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

Introduction

Patients 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 Methods

A 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 3 months after the index recurrent event.

Results

Fifty-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 2.3 months (range 0.1 to 30.4 months). 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.

Conclusion

Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancer-associated thrombosis despite anticoagulant therapy.     

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

Background and Objective

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.

Patients and Methods

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.

Results

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.

Conclusions

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.     

Unprovoked proximal venous thrombosis is associated with an increased risk of asymptomatic pulmonary embolism

Introduction

Pulmonary embolism (PE) is common in patients with deep venous thrombosis (DVT). The outcome of DVT with concomitant symptomatic PE is worse than the outcome of isolated DVT. The risk factors for DVT and simultaneous asymptomatic PE have not been systematically studied yet.

Aim

To evaluate the frequency and risk factors for asymptomatic PE in patients with DVT.

Patients/methods

In 155 consecutive patients with a first episode of DVT and no PE symptoms, a ventilation-perfusion lung scan was performed. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated and concentrations of D-dimer, high-sensitivity CRP (hsCRP), tissue plasminogen activator (t-PA) and troponin were measured. Laboratory tests for thrombophilia were performed.

Results

Asymptomatic PE was present in 36% of patients. No differences in gender, age, BMI and WHR were found between the patients with and without PE. PE was more common in patients with proximal DVT than in those with distal DVT (42% vs. 17%, p < 0.01), and in patients with unprovoked DVT compared to patients with provoked DVT (51% vs. 28%, p < 0.01). The risk of silent PE was the highest in patients with unprovoked proximal DVT (OR, 6.9; 95% CI, 2.3–21.0). Patients with asymptomatic PE had significantly higher values of D-dimer, hsCRP, t-PA and troponin than patients with isolated DVT.

Conclusions

Asymptomatic PE affected more than one third of patients with a first DVT. Unprovoked proximal DVT is the most important risk factor for the occurrence of silent PE.     

The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin

Introduction

Heparin is known to efficiently attenuate metastasis in various tumour models by different mechanisms including inhibition of tumour cell contacts with soluble and cellular components such as inhibition of heparanase or P- and L-selectin. We recently showed that heparin efficiently binds to VLA-4 integrin in melanoma cells in vitro. Here we describe VLA-4 integrin as a mediator of melanoma metastasis that is inhibited by the low molecular weight heparin (LMWH) Tinzaparin.

Materials and Methods

sh-RNA-mediated knock-down of VLA-4 integrin in B16F10 murine melanoma cells (B16F10-VLA-4kd) was performed and cell binding characteristics were investigated in vitro. Experimental metastasis of B16F10-VLA-4kd and B16F10 cells and interference by Tinzaparin were analysed in mice.

Results

VLA-4 knock-down of B16F10 cells resulted in loss of VCAM-1 binding, but preserved the capacity to bind platelets through P-selectin. The observed reduced metastasis of B16F10-VLA-4kd cells confirmed the role of VLA-4 in this process. However, loss of melanoma VLA-4 function hardly further affected reduction of metastasis in P-selectin deficient mice. Tinzaparin treatment of mice injected with B16F10 and B16F10-VLA-4kd cells significantly reduced metastasis suggesting its potential to block both P- and L-selectin and VLA-4 in vivo. The use of N-acetylated heparin, which has no VLA-4 binding activity but blocks P- and L-selectin was less efficient than Tinzaparin in mice injected with B16F10 cells and B16F10-VLA-4kd cells.

Conclusion

These findings provide evidence that heparin inhibits experimental melanoma metastasis primarily by blocking VLA-4 and P-selectin.     

Molecular basis and thrombotic manifestations of antithrombin deficiency in 15 unrelated Chinese patients

Introduction

Antithrombin (AT) deficiency is associated with an increasing risk of thrombosis.

Materials and methods

15 unrelated patients with AT deficiency defined by thrombophilic assays were recruited and detailed clinical information about patients, focusing on the personal and family history of thromboembolism (TE), were recorded. Mutation analysis was performed by direct sequencing of an AT gene (SERPINC1) in the patients and their family members.

Results

A total of 15 heterozygous causative mutations, each being identified in one family, were identified. Five mutations (33.3%) were reported here for the first time, including three null mutations (Ser36X, Lys70X and Try307X) and two missense mutations (Phe123Cys and Leu340Phe) probably impairing the structural integrity and stability of protein based on the AT structural analysis. Of the 15 patients, 33.3% (5/15) had additional risk factors and only one patient presented with additional genetic alteration causing an early onset of thrombosis. Fourteen patients (93.9%) suffered from multisite recurrent thrombotic episodes after a first episode of thrombosis. 93.3% of the patients experienced deep vein thrombosis (DVT) and 40.0% presented with mesenteric venous thrombosis (MVT). In addition, both venous and arterial thrombosis was present in two unrelated patients. 51.0% subjects with AT deficiency in the 15 unrelated pedigrees experienced TE events.

Conclusions

Prophylactic anticoagulation may be suggested in AT-deficient patients to avoid the recurrent and multisite thrombosis. The association of primary MVT and AT deficiency is highlighted.     

Incidence and time course of asymptomatic deep vein thrombosis with fondaparinux in patients undergoing total joint arthroplasty

Introduction

There are many reports concerning fondaparinux prophylaxis of asymptomatic deep vein thrombosis (DVT) after total hip arthroplasty (THA) or total knee arthroplasty (TKA), but little is known about the time course of aymptomatic DVT development during the administration of fondaparinux. The aim of the present study was to define the incidence and time course of aymptomatic DVT development during administration of fondaparinux, and to assess the efficacy of fondaparinux in resolving DVT.

Materials and Methods

We studied consecutive71 patients who underwent THA surgery, and 30 patients who underwent TKA surgery with fondaparinux prophylaxis. Patients received once-daily subcutaneous injections of 2.5 mg of fondaparinux for 14 days after surgery. DVT was diagnosed by ultrasonography, and it was scheduled on the day of surgery on day 1, day 4, and day 14 after surgery.

Results

In patients who received fondaparinux for 14 days after THA surgery, the incidence of DVT was 0% on the day of the surgery, 13.6% at day 1, 27.1% at day 4, and 11.9% at day 14. In patients who received fondaparinux for 14 days after TKA surgery, the incidence of DVT was 4.2% on the day after surgery, 50.0% at day 1, 58.3% at day 4, and 20.8% at day 14. The incidence of DVT after THA or TKA surgery at day 14 was significantly reduced compared to that at day 4.

Conclusion

The incidence of asymptomatic DVT up to day 4 was high, but with 14 days continued treatment of fondaparinux, the incidence of asymptomatic DVT occurring at postoperative day 4 was significantly reduced at day 14.     

Development of a new laboratory test to evaluate antithrombin resistance in plasma

Introduction

We recently reported a variant prothrombin (p.Arg596Leu: prothrombin Yukuhashi) that confers antithrombin resistance to patients with hereditary thrombosis. To detect antithrombin resistance in plasma, we devised a laboratory test analyzing the kinetics of thrombin inactivation using antithrombin.

Materials and Methods

After incubation with prothrombin activator components (phospholipids, CaCl₂, and snake venom), samples were treated with excess antithrombin in the presence or absence of heparin for various time periods. Subsequently, H-D-Phe-Pip-Arg-p-nitoranilide was added and changes in absorbance/min (ΔA/min) were measured at 405 nm.

Results

After 1 min inactivation using antithrombin and heparin, the relative residual thrombin activity of recombinant mutant prothrombin (34.3% ± 2.2%) was higher than that of the wild-type (6.3% ± 1.2 %). After 30 min without heparin, the relative residual thrombin activity of recombinant mutant prothrombin (95.8% ± 0.4%) was higher than that of the wild-type (10.1% ± 1.7%), indicating that this assay could detect antithrombin resistance of the variant 596Leu prothrombin. Moreover, warfarinized plasmas from 2 heterozygous patients with prothrombin Yukuhashi mutation clearly showed higher values of the relative residual thrombin activity than those from 5 thrombosis patients lacking the mutation in the presence or absence of heparin.

Conclusions

We have devised a laboratory test to detect antithrombin resistance in plasma by analyzing the kinetics of thrombin inactivation using antithrombin. This assay may be useful for detecting antithrombin resistance in plasma, even in warfarinized patients.     

Clinical course and predictive factors for complication of inferior vena cava filters

Rationale

The use of inferior vena cava (IVC) filters is associated with various complications. We aimed to elucidate the clinical course and predictive factors for complications of IVC filters, especially IVC penetration

Methods

A retrospective observational study was performed in 45 adult patients with retrievable IVC filters and follow-up computed tomography (CT) between January 2003 and December 2012. Primary outcomes were the prevalence and predictive factors of IVC penetration. Secondary outcome was other complications of IVC filters.

Results

IVC penetration following filter placement occurred in 87.6% of patients, and 57.8% of those involved significant penetration. Embedding of filter tips, suggestive of lateral tilting, was observed in 51.1%. Both Vertebral body erosions and aortic penetrations were seen in 4.4%, but they were asymptomatic. Longer indwelling duration of the IVC filter was significantly associated with a higher grade of IVC penetration, and the risk of significant IVC penetration increased in patients with the filter indwelling time of more than 20 days and an IVC diameter of less than 24.2 mm.

Conclusions

In patients with a retrievable IVC filter, IVC penetration on CT was common, and significant IVC penetration was associated with a longer indwelling time of the IVC filter and a lesser IVC diameter.     

MiR-150 enhances the motility of EPCs in vitro and promotes EPCs homing and thrombus resolving in vivo

Introduction

Deep venous thrombosis (DVT) is one of the common peripheral vascular diseases. The recruitment and migration of bone marrow-derived endothelial progenitor cells (EPCs) to the sites of venous thrombus are necessary in the process of thrombus organization and recanalization. Our objective was to investigate the functional role of miR-150 in rat EPCs and its potential application in deep venous thrombosis.

Materials and Methods

Rat EPCs were cultured and transfected with miR-150 mimics and inhibitor. Wound healing assay, transwell migration assay and matrigel tube formation assay were performed to elucidate the effect of miR-150 of rat EPCs. Lentiviral construct expressing miR-150 was transfected into EPCs and the EPCs were injected to rat models of DVT. The rats were sacrificed on the day of 7 and 14 after the transplantation and the histological study was performed. Luciferase reporter assay and Western blot were performed to evaluate rat miR-150 regulates the expression of c-Myb.

Results

MiR-150 significantly promoted the migration and tube formation ability of EPCs in vitro and enhanced EPCs’ homing, organization and resolution ability in vivo. Overexpression of miR-150 significantly reduced the protein level of c-Myb and repressed the activity of a luciferase reporter containing both of the two predicted miR-150 binding sites in c-Myb 3’-UTR, indicating that c-Myb may be a miR-150 target gene.

Conclusion

MiR-150 enhanced the migration, tube formation, homing, thrombus recanalization and resolution ability of rat EPCs. Restoring miR-150 in EPCs revealed potential application in DVT therapy.     

Efficacy and Safety of Anticoagulant Therapy for the Treatment of Acute Cancer-Associated Thrombosis: A Systematic Review and Meta-Analysis

Background

Current clinical practice guidelines all recommend the use of therapeutic doses of low molecular weight heparins (LMWH) for the initial and long-term treatment of cancer-related thrombosis. The use of vitamin-K antagonists (VKA) is acceptable if LMWH is not available. Direct oral anticoagulants (DOACs) have been shown to be comparable to conventional therapy for the acute treatment of VTE but their efficacy and safety in cancer patients remains uncertain.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the EBM reviews. Randomized controlled trials (RCTs) reporting rates of recurrent VTE and major bleeding in cancer patients were included. Relative risks (RR) (95% confidence intervals (CI)) for these outcomes were generated.

Results

A total of 9 RCTs (2310 patients) were included in our analysis. In comparison to VKA, LMWH showed a significant reduction in recurrent VTE events (RR: 0.52; 95% CI: 0.36 to 0.74) whereas DOACs did not (RR: 0.66; 95% CI: 0.39 to 1.11). LMWH was associated with a non significant increase in the risk of major bleeding (RR: 1.06; 95% CI: 0.5 to 2.23) whereas DOACs showed a non significant reduction (RR: 0.78; 95% CI: 0.42 to 1.44). Annualized risks of recurrent VTE and major bleeding among patients randomized to VKA were higher in the LMWH studies as compared to the studies assessing DOACs suggesting that a higher risk cancer population were enrolled in the LMWH studies.

Conclusions

LMWH should be used for the treatment of acute cancer-associated thrombosis. The use DOACs cannot be supported until trials comparing them to LMWH are conducted.     

Safety of Chemical DVT Prophylaxis in Severe Traumatic Brain Injury with Invasive Monitoring Devices

Background

Patients with traumatic brain injuries (TBIs) have an increased risk of developing a deep vein thrombosis (DVT), but the risk of hemorrhage expansion with intracranial monitoring devices remains unknown. We sought to determine the safety of chemical DVT prophylaxis in severe TBI patients with invasive intracranial pressure monitors.

Methods

We retrospectively reviewed all patients with severe TBI admitted to the neurosurgical intensive care unit of a large tertiary care center over a three-year period.

Results

155 patients were included with an incidence of DVT of 12 %. The median length of time to a stable head CT was 2 days, and the median time to initiation of chemical DVT prophylaxis was 3.6 days. The odds of DVT increased with intraparenchymal hemorrhage [OR 7.21, 95 % CI (1.43–36.47), p = 0.0169], non-White ethnicity [OR 7.86, 95 % CI (1.23–50.35), p = 0.0295], female gender [OR 13.93, 95 % CI (2.47–78.73), p = 0.0029], smoking [OR 4.32, 95 % CI (1.07–17.51), p = 0.0405], no anticoagulation [OR 25.39, 95 % CI (4.26–151.48), p < 0.001], and an IVC filter [OR 15.82, 95 % CI (3.14–79.76), p < 0.001]. Twenty-eight (18 %) of these subjects experienced in-hospital mortality. The risk of in-hospital death was significantly increased among those who did not receive anticoagulation. This study found no association between DVT formation, hemorrhage expansion, or increased risk from invasive monitoring devices between various doses of unfractionated heparin (UH) and low-molecular-weight heparin (LMWH).

Conclusion

We conclude that DVT prophylaxis with either LMWH or UH is safe with intracranial pressure monitors in place.

     

Association of F11 polymorphism rs2289252 with deep vein thrombosis and related phenotypes in population of Latvia

Introduction

Deep vein thrombosis (DVT) has a strong inherited predisposition that is partly explained by the strong genetic risk factors such as mutations in factor V, prothrombin, antithrombin III, protein C and S genes. Only recently the first GWAS have been performed on DVT resulting in discovery of novel genetic variants, however, the information on the common polymorphisms predisposing to the risk of DVT is still scarce.

Materials and Methods

Here we selected six SNPs (rs5361 in SELE, rs2066865 in FGG, rs2227589 in SERPINC1, rs1613662 in GP6, rs13146272 in CYP4V2, rs2289252 in F11) reported to be associated with venous thrombosis conditions and studied the association of these common variants in selected case (n = 177) and control (n = 235) groups from population of Latvia. Genotyping was performed using TaqMan hybridization probe SNP genotyping assay.

Results

Patients with DVT had a significantly higher frequency of F11 rs2289252 polymorphism (p = 0.001; OR [95%CI] = 1.61 [1.20-2.14]). When stratified by recurrence of DVT the tendency was observed that the same SNP had higher OR value in group of DVT patients with repeated episodes of DVT compared to patients with single DVT episode (p = 0.009; OR [95%CI] = 2.27[1.22-4.21] and p = 0.009; OR [95%CI] = 1.52[1.11-2.08] respectively), but due to limited group of cases this finding should be replicated.

Conclusion

We conclude that F11 gene variant rs2289252 contribute to inherited forms of DVT incidence and correlation of other analysed SNPs should be explored in populations with greater sample size and associated with various thrombosis related traits.     

Overuse of Compression Ultrasound for Patients with Lower Extremity Cellulitis

Background

Compression ultrasound (CUS) is often ordered in hospitalized patients with cellulitis to assess for deep vein thrombosis (DVT). Despite this common practice, the rate of use and utility of CUS has not been well described.

Methods

We conducted a retrospective cohort study of adult patients with lower extremity cellulitis hospitalized between October 1, 2008 and September 30, 2013 at an academic medical center. Cases meeting inclusion criteria were reviewed for the use of CUS, the indication for CUS, the occurrence of DVT, and the 3 month follow-up occurrence of DVT after discharge.

Results

A total of 239 patients were identified using ICD-9 coding data with a discharge diagnosis of cellulitis or abscess of leg. Of these, 183 met criteria for inclusion in the study, 133 of whom had CUS to assess for DVT (73%). Of the 133 who received CUS, 11 studies found DVTs (8%). Of the 11 DVTs, 8 had been previously diagnosed, and 3 were new. Of the new DVTs, only one was ipsilateral to the leg with cellulitis.

Conclusion

Most patients admitted with lower extremity cellulitis received CUS to assess for DVT. Despite this common practice, the rate of acute ipsilateral DVT was low and matched the rate of acute contralateral DVT. Previously diagnosed DVTs were commonly re-imaged. Overall the use of CUS had minimal impact on patient management and the routine use of CUS to assess for DVT in hospitalized patients with cellulitis appears to be unnecessary.     

Incidence of thrombosis in children with tunneled central venous access devices versus peripherally inserted central catheters (PICCs)

Introduction

The recent proliferation of deep vein thrombosis in children has been attributed to the increased use of central venous catheters, specifically tunneled lines and peripherally inserted central catheters. A formal comparison of the incidence rate for deep vein thrombosis between tunneled lines and peripherally inserted central catheters has not been undertaken.

Methods

Children < 18 years of age who were admitted to Children’s Hospital Los Angeles from July, 2005 to July, 2012 were eligible for inclusion. Data were extracted from the hospital discharge database which includes data on all procedures and up to 20 diagnoses per admission. Diagnoses and procedures were identified by International Classification of Disease, Ninth Revision coding. Patients were excluded if they received more than one central line. Data collected included type of central line, deep vein thrombosis event, and underlying medical illnesses classified according to chronic complex conditions.

Results

Over the seven year study period there was an overall rate of 73 deep vein thromboses per 10,000 hospital discharges. Of the 6915 eligible subjects, 181 had a deep vein thrombosis for an overall incidence rate of 2.6%. There were 152 thrombi (2.6%) in subjects with peripherally inserted central catheters and 29 thrombi (3.1%) in subjects with tunneled lines [OR = .83 (0.55, 1.29), p = 0.38].

Conclusion

Despite the relative ease and simplicity of use of peripherally inserted central catheters leading to a substantial rise in their use, this study demonstrates that such lines pose a substantial risk for venous thrombosis and no difference in incidence was detected between such lines and tunneled lines.     

Two years outcome of isolated distal deep vein thrombosis

Background

Isolated distal deep vein thrombosis (IDDVT) is frequently found in symptomatic outpatients, but its long term outcome is still uncertain.

Aims

To assess IDDVT long term outcome and the impact of IDDVT characteristics on outcome.

Methods

In a prospective, single center study we enrolled symptomatic outpatients in whom IDDVT was detected by whole-leg compression ultrasonography. Patients with provoked IDDVT were treated with low molecular weight heparins (LMWH) for 30 days while those with unprovoked IDDVT received with vitamin K antagonists (VKA) for three months. The primary end-point was the rate of the composite of pulmonary embolism (PE), proximal deep vein thrombosis (DVT), and IDDVT recurrence/extension during 24 month follow-up.

Results

90 patients (age 61 ± 18, male 48.9%) were enrolled. Risk factors for thrombosis were reduced mobility (34.4%), obesity (25.3%), surgery (15.6%), and previous DVT (15.6%) and cancer in 8 patients (8.9%). Eighty-eight patients were treated (56 with LMWH and 32 with VKA). During follow-up (median 24 ± 2 months), 17 events were recorded, which included 3 PE (two in cancer patients), 4 proximal DVTs (one in cancer patient) and 10 IDDVT. Male sex (HR 4.73 CI95%: 1.55-14.5; p = 0.006) and cancer (HR 5.47 CI95%: 1.76-17.6; p = 0.003) were associated with a higher risk of complications, whereas IDDVT anatomical characteristics, anticoagulant therapy type, and provoked IDDVT were not.

Conclusions

The risk of recurrent venous thromboembolism after IDDVT may be relevant in male patients or in patients with active cancer. Larger studies are needed to address this issue.     

Low molecular weight heparin-induced increase in chylomicron-remnants clearance,is associated with decreased plasma TNF-α level and increased hepatic lipase activity

Objective

The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNFα-mediated inflammatory response. This, together with the known negative effect of TNF-α on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal.

Methods

Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8 hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF-α were measured.

Results

Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P < 0.01). Additionally, enoxaparin decreased plasma TNF-α by 22% (P < 0.01), increased hepatic lipase (HL) activity by 81% (P < 0.01), along with a 2-fold increase in ISI (P < 0.01). The decrease in CMR correlated with the reduction in TNFα and the increase in ISI and HL activity (R = 0.48, -0.68, - 0.56, respectively, p < 0.05). Significant correlations were also found between the reduction in TNFα and both the increase in ISI and increase in HL activity (R = - 0.43, -0.54, respectively, P < 0.05).

Conclusions

The association of the effect on post-prandial metabolism, plasma TNFα level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.     

Factor VIII contributes to platelet-fibrin thrombus formation via thrombin generation under low shear conditions

Introduction

Thrombus growth under low blood flow velocity plays an important role in the development of deep venous thrombosis (DVT). Increased plasma levels and activities of coagulation factor VIII (FVIII) comprise risk factors for DVT and pulmonary thromboembolism.

Objective

To localize FVIII in human venous thrombi of DVT and to determine whether FVIII contributes to thrombus formation under low shear conditions.

Methods

The localization of FVIII in venous thrombi obtained from patients with DVT was examined by immunohistochemistry. The role of FVIII in thrombus formation was investigated using a flow chamber system. Venous blood from healthy volunteers were incubated with an anti-FVIII monoclonal antibody (VIII-3776) or non-immunized mouse IgG₁. Blood samples were perfused on immobilized type III collagen at wall shear rates of 70/s and 400/s and then the surface area covered by platelets and fibrin was morphometrically evaluated. Prothrombin fragment 1+2 (PF1+2) generation was measured before and after perfusion.

Results

Venous thrombi of DVT comprised a mixture of platelets, fibrin and erythrocytes. Factor VIII appeared to be colocalized with glycoprotein IIb/IIIa, fibrin and von Willebrand factor in the thrombi. VIII-3776 specifically recognized the light chain of FVIII and prolonged the activated partial thromboplastin time (aPTT), but not prothrombin time (PT). The antibody significantly reduced platelets and fibrin covering, as well as PF1+2 generation at wall shear rates of 70/s and 400/s.

Conclusions

These results suggest that FVIII contributes to platelet aggregation and fibrin formation via thrombin generation under low shear conditions.     

Who are at risk for thromboembolism after arthroplasty? A systematic review and meta-analysis

Background

Thromboembolism, including deep venous thrombosis and pulmonary embolism, is a grave threat to patients undergoing total joint replacement. Using a systematic review and meta-analysis we asked whether gene mutations or polymorphisms could be risk factors for thrombosis after arthroplasty.

Methods

We performed a comprehensive search of Medline, PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure (CNKI), and Google Scholar, and identified 19 studies detailing genetic investigations of patients with thromboembolism following joint replacement.

Results

Our meta-analyses included 5149 patients who underwent arthroplasty surgery. Significant associations with venous thromboembolism were identified for factor G1691A (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.03 - 1.94, p = 0.03), prothrombin G20210A (OR 2.16, 95% CI, 1.27- 3.69, p = 0.005), and MTHFR/C677T/TT (OR 2.36, 95% CI 1.03 - 5.42, p = 0.04) in Caucasian populations. No significant gene mutation was identified in Asian populations.

Conclusion

This study suggests a way to identify patients scheduled for arthroplasty who are at higher risk of thrombosis, enabling individualized treatment.     

Risk of deep vein thrombosis in patients with cellulitis and erysipelas : A systematic review and meta-analysis

Introduction

The occurrence of deep vein thrombosis (DVT) is often considered in patients with cellulitis and erysipelas because of the common presentation of unilateral limb swelling, erythema and pain. Different authors however have reached different conclusions about the prevalence of DVT in these patients and for the need for compression ultrasound (CUS). The purpose of this study is to determine the prevalence of DVT in patients with cellulitis and erysipelas, and inform the utility of CUS.

Methods

A systematic literature search was conducted of Medline and Cochrane for studies that reported groups of patients with cellulitis or erysipelas who had CUS to evaluate for DVT. Study quality assessment was based on the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. The incidence rates from the included studies were pooled using a random-effects model to calculate an overall DVT rate. Individual and pooled DVT rates with corresponding upper and lower limits were graphed as a forest plot. Between-study heterogeneity was estimated using the I² statistic.

Results

Nine studies were included totaling 1054 patients with cellulitis or erysipelas with 18 DVTs. The overall pooled incidence rate was 2.1% (95% confidence interval, 0.5%-9.1%) for proximal DVT and 3.1% (95% confidence interval, 1.9%-4.9%) for any DVT. When analyzed separately, the pooled incidence rate for the three retrospective studies was 1.1% (95% CI, 0.6%-2.2%), while the rate for the six prospective studies was 7.8% (95% CI, 4.2%-14.2%).

Conclusion

The risk of DVT in cellulitis and erysipelas is low compared to the average risk of patients referred for CUS and comparable to low risk patients as determined by the commonly employed Wells criteria.