Charles W. Francis

Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). CONCLUSIONS Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer

PURPOSE To develop guideline recommendations for the use of anticoagulation in the prevention and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS A comprehensive systematic review of the medical literature on the prevention and treatment of VTE in cancer patients was conducted and reviewed by a panel of content and methodology experts. Following discussion of the results, the panel drafted recommendations for the use of anticoagulation in patients with malignant disease. RESULTS The results of randomized controlled trials of primary and secondary VTE medical prophylaxis, surgical prophylaxis, VTE treatment, and the impact of anticoagulation on survival of patients with cancer were reviewed. Recommendations were developed on the prevention of VTE in hospitalized, ambulatory, and surgical cancer patients as well as patients with established VTE, and for use of anticoagulants in cancer patients without VTE to improve survival. CONCLUSION Recommendations of the American Society of Clinical Oncology VTE Guideline Panel include (1) all hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications; (2) routine prophylaxis of ambulatory cancer patients with anticoagulation is not recommended, with the exception of patients receiving thalidomide or lenalidomide; (3) patients undergoing major surgery for malignant disease should be considered for pharmacologic thromboprophylaxis; (4) low molecular weight heparin represents the preferred agent for both the initial and continuing treatment of cancer patients with established VTE; and (5) the impact of anticoagulants on cancer patient survival requires additional study and cannot be recommended at present.

Development and validation of a predictive model for chemotherapy-associated thrombosis

Risk of venous thromboembolism (VTE) is elevated in cancer, but individual risk factors cannot identify a sufficiently high-risk group of outpatients for thromboprophylaxis. We developed a simple model for predicting chemotherapy-associated VTE using baseline clinical and laboratory variables. The association of VTE with multiple variables was characterized in a derivation cohort of 2701 cancer outpatients from a prospective observational study. A risk model was derived and validated in an independent cohort of 1365 patients from the same study. Five predictive variables were identified in a multivariate model: site of cancer (2 points for very high-risk site, 1 point for high-risk site), platelet count of 350 x 10(9)/L or more, hemoglobin less than 100 g/L (10 g/dL) and/or use of erythropoiesis-stimulating agents, leukocyte count more than 11 x 10(9)/L, and body mass index of 35 kg/m(2) or more (1 point each). Rates of VTE in the derivation and validation cohorts, respectively, were 0.8% and 0.3% in low-risk (score = 0), 1.8% and 2% in intermediate-risk (score = 1-2), and 7.1% and 6.7% in high-risk (score >/= 3) category over a median of 2.5 months (C-statistic = 0.7 for both cohorts). This model can identify patients with a nearly 7% short-term risk of symptomatic VTE and may be used to select cancer outpatients for studies of thromboprophylaxis.

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update 2014

PURPOSE To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts. RESULTS Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations. RECOMMENDATIONS Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.

Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy

PCI on CEC counts or other endothelial markers were not investigated [5]. Dignat-George et al. [6] reported similar CEC counts in the FV vs. femoral artery following PCI (n 1⁄4 10). In a further small study (n 1⁄4 15), these investigators noted a significant increase in peripheral blood CECs, on comparing blood taken immediately post-PCI (15.9 ± 3.7 cells mL; P 1⁄4 0.001) compared with preprocedural counts (2.4 ± 0.9 CEC mL) [5]. The observed broadly similar rise in CEC counts, following PCI, regardless of the sample site, would appear to suggest that PCI leads either to widespread endothelial perturbation and/or a rapid equilibration of responses. Contrary to our initial hypothesis, we cannot presume that the increased CEC counts represent specific coronary artery endothelial shedding. Passage of the coronary guide catheter, angioplasty guide wire and/or balloon (±stent) into the aorta and coronary vasculature may have resulted in generalized CEC release, but we found no significant change in coronary osCECs/VWFwith contrast. As CECandVWFsamplingwasonlyperformedat two timepoints (immediately pre-PCI and post-PCI) we cannot excluded the possibility that we may have missed an abrupt rise in local release of VWF that may have been detected by more frequent and protracted sampling post-PCI. Finally, the autonomic procedural stress might engender a disseminated endothelial shedding response throughout the endothelium circulation. In conclusion, this study showed no significant differences in baseline CEC counts or VWF levels between the AR, CS and RFV. However, PCI was associated with a significant increase in CECs, but not VWF, across all three sampling sites. Acknowledgements

Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.

Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% [P = .02 vs enoxaparin], 34% [P < .001 vs enoxaparin], and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latters more intense and prolonged dosing.

Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients

Venous thromboembolism (VTE) contributes to morbidity and mortality in cancer patients and is a frequent complication of anticancer therapy. In the current study, the frequency, risk factors, and trends associated with VTE were examined among hospitalized cancer patients.

Thromboembolism in Hospitalized Neutropenic Cancer Patients

PURPOSE Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized cancer patients receiving current chemotherapy regimens is not known. We investigated venous and arterial thromboembolism and associated outcomes in hospitalized cancer patients actively receiving therapy, as identified by neutropenia. METHODS We conducted a retrospective cohort study using the discharge database of the University HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074 hospitalizations between 1995 and 2002 at 115 medical centers in the United States. RESULTS Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous thromboembolism and 1.5% developing arterial thromboembolism during the first hospitalization. Patients with lymphoma and leukemia accounted for one third of venous and nearly one half of arterial events. Clinical variables most frequently associated with thromboembolism were age > or = 65 years; primary site of cancer, including lung, GI, gynecologic, and brain; and comorbidities, including infection, pulmonary and renal disease, and obesity. In-hospital mortality was significantly greater in patients with venous (odds ratio [OR] = 2.01; 95% CI, 1.83 to 2.22) or arterial thromboembolism (OR = 5.04; 95% CI, 4.38 to 5.79). From 1995 to 2002, there was a 36% increase in venous events and a 124% increase in arterial events (P < .0001 for trend). CONCLUSION Thromboembolism is frequent in hospitalized neutropenic cancer patients, including in perceived low-risk subgroups such as patients with hematologic malignancies and nonmetastatic disease, and seems to be increasing. Thromboembolism is associated with increased in-hospital mortality. Increased efforts at thromboprophylaxis are warranted.

Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots.

Fibrinolysis is accelerated in vitro in an ultrasound field, and externally applied high frequency ultrasound also accelerates thrombolysis in animal models. Although the mechanism of this effect is not known, ultrasound does not cause mechanical disruption of clots but rather accelerates enzymatic fibrinolysis. To determine if accelerated fibrinolysis could be related to increased transport of enzyme into clot, we have examined the effect of insonification on the distribution of plasminogen activator between clot and surrounding fluid in vitro. Plasma clots were overlayed with plasma containing 125I-radiolabeled, active-site-blocked recombinant tissue plasminogen activator (rt-PA) and incubated in the presence of 1-MHz ultrasound at 4 W/cm2 or in the absence of ultrasound. The rate of uptake of rt-PA was significantly faster in the presence of ultrasound, reaching 15.5 +/- 1.4% at 4 h compared to 8.2 +/- 1.0% in the absence of ultrasound (p < 0.0001). Similarly, ultrasound increased transport of enzyme from the clot into the surrounding fluid. To determine the effect of ultrasound on the spatial distribution of enzyme, plasma clots were overlayed with plasma containing radiolabeled rt-PA and incubated in the presence or absence of ultrasound. The clots were then snap-frozen, and the radioactivity in serial cryotome sections was determined. Exposure to ultrasound altered the rt-PA distribution, resulting in significantly deeper penetration of rt-PA into the clots. We conclude that exposure to ultrasound increases uptake of rt-PA into clots and also results in deeper penetration. These effects of ultrasound on enzyme transport may contribute to the accelerated fibrinolysis observed in an ultrasound field.

Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer.

Purpose: Hemostatic activation is common in pancreatic cancer and may be linked to angiogenesis and venous thromboembolism. We investigated expression of tissue factor (TF), the prime initiator of coagulation, in noninvasive and invasive pancreatic neoplasia. We correlated TF expression with vascular endothelial growth factor (VEGF) expression, microvessel density, and venous thromboembolism in resected pancreatic cancer. Experimental Design: Tissue cores from a tri-institutional retrospective series of patients were used to build tissue microarrays. TF expression was graded semiquantitatively using immunohistochemistry in normal pancreas (n = 10), intraductal papillary mucinous neoplasms (n = 70), pancreatic intraepithelial neoplasia (n = 40), and resected or metastatic pancreatic adenocarcinomas (n = 130). Results: TF expression was observed in a majority of noninvasive and invasive pancreatic neoplasia, including 77% of pancreatic intraepithelial neoplasias, 91% of intraductal papillary mucinous neoplasms, and 89% of pancreatic cancers, but not in normal pancreas. Sixty-six of 122 resected pancreatic cancers (54%) were found to have high TF expression (defined as grade ≥2, the median score). Carcinomas with high TF expression were more likely to also express VEGF (80% versus 27% with low TF expression, P < 0.0001) and had a higher median MVD (8 versus 5 per tissue core with low TF expression, P = 0.01). Pancreatic cancer patients with high TF expression had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (P = 0.04). Conclusions: TF expression occurs early in pancreatic neoplastic transformation and is associated with VEGF expression, increased microvessel density, and possibly clinical venous thromboembolism in pancreatic cancer. Prospective studies evaluating the role of TF in pancreatic cancer outcomes are warranted.