Deep vein thrombosis: update on diagnosis and management.

Diagnosis of deep vein thrombosis (DVT) requires a multifaceted approach that includes clinical assessment, evaluation of pre-test probability, and objective diagnostic testing. Common symptoms and signs of DVT are pain, swelling, erythema and dilated veins in the affected limb. The pre-test probability of DVT can be assessed using a clinical decision rule that stratifies DVT into "unlikely" or "likely". If DVT is "unlikely", refer for D-dimer test. If the D-dimer level is normal, DVT can be excluded; if the D-dimer level is increased, refer for compression ultrasound. If DVT is "likely", refer for compression ultrasound. When DVT is confirmed, anticoagulation is indicated to control symptoms, prevent progression and reduce the risk of post-thrombotic syndrome and pulmonary embolism. Anticoagulation may consist of a parenteral anticoagulant overlapped by warfarin or followed by a direct oral anticoagulant (DOAC) (dabigatran or edoxaban), or of a DOAC (apixaban or rivaroxaban) without initial parenteral therapy. DOACs are the preferred treatment for DVT because they are at least as effective, safer and more convenient than warfarin. DOACs may require dose reduction or avoidance in patients with renal dysfunction, and should be avoided in pregnancy. Recent evidence shows that DVT in patients with cancer may be treated with edoxaban (after discontinuation of 5 days of initial heparin or low molecular weight heparin [LMWH]) or rivaroxaban if patients prefer not to have daily injections of LMWH, but the risk of gastrointestinal bleeding is higher with DOACs than with LMWH in patients with gastrointestinal cancer.

Pulmonary embolism: update on diagnosis and management.

Pulmonary embolism (PE) is a potentially life-threatening condition, mandating urgent diagnosis and treatment. The symptoms of PE may be non-specific; diagnosis therefore relies on a clinical assessment and objective diagnostic testing. A clinical decision rule can determine the pre-test probability of PE. If PE is "unlikely", refer for a D-dimer test. If the D-dimer result is normal, PE can be excluded. If D-dimer levels are increased, refer for chest imaging. If PE is "likely", refer for chest imaging. Imaging with computed tomography pulmonary angiogram is accurate and preferred for diagnosing PE, but may detect asymptomatic PE of uncertain clinical significance. Imaging with ventilation-perfusion (VQ) scan is associated with lower radiation exposure than computed tomography pulmonary angiogram, and may be preferred in younger patients and pregnancy. A low probability or high probability VQ scan is helpful for ruling out or confirming PE, respectively; however, an intermediate probability VQ scan requires further investigation. The direct oral anticoagulants have expanded the anticoagulation options for PE. These are the preferred anticoagulant for most patients with PE because they are associated with a lower risk of bleeding, and have the practical advantages of fixed dosage, no need for routine monitoring, and fewer drug interactions compared with vitamin K antagonists. Initial parenteral treatment is required before dabigatran and edoxaban.

Quantitative chemical shift-encoded MRI is an accurate method to quantify hepatic steatosis.

PURPOSE: To compare the accuracy of liver fat quantification using a three-echo chemical shift-encoded magnetic resonance imaging (MRI) technique without and with correction for confounders with spectroscopy (MRS) as the reference standard. MATERIALS AND METHODS: Fifty patients (23 women, mean age 56.6 ± 13.2 years) with fatty liver disease were enrolled. Patients underwent T2-corrected single-voxel MRS and a three-echo chemical shift-encoded gradient echo (GRE) sequence at 3.0T. MRI fat fraction (FF) was calculated without and with T2* and T1 correction and multispectral modeling of fat and compared with MRS-FF using linear regression. RESULTS: The spectroscopic range of liver fat was 0.11%-38.7%. Excellent correlation between MRS-FF and MRI-FF was observed when using T2* correction (R(2) = 0.96). With use of T2* correction alone, the slope was significantly different from 1 (1.16 ± 0.03, P < 0.001) and the intercept was different from 0 (1.14% ± 0.50%, P < 0.023). This slope was significantly different than 1.0 when no T1 correction was used (P = 0.001). When T2*, T1, and spectral complexity of fat were addressed, the results showed equivalence between fat quantification using MRI and MRS (slope: 1.02 ± 0.03, P = 0.528; intercept: 0.26% ± 0.46%, P = 0.572). CONCLUSION: Complex three-echo chemical shift-encoded MRI is equivalent to MRS for quantifying liver fat, but only with correction for T2* decay and T1 recovery and use of spectral modeling of fat. This is necessary because T2* decay, T1 recovery, and multispectral complexity of fat are processes which may otherwise bias the measurements.

A pragmatic approach to embedding patient blood management in a tertiary hospital.

BACKGROUND: We describe the implementation and impact of a patient blood management program (PBMP) in an Australian teaching hospital. STUDY DESIGN AND METHODS: A PBMP was introduced at a single tertiary care hospital in 2009 as a pilot for the Western Australian Health Department statewide PBMP. The first 3 years of interventions aimed to make effective use of preoperative clinics, manage perioperative anemia, improve perioperative hemostasis, reduce blood sample volumes, and implement restrictive transfusion triggers and a single-unit transfusion policy. RESULTS: Between 2008 and 2011, admissions to Fremantle Hospital and Health Services increased by 22%. Using 2008 as a reference year, the mean number of red blood cell (RBC) units per admission declined 26% by 2011. Use of fresh-frozen plasma and platelets showed 38 and 16% declines, respectively. Cryoprecipitate increased 7% over the 4-year period. For elective admissions between 2008 and 2011, the leading decline in RBC transfusion rate was seen in cardiothoracic surgery (27.5% to 12.8%). The proportion of single RBC unit use increased from 13% to 28% (p < 0.001), and the proportion of double units decreased from 48% to 37% (p < 0.001). CONCLUSION: This is the first tertiary hospital in Australia to establish a multidisciplinary multimodal PBMP. Interventions across disciplines resulted in decreased use of RBC units especially in orthopedic and cardiothoracic surgery. Continuing education and feedback to specialties will maintain the program, improve patient outcomes, and decrease the transfusion rate.

Prothrombinex-VF use in warfarin reversal and other indications.

OBJECTIVE: To assess the use of Prothrombinex-VF powder for injection (PTX-VF) at Royal Perth Hospital and analyse the efficacy and safety profile of PTX-VF. DESIGN, SETTING AND PATIENTS: A prospective observational audit of PTX-VF use, conducted by reviewing medical records and laboratory and imaging results for all patients prescribed PTX-VF from 1 November 2009 to 1 May 2010. MAIN OUTCOME MEASURES: Data on indication, diagnosis, comorbidities, dose of PTX-VF, fresh frozen plasma (FFP) and vitamin K, coagulation parameters before and after PTX-VF administration, and adverse effects. RESULTS: 334 vials of PTX-VF were administered to 84 patients over 107 prescriptions. Indications were warfarin reversal, intraoperative bleeding and coagulopathy (66, 20 and 21 prescriptions, respectively). PTX-VF with FFP was compared with PTX-VF alone for warfarin reversal and there was a significant decrease in international normalised ratio (INR) that was independent of group (P < 0.001). Lower doses of PTX-VF (< 25 IU/kg) were compared with higher doses (25-50 IU/kg) for warfarin reversal and decrease in INR was significant, independent of group (P = 0.002). PTX-VF was administered for intraoperative bleeding in 18 patients who had not been treated with warfarin. No hypersensitivity reactions, thrombotic complications or worsening of disseminated intravascular coagulation occurred during 7-day follow-up. CONCLUSION: For warfarin reversal, lower doses of PTX-VF (< 25 IU/kg) and PTX-VF without FFP were effective. PTX-VF was also used in intraoperative bleeding and non-warfarin coagulopathy. No adverse events were associated with PTX-VF.

Safety and parents´ acceptance of ultrasound contrast agents in children and adolescents - contrast enhanced voiding urosonography and contrast enhanced ultrasound.

AIMS: To evaluate the safety of the contrast enhanced voiding urosonography (ceVUS) and contrast enhanced ultrasound (CEUS) in children and adolescence and to receive data about parents' acceptance of intravesical and intravenous application of sulfur hexafluoride. MATERIAL AND METHODS: In this prospective, single centre study conducted over a 1 year study period, parents of 56 children (f/m=32/24; mean age 3.1 years; range 3 weeks - 15.9 years) with ceVUS and of 30 children (f/m=15/15; mean age 10.5 years; range 2 months - 17.7 years) with CEUS agreed to be included. A standardized telephone survey about the acceptance of the parents during and after the procedure as well as the adverse events (AE) were conducted within three days of the examination. RESULTS: The parents would agree with the use of both ceVUS and CEUS as a diagnostic tool again in 96% (54/56) or 100% (30/30) of the cases, respectively and 92.9% (52/56) would prefer ceVUS to voiding cystourethrography (VCUG). In addition, 83.3% (25/30) would prefer CEUS to CT and 73.3% (22/30) would prefer CEUS to MRI. AE were reported in 3.6% after ceVUS (2/56; skin rash, mild fever) and in 3.3% after CEUS (1/30; vomiting). AE were subacute and self­limited. CONCLUSIONS: The vast majority of parents prefer ceVUS and CEUS to VCUG, CT or MRI because of the safety profile of the contrast agent and diagnostic accuracy.

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?-A Systematic Review.

BACKGROUND: Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. OBJECTIVES: To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. RESULTS AND DISCUSSION: We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. CONCLUSION: The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

How can the results of the COMPASS trial benefit patients with coronary or peripheral artery disease in Poland?

Aspirin decreases the risk of recurrent thrombotic events in patients with coronary artery disease or peripheral artery disease but the risk of recurrent events remains high. Long­term dual antiplatelet therapy or the combination of aspirin and warfarin further reduces the risk of recurrent events, but at the cost of increased bleeding, and neither of these treatments reduce mortality. The COMPASS (Cardiovascular Outcomes in People Using Anticoagulation Strategies) randomized controlled trial involving 27 395 patients from 602 sites in 33 countries (Poland: 9 sites, 518 patients) tested whether low­dose anticoagulant therapy with the coagulation factor Xa inhibitor rivaroxaban given alone or combined with aspirin reduced thrombotic risk compared with aspirin in patients with apparently stable chronic coronary and/or peripheral artery disease. In patients treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily, compared with aspirin alone, the primary outcome of the composite of cardiovascular death, stroke, or myocardial infarction was decreased by 24% (hazard ratio, 0.76; 95% confidence interval, 0.66 to 0.86; P <0.001), and mortality by 18% at the cost of a 70% increase in major bleeding but no significant increase in fatal or intracranial bleeding. Results were consistent in patients with coronary artery disease or peripheral artery disease, and the greatest absolute benefit was evident in the highest risk patients, including those with polyvascular disease, mild or moderate heart failure, chronic kidney disease, or diabetes. These results establish the combination of low­dose rivaroxaban and aspirin as a highly effective treatment to decrease morbidity and mortality rates in patients with atherosclerotic vascular disease..

In Vitro Reversal of the Anti-Aggregant Effect of Ticagrelor Using Untreated Platelets.

BACKGROUND: Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. METHODS AND RESULTS: Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. CONCLUSION: Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.

Iodine-131 rituximab radioimmunotherapy with BEAM conditioning and autologous stem cell transplant salvage therapy for relapsed/refractory aggressive non-Hodgkin lymphoma.

A standard salvage therapy of relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) comprises autologous stem cell transplantation (ASCT) after chemotherapy conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM) regimen. However, the achievement of long-term disease-free survival remains challenging. We have introduced concomitant (131)I-rituximab radioimmunotherapy (RIT) in an attempt to effect the elimination of lymphoma cells. Our phase II physician-sponsored study of 16 consecutive patients with relapsed, refractory, aggressive B-cell NHL reports a median 44 month follow-up after (131)I-rituximab-BEAM conditioning therapy and ASCT. Prospective personalized dosimetry performed in each patient limited the whole body radiation absorbed dose to 0.75 Gy. RIT (131)I-rituximab was administered on an outpatient basis on day -15 before ASCT. The BEAM conditioning regimen was commenced on day -6. Evaluable engraftment data are available for 15 patients who had 16 ASCTs. Engraftment was achieved in all patients, 15 out of 16 ASCTs achieved a complete response, and 1 out of 15 ASCTs achieved a partial response. Twelve out of sixteen patients remained alive and disease free at a median of 44 months (range 4-108 months) post-ASCT. This study suggests that the addition of (131)I-rituximab RIT to BEAM conditioning, before ASCT, for relapsed or primary refractory B-cell NHL improves disease eradication, compared with BEAM conditioning alone, without significant additional toxicity. In particular, there is an impression of improved disease control in the subset of patients with transformed follicular and mantle cell lymphomas.

Assessing iron overload: are we there yet?

Iron overload occurs in many hematologic disorders and causes significant morbidity. The advantages of MRI in quantifying liver iron concentration continue to mount, and the association between iron overload and increased mortality after allogeneic stem cell transplant needs further attention.

7.1 T MRI to assess the anterior segment of the eye.

PURPOSE: Visualization of the anterior segment and biometric evaluation of the entire crystalline lens pose significant challenges for imaging techniques because of tissue-induced distortion artifacts. The present study was conducted to demonstrate the advantages of high-resolution magnetic resonance imaging (micro-MRI) for visualizing the anterior segment. METHODS: High-resolution MR ocular images were acquired on an ultra-high-field MR unit using a two-channel coil with four coil elements and T(2)-weighted turbo spin echo sequences ex vivo in pig, rabbit, monkey, and human donor eyes and in vivo in rabbits. Tissue heating, reproducibility, and signal-to-noise ratio were investigated in vivo. Monkey eye lens thickness (LT) was also measured using A-scan ultrasonography (US). RESULTS: Anterior segment details of phakic eyes were obtained ex vivo (pig, rabbit, monkey, and human donor eyes) with pixel matrix size 512 × 512 (in-plane resolution 80 × 80 µm) and in vivo (rabbit eyes) with pixel matrix size 320 × 320 (in-plane resolution 125 × 125 µm). Complete quantification of lens dimensions as they correlate with the sulcus-sulcus and angle-angle plane can be performed. In LT determinations in monkey eyes, no significant difference was detected between micro-MRI and A-scan US (P > 0.05, Mann-Whitney U test). Biometric analysis of one pseudophakic monkey eye confirmed the absence of relevant distortion artifacts. CONCLUSIONS: Micro-MRI allows ex vivo and in vivo visualization and quantification of the spatial arrangement of the anterior eye segment. Imaging of the retroiridian region, including the entire crystalline lens, overcomes a number of major limitations in the quantitative evaluation of the anterior segment.