Chronic Venous Thromboembolism Research Articles

Use of New Oral Anticoagulants in the Treatment of Venous Thromboembolism and Thrombotic Prophylaxis.

Thrombo-embolism of the venous system consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE) is common and associated with high morbidity and mortality. Symptomatic venous thromboembolism (VTE) manifests in about 1/3 of cases as PE and 2/3 as DVT. There is a strongly compound between early mortality after venous VTE and PE, age, malignancies and cardiovascular diseases. Anticoagulation therapy is the main therapeutic approach for the treatment of acute VTE and to prevent recurrent VTE events. For decade's classic anticoagulants like heparin, low-molecular-weight heparins (LMWHs), fondaparinux, and vitamin K antagonists have been the gold standards in therapy and are widely used. Novel oral anticoagulants (NOAC) like the direct thrombin inhibitor (dabigatran etexilate) and the direct factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban) have been introduced to overcome the drawbacks of vitamin K antagonists. The efficacy and safety of these NOAC have been investigated in several randomized trials. Here we want to give an overview about the NOACS in the treatment of acute and chronic VTE and their use for primary prevention of acute VTE.

Prognostic Implications of Imaging-Based Bone Marrow Assessment in Lymphoma: 18F-FDG PET, MR Imaging, or 18F-FDG PET/MR Imaging?

2017 Objectives To evaluate FDG-PET/CT as a potential molecular imaging modality for venous thromboembolism (VTE) in a prospective, observational proof-of-concept pilot study. Methods Patients with proven deep venous thrombosis or pulmonary embolism (DVT+/PE+) or disproven DVT or PE (DVT-/PE-) were eligible. Exclusion criteria (non-inclusion) were: Age Results Eleven patients were included: Two women and nine men with a mean age of 65 years (range 50-78 years); seven DVT+, four DVT-, four PE+, and no PE- (four patients were both DVT+ and PE+). The duration of symptoms prior to inclusion was 2-7 days for the DVT+ patients, and 2 weeks-5 months for the PE+ patients. All seven DVT+ patients showed abnormal FDG uptake in the corresponding leg, while none of the DVT- patients or the PE+ patients showed abnormal FDG uptake in the venous vasculature. Conclusions Our results substantiate the potential role of FDG-PET/CT in VTE, especially for DVT with all DVT+ being positive and all DVT- being negative. The results from lung scan positive patients are likely due to non-specificity of the latter modality in determining the age of the clots. Therefore, the results from FDG-PET/CT images could actually represent the true nature of older and inactive PE. Although further studies are warranted for definite clarification, FDG-PET/CT may give rise to a paradigm shift in both diagnostic and therapeutic strategies for the management of VTE by screening the entire body for VTE and underlying occult malignancies, and by differentiating acute from chronic VTE.

Novel Anticoagulant Use for Venous Thromboembolism: A 2013 Update

Many pharmacologic options are available for prevention and treatment of venous thromboembolism (VTE). The anticoagulant selected may vary according the individual patient situation such as the acute versus chronic setting, renal function and indication for either VTE prevention or treatment. Established methods of pharmacologic prophylaxis agents include heparinoids, injectable anti-Xa inhibition and vitamin K antagonists (VKA). The novel anticoagulants have recently been incorporated into orthopedic surgery prophylaxis pathways and can be used for VTE treatment. Chronic VTE management, however, has largely been managed with the use VKA. The advantages of VKA include low cost, familiarity with use, and established protocols to manage catastrophic bleeding. VKA use, however, poses hurdles including the fact that correct dosing can be empiric, the existence of multiple potential medication and dietary interactions, and the possiblity for complications when anticoagulation levels are not well monitored. In contrast, the novel anticoagulants offer ease of dosing, reliable pharmacokinetics and low risk of interactions with other medications or diet. Potential hazards of the novel anticoagulants include high costs, questionable therapeutic benefit in those with poor adherence, a reliance on renal clearance, lack of reliable reversibility in the event of catastrophic bleeding, as well as incomplete familiarity with use by the general practitioner. Although clinical trials demonstrate promise of greater applicability of use of these novel agents, hospital systems will need to simultaneously create a plan for appropriate management of the use of these agents, an anticoagulation stewardship program. As guidelines are adopted to prevent and manage VTE, an appreciation for this new level of complexity is essential.

Small bowel angiodysplasia and novel disease associations: a cohort study

Objective.Gastrointestinal angiodysplasias recurrently bleed, accounting for 3–5% of obscure gastrointestinal bleeding. The advent of small bowel capsule endoscopy (SBCE) has led to an increased recognition of small bowel angiodysplasias (SBAs) but little is known about their etiology. Previous small cohorts and case reports suggest an equal gender incidence and associations with cardiovascular disease, renal impairment, and coagulopathies. Methods.Patients with SBA were identified from our SBCE database. A control group, in whom gastrointestinal bleeding had been excluded, was also identified. Information on patient demographics, past medical/surgical/social history and medications was prospectively obtained. Results.A total of 82 patients and 95 controls were identified. Data was available from 81% (n = 66) of SBA patients. The mean age of patients and controls was 66.9 years (35–90) and 69.2 years (54–77), and 60% (n = 40) and 58% (n = 55) were females, respectively. There was a higher rate of all comorbidities in the SBA group 92% (61/66) versus controls 76% (72/95) p < 0.002. Significant associations were found with: hypertension (odds ratio [OR] 2.8), ischemic heart disease (OR 4.25), arrhythmias (OR 4.36), valvular heart disease (OR 18), congestive heart failure (OR 4.22), chronic kidney disease (CKD) (OR 8.4), chronic respiratory conditions (OR 2.0), and previous venous thromboembolism (VTE) (OR 6.4). Anticoagulant use was higher in patients with SBA, 50% (n = 33) versus 27% (n = 26) of controls, p < 0.002, specifically warfarin and asasantin retard. Conclusions.SBA occurs in elderly patients with cardiovascular disease and CKD, as previously suggested. This study identifies a previously unrecognised risk in females, patients with chronic respiratory conditions and VTE, and the use of warfarin and asasantin retard. These associations should raise awareness of possible underlying SBA in risk patients with anemia.

Acute on Chronic Venous Thromboembolism on Therapeutic Anticoagulation

A case of proximal venous thromboembolism in a patient who presented to the ED with lower extremity pain is presented. Making this diagnosis is very important as fifty percent of patients with symptomatic proximal DVTs will go on to develop PE without treatment. This report underscores the utility of bedside ultrasonography in the emergency department.

Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism

Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown. In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997-2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31-90 days; or chronic > or =91 days). Decisions to provide "bridging" low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%; P<0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6-14.5; P=0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1-21.7; P=0.001), and death (HR, 32.7; 95% CI, 4.3-251.2; P=0.0008). Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.

D‐dimer for the diagnosis of venous thromboembolism in children

To the Editor: Venous thromboembolism (VTE), including both deep venous thrombosis (DVT) and pulmonary embolism (PE), is an important cause of morbidity and mortality in children. Although there is heightened awareness of this disease and its risk factors in children, there has been minimal evaluation of diagnostic tests (clinical prediction models, imaging modalities, and D-dimer assays) in children compared to adults.(1) ELISA based D-dimer assays have excellent sensitivity for the diagnosis of VTE in adults and this may permit the exclusion of VTE.(2) However, the utility of D-dimer assays for VTE in children has not been evaluated. We performed a retrospective chart review of patients ≤21 years of age at Johns Hopkins Hospital with suspected VTE, imaging studies, and quantitative D-dimer. We used a discharge and billing database to identify patients and extracted information on potential risk factors, clinical findings, laboratory and imaging studies, and treatment. D-dimer was measured with an immunoturbidimetric assay on a Blood Coagulation System (BCS) analyzer (Advanced D-dimer; Dade-Behring) per the manufacturer's specifications. We identified 33 patients (20 male and 13 female) with diagnostic imaging studies and measurement of D-dimer within 72 hours. Twenty-six had acute VTE (15 DVT, 3 PE and 8 both], 6 with unchanged chronic VTE (5 DVT and 1 PE), and 1 without VTE (suspected PE). Most patients had multiple acquired risk factors for VTE with central venous catheters (54%), infections (40%), and immobility (42%) most frequent. D-dimer was significantly elevated in children with VTE (median 5.0, IQR 2.05-16.44) compared to children with negative evaluations for acute VTE (median 1.58, IQR 1.46-3.11, P 40 years old, 0.43-2.24 mg/L) and children (2-12 years old, 0.4-2.27 mg/L). Figure 1 D-dimer (log-scale) by diagnosis and the normal range for children 2 – 12 years of age We found that the D-dimer test was sensitive but only moderately specific for the diagnosis of VTE in children, and that the performance varied with the chosen cut-off. This assay is approved for the diagnosis of VTE in adults; the cut-off is 1.6 mg/L as the normal range is significantly higher than many D-dimer assays.(3) A D-dimer 1.75 mg/L was 92% sensitive (95% CI 75 – 99) and 57% specific (95% CI 18 – 90). Raising the threshold of the D-dimer to >2 mg/dl decreased the sensitivity to 77% (95% CI 56 – 91) while increasing the specificity to 71% (95% CI 29 – 96) for the diagnosis of VTE (Table 1). In a previous study of hospitalized adults from our institution,(4) the sensitivity of this test at a threshold of 2 mg/L was comparable (70% in adults versus 77% in children), however the specificity was considerably lower (42% in adults versus 71% in children). We calculated the area under the ROC [0.86 (95% CI 0.72-1.0)] to assess the performance of the D-dimer test to diagnose VTE. The greater the area under the curve, the better the performance of the diagnostic test with an area of 0.5 corresponding to a test that performs no better than flipping a coin. Table 1 Diagnostic Test Characteristics by Cut-Off (95% CI) While the utility of the D-dimer testing has been studied extensively in adults, its performance for the diagnosis of VTE in pediatric patients has not been evaluated. A report of children with PE from a single institution described elevated levels of D-dimer in 6 of 10, but the normal range was not described.(5) In children with acute thrombotic events, elevated D-dimer was found to be predictive of poor outcome (persistent thrombosis, VTE recurrence, or post-thrombotic syndrome); however, measurement of D-dimer was semi-quantitative and its predictive value for the diagnosis of VTE was not reported.(6) In both adults and children, an elevated D-dimer after treatment of VTE appears to be a risk factor for recurrent thrombus.(6-8) To our knowledge, this is the first report that describes the sensitivity of D-dimer measurements for the diagnosis of VTE in children. The incidence of VTE is significantly lower in children than adults, but perhaps even more challenging to diagnose. Compression ultrasonography of the lower extremities (sensitivity 91% and specificity 99%)(9) and MR venography (sensitivity 92% and specificity 95%)(10) have only been validated against the gold standard (contrast venography) in adults. D-dimer assays, in particular automated assays with rapid turn around times like the immunoturbidimetric assay used in this study, offer several advantages over other diagnostic modalities for VTE. They are relatively inexpensive and readily available in the outpatient and inpatient setting. A normal level in adults may potentially exclude VTE and avoid the need for expensive and time consuming imaging studies. Further prospective trials are necessary to validate our findings in children, as well as to address the utility of the D-dimer in selected subsets of pediatric patients.

Detection of Venous Thromboembolism by Proteomic Serum Biomarkers

BackgroundAvailable blood assays for venous thromboembolism (VTE) suffer from diminished specificity. Compared with single marker tests, such as D-dimer, a multi-marker strategy may improve diagnostic ability. We used direct mass spectrometry (MS) analysis of serum from patients with VTE to determine whether protein expression profiles would predict diagnosis.Methods and ResultsWe developed a direct MS and computational approach to the proteomic analysis of serum. Using this new method, we analyzed serum from inpatients undergoing radiographic evaluation for VTE. In a balanced cohort of 76 patients, a neural network-based prediction model was built using a training subset of the cohort to first identify proteomic patterns of VTE. The proteomic patterns were then validated in a separate group of patients within the cohort. The model yielded a sensitivity of 68% and specificity of 89%, which exceeded the specificity of D-dimer assay tested by latex agglutination, ELISA, and immunoturbimetric methods (sensitivity/specificity of 63.2%/60.5%, 97.4%/21.1%, 97.4%/15.8%, respectively). We validated differences in protein expression between patients with and without VTE using more traditional gel-based analysis of the same serum samples.ConclusionProtein expression analysis of serum using direct MS demonstrates potential diagnostic utility for VTE. This pilot study is the first such direct MS study to be applied to a cardiovascular disease. Differences in protein expression were identified and subsequently validated in a separate group of patients. The findings in this initial cohort can be evaluated in other independent cohorts, including patients with inflammatory conditions and chronic (but not acute) VTE, for the diagnosis of VTE.

Long-Term Therapy of Venous Thromboembolism in Cancer Patients

Venous thromboembolism (VTE) is a common complication in cancer patients that results in significant morbidity and mortality. Long-term treatment options for cancer patients who experience VTE include vitamin K antagonists (VKAs), low molecular weight heparins (LMWHs), and inferior vena caval (IVC) filters. Cancer patients have a two- to fourfold higher risk for experiencing recurrent VTE and major bleeding during chronic VKA therapy than patients without malignancies. Recent randomized clinical trials have shown that LMWHs rather than oral VKAs are preferred for initial chronic treatment of VTE in patients with advanced cancer. One factor potentially limiting the broader use of LMWH for chronic therapy in the United States is its higher acquisition cost. Efficacy, cost, drug availability, patient comorbidities, and concomitant medications all need to be considered when selecting chronic VTE therapy. Cancer patients with VTE should be treated for as long as their disease is active to minimize the incidence of recurrence. Use of IVC filters should generally be reserved for patients at high risk for recurrent VTE who have contraindications to anticoagulation. Several new anticoagulants are being investigated that promise greater therapeutic choices and potentially better outcomes for cancer patients with VTE.

Negative spiral CT in acute pulmonary embolism

Purpose: To retrospectively evaluate the clinical outcome of non-anticoagulated patients with clinically suspected acute pulmonary embolism (PE) and no symptoms or signs of deep venous thrombosis (DVT) following a negative contrast medium-enhanced spiral CT of the pulmonary arteries (s-CTPA). Material and Methods: During a 24-month period, 739 of 751 patients underwent s-CTPA with acceptable diagnostic quality for clinically suspected acute PE. All patients who had a CT study not positive for PE were followed up with a questionnaire, a telephone interview and review of all medical reports, including autopsies and death certificates for any episodes of venous thromboembolism (VTE) during a 3-month period. Results: PE was diagnosed in 158 patients. Of the remaining 581 patients with a negative s-CTPA, 45 patients were lost to follow-up. 88 patients were excluded because of anticoagulation treatment (cardiac disorder n=32, chronic VTE or acute symptomatic DVT n=31, PE diagnosed at pulmonary angiography n=1, thrombus prophylaxis during diagnostic work-up or other reasons than VTE n=24) and 7 patients undergoing lower extremity venous studies because of symptoms of DVT (all negative). Thus, 441 patients with a negative s-CTPA and no DVT symptoms, venous studies or anticoagulant treatment constituted the follow-up cohort. Four of these patients had proven VTE (all PE) during the 3-month follow-up period. Two of the PE episodes contributed to the patient's death. Conclusion: Patients with clinically suspected acute PE, no symptoms or signs of DVT and a negative single slice s-CTPA using 3–5 mm collimation, may safely be left without anticoagulation treatment unless they are critically ill, have a limited cardiopulmonary reserve and/or if a high clinical suspicion remains.

Negative spiral CT in acute pulmonary embolism

To retrospectively evaluate the clinical outcome of non-anticoagulated patients with clinically suspected acute pulmonary embolism (PE) and no symptoms or signs of deep venous thrombosis (DVT) following a negative contrast medium-enhanced spiral CT of the pulmonary arteries (s-CTPA). During a 24-month period, 739 of 751 patients underwent s-CTPA with acceptable diagnostic quality for clinically suspected acute PE. All patients who had a CT study not positive for PE were followed up with a questionnaire, a telephone interview and review of all medical reports, including autopsies and death certificates for any episodes of venous thromboembolism (VTE) during a 3-month period. PE was diagnosed in 158 patients. Of the remaining 581 patients with a negative s-CTPA, 45 patients were lost to follow-up. 88 patients were excluded because of anticoagulation treatment (cardiac disorder n=32, chronic VTE or acute symptomatic DVT n=31, PE diagnosed at pulmonary angiography n=1, thrombus prophylaxis during diagnostic work-up or other reasons than VTE n=24) and 7 patients undergoing lower extremity venous studies because of symptoms of DVT (all negative). Thus, 441 patients with a negative s-CTPA and no DVT symptoms, venous studies or anticoagulant treatment constituted the follow-up cohort. Four of these patients had proven VTE (all PE) during the 3-month follow-up period. Two of the PE episodes contributed to the patient's death. Patients with clinically suspected acute PE, no symptoms or signs of DVT and a negative single slice s-CTPA using 3-5 mm collimation, may safely be left without anticoagulation treatment unless they are critically ill, have a limited cardiopulmonary reserve and/or if a high clinical suspicion remains.

Severe pulmonary hypertension: data from the Swiss Registry.

Severe pulmonary hypertension (PH) is a rare disease with a dismal prognosis if untreated. Progress in diagnosis and in the development of effective therapeutic options has created new interest in this pathology. There are, however, only limited data on the prevalence of severe PH unrelated to chronic left ventricular failure or COPD, on the associated conditions and on the parameters with a prognostic impact. With the aid of a retrospective registry we have collected data from 5 centres in Switzerland and attempted to answer the above questions. Data on patients with PH from 4 university facilities (Zurich, Basle, Geneva and Lausanne) and one well-defined geographical area (Ticino) were retrospectively collected and analysed up to December 1999. Clinical and haemodynamic parameters and associated diseases were noted. We were also interested in the age distribution of the patients and the year of diagnosis of PH. We found 106 patients with severe PH (43 men, 63 women, median age 43 years); 79% were in NYHA class III or IV. There was a steep rise in diagnosis of PH after 1995. In 74% PH was either primary or associated with collagen vascular disease or thromboembolic disease. By the end of the observation period 30% of the patients had died. The best distinguishing parameters between surviving patients and those who eventually died were the 6-minute walking test (363 vs. 235 metres, p = 0.002), the NYHA class (II vs III/IV, p = 0.015), and mixed venous saturation (66.5 vs. 57.9%, p = 0.006). Therapy consisted of calcium antagonists in 18% and of (inhaled) prostanoids, chiefly iloprost, in 33%. Seven patients underwent lung transplantation. We conclude that PH is diagnosed more often as diagnostic and therapeutic options improve; that primary forms, and those associated with collagen vascular disease and with chronic venous thromboembolism, make up three-quarters of the aetiologies; and that the 6-minute walking test, the functional class and mixed venous saturation are the best prognostic parameters.

Severe pulmonary hypertension: data from the Swiss Registry.

Severe pulmonary hypertension (PH) is a rare disease with a dismal prognosis if untreated. Progress in diagnosis and in the development of effective therapeutic options has created new interest in this pathology. There are, however, only limited data on the prevalence of severe PH unrelated to chronic left ventricular failure or COPD, on the associated conditions and on the parameters with a prognostic impact. With the aid of a retrospective registry we have collected data from 5 centres in Switzerland and attempted to answer the above questions. Data on patients with PH from 4 university facilities (Zurich, Basle, Geneva and Lausanne) and one well-defined geographical area (Ticino) were retrospectively collected and analysed up to December 1999. Clinical and haemodynamic parameters and associated diseases were noted. We were also interested in the age distribution of the patients and the year of diagnosis of PH. We found 106 patients with severe PH (43 men, 63 women, median age 43 years); 79% were in NYHA class III or IV. There was a steep rise in diagnosis of PH after 1995. In 74% PH was either primary or associated with collagen vascular disease or thromboembolic disease. By the end of the observation period 30% of the patients had died. The best distinguishing parameters between surviving patients and those who eventually died were the 6-minute walking test (363 vs. 235 metres, p = 0.002), the NYHA class (II vs III/IV, p = 0.015), and mixed venous saturation (66.5 vs. 57.9%, p = 0.006). Therapy consisted of calcium antagonists in 18% and of (inhaled) prostanoids, chiefly iloprost, in 33%. Seven patients underwent lung transplantation. We conclude that PH is diagnosed more often as diagnostic and therapeutic options improve; that primary forms, and those associated with collagen vascular disease and with chronic venous thromboembolism, make up three-quarters of the aetiologies; and that the 6-minute walking test, the functional class and mixed venous saturation are the best prognostic parameters.