Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment

Introduction

Thrombotic events (TE) are well documented in patients with acute lymphoblastic leukemia (ALL). They occur due to a combination of disease, host and treatment-related risk factors. Low molecular weight heparin (LMWH) has been found to be effective and safe in children with ALL during L-asparaginase treatment. At present, whether or not to give primary anticoagulant prophylaxis for TE during induction or reinduction courses to children with ALL is controversial. Our group investigated the use of LMWH as a prophylactic treatment for ALL children with a genetic prothrombotic predisposition.

Methods

Eighty consecutive children with ALL treated between the years 1999 and 2008 were studied. Genetic analysis of factor V Leiden (G1691A) and prothrombin (G20210A) gene mutations were done at diagnosis. LMWH was given once daily subcutaneously at a dose of 1 mg/kg, starting with the first dose of L-asparaginase (day 12 of induction, day 8 of consolidation) until one week after the last dose (day 40 of induction, day 25 of consolidation), to patients with inherited thrombophilia stemming from either factor V Leiden or prothrombin gene mutation.

Results

Eighteen patients were found to have a genetic predisposition for TE, all of them received prophylactic LMWH. Six of the 80 (7.5%) patients developed thromboembolic events. Three of these six had a prothrombin (PT) gene mutation and received prophylactic LMWH. No TE event occurred in patients with factor V Leiden mutation receiving prophylactic LMWH.

Conclusion

It is suggested that patients with ALL and PT gene mutation may have a higher risk of clotting complications in comparison to patients with factor V Leiden mutation. A randomized trial of LMWH should be performed to assess its safety and efficacy in preventing venous TE.     

Venous thromboembolism risk assessment and thromboprophylaxis among hospitalized acute medical patients in China - the RAMP study

Background

In developed countries, hospitalized patients with acute medical conditions are at significant risk for venous thromboembolism (VTE). Little is known about VTE risk and prophylaxis practices in China.

Objective

To determine the VTE risk and the frequency of recommended VTE prophylaxis in hospitalized Chinese patients with acute medical conditions.

Methods

Multi-center, cross-sectional, observational study. Eligibility criteria: ≥ 30 years, admitted to an intensive care unit (ICU)/coronary care unit (CCU) for acute medical illness, had ≥ 1 VTE risk factor/1 disease that predisposes to VTE, and provided informed consent. We used 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines to assess VTE risk and the frequency of recommended VTE prophylaxis.

Results

1247 patients from 19 hospitals in 11 cities across 11 provinces of China were enrolled from July 2007 to June 2008. 57.3% patients had > 2 VTE risk factors. Only 20.2% received ACCP-recommended VTE prophylaxis (CCU patients: 22.7%, ICU patients: 16.9%, p = 0.0117).

Limitations

Excluding some patients with VTE risk factors did not allow assessment of the prevalence of VTE risk in the acute hospital-care setting. We could not determine whether the duration of prophylaxis complied with the ACCP recommendations. Our results may not be representative of hospitals in small cities/rural areas in China.

Conclusions

The prevalence of VTE risk factors in Chinese patients was similar to that in developed countries; however, only a small proportion of eligible patients received the recommended VTE prophylaxis. Our findings highlight the need for dissemination and implementation of appropriate VTE prophylaxis guidelines in China.     

Characterization of negatively charged phospholipids and cell origin of microparticles in women with gestational vascular complications

Introduction

Gestational vascular complications (GVC) are a major cause of maternal and fetal morbidity which can be potentially reduced by LMWH. Microparticles (MPs) are involved in thrombosis and inflammation. However, characterization and role of MPs in GVC have not been elucidated.

Materials and Methods

MPs were isolated from non-pregnant women, healthy pregnant women, women with GVC (hypertension or preeclamptic toxemia (PET)) and women with a history of pregnancy complications who were treated with LMWH. MP count, cell origin and expression of negatively charged phospholipids were evaluated.

Results

Total numbers of MPs were similar in the study cohorts, with a non-significant trend toward an increase in the pregnant groups, while percentage of MPs bearing negatively charged phospholipids was significantly reduced in all the pregnancy groups. Endothelial CD144-MPs were elevated in the GVC groups compared to the healthy pregnant cohort. Endothelial CD31 +/CD41-MPs were decreased in the LMWH group compared to women with PET. Percentage of placental trophoblast MPs was similar in all pregnancy groups and platelet MPs were reduced in healthy pregnant compared to non-pregnant women. Notably, percent of MPs bearing negatively charged phospholipids correlated only with platelet MPs, but not with endothelial, trophoblast or leukocyte MPs.

Conclusion(s)

Presence of negatively charged phospholipids cannot be considered universal characteristics of MPs in pregnancy. MPs may reflect the vascular injury characterizing GVC pathology.     

A case series of LMWH use in pregnancy: Should trough anti-Xa levels guide dosing?

Introduction

Pregnancy is a thrombogenic state, increasing the risk for venous thromboembolism (VTE), and the risk of valve thrombosis amongst women with mechanical heart valves (MHV). While low molecular weight heparins (LMWH) are generally dosed based on weight (i.e., enoxaparin 1 mg/kg every 12 hours), data in pregnant women have shown that weight-based dosing does not consistently achieve target anti-Xa levels. In women with MHV, our practice includes titrating LMWH doses to target both trough and peak anti-Xa levels, while for those with VTE peak anti-Xa levels guide dosing.

Materials/Methods

This retrospective case series included pregnant women requiring LMWH treatment doses with at least 3 peak (+/− trough) anti-Xa levels. Our primary objective was to describe the actual LMWH dose required to achieve targeted anti-Xa levels relative to weight-based dosing in patients with MHV. Secondarily, we compared the same for VTE patients; compared actual dosing between those with MHV and VTE; and examined maternal and fetal outcomes.

Results/Conclusion

Women with MHV (N = 4) required greater than weight-based dosing of enoxaparin (1.35 mg/kg Q12H) to achieve targeted anti-Xa levels. Importantly, achieving target peak anti-Xa levels did not always ensure maintenance of minimum trough levels. VTE patients (N = 12) did not require more enoxaparin (0.96 mg/kg Q12H) than weight based dosing. MHV patients received more enoxaparin compared to VTE patients (P < 0.001). No bleeding or clotting complications were associated with LMWH administration. In pregnant women with MHV at high risk of thromboembolism, LMWH dosing guided by trough and peak anti-Xa levels should be considered.     

The consequences of anxious temperament for disease detection, self-management behavior, and quality of life in Type 2 diabetes mellitus

Objective

The purpose of this study is to examine the consequences of anxious temperament for disease detection, self-management behavior, and quality of life in Type 2 diabetes mellitus (T2DM).

Method

A sample of 204 individuals newly diagnosed with T2DM completed measures of anxious temperament, self-management behavior, and quality of life; participants also supplied a blood sample for glycated hemoglobin (A1C) analysis at initial diagnosis (baseline) and at 6-month follow-up (as indicators of disease progression at diagnosis and achieved glycemic control, respectively).

Results

Anxious temperament was inversely associated with A1C at both baseline and at 6-month follow-up. However, the association between anxious temperament and A1C at follow-up was mostly accounted for by the association between anxious temperament and baseline A1C and not by the uptake of self-management behaviors after diagnosis. Higher levels of anxious temperament were also associated with an increased likelihood of having been diagnosed with a prediabetic condition but were associated with poorer quality of life at both time points.

Conclusion

Anxious temperament appears to be a double-edged sword that may facilitate early detection but not subsequent behavioral or emotional adjustment to T2DM.     

The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) has been proposed to be a risk factor for venous thromboembolic disease (VTE). However, no series published to date has been population-based or included a control group with similar comorbidities to people with MGUS.

Patients/Methods

We reviewed the records of all the male veterans in a single VA healthcare system with MGUS between January 1, 1996 and December 31, 2005. We compared the rate of VTE in 166 patients with MGUS with the rate of VTE in an age-matched control group of 465 patients who had tested negative for monoclonal gammopathy by serum protein electrophoresis (SPEP).

Results

The VTE rate in the MGUS group was 2.2 per 100 person-years, which was not significantly different from the rate in the control group, 1.4 per 100 person-years (HR 1.38, CI 0.63-3.01, p = 0.42). Most VTE events occurred within 4 months of the diagnosis of MGUS. In univariate analysis, albumin level (HR 0.21, CI 0.1-0.41, p < 0.001), abnormal leukocyte count (HR 2.53, CI 1.09-5.86, p = 0.03), and history of prior VTE (HR 4.41, CI 1.69-11.54, p = 0.003) were associated with increased risk of VTE. On multivariate analysis, albumin level and history of prior VTE remained significant, but presence of MGUS was still not significantly associated with VTE risk.

Conclusion

Our results suggest that the increased rate of VTE in people with MGUS may be primarily due to other underlying conditions that led to testing for a monoclonal gammopathy rather than to the monoclonal gammopathy itself.     

Circulating microparticles and risk of venous thromboembolism

Introduction

Circulating microparticles (MPs) may trigger a hypercoagulable state, leading to thrombotic complications. Data on their association with venous thromboembolism (VTE) are few and inconsistent.

Materials and methods

To investigate whether or not high levels of MPs are associated with an increased risk of VTE, we carried out a case-control study on 186 patients with a first, objectively diagnosed, episode of VTE and 418 healthy controls. Plasma levels of circulating MPs were measured by flow cytometry.

Results

Patients had higher median plasma levels of total MPs than controls (2184 per μL vs 1769 per μL, p < 0.0001). The risk of VTE increased progressively with increasing MPs, with a linear dose-response effect in the log odds. Individuals with MPs above the 90th percentile of the controls’ distribution (P₉₀ = 3263 per μL) had a 5-fold increased risk of VTE than those with MPs below the 10th percentile of controls (P₁₀ = 913 per μL), independently of sex, age, body mass index, thrombophilia, and plasma factor VIII levels [adjusted odds ratio: 5.30 (95%CI: 2.05-13.7)]. Using the 95th percentile of controls as cut-off (P₉₅ = 4120 per μL), the adjusted odds ratio was 2.20 (1.01-4.79) for individuals with MPs > P₉₅ compared with those having MPs ≤ P₉₅. After exclusion of individuals with antiphospholipid antibodies and hyperhomocysteinemia, the interaction between MPs > P₉₅ and thrombophilia increased the VTE risk from 1.63 (0.60-4.50) to 6.09 (1.03-36.1).

Conclusions

High levels of circulating MPs are a possible independent risk factor for VTE.     

Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS)

Introduction

Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population.

Materials and methods

The study included renally impaired patients ≥ 70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n = 269) or activated partial thromboplastin time-adjusted UFH twice daily (n = 270). After acute management both groups received vitamin K antagonist to day 90.

Results

The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p = 0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p = 0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group.

Conclusion

The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.     

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of venous thromboembolism in Chinese population

Introduction

Endothelium derived nitric oxide (NO) is a key mediator of vascular homeostasis. Endothelial nitric oxide synthase (eNOS) gene, by affecting the expression and functional activity of the eNOS enzyme, thereby reducing NO availability, may be implicated in venous thromboembolism (VTE). We investigated the eNOS G894T polymorphism in VTE patients in the Chinese population.

Materials and methods

A case-control study was conducted in a general hospital. Blood samples, collected from 462 consecutive patients with VTE and 462 healthy controls, were used for DNA extraction. Single nucleotide polymorphisms (SNP) of eNOS (894 G/T) were determined by allele specific-polymerase chain reaction (ARMS-PCR) analysis.

Results

The eNOS 894 G/T polymorphism alleles distribution was in agreement with the principle of Hardy-Weinberg equilibrium. The prevalence of homozygote, heterozygote and pathological homozygote for the eNOS G894T polymorphism in VTE patients was 79.7%, 18.1% and 2.2%, respectively (controls: 86.6%,12.3% and 1.1%). T allele distribution in the VTE (11.3%) and especially the male VTE patients (12.5%) was more common than in healthy controls (7.3%). The frequency of GT + TT genotype was significantly higher among the age ≤ 55 years patients in VTE group than in controls (20.1% vs. 12.2%, P = 0.033).

Conclusion

Our result demonstrates that the 894 G/T polymorphism variant of eNOS is a risk factor for VTE in Chinese population.     

Peri-procedural anticoagulation management of mechanical prosthetic heart valve patients

Introduction

To estimate the three-month cumulative incidence of thromboembolism and bleeding among mechanical heart valve (MHV) patients receiving peri-procedural anticoagulation management, consecutive MHV patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management over the seven-year period, 1997-2003, were followed for three months for thromboembolism, bleeding and vital status.

Materials and Methods

Warfarin was stopped 4-5 days prior to the procedure, and re-started after the procedure as soon as hemostasis was assured. The decision to provide bridging therapy with low molecular weight (LMWH) or unfractionated (UFH) heparin was individualized and based on the estimated risks of TE and bleeding.

Results

556 MHV patients (372 aortic only, 136 mitral only, 48 with multiple valves) underwent 580 procedures. The three-month cumulative incidence of thromboembolism was 0.9% which included: cerebral ischemia (n = 3), unstable angina (n = 1), acute myocardial infarction (n = 1). None were fatal. The cumulative incidence of major bleeding was 3.6% and fatal in 0.2%. The incidence of major bleeding events did not differ by postoperative anticoagulant strategy whether LMWH (3.7%), UFH (6.1%), or no heparin (2.4%) was used (p = 0.26).

Conclusions

The three-month cumulative incidence of thromboembolism among MHV patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Whereas bleeding exceeds thromboembolic complications, our current practice is to restart warfarin as soon as possible post-procedure. Post-procedural heparin use is reserved for patients with the highest thromboembolic risk (mitral MHV, multiple MHVs, MHV with prior stroke or atrial fibrillation) waiting at least 48 hours before initiating.     

Risk factors for venous thromboembolism in pre-and postmenopausal women

Introduction

Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women.

Method

In a nationwide case-control study we included as cases 1470 women, 18 to 64 years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Results

The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status.

Conclusion

Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.     

The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy

Background

Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulant during pregnancy for prevention or treatment of VTE. However, the size of the associated risk of postpartum haemorrhage (PPH) is unknown.

Objective

To assess the bleeding risk of high dose LMWH, also in relation to time between last dose LMWH and delivery.

Material and methods

From 1999 to 2009, we followed 88 pregnant women who were started on therapeutic anticoagulation. Controls were pregnant women without LMWH, matched 1:4 for parity, mode of delivery, age, gestational age and delivery date. PPH was defined as > 500 ml blood loss for vaginal delivery (severe PPH in vaginal delivery as > 1000 ml) and > 1000 ml for cesarean section (CS). Women were divided into subgroups by the interval between last dose of anticoagulation and delivery (< 12, 12-24 hrs, > 24 hrs).

Results

Risk of PPH after vaginal delivery was 30% and 18% for LMWH-users and non-users, respectively (OR 1.9, 95%CI 1.1-3.5). Risk of severe PPH after vaginal delivery was not different (5.6 vs 5.0%; OR 1.1; 0.4-3.6). Risk of PPH after CS was 12% in LMWH-users and 4% in non-users (OR 2.9; 0.5-19.4). Both events of LMWH-users occurred after emergency CS. The risk of PPH associated with delivery within 24 hours after last dose of LMWH was 1.2 fold higher (95%CI 0.4-3.6) compared to a larger interval.

Conclusion

High dose LMWH carries an increased risk of more than 500 mL blood loss after vaginal delivery. However, this results not in more clinical relevant severe PPHs. The interval between last dose of LMWH and delivery does not influence the risk of PPH.     

Effectiveness and safety of thromboprophylaxis with enoxaparin in medical inpatients

Background

Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism. Although effective prophylaxis exists for medical patients, there is little information outside of clinical trials. We will analyze our experience in the prophylaxis of VTE with enoxaparin in hospitalized medical patients.

Material and methods

We studied all of the patients ≥ 15 years admitted for emergency care to all of the medical departments of the hospital, except for the Hematology Department, between 1/April/1999 and 31/December/2005. The patients’ age, sex, Charlson comorbidity index (CCI), whether they received prophylaxis with enoxaparin or not, dose, VTE, bleeding, thrombocytopenia, and mortality were analyzed.

Results

40,349 patients were included, of which 55.87% were male, with an average age of 67.56, and an average CCI of 4.99. There were 19,834 patients who did not receive prophylaxis for which the rate of incidence of VTE was 0.61%, mortality 8.75%, bleeding 1.38%, and thrombocytopenia 0.04%. Prophylactic enoxaparin was administered to 20,515 patients, for which the rate of incidence of VTE was 0.44%, mortality 10.71%, bleeding 1.1%, and thrombocytopenia 0.04%. The adjusted Odds Ratio (OR) for VTE was 0.65 (95% confidence interval [95% CI] 0.49 to 0.87). The adjusted OR for mortality was 0.84 (95% CI 0.78 to 0.9). With the adjusted data, the number needed to treat (NNT) for VTE was 470.3 (95% CI 278.4 to 1413.3), and the NNT for mortality was 77.2 (95% CI 54.6 to 130.3).

Conclusion

Thromboprophylaxis with enoxaparin in hospitalized medical patients is associated with a lower incidence of VTE and mortality, and is safe.     

Association of elevated NTproBNP with recurrent thromboembolic events after acute pulmonary embolism

Introduction

N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is a predictor of adverse short-term clinical outcomes in patients with acute pulmonary embolism (APE), but its long-term prognostic value remains largely undefined. The aim of this study was to assess the value of plasma NTproBNP with regard to recurrent venous thromboembolism (VTE).

Materials and Methods

NTproBNP levels were measured in 224 consecutive patients with the first episode of acute pulmonary embolism occurring from January 2005 through October 2010. Patients were categorized into two groups by NTproBNP reference range. Follow-ups were performed at 3, 6, and 12 months and yearly thereafter. The primary end point was symptomatic, recurrent fatal or nonfatal VTE.

Results

NTproBNP was elevated in 158 (70.5%) patients and not elevated in 66 (29.5%) patients. After a mean follow-up period of 31.0 ± 19.4 months, patients with elevated NTproBNP showed an increased risk of recurrent VTE (20 patients, 12.7%) compared to those without elevated NTproBNP (only 1 patient, 1.5%) (P = 0.009). Of the 7 deaths related to pulmonary embolism, 6 occurred in patients with elevated NTproBNP compared to patients with normal NTproBNP (1 of 7 deaths). In a multivariate analysis stratified by oral anticoagulant treatment duration, elevated NTproBNP was an independent predictor of recurrent VTE (hazard ratio, 9.32; P = 0.02).

Conclusions

Elevated NTproBNP is associated with recurrent VTE in acute pulmonary embolism patients.     

The incidence and risk factors of recurrent venous thromboembolism during pregnancy

Introduction

Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode.

Materials and Methods

This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis).

Results and Conclusions

The incidence of recurrent VTE was 7.6% (n = 28).Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis.In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p < 0.001; group A vs. C: 5.7% vs. 30.0%, p = 0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p = 0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p = 0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p < 0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.     

Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study

Introduction

Because the risk of venous thromboembolism (VTE) associated with progestin is uncertain, we tested oral contraceptives, estrogen and progestin as independent VTE risk factors.

Materials and Methods

Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN women with objectively-diagnosed incident VTE over the 13-year period, 1988-2000 (n = 726) and one to two Olmsted County women per case matched on age, event year and duration of prior medical history (n = 830), and reviewed their complete medical history in the community for previously-identified VTE risk factors (i.e., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, varicose veins and pregnancy/postpartum), and oral contraceptive, oral estrogen, and oral or injectable progestin exposure. Using conditional logistic regression we tested these hormone exposures as VTE risk factors, both unadjusted and after adjusting for previously-identified VTE risk factors.

Results

In unadjusted models, oral contraceptives, progestin alone, and estrogen plus progestin were significantly associated with VTE. Individually adjusting for body mass index (BMI) and previously-identified VTE risk factors, these effects remained essentially unchanged except that progestin alone was not associated with VTE after adjusting for active cancer. Considering only case-control pairs without active cancer, progestin alone was positively but non-significantly associated with VTE (OR = 2.49; p = 0.16). Adjusting for BMI and previously-identified VTE risk factors including active cancer, oral contraceptives, estrogen alone, and progestin with or without estrogen were significantly associated with VTE.

Conclusions

Oral contraceptives, estrogen alone, estrogen plus progestin, and progestin with or without estrogen are independent VTE risk factors.     

The role of IL-6, IL-8 and MCP-1 and their promoter polymorphisms IL-6 -174GC, IL-8 -251AT and MCP-1 -2518AG in the risk of venous thromboembolism: a case-control study

Introduction

Cytokines increased the risk of venous thromboembolism (VTE) in some case-control studies, but not in a prospective study. Data concerning the role of cytokines in the risk of VTE are limited. We examined in a case-control study the association of VTE and levels of interleukin (IL)-6, IL-8 and monocyte chemotactic protein-1 (MCP-1) and assessed whether promoter polymorphisms (IL-6 -174GC, IL-8 -251AT, MCP-1 -2518AG) would affect the thrombotic risk and cytokine levels.

Materials and methods

The study included 119 patients (94 women) with a first event of VTE aged between 18-60 years, and 126 healthy controls (100 women) matched for age (± 5 years). Blood was collected > 7 months after the thrombotic event. Odds ratios (ORs) were calculated per increase of cytokines levels by 1 pg/mL.

Results

ORs adjusted for age and sex were 1.520 [95% Confidence Interval (CI) 1.177 - 1.962] for IL-6, 1.095 (95% CI 1.002 - 1.196) for IL-8 and 1.000 (0.988 - 1.012) for MCP-1. With additional adjustment for ethnic composition, body mass index (BMI) and high sensitive C-reactive protein (hs-CRP), risk estimates remained significant for IL-6 and became of borderline statistical significance for IL-8. Polymorphisms did not influence the thrombotic risk and the cytokine levels in study participants.

Conclusion

VTE was associated with IL-6 and IL-8 levels, and for IL-6 this association was independent of BMI and hs-CRP. Thus far, a causal relationship between inflammation and VTE remains to be clarified and more prospective data are warranted.     

The association of antiphospholipid antibodies with intrauterine fetal death: a case-control study

Introduction

Over the past few decades it has been recognized that antiphospholipid antibodies are associated with pregnancy loss. Other placenta-mediated pregnancy complications have also been associated with the presence of antiphospholipid antibodies. Most studies have measured antiphospholipid antibodies near the time of the event investigated.

Objectives

To investigate the association of antiphospholipid antibodies and a history of intrauterine fetal death (IUFD) in a case-control design.

Materials and methods

A case-control study of 105 women with a history of IUFD after 22 gestational weeks and 262 controls with live births. The prevalence of lupus anticoagulant, anticardiolipin- and anti-β2-glycoprotein 1 antibodies were measured 3-18 years after the event of IUFD.

Results

Total 9.5% of women with a history of IUFD and 5.0% of controls had at least one positive test for antiphospholipid antibodies (OR 2.0; 95% confidence interval (CI) 0.9-4.8). Women with a history of IUFD were significantly more often positive for lupus anticoagulant compared to controls (OR 4.3; 95% CI 1.0-18.4). The association of lupus anticoagulant with a history of IUFD was confined to women positive for other antiphospholipid antibodies in addition to lupus anticoagulant. Being positive for anti-β2-glycoprotein 1 or anticardiolipin antibodies alone was not significantly associated with a history of IUFD.

Conclusions

Women with a history of IUFD after 22 gestational weeks were more often lupus anticoagulant positive. The association was confined to women with multiple positivity for antiphospholipid antibodies, although firm conclusions on the importance of multiple positivity cannot be made from this study.     

Peri-procedural bridging with low molecular weight heparin in patients receiving warfarin for venous thromboembolism: A pediatric experience

Introduction

The incidence of venous thromboembolism (VTE) in children appears to be increasing, and warfarin remains one of the few standard anticoagulants used for secondary VTE prevention. When invasive procedures are required in adults with high TE risk who are receiving warfarin, low-molecular weight heparin (LMWH) bridging is recommended, based mainly upon observational evidence; in children, no such studies have been published. We sought to determine the risks of recurrent TE (both VTE and arterial TE [ATE]) and major bleeding with peri-procedural LMWH bridging in children receiving warfarin for VTE.

Methods

Children (age ≤ 21 years of age at the time of bridge) receiving warfarin for VTE and undergoing a standardized clinical care protocol for peri-procedural LMWH bridging were enrolled and followed in an institution-based prospective inception cohort study at Children's Hospital Colorado between March 2006 and February 2012. Outcomes were assessed at 30 days post-procedure, and followed International Society on Thrombosis and Haemostasis guidelines.

Results

Seventeen children comprised the cohort, with a total of 23 bridging episodes. Median age at bridging episode was 17.5 years (range, 12 to 21 years). In 22% of bridging episodes, indication was for major surgery. Median duration of LMWH administration prior to procedure was 6 days (range, 4-10 days); median duration off anticoagulation peri-procedurally was 1.5 days (range: 1-2 days). The risks of major bleeding, recurrent VTE, and ATE at 30 days post-procedure were 4.3% (1/23), 0% and 0%, respectively.

Conclusions

This study provides important preliminary data on safety and efficacy of perioperative LMWH bridging for adolescent VTE patients receiving warfarin. Larger collaborative pediatric studies are warranted to substantiate these findings and to investigate prognostic factors of bleeding and recurrent TE in this setting.