Low Molecular Weight Heparin In Patients Research Articles

Use of Low Molecular Weight Heparin (LMWH) in Thrombocytopenic Patients with Hematologic Malignancy-Associated Venous Thromboembolism (VTE)

Introduction:The management of hematologic malignancy-associated VTEin patients with moderate to severe thrombocytopenia is unclear. Clinical trials of anticoagulants in VTE exclude such patients, hence do not inform the risk of bleeding or clot progression. Consensus-based guidelines recommend case-by-case consideration for either platelet transfusion to maintain platelet count >50,000/µL and therapeutic anticoagulation, or 50% dose reduction in LMWH (J Thromb Haemost. 2013 Jan;11(1):56-70.; Curr Oncol. 2015 Apr;22(2):144-55). At our institution, our approach is to use prophylactic dose LMWH for patients with platelet count ≤50,000/µL.Method:This is a single-center retrospective study of 128 adult patients with hematologic malignancies, who were diagnosed with VTE. Patients were identified from hospital research database. The diagnoses were verified after the review of medical records. The platelet count was assessed during the period of anticoagulation for VTE. The outcomes of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Bleeding and clot recurrence was assessed until the last follow-up (median of >1 month). Fisher's Exact test was used to test the association between two categorical variables, and Analysis of Variance (ANOVA) was used to test the association between a continuous variable and a categorical variable.Results:Characteristics of the study population were as follows: 51% male, 47% non-Hodgkin lymphoma, 20% acute leukemia/myelodysplastic syndrome, 40% status-post hematopoietic stem cell transplant, 9% with creatinine >2 mg/dl, 36% with pulmonary embolism and 28% with catheter-related VTE. Forty six patients (36%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 9000/µL( range 2000-45,000/µL) versus 166,000/µL (range 50,000-389,000/µL) in those without (p<0.001). The median duration of significant thrombocytopenia in the first group was 10 days (range 1-68 days). Therapy during the period of significant thrombocytopenia included prophylactic dosing of LMWH (46%), therapeutic dose of LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%) and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At last follow-up, the risk of bleeding (p=0.65) and clot progression (p=0.81) were similar in the two groups (Table 1).Conclusion:Within the limits of this retrospective study, cautious use of dose-adjusted LMWH in thrombocytopenic patients with hematologic malignancy-associated VTE may be safe. A prospective trial of prophylactic dose LMWH in patients with VTE during thrombocytopenia is required to confirm the safety and, to some extent, efficacy of such an approach.Table 1Outcome of patients with VTEOutcomeThrombocytopenic cohort (Platelet count ≤50,000/µL)Patients without significant thrombocytopenia (Platelet count >50,000/µL)p-valueBleeding after VTE treatment0.65No38 (82.6%)75 (91.5%)Minor (without significant clinical implications)1 (2.2%)1 (1.2%)Clinically significant (causing drop in hemoglobin; requiring transfusion or other interventions)4 (8.7%)5 (6.1%)Missing3 (6.5%)1 (1.2%)Clot progression or recurrence at last follow-up0.81No35 (76.1%)67 (81.7%)Yes9 (19.6%)15 (18.3%)Missing2 (4.3%)0 DisclosuresVose:Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage:Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

Management of Perioperative Anticoagulation in Patients with VWD

▪Objectives: von Willebrand disease (VWD) is the most common hereditary bleeding disorder. This study reviews the management of perioperative anticoagulation in patients with VWD undergoing surgical procedures. Risk factors for VTE with von Willebrand factor (VWF) concentrate use are older age, previous VTE, obesity, surgery, hormone replacement therapy use, antifibrinolytic therapy use and high post infusion FVIII levels. Currently, there are few data from randomized clinical trials assessing efficacy and possible complications of perioperative VTE prophylaxis in VWD patients.Methods: A total number of 116 surgeries were performed (minor: n=64 and major: n=52) in this retrospective, single-centre study. They were divided into groups of perioperative non-anticoagulation (n=54) and perioperative anticoagulation (n=62), who all received coagulation factor concentrate (CFC). Sub-analyses were done according to the type of concentrate used. Anticoagulation was performed using different low molecular weight heparins (LMWH) according to standard protocols or body-weight adapted doses in patients with either elevated body-mass-index or additional thrombosis risk factors. Blood samples had been collected pre- and post-surgery (up to 21 days) to analyse PT, aPTT, PFA, and trough levels of FVIII coagulant activity (FVIII:C), VWF activity (VWF:GPIbM) and antigen (VWF:Ag), respectively. Furthermore, the median doses of CFC/kg and the median total number of infusions were calculated. The rates of clinically overt thrombosis as well as bleeding were assessed during the post-operative phase.Results: The majority of patients suffered from VWD type 1 (104), 9 patients with type 2A, 2 with type 2M and 1 with type 3 VWD. Humate-P (H) was used in 55 patients and 61 patients received Wilate (W). Using W, we found parallel curves for FVIII:C, VWF-antigen and VWF:GPIbM, respectively. Using H, less concordance between VWF:Ag and VWF:GPIbM was visible and FVIII:C tends to increase between D3 to D10 in spite of decreasing VWF:Ag and VWF:GPIbM. This observation was visible in minor as well as major surgical procedures. LMWH (Enoxaparin, Nadroparin and Certaparin) were used in doses between 30 and 100 mg/injection (mean 46.0 ± 18.5 mg/injection) and a mean of 32.2 ± 24.6 injections in total (range: 8-112). In one patient a significant haematoma occurred (1/116; 0.9%), also one thrombotic event was documented in a different patient (1/116; 0.9%).Conclusion: Using standard dose LMWH in patients with no overt increased thrombosis risk as well as body-weight-adapted LMWH in high risk patients seem to be safe and effective in VWD patients receiving coagulation factor concentrate perioperatively. However, prospective randomized comparative studies are required to determine the optimal indication as well as type of anticoagulation according to the CFC treatment regimen in this setting. DisclosuresNo relevant conflicts of interest to declare.

Low molecular weight heparin once versus twice for thromboprophylaxis following esophagectomy: a randomised, double-blind and placebo-controlled trial.

Venous thromboembolism (VTE) remained common complication following surgical resection of esophageal cancer. In this prospective randomized double-blind placebo-controlled trial (NCT01267305), we aim to compare the safety and efficacy between low molecular weight heparin (LMWH) once-daily (QD) and twice-daily (BID) for the prophylaxis of VTE following esophagectomy. During August 2012 to July 2013, patients underwent esophagectomy were randomly assigned to nadroparin calcium QD (4,100 AxaIU qd + placebo qd, group QD), or nadroparin calcium BID (4,100 AxaIU q12h, group BID) in the prophylaxis of VTE. All patients received thrombelastography (TEG) before and 0/24/48/72 hours after operation. Daily vascular ultrasound of lower extremities was followed during the first 7 postoperative days to confirm the suspected deep venous thrombosis (DVT). Cumulatively postoperative chest drainage at 72 hours after the surgery was collected to identify the difference in volume and red blood cell (RBC) counts between the two groups. Any bleeding events and thromboembolic events were also documented. A total of 117 patients were enrolled in this study, and 111 eligible patients were randomly assigned (group QD: 55 patients; group BID: 56 patients). Patients' clinical features were close between the two groups. TEG analysis [R time, K time, alpha angel and maximum amplitude (MA)] before and instantly after operation showed nearly identical results. However, compared with group QD, all TEG measurements of 24/48/72 hours postoperatively showed significantly prolonged R time and K time, and decreased alpha angel in group BID. In ultrasound follow-ups, a total of four cases of DVT (four cases in group QD and no case in group BID) were found in this cohort (7.27% versus 0%, P=0.046), and one case of pulmonary embolism (PE) (in group QD) was observed. The incidence of VTE was lower in group BID (9.09% versus 0%, P=0.032). At 72 hours after surgery, the cumulative volume of chest drainage were close between these two groups (1,001.39±424.58 versus 1,133.61±513.93 mL, P=0.406). RBC counts in chest drainage were also identical between two groups [(2.56±1.98)×10(5) versus (2.71±4.67)×10(5), P=0.61]. No patient died due to VTE or bleeding events. For the prophylaxis of VTE, BID LMWH provided more potent efficacy and equal safety when compared to QD LMWH in patients undergoing selective esophagectomy. Further study based on larger population is required to confirm these findings.

Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis: the Cancer-DACUS Study.

We evaluated the role of residual vein thrombosis (RVT) to assess the optimal duration of anticoagulants in patients with cancer who have deep vein thrombosis (DVT) of the lower limbs. Patients with active cancer and a first episode of DVT treated with low molecular weight heparin (LMWH) for 6 months were eligible. Patients were managed according to RVT findings: those with RVT were randomly assigned to continue LMWH for an additional 6 months (group A1) or to discontinue it (group A2), and patients without RVT stopped LMWH (group B). The primary end point was recurrent venous thromboembolism (VTE) during the 1 year after disconinuation of LMWH, and the secondary end point was major bleeding. Analyses are from the time of random assignment. Between October 2005 and April 2010, 347 patients were enrolled. RVT was detected in 242 patients (69.7%); recurrence occurred in 22 of the 119 patients in group A1compared with 27 of 123 patients in group A2. The adjusted hazard ratio (HR) for group A2 versus A1 was 1.37 (95% CI, 0.7 to 2.5; P = .311). Three of the 105 patients in group B developed recurrent VTE; adjusted HR for group A1 versus B was 6.0 (95% CI, 1.7 to 21.2; P = .005). Three major bleeding events occurred in group A1, and two events each occurred in groups A2 and B. The HR for major bleeding in group A1 versus group A2 was 3.78 (95% CI, 0.77 to 18.58; P = .102). Overall, 42 patients (12.1%) died during follow-up as a result of cancer progression. In patients with cancer with a first DVT, treated for 6 months with LMWH, absence of RVT identifies a population at low risk for recurrent thrombotic events. Continuation of LMWH in patients with RVT up to 1 year did not reduce recurrent VTE.

The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta‐analysis of randomized trials

Tumors may exploit the coagulation system to enhance the survival and dissemination of cancer cells. Some studies have suggested that heparin and low molecular weight heparin (LMWH) have antitumor effects. We reported a previous meta-analysis that suggested a modest improvement in overall survival with the use of LMWH in patients with cancer. Herein, we present the results of an updated systematic review and meta-analysis. To evaluate the effect of LMWH as compared with placebo or no anticoagulant on the overall survival in patients with solid cancers. We conducted a systematic review and meta-analysis of randomized trials evaluating the use of LMWH vs. placebo or no anticoagulant in cancer patients without venous thrombosis. A meta-analysis was conducted with a random-effects model, and data were analyzed by the use of odds ratios (ORs) and relative risks (RRs) calculated for 1-year overall mortality. We identified 724 potentially relevant studies, nine of which met our inclusion criteria, and reported data on 1-year overall mortality. Studies were heterogeneous regarding types of cancer and interventions, and included 5987 patients, 98.4% of whom had advanced-stage disease (III and IV). There was no discernible effect on mortality with the use of LMWH (pooled OR0.87, 95%CI0.70-1.08; RR0.94, 95%CI0.86-1.04). In contrast to the previous study, these results did not show a survival benefit in cancer patients receiving LMWH. The effect of LMWH on overall survival in patients with limited-stage disease still is unknown.

Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis

IntroductionPatients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis. Material and MethodsA retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3months after the index recurrent event. ResultsFifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3months (range 0.1 to 30.4months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. ConclusionEscalating the dose of LMWH seems effective and safe for managing patients with recurrent cancer-associated thrombosis despite anticoagulant therapy.

Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: systematic review and meta‐analysis

Low molecular weight heparins (LMWHs) are not approved for patients with mechanical heart valves (MHVs). However, in several guidelines, temporary LMWH off-label use in this clinical setting is considered to be a valid treatment option. Therefore, we reviewed the efficacy and safety of LMWHs in patients with MHVs. MEDLINE and CENTRAL databases were searched from inception to June 2013. Review articles and references were also searched. We included experimental and observational studies that compared LMWHs with unfractionated heparin (UFH) or vitamin K antagonists (VKAs). Data were analyzed and pooled to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for thromboembolic and major bleeding events. Statistical heterogeneity was evaluated with the I(2) -test. Nine studies were included: one randomized controlled trial (RCT) and eight observational studies, with a total of 1042 patients. No differences were found between LMWHs and UFH/VKAs in the risk of thromboembolic events (OR 0.67; 95% CI 0.27-1.68; I(2) = 9%) or major bleeding events (OR 0.66; 95% CI 0.36-1.19; I(2) = 0%). The best evidence available might support the temporary use of LMWHs as a prophylactic treatment option in patients with MHVs. However, conclusions are mostly based on observational data (with large CIs), and an adequately powered RCT is urgently needed in this clinical setting.

Co-administration of low molecular weight heparin enhances the profibrinolytic effect of warfarin through different mechanisms

Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance. Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively. In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis. Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings.

Direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE), is a serious complication of cancer and its treatment. Patients with cancer have 4- to 7-fold higher risk of developing VTE than those without cancer [1]. Cancer patients with concurrent VTE have approximately 12% risk of bleeding during anticoagulation therapy and up to 25% annual risk of recurrent VTE [1]. The occurrence of VTE may also cause a delay or discontinuation of anti-cancer treatments, including chemotherapy and surgery [2]. Therefore, development of VTE in cancer patients has been associated with an increased risk of death [1]. In general, patients with VTE require anticoagulation therapy to prevent thrombus extension and death, which was largely associated with fatal PE, and to prevent recurrence in the long-term [2]. Traditionally, warfarin has been a common treatment strategy for patients with VTE; the use of warfarin in cancer patients, however, might be limited by complications of cancer and its treatment, including drug reactions, malnutrition, and the frequent need for dose adjustment [3]. As a result, low-molecular-weight-heparin (LMWH) was introduced as a suitable alternative anticoagulant because of few drug interactions and lack of requirement for routine laboratory monitoring; thus, it has been actively investigated in the treatment of cancer-associated VTE. A decade ago, the results of the phase III CLOT trial, which compared initial and maintenance therapy with dalteparin to warfarin therapy after initial dalteparin treatment in patients with cancer-associated VTE, were reported [4]. In this study, long-term dalteparin therapy was significantly associated with lower rates of 6-month cumulative incidence of recurrent VTE (9% vs. 17%) [4]. Since this study, LMWH has been the standard of care for initial and long-term therapy of patients with cancer-associated VTE. However, LMWH for long-term therapy requires a daily subcutaneous injection for cancer patients with VTE, which makes them feel uncomfortable. Thus, unmet needs are still present in the management of cancer-associated VTE.

Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance?

Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.

Low molecular weight heparin for prevention of microvascular occlusion in digital replantation

The success of digital replantation is highly dependent on the patency of the repaired vessels after microvascular anastomosis. Antithrombotic agents are frequently used for preventing vascular occlusion. Low molecular weight heparin (LMWH) has been reported to be as effective as unfractionated heparin (UFH) in peripheral vascular surgery, but with fewer adverse effects. Its benefit in microvascular surgery such as digital replantation is unclear. To assess whether subcutaneous LMWH treatment improves the salvage rate of the digits in patients with digital replantation after traumatic amputation. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (October 2012), CENTRAL (2012, Issue 10) and trials databases. In addition, the authors searched PubMed, CNKI (China National Knowledge Infrastructure) and CEPS (Chinese Electronic Periodical Services), and sought additional trials from reference lists of relevant publications. We selected randomised or quasi-randomised controlled trials of LMWH in patients who received digital replantation. Two review authors independently extracted data and assessed the risk of bias of the included trials. Disagreements were resolved by discussion. Two randomised trials involving 114 patients with at least 122 replanted digits met the inclusion criteria and were included. Both trials compared the efficacy and safety of LMWH with UFH. We found no trials comparing LMWH with placebo or other anticoagulants. The data from the two included studies were insufficient for meta-analysis. The overall success rate of replantation did not differ between the LMWH and UFH groups, 92.3% versus 89.2% in one trial (risk ratio (RR) 1.03; 95% confidence interval (CI) 0.87 to 1.22) and 94.3% versus 94.15% in the other trial (RR 1.00; 95% CI 0.89 to 1.13). The incidence of both postoperative arterial and venous insufficiency were reported in one trial and did not significantly differ between the LMWH and UFH groups (RR 1.08; 95% CI 0.16 to 7.10 and RR 0.81; 95% CI 0.20 to 3.27, respectively). Direct and indirect causes of microvascular insufficiency were not reported in the trials. Different methods were used to monitor the adverse effects related to anticoagulation in the two trials. Bleeding tendency was monitored for the LMWH and UFH groups in one trial and was reported by the incidence of wound haemorrhage (11.5% versus 17.9%; RR 0.65; 95% CI 0.17 to 2.44), ecchymoses (3.8% versus 10.7%; RR 0.36; 95% CI 0.04 to 3.24), haematuria (3.8% versus 7.1%; RR 0.54; 95% CI 0.05 to 5.59), nasal bleeding (0% versus 7.1%; RR 0.21; 95% CI 0.01 to 4.28), gingival bleeding (0% versus 10.7%; RR 0.15, 95% CI 0.01 to 2.83) and faecal occult blood (0% versus 3.6%; RR 0.36; 95% CI 0.02 to 8.42). The bleeding tendency was increased in the UFH group but this was not statistically significant. This trial also monitored coagulability changes using parameters such as antithrombin activity, factor Xa activity, bleeding time, clotting time and activated partial thromboplastin time (aPTT). No comparison was made between the LMWH and UFH groups but all data consistently showed that coagulability was reduced more in the UFH group than in the LMWH group. The other trial reported a postoperative decrease in platelet count in the UFH group (preoperative 278.4 ± 18.7 x 10(9)/L, postoperative 194.3 ± 26.5 x 10(9)/L; P < 0.05) but not in the LMWH group (preoperative 260.8 ± 32.5 x 10(9)/L, postoperative 252.4 ± 29.1 x 10(9)/L; P > 0.05). Current limited evidence based on two small-scaled low-to-medium quality randomised trials found no differences in the success rate of replantation between LMWH and UFH, but a lower risk of postoperative bleeding and hypocoagulability after the use of LMWH. Further well-designed and adequately powered clinical trials are warranted.

Low molecular weight heparin in patients undergoing free tissue transfer following head and neck ablative surgery: review of efficacy and associated complications

Most microsurgeons report the use of anticoagulants in their routine practice. Anti-Xa concentrations are preferentially used to monitor treatment with low molecular weight heparin (LMWH). The aim of this retrospective study was to measure the therapeutic response to standard dosing with LMWH (using anti-Xa) in patients after ablative and reconstructive surgery for head and neck cancer, and to review the associated risk of bleeding. We retrospectively reviewed 153 patients who had undergone resection of primary or recurrent tumours of the head and neck with free flap reconstruction. In total, 173 free flap procedures were completed. Medical records were reviewed to find the anticoagulation regimen used, anti-Xa result, patients’ weight, and any associated complications. Fourteen patients returned to theatre because of bleeding; of these no cause was identified in 6 and a haematoma was evacuated. The distribution of unexplained haematoma was similar for all dose regimens of dalteparin. Anti-Xa results were available in 47 cases, and of these, 22 (47%) were within the prophylactic range (0.2IU/ml or more). Our results highlight the high incidence of inadequate response to standard prophylactic doses of LMWH in patients with head and neck cancer. Increasing the dose of dalteparin does not seem to increase the risk of bleeding or formation of a haematoma. These findings may be transferable to other surgical specialties.

Is low-molecular-weight heparin safe for venous thromboembolism prophylaxis in patients with traumatic brain injury? A Western Trauma Association multicenter study

Venous thromboembolism (VTE) is a significant risk in trauma patients. Although low-molecular weight heparin (LMWH) is effective in VTE prophylaxis, its use for patients with traumatic intracranial hemorrhage remains controversial. The purpose of this study was to evaluate the safety of LMWH for VTE prophylaxis in blunt intracranial injury. We conducted a retrospective multicenter study of LMWH chemoprophylaxis on patients with intracranial hemorrhage caused by blunt trauma. Patients with brain Abbreviated Injury Scale score of 3 or higher, age 18 years or older, and at least one repeated head computed tomographic scan were included. Patients with previous VTE; on preinjury anticoagulation; hospitalized for less than 48 hours; on heparin for VTE prophylaxis; or required emergent thoracic, abdominal, or vascular surgery at admission were excluded. Patients were divided into two groups: those who received LMWH and those who did not. The primary outcome was progression of intracranial hemorrhage on repeated head computed tomographic scan. The study included 1,215 patients, of which 220 patients (18.1%) received LMWH and 995 (81.9%) did not. Hemorrhage progression occurred in 239 of 995 control subjects and 93 of 220 LMWH patients (24% vs. 42%, p < 0.001). Hemorrhage progression occurred in 32 patients after initiating LMWH (14.5%). Nine of these patients (4.1%) required neurosurgical intervention for hemorrhage progression. Patients receiving LMWH were at higher risk for hemorrhage progression. We were unable to demonstrate safety of LMWH for VTE prophylaxis in patients with brain injury. The risk of using LMWH may exceed its benefit. Therapeutic study, level IV.

The Therapeutic Management of Bleeding and Thrombotic Disorders Complicating CNS Malignancies

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

Compliance of recommendations with French clinical practice in the management of thromboembolism in patients with cancer: The CARMEN study.

1580 Background: Long-term treatment with low-molecular-weight heparin (LMWH) is recommended for treatment of venous thromboembolism (VTE) in cancer patients. Few data are available on compliance in this population. Our study measured whether the management of VTE in patients with cancer was consistent with French recommendations. Methods: Compliance with recommendations (CR+) was analysed according to malignancy and VTE from a 500-patient cross-sectional observational study run between May and October 2010. CR+ was defined as the compliance to initial 10-day treatment followed by long-term LMWH for at least 3 months, avoiding LMWH in patients with renal insufficiency (SRI). All inpatients with a diagnosis of cancer and VTE of less than 6 months were included in the study. Results: Of 500 patients included in 47 centers, 242 (49%) were male, 81 (18%) had local (T+), 83 (18%) had loco-regional (N+) and 287 (64%) had metastatic malignancies. Malignancies were gastro-intestinal (25%), gynaecologic (23%), pulmonary (21%), haematological (14%), urologic (10%) or other (8%). Twelve patients had SRI. Overall, treatment was CR+ in 289/500 patients (58% [95% CI 53%-62%]). Out of 12 patients with SRI only 3 (25%) were treated long-term with vitamin K antagonists (VKA), as usually recommended. Tumour site influenced CR+ (p=0.02). Treatment for haematological malignancy was poorly compliant with recommendations (32%) while patients with lung malignancy had the best compliance (68%). TNM stage and VTE location had no influence on treatment compliance. Conclusions: In French practice, treatment of cancer-related VTE is CR+ in 58% of cases. TNM stage and VTE location do not influence compliance which remains insufficient, especially in patients with haematological malignancy. [Table: see text]

P10 Risks of low molecular weight Heparin in suspected pulmonary embolism

BackgroundNational Patients Safety Agency (NPSA) issued a statement in July 2010 highlighting the risks associated with the prescription of low molecular weight Heparins (LMWHs). Evidence of harm has been reported...

Prospective Evaluation of the Risk of Thromboembolic Complications in Patients Treated with Lenalidomide-based Therapy and Genetic Associations

Abstract▪2872▪This icon denotes a clinically relevant abstractThe introduction of IMiDs (thalidomide, lenalidomide and recently pomalidomide) has been a major advance in the treatment of multiple myeloma. These agents have shown significant efficacy both in the relapsed/refractory setting and at the initial therapy of the disease, especially when combined with dexamethasone. However, it has been recognized that all IMiDs are associated with a significant increase in the risk of thromboembolic complications, especially when they are combined with high dose dexamethasone and chemotherapy. Genetic and environmental factors may modulate the risk for venous thromboembolism (VTE). Specific genetic polymorphisms have been associated with an increased risk of thromboembolic complications in patients treated with thalidomide-based regimens and who did not receive standard thromboprophylaxis. These single nucleotide polymorphisms (SNPs) have not been evaluated in patients treated with lenalidomide.In order to evaluate the frequency of thromboembolic complications in patients treated with lenalidomide, we analyzed 200 patients treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients treated with lenalidomide-based regimens received low dose aspirin, unless there was a clear indication for other form of thromboprophylaxis (low molecular weight heparins (LMWH) or warfarin) due to: atrial fibrillation, prior thromboembolic event or immobilization (Dimopoulos et al, Leukemia 2011;25 :749–60). We also screened 6 SNPs that have been associated with increased VTE risk in patients treated with thalidomide by direct sequencing of peripheral blood derived genomic DNA. The analysis included ALDH1A1 (rs610529), CHEK1 (rs506504), CINP (rs7011), NFKB1 (rs3774968), TNFRSF17 (rs19222317), XRCC5 (rs2440) in 83 patients who received lenalidomide-based therapy.Sixty seven patients were previously untreated: 54 received first line therapy with lenalidomide plus low dose (weekly) dexamethasone (Rd) and 13 received lenalidomide with melphalan and prednisone (MPR). Among 133 previously treated patients, 84 received lenalidomide plus high dose dexamethasone (RD) and 49 received lenalidomide plus high dose dexamethasone with bortezomib (BRD). Thromboprophylaxis consisted of low dose aspirin (100 mg daily) in 165 (82.5%) patients, LMWH in 20 (10%) patients and warfarin in 15 (7.5%) patients.Eleven patients (5.5%) suffered a venous thromboembolic event (VTE), which included 8 episodes of deep vein thrombosis (DVT) while 3 patients suffered pulmonary embolism. None of the patients died because of the VTE. All VTEs occurred in patients who were receiving aspirin prophylaxis, thus, the frequency of VTE in patients receiving aspirin was 7% vs. 0% for patients receiving LMWH or warfarin. The frequency of VTEs was 9.4% for previously untreated and 5.4% for previously treated patients. Among previously treated patients, 5.6% of patient receiving RD suffered a VTE vs. 4.9% receiving BRD.We then analyzed 73 patients who received low dose aspirin, 7 of which developed VTE, for possible associations of VTE risk with specific SNPs. A trend towards increased risk for VTEs was found for 3 SNPs in genes involved in response to DNA damage and cytokine mediated apoptosis. The frequency of SNPs in patients that developed VTE vs. the ones without a thromboembolic event is the following: CHEK1_rs506504 (11% vs. 0%), XRCC5_rs2440 (15% vs. 8%) and NFKB1_rs3774968 (17% vs. 7%). For patients carrying all three SNPs, VTE rates were 50%.In conclusion, the frequency of VTE in patients treated with lenalidomide-based regimens was 5.5% but all events appeared in patients who received thromboprophylaxis with low dose aspirin. The administration of LMWH in patients at high risk for thromboembolic complications (atrial fibrillation, prior thromboembolic event or immobilization) may abrogate the risk of VTE. The identification of SNPs that confer susceptibility to thrombosis in patients treated with lenalidomide may help stratify patients according to risk for VTE and guide the choice of appropriate thromboprophylaxis. Disclosures:Dimopoulos:Celgene: Honoraria.

Safety and Efficacy of Heparin or Enoxaparin Prophylaxis in Blunt Trauma Patients With a Head Abbreviated Injury Severity Score &gt;2

Timing and type of chemoprophylaxis (CP) that should be used in patients with traumatic brain injury (TBI) remains unclear. We reviewed our institutions experience with low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in TBI. The charts of all TBI patients with a head abbreviated injury severity score >2 (HAIS) and an intensive care unit length of stay >48 hours admitted during a 42-month period between 2006 and 2009 were reviewed. CP was initiated after intracranial hemorrhage was considered stable. We reviewed all operative notes and radiologic reports in these patients to analyze the rate of significant intracranial hemorrhagic complications, deep venous thrombosis, or pulmonary embolus. A total of 386 patients with TBI were identified; 158 were treated with LMWH and 171 were treated with UFH. HAIS was significantly different between the LMWH (3.8 ± 0.7) and UFH (4.1 ± 0.7) groups; the time to initiation of CP was not. The UFH group had a significantly higher rate of deep venous thrombosis and pulmonary embolus. Progression of ICH that occurred after the initiation of CP was significantly higher in the UFH-treated patients (59%) when compared with those treated with LMWH (40%). Two patients in the UFH group required craniotomy after the initiation of CP. LMWH is an effective method of CP in patients with TBI, providing a lower rate of venous thromboembolic and hemorrhagic complications when compared with UFH. A large, prospective, randomized study would better evaluate the safety and efficacy of LMWH in patients suffering blunt traumatic brain injury.

Guidelines on oral anticoagulation with warfarin – fourth edition

Guidelines on oral anticoagulation with warfarin – fourth edition

Comparison of Low Molecular Weight Heparin With Unfractionated Heparin During Percutaneous Coronary Interventions: A Meta-Analysis

To conduct a meta-analysis of the current evidence to evaluate the safety and efficacy of low molecular weight heparin (LMWH) as compared to unfractionated heparin (UFH). Several studies have demonstrated the therapeutic advantage of LMWH over UFH in the medical management of acute coronary syndromes. However, evidence comparing the 2 in percutaneous coronary interventions (PCI) is inconclusive. Previously published meta-analysis did not include some large-scale trials. We performed a systematic literature search for randomized clinical trials that compared LMWH and UFH in urgent or elective PCI. Studies that evaluated efficacy end points [composite of nonfatal myocardial infarction (MI) and death with or without target vessel revascularization] and bleeding end points were included. Studies were excluded if they involved coadministration of thrombolytics. Data were extracted on an intention-to-treat basis. Heterogeneity of the studies was analyzed by Cochran Q statistics. The Mantel-Haenszel fixed-effect model was used to calculate combined relative risks for outcomes where studies were homogenous and the random effect model when the studies were heterogenic. Fourteen studies involving 12,394 patients were included. The efficacy and bleeding risk of LMWH in patients undergoing PCI were comparable with UFH. A subgroup analysis of studies using intravenous or intraarterial administration of LMWH, demonstrated them to be safer than UFH with comparable efficacy. LMWH is at least as efficacious and safe as UFH in patients undergoing PCI. Additionally, evidence suggests that LMWH, when used intravenously, is associated with lower bleeding risks when compared with UFH.