Factors associated with the development of superficial vein thrombosis in patients with varicose veins

Introduction

Superficial vein thrombosis (SVT) is a common and controversial clinical entity. Recent studies have demonstrated that SVT should be seen as a venous thromboembolism (VTE). The objective of this study was to investigate the prevalence of thrombophilia defects and to estimate the role of age, sex and body mass index (BMI) in patients with varicose veins (VVs) and SVT.

Materials and Methods

A total of 230 patients with VVs, 128 with, and 102 without SVT underwent thrombophilia testing included factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase and plasminogen activator inhibitor- 1 mutations, protein C, protein S (PS), anti-thrombin III and plasminogen deficiencies and levels of A₂ antiplasmin, activate protein C resistance and lupus anticoagulant. According to Clinical- Etiology- Anatomy- Pathophysiology (CEAP) classification patients were categorized in two subgroups: moderate disease (C_2,3) and severe disease (C_4,5,6). Age and body mass index were also assessed.

Results

The prevalence of thrombophilia defects was significantly higher in patients with moderate disease and SVT (p = 0.002). In the C_2,3 group, SVT was associated with PS deficiency (p = 0.018), obesity (p < 0.001), male gender (p = 0.047) and age (p < 0.001). There were no significant differences in patients with severe disease.

Conclusions

Age, male sex, obesity and PS deficiency are factors associated with SVT development among patients with VVs having moderate disease (C_2,3).     

Antithrombin deficiency in three Japanese families: One novel and two reported point mutations in the antithrombin gene

Introduction

Inherited antithrombin (AT) deficiency is associated with a predisposition to familial venous thromboembolic disease. We analyzed the AT gene in three unrelated patients with an AT deficiency who developed thrombosis.

Materials and Methods

We analyzed the SERPINC1 gene in three patients. Additionally, we expressed the three mutants in the COS-1 cells and compared their secretion rates and levels of AT activity with those of the wild-type (WT).

Results

We identified three distinct heterozygous mutations of c.2534C>T: p.56Arginine → Cysteine (R56C), c.13398C>A: p.459Alanine → Aspartic acid (A459D) and c.2703C>G: p.112 Proline → Arginine (P112R). In the in vitro expression experiments, the AT antigen levels in the conditioned media (CM) of the R56C mutant were nearly equal to those of WT. In contrast, the AT antigen levels in the CM of the A459D and P112R mutants were significantly decreased. The AT activity of R56C was decreased in association with a shorter incubation time in a FXa inhibition assay and a thrombin inhibition-based activity test. However, the AT activity of R56C was comparable to that of WT when the incubation time was increased.

Conclusions

We concluded that the R56C mutant is responsible for type II HBS deficiency. We considered that the A459D and P112R mutants can be classified as belonging to the type I AT deficiency.     

Low level of factor V is associated with development of deep-vein thrombosis in Japanese patients

Background

Factor V, having two functions (procoagulant and anticoagulant), is a key factor in blood coagulation, and low plasma levels of factor V may be a risk factor for thrombosis.

Objective

The levels of plasma factor V antigen (FV:Ag), and the phospholipid binding capability of Factor V (FV:PL-bound) were evaluated in patients with deep-vein thrombosis (DVT).

Methods

Levels of FV:Ag, and FV:PL-bound were expressed as a percentage of the normal level found in pooled plasma from control subjects. One hundred and twenty-three Japanese patients with deep-vein thrombosis (DVT) were included, with 100 age and sex-matched healthy control subjects.

Results

The FV:Ag, and FV:PL-bound values were significantly lower in DVT patients than in healthy subjects (p < 0.05 and p < 0.005, respectively). Among the 123 patients, 30 for FV:Ag (24.4%), and 32 for FV:PL (26%) had less than the arbitrary cutoff point (set at the 5th percentile of the value for FV:Ag and FV:PL-bound from healthy subjects), and the odds ratios (ORs) were 6.1 (95% confidence interval [CI], 2.3-16.5) and 6.7 (95%CI, 2.5-17.9), respectively. When patients with a deficiency of natural anticoagulants (antithrombin, protein C, and protein S) were excluded from the analysis, the ORs increased for all patients (6.6 for FV:Ag (95%CI, 2.4-18.3) and 7.4 for FV:PL-bound (95%CI, 2.7-20.3). Moreover, twenty-one (17%) of the 123 DVT patients, and 1 (1%) of 100 control subjects had values below the cutoff points for both FV:Ag and FV:PL-bound, and the OR was 21.6 (95%CI, 2.85-163.1).

Conclusions

These results suggest that low levels of factor V are associated with development of DVT, and may be a predictor for DVT.     

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.     

Normal reference ranges of antithrombin,protein C and protein S: Effect of sex,age and hormonal status

Introduction

Antithrombin (AT), protein C (PC) and protein S (PS) deficiencies are risk factors for venous thromboembolism. Overlapping values between heterozygous carriers and normal individuals often make a correct classification of a deficiency difficult. The aim of this study was to investigate the effect of sex, age, menopause and hormone therapy on natural anticoagulant plasma levels in a large group of healthy individuals, and to evaluate the need of separate reference ranges.

Materials and Methods

AT and PC were measured with a chromogenic assay, antigenic free PS with an ELISA test. To evaluate the effect of sex, age, oral contraception, hormonal status (and their interaction) on AT, PC and PS levels, linear regression models were used. Biological relevance and the value of the normal deviate z were chosen as rules to decide for separate reference ranges.

Results

The study population consisted of 1837 healthy adult individuals (741 men, 1096 women), aged 18-85 years (median age: 44 years). In men AT levels decreased after the age of 50 years. Men had higher levels of PS than women, particularly at young ages. In women, after correction for menopause, only PC levels increased with age. Menopause affected AT and PS, but not PC levels. Oral contraceptive intake was associated with a decrease of AT and PS, and an increase of PC levels.

Conclusions

For AT, PC and PS, sex- and age-specific normal reference ranges can be useful, in order to better discriminate true carriers of a natural anticoagulant deficiency.     

Comparison of catheter-related large vein thrombosis in centrally inserted versus peripherally inserted central venous lines in the neurological intensive care unit

Objective

To compare cumulative complication rates of peripherally (PICC) and centrally (CICVC) inserted central venous catheters, including catheter-related large vein thrombosis (CRLVT), central line-associated bloodstream infection (CLABSI), and line insertion-related complications in neurological intensive care patients.

Methods

Retrospective cohort study and detailed chart review for 431 consecutive PICCs and 141 CICVCs placed in patients under neurological intensive care from March 2008 through February 2010. Cumulative incidence of CRLVT, CLABSI, and line insertion-related complications were compared between PICC and CICVC groups. Risk factors for CRLVT including mannitol therapy during dwell time, previous history of venous thromboembolism, surgery longer than 1 h during dwell time, and line placement in a paretic arm were also compared between groups.

Results

During the study period, 431 unique PICCs were placed with cumulative incidence of symptomatic thrombosis of 8.4%, CLABSI 2.8%, and line insertion-related complications 0.0%. During the same period, 141 unique CICVCs were placed with cumulative incidence of symptomatic thrombosis of 1.4%, CLABSI 1.4%, and line insertion-related complications 0.7%. There was a statistically significant difference in CRLVT with no difference in CLABSI or line insertion-related complications.

Conclusions

In neurological critical care patients, CICVCs appear to have a better risk profile compared to PICCs, with a decreased risk of CRLVT. As use of PICCs in critical care patients increases, a prospective randomized trial comparing PICCs and CICVCs in neurological critical care patients is necessary to assist in choosing the appropriate catheter and to minimize risks of morbidity and mortality associated with central venous access.     

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.     

A systematic review on the effect of aspirin in the prevention of post-operative arterial thrombosis in patients undergoing total hip and total knee arthroplasty

Introduction

Major surgery is associated with increased risk of venous thromboembolism (VTE), which is decreased by anticoagulant drugs. Evidence is growing that major surgery is associated with increased risk of arterial thrombosis (AT). With the aim of testing aspirin ability in reducing the risk of post-operative AT, we performed a systematic review of studies in which acetylsalicylic acid (ASA) was compared to anticoagulant drugs in VTE prophylaxis of patients undergoing total hip replacement (THR) or total knee replacement (TKR).

Materials and Methods

Studies were identified by reviewing the reference of the ACCP guidelines and by electronic search of MEDLINE database from January 2012 to December 2013 and of the web database www.trialresultscenter.org.

Results

We analyzed 5 of the 78 studies that were identified by our search strategy; they included 5179 patients; the median follow-up was 90 days. The incidence of post-operative AT tended to be lower in ASA-treated patients, compared to anticoagulant-treated patients, although the difference did not reach statistical significance (OR 0.56, 95%CI 0.23-1.35). In contrast, the incidence of post-operative VTE tended to be higher in ASA-treated patients, compared to anticoagulant-treated patients (1.48, 95% CI 0.93-2.36).

Conclusions

Due to the heterogeneity and low quality of the studies, which do not allow firm conclusions, it is uncertain whether aspirin is effective in reducing the incidence of postoperative AT. Our results do emphasize the need for developing specifically designed studies to test the safety and efficacy of ASA in the prevention of post-operative AT.     

Residual vein thrombosis and onset of post-thrombotic syndrome: Influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene

Background

Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades.In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome.

Patients/Methods

In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity.Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n = 85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n = 83). All patients were treated according to current protocols and re-examined after 3, 12 and 36 months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome.

Results

We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36 months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment.

Conclusions

These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis.     

Genetic variants in Cell Adhesion Molecule 1 (CADM1): A validation study of a novel endothelial cell venous thrombosis risk factor

Introduction

In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family.

Materials and methods

We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n = 194), low protein S levels (n = 23), high factor VIII activity (n = 165) or factor V Leiden carriers (n = 580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls.

Results

We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels.

Conclusions

In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.     

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.     

Sources of variation in factor VIII, von Willebrand factor and fibrinogen measurements: Implications for detecting deficiencies and increased plasma levels

Objectives

Differences in pre-analytical and assay conditions, inappropriate reference ranges, or inflammation may have the potential to impair clinical decisions based on measurements of factor VIII (FVIII), von Willebrand factor (VWF) and fibrinogen (Fg). This study examined the impact on FVIII, VWF and Fg in plasma of freezing and thawing, different citrate anticoagulant concentrations, and inflammation, as determined by high-sensitivity C-reactive protein (hsCRP).

Materials and Methods

FVIII was determined prior to freezing and after thawing using a one-stage clotting assay (FVIII:C), an amidolytic assay (FVIII:AM) and an enzyme immunoassay (FVIII:Ag). Samples were anticoagulated with 106 or 129 mmol/L of citrate. FVIII, VWF and Fg were quantified in 300 individuals to establish reference ranges and to investigate associations with hsCRP.

Results

Freezing and thawing reduced FVIII:C and FVIII:AM markedly. FVIII coagulant activities were not significantly different between samples anticoagulated with 106 or 129 mmol/L of citrate, respectively. FVIII, VWF and Fg were significantly associated with hsCRP. FVIII:C was greater than FVIII:AM and FVIII:Ag in all experiments, indicating that the presence of activated FVIII may lead to overestimation of FVIII:C.

Conclusions

Standardized freezing and thawing of plasma samples appears to be indispensable if reliable FVIII results are to be obtained. Because inflammation can potentially mask deficiency states or mimic an increased risk of thrombosis, FVIII, VWF and Fg determinations should be supplemented by measurements of hsCRP.     

Haplotypes of the endothelial protein C receptor gene and Behçet's disease

Introduction

Behçet's disease is a vasculitis of unknown cause in which thrombosis occurs in about 25% of patients. Two haplotypes of the endothelial protein C receptor gene, H1 and H3, are associated with the risk of thrombosis. Thus, the objective of this study was to evaluate the influence of these haplotypes on the thrombosis risk in Behçet's disease.

Material and Methods

We evaluated the H1 and H3 haplotypes in 87 patients with Behçet's disease, 19 with and 68 without a history of thrombosis, and in 260 healthy individuals. We also measured protein C, activated protein C, and soluble endothelial protein C receptor levels in all individuals.

Results

The presence of the H1 haplotype seemed to protect Behçet's patients against thrombosis (odds ratio 0.21; 95% CI 0.1-0.8; p = 0.023), whereas the frequency of the H3 haplotype was lower in patients than in control individuals (0.19; 0.1-0.5; p = 0.006). Furthermore, the H1 haplotype was associated with increased levels of activated protein C, whereas the H3 haplotype was associated with the highest soluble endothelial protein C levels. Moreover, activated protein C levels were lower in patients with than in patients without posterior uveitis (p < 0.001).

Conclusions

These findings indicate that the H1 haplotype protects Behçet's patients from thrombosis, likely via increased levels of activated protein C, whereas individuals carrying the H3 haplotype seem to be protected from the clinical manifestations associated with Behçet's disease, probably via increased soluble endothelial protein C levels.     

Unexplained infertility: association with inherited thrombophilia

Introduction

Unexplained infertility represents one of the most common diagnoses in fertility care. Attention is being paid to the association between inherited thrombophilia and infertility causes. In this study we investigated the prevalence of inherited thrombophilia according to infertility causes.

Materials and methods

We studied Prothrombin gene G20210A mutation, Factor V Leiden, deficiencies in protein S and C and antithrombin in 930 Caucasian infertile women referred to Fertility Center of the Department of Sciences for Woman and Child's Health, University of Florence, of whom 230 with unexplained, 195 female and 283 male infertility, and in 240 women who have conceived naturally without hormonal stimulation therapy.

Results

A significant relationship between inherited thrombophilia [OR 95%CI 1.97 (1.05-3.68), p = 0.03] and unexplained infertility was observed, whereas no association between thrombophilia and female and male infertility was found. Significantly higher prevalence of prothrombin gene mutation in unexplained infertile women in comparison to that observed in fertile women was observed (5.7% vs 2.1% p = 0.04); the prevalence of the other thrombophilia determinants was higher, even if not significantly, in the unexplained infertile group.

Conclusions

This study demonstrates the relationship between inherited thrombophilia and unexplained infertility, thus suggesting the contribution of genetic components in modulating unexplained infertility, behind anovulation, male and tubal factor.     

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.     

Mortality and recurrence after treatment of VTE: long term follow-up of patients with good life-expectancy

Introduction

After completed anticoagulant treatment for acute VTE, both the subsequent mortality and risk of recurrent VTE are high, probably related to the frequent presence of serious disease in these patients.The aim of the study was to determine survival and recurrence in selected patients with good life-expectancy, and to evaluate risk factors.

Methods

The 323 patients were followed for median 7.4 years (range 4.1-11.9) after cessation of anticoagulation. Survival analysis and Cox-regression were used for univariate and multivariate analysis.

Results

The cumulative incidence of survival after 5 years was 93.4%. Standardised mortality ratio was 1.42 for men and 1.28 for women. Patients without a transient risk factor prior to the index VTE were associated with higher risk of mortality compared to risk of mortality in patients with a transient risk factor (hazard ratio (HR) 2.81; 95% CI 1.40-5.62). Recurrence of VTE after 5 years was 19.0%. A persistent risk factor or a spontaneous VTE was associated with higher risk of recurrence compared to a transient risk factor (HR 2.39; 95% CI 1.44-3.95). Elevated D-dimer levels increased the risk, and immobilisation prior to the index VTE reduced the risk of recurrence. Sex, age and thrombophilia were not independent risk factors for recurrence.

Conclusions

Despite a low mortality rate in this selected cohort, the recurrence rate and risk factors for recurrence were similar to findings reported in unselected populations. VTE unrelated to a transient risk factor was associated with increased mortality compared to mortality in patients with a transient risk factor.     

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.     

Incidental venous thromboembolism detected by PET-CT in patients with cancer: Prevalence and impact on survival rate

Introduction

People with cancer are at increased risk of incidental venous thromboembolism (VTE) and PET-CT imaging is commonly used in this population. However, the prevalence of incidental VTE detected by PET-CT in patients with cancer and its impact on survival are unknown.

Materials and Methods

This retrospective study was approved by the local Institutional Review Board. 1331 consecutive adult patients with cancer who underwent PET-CT examination between 2009 and 2012 were included in the study (mean age: 57 ± 15 years). PET-CT reports were reviewed to identify patients with incidental VTE at the time of examination. Survival rates were assessed with Kaplan-Meier curves. The Cox proportional hazards model was used to determine the association between incidental VTE and overall survival, after controlling for clinical variables.

Results

Incidental VTE was detected in 19 patients (1.4%). Patients with genitourinary malignancies, colorectal cancer and lung cancer had the highest rates of incidental VTE at PET-CT. At multivariate analysis, incidental VTE detected by PET-CT was associated with worse overall survival independently of patient age, hospitalization status at time of PET-CT examination, and the presence of metastatic disease (Hazard ratio = 2.03; 95% confidence interval = 1.08-3.81, p = 0.028).

Conclusion

Incidental VTE was detected in 1.4% of adult patients with cancer undergoing PET-CT imaging. Diagnosis of incidental VTE at PET-CT imaging was associated with worse overall survival in this population.     

Biomarkers for post thrombotic syndrome: A case-control study

Introduction

There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed.The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS.

Materials and Methods

Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2 years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI.A panel of predefined biomarkers was measured in venous blood.

Results

D-dimer showed a decreasing trend from cases to controls to HI; p = 0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p = 0.032, and HI; p = 0.017. APC-ratio was significantly lower in cases compared to controls; p = 0.032, and HI; p = 0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p = 0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p = 0.029.

Conclusions

Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63 months since the last DVT.     

Antithrombin-resistant prothrombin Yukuhashi mutation also causes thrombomodulin resistance in fibrinogen clotting but not in protein C activation

Introduction

Prothrombin Yukuhashi (p.Arg596Leu) mutation can result in thrombophilia associated with antithrombin (AT) resistance. Mutant thrombin, an active form of prothrombin Yukuhashi, demonstrated moderately lower clotting activity than the wild-type but substantially impaired the formation of the complex with AT. However, the effects of the mutation on the thrombomodulin (TM)–protein C (PC) anticoagulant system have not been previously elucidated.

Materials and Methods

We prepared recombinant wild-type and mutant prothrombins, converted to thrombins using Oxyuranus scutellatus venom, and performed fibrinogen-clotting assays with or without recombinant soluble TM (rTM). We also evaluated activated PC (APC) generation activity of recombinant thrombins by measuring APC activity after incubation with human PC in the presence or absence of rTM.

Result and Conclusions

rTM treatment reduced the relative fibrinogen-clotting activity of the wild-type down to 8.4% in a concentration-dependent manner, whereas the activity of the mutant was only decreased to 44%. In the absence of rTM, APC generation activity (?A/min at 405 nm) was fairly low (0.0089 for the wild-type and 0.0039 for the mutant). In the presence of rTM, however, APC generation activity was enhanced to 0.0907 (10.2-fold) for the wild-type and to 0.0492 (12.6-fold) for the mutant, and the relative activity of the mutant with rTM was 54% of that of the wild-type. These data suggested that the prothrombin Yukuhashi mutation may cause TM resistance in terms of inhibition of fibrinogen clotting; this may contribute to susceptibility to thrombosis, although the enhancing effect of APC generation can be maintained.