholipid antibodies. This study shows that rivaroxaban can interfere with conventional LAC assays. The taipan venom time/ecarin time ratio may be a good alternative for the detection of LAC in patients using rivaroxaban.Introduction: Cancer greatly increases the risk of venous thromboem-bolism (VTE). Here, we investigated the contribution of microparti-cle-dependent procoagulant activity to the prothrombotic state in these patients. Methods: In 43 cancer patients without VTE at entry and 22 healthy volunteers, markers of in vivo and microparticle-dependent coagulation were measured and patients were prospectively followed for 6 months for the development of VTE. Procoagulant activity of microparticles (MPs) was measured using a phospholipid dependent test (STA Procoag PLL), a factor Xa-generation assay (Xa-assay) with and without anti-tissue factor (TF), and a fibrin generation test (FGT) with and without anti-factor VII(a). Results: Markers of in vivo coagulation activation and total number of circulating MPs were elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/L, D-dimer 0.76 vs. 0.22 mg/L and 5.53 x 106 vs. 3.37 x 106 microparticles per mL; all P <0.001). Five cancer patients (12%) developed VTE during follow-up. Patients with VTE had comparable levels of coagulation activation markers and phos-pholipid dependent MP procoagulant activity. However, TF-mediated Xa-generation (0.82 vs. 0.21 pg/mL, P = 0.016) and the VIIa-dependent FGT (13% vs. 0%, P = 0.036) were higher in the VTE group compared with the non-VTE group.

Antikoagulationstherapie bei venöser Thromboembolie

ZusammenfassungVenöse Thromboembolien (VTE) stellen mit einer Inzidenz von etwa 1 : 1 000 eine häufige Morbiditäts- und Mortalitätsursache dar. Dabei weisen die betroffenen Patienten individuelle Risikoprofile sowohl hinsichtlich des Rezidivs als auch der antikoagulationsassoziierten Blutung auf, welche durch endogene Faktoren (beispielsweise genetisch determinierte Thrombophilie), viel häufiger aber durch exogene Faktoren (zugrundeliegende Erkankung) charakterisiert werden. Diese Heterogenität resultiert in Besonderheiten der VTE-Therapie, auf die in dieser Darstellung eingegangen werden soll.AbstractVenous thromboembolism (VTE) is a common cause of morbidity and mortality with an estimated annual incidence of 1 : 1,000. Patients show individual risk profiles with regard to recurrent VTE and treatment-associated bleeding, which are characterized by the presence of endogenous factors (such as hereditary thrombophilic disorders), but much more by exogenous factors (underlying disease). This results in risk-adapted therapeutic recommendations, which will be discussed in the following review.Venous thromboembolism (VTE) is a common cause of morbidity and mortality with an estimated annual incidence of 1 : 1,000. Patients show individual risk profiles with regard to recurrent VTE and treatment-associated bleeding, which are characterized by the presence of endogenous factors (such as hereditary thrombophilic disorders), but much more by exogenous factors (underlying disease). This results in risk-adapted therapeutic recommendations, which will be discussed in the following review.

International registry on the treatment of unsuspected pulmonary embolism in cancer patients

Background: In cancer patients, clinically unsuspected pulmonary embolism (PE) represents a relatively common finding on computed tomography scans performed as part of the oncological follow-up. Patients with unsuspected PE may be at risk to develop symptomatic venous thromboembolism (VTE) and appear to have an increased mortality rate compared to patients without VTE. Current guidelines suggest the same initial and longterm anticoagulation for unsuspected VTE as for patients with symptomatic thrombosis. Based on these indications, cancer patients with unsuspected PE would be anticoagulated for at least 6 months or until the disease is active, which in most cases would mean indefinite treatment. In fact, dedicated studies on the treatment of unsuspected PE are missing, leaving doubts over the need for (indefinite) anticoagulation which exposes these patients to an increased risk of major bleeding events. Objectives: to evaluate the current treatment approaches for unsuspected PE and to assess their efficacy and safety in a large prospective cohort of cancer patients. Design and study population: Multicenter, international, prospective registry. All ambulatory or hospitalized cancer patients with a first diagnosis of unsuspected PE will be eligible for the study. Both solid and hematological cancers at any stage of disease will be considered for inclusion. Patients will be excluded in case of: 1) age

The Search for Deep Vein Thrombosis

Deep vein thrombosis (DVT) and pulmonary embolism (PE) represent two clinical manifestations of the same disease. Therefore, the search for DVT is an integral part of the diagnostic workup of PE. However, out of the wide range of possible tests for diagnosing DVT, only few show acceptable sensitivity and specificity, which also may vary depending on the diagnostic setting in which these tests are performed. This chapter describes the diagnostic procedures for DVT testing, namely clinical examination, pretest probability scores, D-dimers, compression ultrasound, and venography, including computed tomographic and magnetic resonance venography. Advantages and limitations, and the interpretation of test results, are discussed. Because compression ultrasound (CUS) has become the method of choice in suspected DVT, different protocols (2-CUS, E-CUS, and C-CUS) and the validity of their results are described in more detail. Notably, even though the available data suggest that venous ultrasound applied as a single test has low diagnostic sensitivity in suspected PE, it should be an integral part of the diagnostic workup of PE. For example, because lung scans often show indeterminate results, the confirmation of DVT by ultrasound may establish the diagnosis of PE in these patients without further tests. The second domain of venous ultrasound is to reduce the number of direct PE-imaging procedures in patients with high pretest probability and/or positive D-dimer, in whom CUS should be applied first, whenever possible. Venous ultrasound can also be particularly useful if PE is suspected in hemodynamically unstable patients, in whom a fast and reliable diagnosis at the bedside is necessary. The confirmation of DVT by ultrasound establishes the diagnosis of PE in these patients and treatment can be initiated without delay.