Treatment Of Recurrent Venous Thromboembolism Research Articles

Impact of Anticoagulant and Antiplatelet on the Thrombotic Risk in Cancer Associated Thrombosis

Introduction: Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain very limited. Although low-molecular-weight heparin (LMWH) monotherapy has been identified as a simple and efficacious regimen. However, treatment of patients with a high risk of bleeding as well as the treatment of recurrent VTE with dose escalation of LMWH, and management in patients with thrombocytopenia represent major challenges. On the other side, Platelet activation is the first response to tissue damage and, may promote chronic inflammation-related cancer, mainly through the release of soluble factors and vesicles that are rich in genetic materials and proteins. Platelets also sustain cancer cell invasion and metastasis formation by fostering the development of the epithelial-mesenchymal transition phenotype, cancer cell survival in the bloodstream and arrest/extravasation at the endothelium. Furthermore, platelets contribute to tumor escape from immune elimination. Hence, we examined the effect of combined lose doses of the LMWH tinzaparin and the antiplatelet GPIIb/IIIa antagonist DMP728 on cancer associated thrombosis (CAT) using thrombelastogrphy. DMP728 is used for inhibiting the binding of Platelet GPIIb/IIIa. Glycoprotein IIb/IIIa is a receptor for fibrin and leads to further the activation of platelets to form blood clots. Aim: To determine the effects of tinzaparin and/or DMP728 on platelet/fibrin clot kinetics using thrombelastography (TEG) in presence or absence of pancreatic cancer cells (SUIT2) that expresses tissue factor. Methods: Human blood collected from healthy volunteers in sodium citrate tubes and treated with different concentrations (0.01, 0.03, 0.1 and 0.3 μg) of Tinzaparin, DMP 728, and/or tinzaparin + DMP728 in presence or absence of pancreatic cancer cells (SUIT 2 cells). We compared the effects on the coagulation time, time to clot initiation and thrombus strength level in vitro. Results: In the absence of SUIT 2 pancreatic cancer cells, thrombelastographic (TEG) have shown that, increasing concentrations of tinzaparin and DMP728 (0.01 - 0.3 μg) were associated with marked increased clotting time (R) and decreased maximum amplitude of the clot formation (MA) in comparison to control. After adding the SUIT 2 pancreatic cancer cells to human blood, shortened the time to clot initiation (R) and increased the clot strength (MA) have been observed. In presence of SUIT2 Pancreatic Cancer Cell, tinzaparin was associated with increased clotting time (R) and decreased maximum amplitude of the clot formation (MA) in comparison to control. However, DMP728 R Value has not shown much effect on clotting time (R) and maximum amplitude of the clot formation (MA). A combination of DMP728 and tinzaparin was associated with a greater synergistic Increase in clotting time (R), with a synergistic decrease in maximum amplitude of the clot formation (MA) (Figure 1). Conclusions: The combination of the LMWH (tinzaparin) and the antiplatelet drug (DMP728) might be a successful approach in the prevention and treatment of cancer associated thrombosis. Disclosures No relevant conflicts of interest to declare.

Effects of Oral Anticoagulant Therapy on Gene Expression in Crosstalk between Osteogenic Progenitor Cells and Endothelial Cells.

Direct oral anti-coagulants (DOACs) are employed in clinical practice for the prevention and treatment of recurrent venous thromboembolism and for the prevention of stroke in non-valvular atrial fibrillation. DOACs directly and reversibly inhibit activated factor X or thrombin and can interfere with other pathophysiological processes such as inflammation, lipid metabolism, and bone turnover. We aimed to evaluate the possible effects of DOACs on osteogenesis and angiogenesis. We treated 34 patients affected by cardiovascular disorders with DOACs; biochemical and molecular analyses were performed before and after three months of treatment. Circulating progenitors (CPs; CD34−, CD45−, CD14−, CD73+, CD105+), which share typical bone marrow stem cell (MSCs) features, were harvested from peripheral blood of the study subjects to monitor the expression of osteogenesis-related genes RUNX2 and SPARC. Human umbilical vein endothelial cells (HUVECs) were used to probe angiogenesis-related VEGF, CD31, and CD105 gene expression. We performed co-culture experiments using a commercial human mesenchymal stem cells line (hMSCs) obtained from bone marrow and HUVECs. Clinical parameters related to bone metabolism, coagulation, renal and liver function, and the lipid profile were evaluated. Values of the C-terminal telopeptide type I collagen (CTX) increased after the treatment. We found a significant increase in osteogenesis marker gene expression in CPs after three months of anticoagulant therapy. An increase in the RUNX2 expression determinant alone was detected instead in hMSCs co-cultured with HUVECs in the presence of treated patients’ sera. The VEGF, CD31, and CD105 marker genes appeared to be significantly upregulated in HUVECs co-cultured with hMSCs in the presence of treated patients’ sera. Under these conditions, new vessel formation increased as well. Our results highlight an unexpected influence of DOAC therapy on osteogenic commitment and vascular endothelial function promotion.

Direct Oral Anticoagulants and Vitamin K Antagonists for Treatment of Deep Venous Thrombosis and Pulmonary Embolism in the Outpatient Setting: Comparative Economic Evaluation.

To date, there have been few economic evaluations, from a Canadian perspective, of direct oral anticoagulants (DOACs) for the prevention of recurrent venous thromboembolism (VTE) in patients with acute unprovoked VTE. As a result, there is a lack of consensus about which treatment strategy should be adopted in the clinical setting. To assess the cost-effectiveness of currently approved anti-coagulant options, in terms of cost per quality-adjusted life-year (QALY) gained, for the prevention of recurrent VTE in patients with unprovoked events managed on an outpatient basis. Microsoft Excel was used to develop a Markov model. Model parameters were determined using published literature, local hospital data, expert opinion, and chart review. The analysis considered the costs associated with pharmaceuticals, laboratory testing, hematologist fees, and treatment of recurrent VTE and major bleeding events. Effectiveness was measured in terms of QALYs, and incremental cost-effectiveness ratios (ICERs) were calculated. For treatment lasting 3 months, apixaban represented the most cost-effective DOAC relative to low-molecular-weight heparin (LMWH) + vitamin K antagonist, with an ICER of $7379.66. For 6 months of treatment, apixaban again represented the most cost-effective treatment, with an ICER of $84.08 per QALY gained, and this drug dominated all the other strategies at 12 months. For lifetime treatment, DOACs were unlikely to be cost-effective, given a maximum willingness to pay of $50 000 to $100 000 per QALY. In a probabilistic sensitivity analysis at 6 months, 46.4% of iterations resulted in apixaban having lower costs and better outcomes than LMWH + vitamin K antagonist, and 78.6% of iterations resulted in an ICER below $100 000. The findings of this study suggest that apixaban is likely cost-effective for treatment durations of 3, 6, and 12 months. However, for indefinite treatment, DOACs were unlikely to be cost-effective.

Fondaparinux for the Treatment of Recurrent Venous Thromboembolism During Low Molecular Weight Heparin Therapy: A Retrospective Case Series.

Abstract 4179 Introduction:Fondaparinux is a synthetic pentasaccharide that exerts its anticoagulant effects by indirectly inhibiting Factor Xa. Large randomized controlled multicenter trials have shown that daily administered subcutaneous fondaparinux at specified weight based dosing is as effective as unfractionated heparin (UFH) and low molecular weight heparin (LMWH) for the initial treatment of venous thromboembolic events (VTE), in conjunction with warfarin. In the case of recurrent DVT or PE, however, there is no standard of care and optimal anticoagulation still remains a challenge. Based on limited data, most patients on warfarin with recurrent VTE would be switched to LMWH or UFH, but the use of fondaparinux in this setting is limited to anecdotal experience. Methods:We report the Indiana University experience with the use of fondaparinux for recurrent DVT or PE, failing therapy with LMWH. This is a retrospective review of 13 patients with recurrent thromboembolism, studied in two hospital settings. The mean age was 37 years (range 23-65), there were 8 females and 5 males, and all the patients had failed enoxaparin (two patients had also progressed on tinzaparin). The underlying medical conditions that predisposed to thromboses varied: sickle cell disease (3), antiphospholipid syndrome (3), cancer (3), May Thurner syndrome (1), and 3 patients with inherited thombophilia (Antithrombin III deficiency, Factor V Leiden and Prothrombin 20210 Gene Mutation). Mean weight was 90.7 kg (range 52-150). Mean time to recurrence on LMWH was 330 days. Fondaparinux was prescribed at 7.5mg daily or 10mg daily, based on body weight. Anti-Factor Xa levels were measured in at least half of the patient population, and response was assessed by clinical improvement or progression. Results:Thirty one percent (4/13) of patients had recurrent thromboembolic episodes (response rate 69%). Time to progression during therapy with fondaparinux was available on 2/4 patients, and was 17 months (range 13-21). No adverse events including bleeding complications or death were reported. Conclusions:Fondaparinux may have efficacy in the treatment of recurrent VTE that has progressed on LMWH. These results are hypothesis generating and should be evaluated prospectively. Disclosures:No relevant conflicts of interest to declare.

Prophylactic and therapeutic anticoagulation for thrombosis—major issues in oncology

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. Primary prevention with pharmacologic agents (or mechanical methods, if anticoagulants are contraindicated) is recommended in all cancer patients hospitalized for surgical or medical reasons. The role of prophylaxis in outpatients is less certain because of the diversity of the patient populations and their cancer treatments with respect to the associated risks of VTE and bleeding. Treatment with low-molecular weight heparin is the recommended first-line approach in cancer patients with newly diagnosed VTE, and is usually continued for a minimum of 3-6 months. Other management issues that require further research include the optimum duration of anticoagulant therapy, the treatment of recurrent VTE, the role of vena cava filters, the effects of VTE and its treatment on quality of life, and the impact of anticoagulants on survival. Newer anticoagulants hold promise in providing more-effective and convenient treatment of VTE in this high-risk population, but further studies are awaited.

The efficacy and safety of low-molecular-weight heparins (LMWHs) compared with vitamin K antagonists (VKAs) in the treatment of recurrent venous thromboembolism (VTE) in patients with cancer: An analysis of randomized clinical trials

9609 Background: Patients with cancer are at higher risk of recurrent venous thromboembolism (VTE) and bleeding complications. Recently, anticoagulant therapies utilizing low-molecular-weight hepar...

Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy

PurposeThe optimal management of patients who have recurrent thromboembolism while being treated with oral anticoagulation therapy is unknown. This study reports managing such patients with extended duration low molecular weight heparin therapy. Subjects and methodsThis study was a retrospective review of the prospective databases of three tertiary care teaching hospitals over a 27-month period. All patients who had recurrent symptomatic thromboembolism while being treated with warfarin were identified. All patients were treated with low molecular weight heparin (dalteparin), 200 U/kg daily. Data were collected for recurrent venous thromboembolism, bleeding, and survival. ResultsEight hundred eighty-seven patients were managed for acute thromboembolism. In 32 patients, symptomatic, objectively documented thromboembolism recurred while they were taking warfarin; 63% of the patients with recurrence had cancer, compared with 30% of patients without recurrence. All recurrences were treated with dalteparin. In 3 patients (9% [95% confidence interval: 2% to 25%]), symptomatic recurrence developed while they were being treated with low molecular weight heparin. Nineteen patients (59%) died while receiving anticoagulation therapy; all deaths but 1 were due to malignancy, and none was due to pulmonary embolism or bleeding. ConclusionsThese results suggest that recurrent venous thromboembolism is more likely to develop in cancer patients while being treated with warfarin and that long-term therapy with low molecular weight heparin may be effective in managing warfarin-failure thromboembolic disease.

Diagnosis and Treatment of Recurrent Venous Thromboembolism

The diagnosis of recurrent venous thromboembolism includes an evaluation of the patient for inherited or acquired disorders, associated with an increased risk of thromboembolism. Treatment depends, in part, on the underlying disease and, in part, on an adequate understanding of the principles of anticoagulant therapy.